Lung cancer is the leading cause of cancer deaths worldwide.¹ Tobacco consumption is the primary cause of lung cancer, accounting for more than 85%–90% of all lung cancer deaths. While tobacco smoking remains the primary cause of lung cancer worldwide, more than 60% of new lung cancer occur in former smokers (smoked ≥ 100 cigarettes per lifetime, quit ≥ 1 year) or never smokers (smoked < 100 cigarettes per lifetime). Moreover, one in five women and one in 12 men diagnosed with lung cancer have never smoked. Environmental tobacco smoke or secondhand smoke, occupational exposure to asbestos, arsenic, nickel, mustard gas, bischloromethyl ether, hexavalent chromium, polycyclic aromatic hydrocarbons, and ionizing radiation are also established risk factors for lung cancer.² Lung cancer susceptibility and risk also are increased in inherited cancer syndromes caused by rare germ-line mutations in p53,³ retinoblastoma,⁴ and other genes.^5,6

The two major forms of lung cancer are non-small cell lung cancer (NSCLC, about 85% of all lung cancers) and small-cell lung cancer (about 15%). Despite advances in early detection and standard treatment, NSCLC is often diagnosed at an advanced stage and has a poor prognosis. NSCLC can be divided into three major histologic subtypes: (1) squamous-cell carcinoma, (2) adenocarcinoma, and (3) large-cell lung cancer. Smoking causes all types of lung cancer but is most strongly linked with small-cell lung cancer and squamous-cell carcinoma; adenocarcinoma is the most common type in patients who have never smoked. ^7–9

Recent trials added new data on screening and diagnostic approach. Those data will be reviewed here.

EARLY DETECTION AND SCREENING

For a screening program to be successful, the burden of the disease in the population must be high, effective treatment must be available, the test must be low risk, reproducible, accessible, cost-effective, and both sensitive and specific, and there should be an effective treatment or intervention for patients identified through early detection, with evidence of early treatment leading to better outcomes than late treatment.

The large majority of NSCLC patients present with symptoms in a late advanced stage, and diagnosis occurs mostly in locally advanced or metastatic disease with a very poor rate of cure. The issue of lung cancer screening has consequently a strong rationale, to increase the detection of early NSCLC potentially cured by surgery.

Although effective mass screening of high-risk groups could potentially be of benefit, randomized trials of screening with the use of chest radiography with or without cytologic analysis of sputum specimens have shown no reduction in lung-cancer mortality.¹⁰

Advances in multidetector computed tomography (CT), however, have made high-resolution volumetric imaging possible in a single breath hold at acceptable levels of radiation exposure.¹¹ Several studies^{10 12–17} have shown that low-dose helical CT of the lung detects more nodules and lung cancers, including early-stage cancers, than does chest radiography.

The National Lung Cancer Screening Trial (NLST),¹⁸ a large prospective randomized trial funded by the National Cancer Institute (NCI), to determine whether screening with low-dose CT, as compared with chest radiography (CXR), would reduce mortality from lung cancer among high-risk persons. In this trial 53,454 participants, between 55 and 74 years of age and a history of heavy smoking, were enrolled. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posterioanterior chest radiography (26,732 participants). Non-calcified nodules measuring 4 mm were considered to be positive, as were abnormalities such as effusions and adenopathy. During median follow-up of 6.5 years, lung cancer–specific mortality was significantly lower in the CT group than in the CXR group—relative reduction of 20.0% (95% CI, 6.8–26.7; P=.004). Deaths attributed to invasive diagnostic procedures and cancer treatments were considered lung cancer–related deaths. The number needed to screen to prevent one lung cancer death was about 320. False-positive screenings were common: 39% of participants in the CT group and 16% in the CXR group had at least one positive screen, and 95% of those results were false-positives. The NLST results show that three annual rounds of low-dose CT screening reduce mortality from lung cancer. However, many questions remain. For example, will radiologists generally be able to duplicate the performance of NLST study radiologists? In the community, will low-dose CT (as opposed to standard-dose CT) be readily available and will evaluation and follow-up of screen-positive patients maximize benefit and minimize harm? Given the high false-positive rate, how should we weigh the costs and morbidity of screening and its sequelae? Because of many pending questions, one should wait for further information before endorsing screening.^19,20 For those patients who want to be screened, physicians need to discuss the possible risks and benefits of screening. While lung cancers may be found, patients are at risk for more radiation exposure and false-positive results. The latter can result in multiple follow-up CTs and possible invasive procedures, with potential added costs, anxiety, and morbidity and mortality rates.²

Despite the great debate around lung cancer screening, which is a complex and controversial topic, recently the National Comprehensive Cancer Network (NCCN) has come out in favor of lung cancer screening in an updated set of guidelines.²¹ It recommends the use of helical low-dose CT screening for selected patients at high risk for the disease—risk assessment and screening modalities are discussed in the guidelines.

CLINICAL MANIFESTATIONS

All patients who present with suspect NSCLC should have a complete and meticulous history and physical examination performed to identify symptoms or physical findings suggestive of locally extensive or metastatic disease, assess pulmonary health status, identify significant comorbidities, and assess overall health status. Each impacts the therapeutic options, patient's ability to tolerate treatment, and disease course in ways that are independent of the disease stage.^20,22

Most symptoms and signs (eg, cough, hemoptysis, and postobstructive pneumonia) are non-specific. However, some signs and symptoms, such as weight loss, bone pain, dysphagia, neurologic abnormalities, superior vena cava syndrome, pericardial effusion, enlarged supraclavicular and scalene lymph nodes, and hepatomegaly or right upper quadrant pain, may suggest extensive disease.

NSCLC may cause paraneoplastic syndromes. These are characterized by endocrinopathy, neurologic disorders, metabolic abnormalities, hematologic disease, or skeletal syndromes and may be the presenting finding or the first sign of recurrence. In addition, paraneoplastic syndromes may mimic metastatic disease and, unless detected, lead to inappropriate palliative rather than curative treatment. In some cases, the pathophysiology of the paraneoplastic syndrome is known, particularly when a hormone with biologic activity is secreted by the tumor or an immunologic-mediated mechanism is involved. Often the paraneoplastic syndrome may be relieved with successful treatment of the tumor.² A detailed description of paraneoplastic syndromes is beyond the scope of this review.

DIAGNOSTIC ASSESSMENT AND STAGING INVESTIGATIONS

Initial evaluation must include performance status, CT of the neck, chest and upper abdomen, including adrenals, complete blood count and platelets, chemistry profile, smoking cessation program (if needed), and pathology review (specific mutations may be a therapy target).²³

Tissue sampling is required to confirm a diagnosis in all patients with suspected lung cancer. Pathologic evaluation is performed to classify the histologic type of the lung cancer, determine the extent of invasion, determine whether it is primary lung cancer or metastatic disease, establish the cancer involvement status of the surgical margins, and do molecular diagnostic studies to determine whether certain gene mutations are present (eg, EGFR mutations).

There are several options for sampling a primary tumor, including: (1) conventional flexible bronchoscopy with forceps biopsy, (2) blind transbronchial fine-needle aspiration, (TBNA), (3) image-guided percutaneous fine-needle aspiration or core-needle biopsy, (4) surgical biopsy, (5) endobronchial ultrasound (EBUS)-guided biopsy, and/or (6) transesophageal endoscopic ultrasound-guided biopsy (EUS).

In patients with suspected metastatic disease, a diagnosis may be confirmed by percutaneous biopsy of a soft tissue mass, lymph node, lytic bone lesion, bone marrow, pleural or liver lesion, or an adequate cell sample obtained from a malignant pleural effusion. In patients with a suspected malignant pleural effusion, if the initial thoracocentesis is negative, a repeat thoracocentesis is recomended.² Series examining the diagnostic rate for malignancy of pleural cytology have reported a mean sensitivity of 60% (range 40%–87%). ^24–27 In patients suspected of having lung cancer with an accessible pleural effusion, if the pleural fluid cytology finding is negative (after at least two thoracocentesis), thoracoscopy is recommended as the next step if establishing the cause of the pleural effusion is thought to be clinically important. Thoracoscopic biopsy of the pleura is safe and can provide a definitive diagnosis with a high degree of accuracy and minimal risk to the patient. The reported sensitivity rate ranges between 80% and 99%. However, percutaneous, closed pleural biopsy is reported to be diagnostic for malignancy in only 50% of cases.²⁸

The diagnostic yield of any biopsy depends on several factors including location and size of the tumor, tumor type, and technical aspects of the procedure. In general, central lesions are more readily diagnosed by bronchoscopic examination, while peripheral lesions are more amenable to transthoracic biopsy.²⁹ Bronchoscopic specimens include bronchial brush, bronchial wash, bronchioloalveolar lavage, and transbronchial biopsy (forceps biopsy, TBNA, and EBUS). Overall sensitivity for bronchoscopic methods is 85%–90%. Transthoracic FNA specimens have also great sensitivity (70%–95%). ^28–31

For patients who have multiple comorbidities or contraindications to invasive biopsy, sputum cytology should be considered, especially for patients with centrally located tumors, but pooled sensitivity is low (66%).²⁸

Non-surgical approaches, surgical approaches, or both may be used to obtain a tissue sample from patients with suspected lymph node metastasis.²³ Depending on the location, lymph node sampling may occur via EBUS, EUS, or blind biopsy. In patients with palpable lymph nodes, a needle biopsy or needle aspiration may be used to obtain a tissue sample. Successful application of the non-surgical approaches may eliminate the need for a surgical staging procedure.

Evaluation of the mediastinal lymph nodes is a key step in the further staging of the patient. To detect mediastinal metastases, patients are routinely investigated with CT and positron emission tomography (PET), followed by mediastinal tissue staging for enlarged (≥10 mm) or PET-positive intrathoracic nodes,^32,33 as imaging alone is inaccurate to replace invasive lymph node staging on tissue specimens. ^34–37 In addition, the visual location of intrathoracic lymph nodes with PET is not always unequivocal because of the low spatial resolution of the PET images. ^38–40 Integrated PET/CT scans theoretically overcome this problem because of the co-acquisition of CT and PET images, resulting in so-called fusion images. However, no difference in accuracy was noted when integrated PET/CT scans were compared with CT scans alone.⁴¹ A prospective study assessed the accuracy of the integrated PET/CT scan in the nodal staging of NSCLC and evaluated if tissue-confirmed lymph node staging by surgery or echo-endoscopy could be avoided.³⁴ This study found that integrated PET/CT scanning has an overall accuracy, which is too low to replace invasive intrathoracic lymph node staging. Another study found that integrated PET/CT provides low sensitivity and accuracy in intrathoracic nodal staging of NSCLC patients and underscore the continued need for histologic diagnosis.⁴²

Undetected preoperatory mediastinal metastases are a major cause of unnecessary thoracotomies, occurring in 28% of patients.³⁶ Unnecessary thoracotomies result in suboptimal treatment, significantly impaired functional health status, and avoidable mortality.^43,44

Mediastinal tissue staging is classically performed by mediastinoscopy, a surgical diagnostic procedure with a sensitivity of approximately 80%.³³ Mediastinal lymph nodes can also be sampled under real-time ultrasound control from either the esophagus (EUS)⁴⁵ or the airways (EBUS).⁴⁶ Combined EUS and EBUS can reach almost all mediastinal nodal stations with a reported sensitivity of 93% (CI_95%, 81%–99%) and 97% specificity (CI_95%, 91%–99%) for establishing the presence of mediastinal disease in lung cancer patients.⁴⁷ Current lung cancer staging guidelines acknowledge endosonography as a minimally invasive alternative to surgical staging (mediastinoscopy) to detect nodal disease,²¹ reducing the need for surgical staging in up to two thirds of patients.^48,49 A study was designed to examine the hypothesis that minimally invasive combined endoscopic procedures were as good as or even better than surgical staging (mediastinoscopy) for the evaluation of mediastinal lymph nodes in patients with lung cancer.⁴⁹ In this study, patients were eligible for mediastinal nodal sampling if they had mediastinal nodes with short axis ≥10 mm on CT or PET-positive mediastinal or hilar nodes or centrally located lung tumor. Patients with proven distant metastasis, irresectable disease (as judged by the thoracic surgeon on the available imaging), or small peripheral lung tumors without evidence of enlarged or PET-positive intrathoracic nodes were not considered for eligibility. The primary outcome was sensitivity for mediastinal nodal metastases. Secondary outcomes were rates of unnecessary thoracotomy and complications. Two hundred forty-one patients were randomized, 118 to surgical staging and 123 to endosonography, of whom 65 also underwent surgical staging. Nodal metastases were found in 41 patients (35%) by surgical staging versus 56 patients (46%) by endosonography (P=.11) and in 62 patients (50%) by endosonography followed by mediastinoscopy (P=.02). This study has shown that commencing mediastinal nodal staging with endosonography significantly improves the detection of nodal metastases and reduces the rate of unnecessary thoracotomies compared with mediastinoscopy alone, in patients with resectable NSCLC. This combined approach, with mediastinoscopy reserved for those patients with negative findings on EBUS/EUS resulted in superior sensitivity and negative predictive value over mediastinoscopy alone. This benefit was not associated with a greater rate of complications. These results are consistent with findings of other studies.⁵⁰

Missing mediastinal nodal metastases during preoperative surgical staging results in patients needlessly undergoing thoracotomy. Because almost all mediastinal nodes can be covered, a combined endosonography (EBUS/EUS) investigation could be superior to mediastinoscopy staging in the detection of nodal disease. Furthermore, endosonography does not require general anesthesia, is preferred by patients,⁵¹ and is considered cost-effective⁵² compared with surgical staging.

Even though this emerging technology of endoscopic study can have excellent results for predicting both positive and negative values, referral centers with highly skilled interventionalists are required to provide these good results.⁵³

Mediastinal node evaluation is straightforward when patients have a positive PET and/or CT scan (≥10 mm). Noteworthy, mediastinal node evaluation is also appropriate for patients with T2/3 and central T1 lesions, even if the PET/CT scan do not suggest mediastinal node involvement.^23,54,55 In other hand, because of the low prior probability of lymph node involvement in patients with peripheral T1, clinical N0 lesions, some authors do not use routine mediastinoscopy in these patients.⁵⁶

Regarding adrenal nodules, it should be noted that adrenal gland nodules or masses may be found by CT in 3%–4% of patients. ^57–59 In patients with lung cancer, most adrenal nodules are benign adenomas (fewer than half are metastasis). All adrenal lesions in patients with suspected lung cancer require direct evaluation if it will determine the disease stage. A malignant adrenal nodule is considered distant metastasis. Conventional CT and MRI imaging of adrenal lesions permits initial characterization of adrenal nodules. Protocols that measure the washout of attenuation following the administration of intravenous contrast significantly improve the sensitivity and specificity of CT for characterizing adrenal lesions. ^60–62 PET imaging may also improve the sensitivity, specificity, and accuracy of adrenal gland imaging.⁶³

An adrenal gland biopsy should be performed if confirmation of the adrenal pathology will determine the disease stage and treatment options. Image-guided fine needle biopsy is the most common approach.⁶³

STAGING SYSTEM

The TNM International Staging System provides useful prognostic information and is used to stage all patients with NSCLC. The various T (tumor size), N (regional node involvement), and M (presence or absence of distant metastasis) are combined to form different stage groups. The 7th edition of the TNM staging system is the most recent version (Table 1).⁶⁴

Four types of staging can be performed in patients with NSCLC. All are based on the TNM staging system:<list list-type="order"> </list>

• The clinical-diagnostic stage (the focus of this review) is based upon medical history, physical examination, laboratory testing, physiologic evaluation, radiologic testing, tissue sampling, and any other investigation undertaken prior to primary therapy. It is assigned the prefix c (p.e. cT3N2M0).

• The surgical-pathologic evaluation is based on the clinical-diagnostic stage plus histopathologic data from the resected tumor. It provides confirmation of the T descriptor, N descriptor, and histologic type. In addition, it takes into account the histologic grade, resection margins, and presence or absence of lymphovascular invasion. The surgical-pathologic stage is assigned the prefix p (p.e. pT3N2M0).

• A retreatment stage is assigned if there is recurrence of disease and a new treatment program is planned.

• An autopsy stage is recorded when a patient dies and has a postmortem examination performed.

Patients who may be a candidate for surgical resection of the NSCLC should undergo complete pulmonary function testing and consultation with a cardiothoracic surgeon.⁶⁵

SUMMARY

When a patient presents with suspected NSCLC, the diagnosis should be confirmed and both the histologic type and disease stage should be determined.

All patients should undergo a detailed history, CT of the neck, chest, and upper abdomen, including adrenals, complete blood count and platelets, chemistry profile, smoking cessation program (if needed), and pathology review.

Undetected mediastinal metastases are a major cause of unnecessary thoracotomies. Unnecessary thoracotomies result in suboptimal treatment, significantly impaired functional health status, and avoidable mortality. To detect mediastinal metastases, patients are routinely investigated with CT and PET, followed by mediastinal tissue staging for enlarged (≥10 mm) or PET-positive intrathoracic nodes. However, integrated PET/CT scanning has an overall accuracy, which is too low to replace invasive intrathoracic lymph node staging. Mediastinal tissue staging is classically performed by mediastinoscopy. Current lung cancer staging guidelines acknowledge endosonography as a minimally invasive alternative to surgical staging (mediastinoscopy) to detect nodal disease. A combined endosonography investigation could be superior to mediastinoscopy staging in the detection of nodal disease (Figure 1).

Staging is based upon the TNM staging system for NSCLC (Table 1)

Disclosure: The authors declare no conflict of interest.

REFERENCES

1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact f eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–236.
2. Horn L, Pao W, Johnson DH. Neoplasms of the Lung. In: Longo D, Kasper D, Jameson JL, Fauci AS. Hauser SL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. Mc Graw Hill Medical, 2011; pp. 737–753.
3. Hwang SJ, Cheng LS, Lozano G, Amos CI, Gu X, Strong LC. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum Genet. 2003;113:238–243.
4. Sanders BM, Jay M, Draper GJ, Roberts EM. Non-ocular cancer in relatives of retinoblastoma patients. Br J Cancer. 1989;60:358–365.
5. Bailey-Wilson JE, Amos CI, Pinney SM, et al. A major lung cancer susceptibility locus maps to chromosome 6q23–25. Am J Hum Genet. 2004;75:460–474.
6. Bell DW, Gore I, Okimoto RA, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet. 2005;37:1315–1316.
7. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367–1380.
8. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nat Rev Cancer. 2007;7:778–790.
9. Spira A, Beane J, Shah V, et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci USA. 2004;101: 10143–10148.
10. Doria-Rose VP, Szabo E. Screening and prevention of lung cancer. In: Kernstine KH, Reckamp KL, eds. Lung cancer: a multidisciplinary approach to diagnosis and management. New York: Demos Medical Publishing; 2010. pp. 53–72.
11. Church TR. National Lung Screening Trial Executive Committee. Chest radiography as the comparison for spiral CT in the National Lung Screening Trial. Acad Radiol. 2003;10:713–715.
12. Pedersen JH, Ashraf H, Dirksen A, et al. The Danish Randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncol. 2009;4:608–614.
13. Lopes Pegna A, Picozzi G, Mascalchi M, et al. ITALUNG Study Research Group. Design, recruitment and baseline results of the ITALUNG trial for lung cancer screening with low-dose CT. Lung Cancer. 2009; 64:34–40.
14. Infante M, Cavuto S, Lutman FR, et al. DANTE Study Group. A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial. Am J Respir Crit Care Med. 2009;180:445–453.
15. Marchianò A, Calabrò E, Civelli E, et al. Pulmonary nodules: volume repeatability at multidetector CT lung cancer screening. Radiology. 2009;251:919–925.
16. Becker N, Delorme S, Kauczor H-U LUSI: the German component of the European trial on the efficacy of multi-slice CT for the early detection of lung cancer. Onkologie. 2008;31(Suppl 1):PO320. [Abstract] 17. Baldwin DR, Duffy SW, Wald NJ, Page R, Hansell DM, Field JK. UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer. Thorax. 2011;66:308–313.
18. The National Lung Screening Trial Research Team. The National Lung Screening Trial: reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409.
19. Brett AS. Journal Watch General Medicine. July 14, 2011.
20. Correspondence. Reduced Lung-Cancer Mortality with CT Screening. N Engl J Med. 2011;365:2035–2038.
21. Colice GL, Shafazand S, Griffin JP, et al. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007; 132:161S–1677S.
22. Ross PJ, Ashley S, Norton A, et al. Do patients with weight loss have a worse outcome when undergoing chemotherapy for lung cancers? Br J Cancer. 2004;90:1905–1911.
23. Colinet B, Jacot W, Bertrand D, et al. oncoLR Health Network. A new simplified comorbidity score as a prognostic factor in non-small-cell lung cancer patients: description and comparison with the Charlson’s index. Br J Cancer. 2005;93:1098–1105.
24. NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines). Non-Small Cell Lung Cancer. Version 2.2012. NCCN.org. Accessed November 9, 2011.
25. Salyer WR, Eggleston JC, Erozan YS. Efficacy of pleural needle biopsy and pleural fluid cytopathology in the diagnosis of malignant neoplasm involving the pleura. Chest. 1975;67:536–539.
26. Nance KV, Shermer RW, Askin FB. Diagnostic efficacy of pleural biopsy as compared with that of pleural fluid examination. Mod Pathol. 1991;4: 320–324.
27. Prakash UB, Reiman HM. Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: analysis of 414 cases. Mayo Clin Proc. 1985;60:158–164.
28. Garcia L, Ducatman BS, Wang HH. The value of multiple fluid specimens in the cytological diagnosis of malignancy. Mod Pathol. 1994;7:665–668.
29. Rivera MP, Mehta AC. American College of Chest Physicians. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132:131S–148S.
30. Milroy R. American College of Chest Physicians. New American College of Chest Physicians Lung Cancer Guidelines: an important addition to the lung cancer guidelines armamentarium. Chest. 2007; 132:744–746.
31. Paone G, Nicastri E, Lucantoni G, et al. Endobronchial ultrasounddriven biopsy in the diagnosis of peripheral lung lesions. Chest. 2005;128: 3551–3557.
32. Gildea TR, Mazzone PJ, Karnak D, Meziane M, Mehta AC. Electromagnetic navigation diagnostic bronchoscopy: a prospective study. Am J Respir Crit Care Med. 2006;174:982–989.
33. De Leyn P, Lardinois D, Van Schil PE, et al. ESTS guidelines for preoperative lymph node staging for nonsmall cell lung cancer. Eur J Cardiothorac Surg. 2007;32:1–8.
34. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA American College of Chest Physicians. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 Suppl):202S–220S.
35. Patterson GA, Ginsberg RJ, Poon PY, et al. A prospective evaluation of magnetic resonance imaging, computed tomography, and mediastinoscopy in the preoperative assessment of mediastinal node status in bronchogenic carcinoma. J Thorac Cardiovasc Surg. 1987;94:679–684.
36. Gonzalez-Stawinski GV, Lemaire A, Merchant F, et al. A comparative analysis of positron emission tomography and mediastinoscopy in staging non-small cell lung cancer. J Thorac Cardiovasc Surg. 2003;126: 1900–1905.
37. Tournoy KG, Maddens S, Gosselin R, Van Maele G, van Meerbeeck JP, Kelles A. Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study. Thorax. 2007;62(8):696–701.
38. Pieterman RM, van Putten JW, Meuzelaar JJ, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med. 2000;343:254–261.
39. Kalff V, Hicks RJ, MacManus MP, et al. Clinical impact of (18)F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study. J Clin Oncol. 2001; 19:111–118.
40. Gould MK, Kuschner WG, Rydzak CE, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann Intern Med. 2003;139:879–892.
41. Cerfolio RJ, Ojha B, Bryant AS, Bass CS, Bartalucci AA, Mountz JM. The role of FDG-PET scan in staging patients with nonsmall cell carcinoma. Ann Thorac Surg. 2003;76:861–866.
42. Vansteenkiste JF, Stroobants SG, De Leyn PR, Dupont PJ, Verbeken EK. Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: a prospective pilot study. The Leuven Lung Cancer Group. Ann Oncol. 1998;9:1193–1198.
43. Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009;361:32–39.
44. Handy JR Jr, Asaph JW, Skokan L, et al. What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery. Chest. 2002;122:21–30.
45. Micames CG, McCrory DC, Pavey DA, Jowell PS, Gress FG. Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis. Chest. 2007;131:539–548.
46. Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009;45: 1389–1396.
47. Wallace MB, Pascual JM, Raimondo M, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA. 2008;299:540–546.
48. Annema JT, Versteegh MI, Veselic M, Voigt P, Rabe KF. Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol. 2005; 23:8357–8361.
49. Tournoy KG, De Ryck F, Vanwalleghem LR, et al. Endoscopic ultrasound reduces surgical mediastinal staging in lung cancer: a randomized trial. Am J Respir Crit Care Med. 2008;177:531–535.
50. Harewood GC, Pascual J, Raimondo M. Economic analysis of combined endoscopic and endobronchial ultrasound in the evaluation of patients with suspected non-small cell lung cancer. Lung Cancer. 2010;67:366–371.
51. Annema JT, van Meerbeeck JP, Rintoul RC. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA. 2010;304:2245–2252.
52. Annema JT, Versteegh MI, Veselic M, et al. Endoscopic ultrasound added to mediastinoscopy for preoperative staging of patients with lung cancer. JAMA. 2005;294:931–936.
53. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA. American College of Chest Physicians. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines. Chest. 2007;132:2025–2205.
54. Iannettoni MD. Staging strategies for lung cancer. Editorial. JAMA. 2010;304:20.
55. Ernst A, Eberhardt R, Krasnik M, Herth FJ. Efficacy of endobronchial ultrasound-guided transbronchial needle aspiration of hilar lymph nodes for diagnosing and staging cancer. J Thorac Oncol. 2009;4:947–950.
56. Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience. J Thorac Oncol. 2009;4:44–48.
57. Medford AR, Bennett JA, Free CM, Agrawal S. Mediastinal staging procedures in lung cancer: EBUS, TBNA and mediastinoscopy. Curr Opin Pulm Med. 2009;15:334–342.
58. Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest. 2006;29:298–302.
59. Lam KY, Lo CY. Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital. Clin Endocrinol (Oxf). 2002;56:95–101.
60. Ettinghausen SE, Burt ME. Prospective evaluation of unilateral adrenal masses in patients with operable non-small-cell lung cancer. J Clin Oncol. 1991;9:1462–1466.
61. Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology. 2002;222:629–633.
62. Blake MA, Kalra MK, Sweeney AT, et al. Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. Radiology. 2006;238:578–585.
63. Kumar R, Xiu Y, Yu JQ, et al. 18F-FDG PET in evaluation of adrenal lesions in patients with lung cancer. J Nucl Med. 2004;45:2058–2062.
64. Bodtger U, Vilmann P, Clementsen P, et al. Clinical impact of endoscopic ultrasound-fine needle aspiration of left adrenal masses in established or suspected lung cancer. J Thorac Oncol. 2009;4:1485–1489.
65. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706–714.

The evidence for a threshold for asbestos related mesothelioma in animals and humans has been reviewed by Ilgren & Browne.¹ “Threshold for tumor induction refers to an upper cumulative dose of potential carcinogen to which an organism may be exposed without observing tumor formation within the lifetime following that exposure”.¹ The dose required to reach such a threshold is measured not just in terms of fiber concentration but also fiber size. This is because fiber size is a well recognized determinant of mesothelioma induction both for length^2,3 and width.^4,5

The fiber size fractions most potent for mesothelioma induction, by length and width, are those referred to as ‘Stanton sized’ fibers. These are greater than 8 µm in length and less than 0.25 µm in width.^6,7 Almost certainly every dust cloud of asbestiform amphibole fibers contain some Stanton size fibers. Exposure to those able to cause mesothelioma contain enough to reach a mesothelioma ‘threshold’.¹ An exposure to a ‘wide’ amphibole asbestos fiber refers to the width that predominates in the dust cloud. Thus, discussion of fiber width is directly related to the issue of mesothelioma threshold. This is why both are discussed in this report.

Confirmation of the role of fiber width for mesothelioma induction should ideally rest upon an epidemiological comparison. ‘Thin’ fibers associated with a high mesothelioma risk should thus be compared with ‘thick’ asbestiform amphibole fiber exposures of the same fiber type where the latter are associated with little or no mesothelioma risk.

Crocidolite appears to be the only fiber type amenable to such a comparative analysis. In a 1985 study, Shedd,⁸ from the US Bureau of Mines, examined the fiber dimensions of crocidolites from the world's four crocidolite mining regions and found:<disp-quote> </disp-quote>

There were measurable morphological differences between crocidolite fibers that correlate with the high reported incidence of mesothelioma in miners and mill employees in the Cape Province of South Africa (Cape SA) and Western Australia (WA), as compared with little or no reported incidence of this cancer in the Transvaal Province of South Africa or Bolivia. … Crocidolites from Western Australia and the Cape Province having more thin fibers than crocidolites from Bolivia and the Transvaal Province.

Shedd⁸ noted Cape SA (81%) and WA (67%–83%) crocidolites contained much higher percentages of Stanton sized fibers than those from the Transvaal (45%–53%) and Bolivia (18%). Unfortunately, detailed epidemiological study of Transvaal crocidolite workers, despite the failure to note a mesothelioma excess in earlier reports,^9,10, could not be extended due to problems attributable to tracing and follow up.

As an opportunity arose to examine the Bolivian crocidolite industry first hand in 2008, we attempted to assess the potential for this fiber to produce mesothelioma following occupational and residential exposure. We have therefore spent the last three years gathering information on the patterns of mesothelioma found in the three largest cities of Bolivia and on the sources and types of exposures to Bolivian crocidolite experienced over the last 70 years since the industry first began. One difficulty encountered during this study was the paucity of company records available including product information. In consequence we have had to rely on personal recollections for some of the background information.

Epidemiological Studies of Bolivia Crocidolite and Mesothelioma

Shedd (1985)⁸ cited Ross (1981)¹¹ regarding the lack of reports of mesothelioma in the Bolivian crocidolite mining areas based on Ross’ failure (personal communication, 1994) to find such reports in the literature. He noted:<disp-quote> </disp-quote>

While the incidence of mesothelioma is reported to be significantly high in the crocidolite mining areas of Western Australia and the Cape Province, … no reports have been found of mesothelioma associated with the crocidolite mining region of Bolivia.

Although this remains true today, no epidemiological studies of the Bolivian crocidolite industry have ever been done nor have the patterns of mesothelioma demography in different parts of Bolivia been studied. We have investigated this issue over the last three years to identify the various exposure sources to Bolivian crocidolite from mining, milling, end product manufacturing and distribution in relation to mesothelioma induction.

The scale of the mining and milling of crocidolite in Bolivia has been small since its inception with only a single mining operator and processor: SISAM SRL.¹² So whilst the mining of Bolivian crocidolite began in the 1940's, it never involved more than a handful of workers at any one time partly because the superficial position of the fiber on the mine site obviated the need for dynamite or drilling, the activities were intermittent partly to accommodate the rainy season, and the humid conditions of the jungle mine site kept the dust levels very low. Similarly, the milling of Bolivian crocidolite took place largely at one plant from 1950 to the present time located in the city of Cochabamba. The plant workforce was small (n < 20) and worker turnover was generally high. In 1989, for example, 40 employees worked in the operations sector: mining and transportation of which five were permanent workers. During the low season, these five workers worked in Cochabamba servicing and repairing the equipment. Therefore, neither the mining nor the milling workforces are amenable to epidemiological analysis. In fact little is known of the health of these workers though we understand no mesotheliomas were ever recorded (Ramirez, 2009; Tejada 2011, personal communications).

Given these limitations, we decided to examine the demographic patterns of mesothelioma in the populations of the three largest cities in Bolivia where residential and commercial exposure to in-place Bolivian crocidolite containing products has taken place for more than 60 years. More details on the nature, production and distribution of these products both inside and outside of Bolivia are given below in the ‘Discussion’. Their use has been considerable and has consisted mainly of roof tiles, shingles, water tanks, and boiler insulation. For example, based on data provided to us through discussions with the Director of the company (Tejada, 2011, personal commun.), approximately 2.5 million kg of Bolivian crocidolite would have been used in the roof tiles in the city of Cochabamba alone. He noted that, historically, shingles and tiles contained up to 30% crocidolite (30 years or more ago). Moreover, the products: roof tiles, shingles and water tanks were less dense and dustier than those produced today.

It had been noticed that the application and repair of the tiles and shingles, particularly when cut to size before being fit to buildings, created significant dust levels (van Orden, 2011 personal communication). In addition, in-place weathering of these crocidolite containing tiles will also release fibers into the general residential environment. This latter fiber erosion from weathered asbestos cement cladding has been demonstrated by various workers to take place through a surface weathering process “whereby the external surfaces are depleted of cement binder to leave loosely bound, asbestos-rich layers on cladding surfaces”.¹³ The process appears to become severe after 20 years or more of exposure particularly for roofing materials. Released fibers were generally found to be free of attached particles and to be present as straight needle fibers in greater proportions for products containing amphiboles. Campopiano et al. said that “The high quantity of asbestos fibers found in the material gathered from the gutters (due to the decay of asbestos cement roofs) is testimony to the fact that a slow and continued release of asbestos fibers takes place from the material. In these cases, the biggest problem is the re-uptake of such fibers in the environment”.¹⁴ A lung burden study of residents from the three cities that are the subject of this study is in progress to examine the release potential of such in-place materials further. This will be published when complete.

Clearly if Bolivian crocidolite was as toxic as many say, clusters of mesothelioma should have been seen after six decades of extensive residential and commercial use. However, as described below, none has been found and the number of mesotheliomas observed to date does not exceed background.

THE DEMOGRAPHY OF MESOTHELIOMA IN BOLIVIA

Bolivia is a country of approximately nine million people. The three largest cities are Santa Cruz (ca 1.5 million), La Paz (1.2 million) and Cochabamba (700 000) (Table 1). Since there is no national cancer registry to which all mesothelioma cases are sent, the assistance of various senior Bolivian pathologists, clinicians and other cancer experts was enlisted in an attempt to determine the demography of mesothelioma. This was done through senior pathologists in each of the three cities who in turn consulted with their clinical colleagues at the major hospitals in their respective regions for cases reported either as ‘mesothelioma’ or ‘?mesothelioma’ in addition to reviewing their own hospital files. The findings of these efforts are as follows:

Cochabamba

Cochabamba is located in central Bolivia (Figure 1) at an altitude of 2500 m. It was founded in 1574. It presently has a population of ca one million largely located in an arid valley surrounded by mountains ca 3500–4000 m in height. Despite its aridity, it is fed by several rivers and a two month rainy season which along with a temperate climate accounts for Cochabamba's reputation as the ‘bread basket’ of Bolivia. Indeed, in the height of the 17^th century silver boom, the Cochabamba valley became the primary source of food for the silver miners in Potosi. By the mid 19^th century, Cochabamba reassumed its position as the nation's granary. As mining shifted away from Potosi to the southwest, Cochabamba thrived and its population gained a reputation for affluence and prosperity.

Cochabamba has six major hospitals: Caja Nacional Salud CNS; Inf. Gastro-enterologico; Viedma University Hospital at the University of San Simon; Seton Hospital; ONS Hospital; Univalle Hospital; and the Workers’ hospital. The senior pathologists at each of these were contacted with the assistance of Professor. Pedro Fernandez, director of the Instituto de Patología of the San Simon University and Dr. Roberto Guardia, Patólogo asistencial y Profesor de la Universidad at the Worker's Hospital. They in turn oversaw a search of their files which was conducted by their various assistants.

Following a review of all of the files from 2003–2009, a total of 22,209 surgical cases included 131 pleural biopsies done via thoroscope of which 53 were identified as adenocarcinomas and nine were compatible with mesothelioma one of which was confirmed as a mesothelioma by immnunohistochemistry (IHC)

The senior pathologists at the other hospitals did not formally review their files but, in consultation with their clinical colleagues, also confirmed the impression that mesothelioma had only rarely been found at their institutions. Thus, Dr. Jose Antonio Moises, a senior pulmonologist only recalled seeing one case of mesothelioma. Dr. Ciro Zabala, a senior gastroenterologist and Director de Planificación at SEDES said he saw very few mesothelioma cases in Cochabamba. He knew of two cases of pleural mesothelioma and several cases of peritoneal mesothelioma. According to Dr. Zabala, the latter were always in association with asbestosis but their work histories were not available. He also knew of two cases of pleural mesothelioma. One case was in a 32-year-old man who worked in La Paz and Cochabamba with ‘shingles’, whose family had owned a factory and built hotels and theatres there. He also had had a biopsy in Italy which suggests he may have lived and worked outside of Bolivia. The other occurred in an ex manager of the Duralit plant that processed Brazilian chrysotile and may also have used Cape blue asbestos early in its history for short periods of time.

Dr. Acosta, the senior pathologist at the GI hospital a major referral center for the City and Province of Cochabamba and the provinces of Beni and Oruro, said he saw one peritoneal mesothelioma in a 40-year-old man in 1979. However, he also said in his 35 years at the hospital he saw very few pleural mesotheliomas.

La Paz

La Paz, founded in 1548 following major gold finds, is located at 3650 m making it the highest capital city in the world (Figure 1). It is situated in a ‘bowl’ surrounded by the Altiplano (a plain 320 km long at 4000 m) and peaks up to 6500 meters. While Sucre is the judicial capital La Paz is the de facto capital of Bolivia where the government executive and legislature work. It is the second largest city in the country and the center for commerce, finance and industry. Some two-thirds of Bolivia's manufacturing is located in ‘El Alto’ a satellite city of nearly one million people which is an extension of urban La Paz with an ongoing influx of immigrants from other parts of the country.

Prof Jaime Rios Dalenz, the current President of the Bolivian division of the International Academy of Pathology who has experience at Temple University Hospital, Philadelphia, IARC/WHO in Lyon, France, and the National Hospital in London is a leading senior pathologist in Bolivia and Director of Pathology at University Mayor San Andres in La Paz conducted the cancer case accession for two time periods, 1978–1982 and 1988–1992. The findings of the case accession including the incidence of pleural and peritoneal tumors have been published in the book by Dalenz: “El Cancer en La Paz, Bolivia. Aspectos Epidemiologicos y de Patologia Geografica”.¹⁵ The case accession was based upon surveys of the populations of La Paz and El Alto by the Cancer Registry of La Paz which was established by Professor Dalenz with the assistance and cooperation of the International Cancer Research Agency, the State University of Louisiana, and the Pan American Health Organization. Briefly, medical centers were visited periodically by the survey group and the medical records were reviewed weekly. The patient's age, sex, health center, origin, primary location, diagnosis, date of diagnosis (la forma de diagnostic) and the ICD code were entered on the Registry database. Diagnoses were based on death certificates using the ninth edition of the International Classification of Oncology Diseases (CIE-O in Spanish). The number studied histologically was not given.

The 1978–1982 Survey

The 1978–1982 survey was conducted in cooperation with the State University of Louisiana during the first three years, and the Pan-American Health Organization for the last two years of the survey. Dr. Pelayo Correa from Louisiana State University and William Haenszel from the Illinois Cancer Council collaborated on the work during this time period. The rates of cancer incidence by sex, adjusted to the population, in its different locations and by 100 000 people, were described. Rates by age group in the archives of the Registry in the Colegio Médico de Bolivia, were also obtained according to population. All the patients with cancer admitted to the hospitals, clinics and institutes were registered with their medical records. All medical data from other institutes, laboratories and death certificates in those cases confirmed histologically were also entered into the registry. The majority of cases were histologically confirmed. The data in Table 2, from Dalenz¹⁵ indicate that the incidence of pleural and peritoneal cancers in La Paz from 1978 to 1982 did not exceed population adjusted rates:

The 1988 and 1992 Survey

The second cancer survey conducted between 1988 and 1992 was conducted with the technical and economic assistance of IARC/WHO under the supervision of Dr. D.M. Parkin, Chief of the Descriptive Epidemiology Unit. The data from 1988 to 1992 in Table 3 also demonstrate no mesothelioma excess for either site in either sex.

Santa Cruz

Santa Cruz de la Sierra is the largest and most populous city of Bolivia and the capital of the department of Santa Cruz. Located in the eastern lowlands at 416 m above sea level, it enjoys a semi-tropical climate all year round. Its vibrant economy makes it the most important commercial and industrial hub in Bolivia (Figure 1 [for location]). It was founded in 1561 but was relatively cut off from the rest of the country until a major highway link with other major centers was completed in 1954. Tropical agriculture boomed after a railway line to Brazil was also opened in the mid 1950's whereupon the city grew prosperously producing crops such as oranges, sugar cane, bananas and coffee.Dr. Edith Claros Mercado, formerly chief of pathology of the Cancer Hospital in Santa Cruz, has practiced pathology in Santa Cruz for the last thirty years. She over saw the search of the diagnostic archives of the four major hospitals in Santa Cruz: the Instituto Oncolójico del Oriente Boliviano (IOOB), the Caja Nacional de salud (CNS), the Hospital de la Caja Petrolera de Salud, the private Laboratorio ONCOS and the Hospital Japonés de Santa Cruz, for any diagnostic entries that stated ‘mesothelioma’ or ‘?mesothelioma’ for the last 10 years. The senior pulmonologists: Dr. Alfredo Ajata; Dr. Jorge Antonio-Mendez; Dr. Ronald Arce; Dr. Roberto Paz and radiologists conducted the searches and interviewed clinicians and radiologists at the various hospitals in Santa Cruz. In addition help was given by an assistant pathologist, Dr. Carolina Henestrosa and three pathology residents

Thirteen cases had the diagnosis of mesothelioma or ‘?mesothelioma’ somewhere in their case records. The details thus provided on the13 cases are shown in Table 4. After consideration of the strength of the diagnoses for these cases we believe at most three are true mesotheliomas with any possible causal association with asbestos exposure. The rarity of the diagnosis was consistent with Dr. Claros’ overall impression that these tumors were very rarely found in Santa Cruz.

DISCUSSION

Our findings suggest the incidence of mesothelioma in the three major cities of Bolivia is not significantly elevated above background.¹⁶ This is so even though Bolivian crocidolite has been used for the past 60 years both commercially and residentially in all three cities. Dalenz¹⁵ did indeed say: “Asbestos is exploited from one zone in the county … At present, there is no indication of a relationship with lung cancer and mesothelioma” (in Bolivia). This is consistent with Shedd's⁸ earlier impressions that mesotheliomas were not reported in the Bolivian crocidolite mining areas.

The most likely explanation for the failure to find a significant elevation of mesotheliomas in these three Bolivian cities, despite the large populations at risk from the long and extensive residential and commercial use of crocidolite containing products as mentioned above and described in more detail below, is related to an increased fiber width distribution and a concomitant reduction in the ‘Stanton fiber size’ fraction. Similar findings also probably explain the paucity of mesotheliomas in the Finnish anthophyllite,¹⁷ South African amosite^9,10 and African Transvaal crocidolite workforces.^18,19 Findings which have been reviewed by others.^5,20 These findings are also consistent with the conclusions reached by Wylie et al.⁵ on the role of fiber width and carcinogenicity.

Virtually no occupational histories were available for the mesothelioma cases reported herein. Of two cases of pleural mesothelioma with some work histories, the 32-year-old man is too young to have contracted mesothelioma from the work he did in La Paz and Cochabamba with ‘shingles’. We know nothing of his family's work history so he conceivably may have incurred causative exposures there. He also had a biopsy in Italy so he might have worked there as well. The other case was in an ex manager of the Duralit plant. Whilst that facility processed Brazilian chrysotile, it also processed small amounts of Cape blue asbestos early in the plant's history so he might have incurred exposure to African crocidolite.

Nonetheless, the number of cases found in this investigation still did not exceed the number expected (> 40) in relation to the size of the populations at risk (> one million people per year on average) and the length of time over which these populations were exposed within the period of latency (> 40 years).

Ascertainment and Exposure Considerations

Some cases of mesothelioma may have been missed due to a failure to reach hospital or shortened natural lifespan. We cannot tell precisely the extent to which these were confounding. However, access to medical care, reliance on traditional medicine and shortened lifespan are related to ethnicity and socio-economic status (SES). Indeed, the lifespan of the poorer segments of society is ca 45 years old ^21–24 and since mesothelioma generally occurs after the age of 50, many in the lower SES groups would have died from competing causes before developing mesothelioma. However, the lifespan of the upper SES groups exceed 70 years which would be adequate to ascertain cases if they were occurring.

Confounding would therefore be more likely if indigenous groups were preferentially affected for these factors and there was no exposure to the segments of the population in the higher socio-economic groups. However, that was not the case. Indeed, many homes in La Paz (eg, in the upscale neighborhood of Achuamani) have blue asbestos shingles. (Tejada, personal communication, 2011). Therefore, significant numbers of people in upper SES groups in La Paz and other cities in Bolivia have been exposed to Bolivian crocidolite but mesothelioma clusters have not been recognized amongst them. This strongly suggests access to medical care was not a limiting factor since they could avail themselves of hospital facilities. The distribution of crocidolite containing products through various social strata is also is well illustrated by the extensive commercial use of crocidolite containing roof tiles and shingles in the major Cochabamba medical center for more than 40 years (Figures 2a & 2b [hospital roof]) and on the roof of the old Calatayud market. (Tejada, personal communication, 2010). Moreover, the size of the populations of the three cites at risk in the upper SES strata were quite sizable over the relevant period of risk, from 1950 to 1990 with a latency of 20 years (see Table 1) and the periods at risk were very long and well within latency for the development of mesothelioma.

Dalenz¹⁵ said “one has to admit that there are cancer cases, particularly in the marginal urban areas, whose population does not have access to medical centers and whose contribution to a sub-registry is difficult to quantify.” Still, in other parts of the world with relatively little access to medical centers (eg., central Mexico,²⁵ New Caledonia²⁶ or Turkey^27,28) historical exposures to dangerous fiber types have occurred for decades and produced clusters of mesotheliomas that were eventually recognized and reported. One would have expected after six decades of continued use of Bolivian crocidolite the same would apply to the so called ‘marginal’ areas of Bolivia and clusters of mesothelioma attributable to the long term use of Bolivian crocidolite would have been found.

A brief summary of the domestic and international distribution and use of these crocidolite containing products is given below as it underscores the extensive distribution of these materials amongst the major populations in Bolivia and to certain specific locations outside the country. It thus emphasizes the extent to which some segments of the Bolivian population have been exposed. Despite these exposure pathways and parameters, no mesothelioma clusters have been identified in relation to the presence of any of these materials.

Domestic Distribution of Bolivian Crocidolite -Containing Products and Exposure Pathways

Cochabamba

The major crocidolite containing products were roof tiles, shingles and water tanks produced primarily by the new Fibrolit plant described below. Historically, at least three crocidolite plants (Ottocar, Banco Minero, and the Old Fibrolit plant) operated near the town center and all were within 2 km of the main hospital complex of the San Simon Medical College. (Figures 3 &  4). At least two more (UNIDO, new Fibrolit) were found just outside the city (Figures 3 &  4) whilst two others (COMACO, YPFB) were in or near the city and used the Bolivian crocidolite in their production lines (see below). These facilities were a source of environmental and residential fiber exposure since, historically fiber spilled downtown during transport to and from the plants.

‘Banco Minera’ plant

There was one ‘Banco Minero’ in each town. These served as ‘mining’ banks (Tejada, personal communication, 2011). In Cochabamba, the Banco Minero was located near the slaughterhouse in a populated area slightly outside the city centre ca 2 km from the main square (Figure 3A) (Tejada, personal communication, 2011). The Banco Minero was started in the 1940's after the Chaco war. It classified fiber for export (Ramirez, personal communication, 2009). After the other plants were established in ca 1950, the Banco Minero took asbestos from many mines and producers. (Tejada, personal communication, 2011). Bags of the mineral were always unloaded manually (Tejada, personal communication, 2011).

‘Old Fibrolit’ plant

The Tejada family home, ca. 1960, was originally one block from main square (Figure 3B). Bags of crocidolite would be delivered there before they went to the Banco Minero for milling and bagging ca. 2 km away (Tejada, personal communication, 2011). The Tejadas eventually bought the Banco Minero plant to supply their own plant and others as well (eg., YPFB oil refineries).

The Tejada (Fibrolit) family processing plant

This plant was originally on Ave America from 1950 to 1982 (Figure 3C). It then moved to km 3 on the Cochabamba to Santa Cruz road also known as Route 4 (Figure 3D). Van Orden and others (2011, personal communication) have given some description of this plant in its present yet ‘historical’ operational state but this has yet to be published. An earlier partial account by Bliss and Ankers is briefly presented here.¹² Their study of the Bolivian crocidolite industry was done on behalf of UNIDO in the late 1980s and is described in Appendix 1. The milling and the fibro-cement plant are presently located adjacent to each other. Both are very elemental. It was been noted that dusty conditions prevailed in each facility.

Although located at least 3 km from the center of Cochabamba, there are various suburban homes and work places nearby which may be subject to environmental residential exposure (Figure 4).

Otacar family plant and factory

The Ottocar family was the biggest buyer of blue asbestos in Cochabamba for many years. It began in 1946 and originally owned both a classifying plant and a production factory for Bolivian crocidolite. (Ramirez, personal communication, 16 April 2009)

Otacar classifying plant

The classifying plant was located in the center of Cochabamba at the corner of Calle Columbia and Miralla Tamulse (Figure 3E). (Ramirez, personal communication, 2009) There was much dust in the air. The building only had a roof and four walls. There was no ventilation. The work continued for 8 h a day. Workers unloaded the crocidolite into jute bags which they put in a small open storage room. It was then taken out of the bags and carried in wheel barrows to be put into the classifier. Most of the fiber was loose. It is not clear where the waste was dumped though some of it may have been purchased by YPFB to make pipe insulation (Gallo & Ramirez, personal communication, 2009). The classified crocidolite was purchased by various companies including YPFB (initially Petrobras), Ottocar, La Belgica owner of the Montero sugar mills in Santa Cruz, and by the Tejada family for Fibrolit.

Otacar production plant

The production plant (Figure 3E) made shingles and tanks from 1950 to 1975.²⁹

UNIDO plant (PLANTA DE ONUDI)

The UNIDO plant had been an experimental processing plant of blue asbestos built by the joint cooperation of UNDP, UNIDO and the Bolivian government, under project DP/BOL/68/520 that began in 1968 in Cochabamba at 9 km on the road to Santa Cruz. The UNIDO plant bought asbestos from Banco Minera. Its former Director, Sr Jiminez Gallo, said that he worked there with blue asbestos from 1973 to 1977 (Gallo, personal communication, 2009). Thirty men were employed at any one time, over the years, amounting to ca 200 in total. While dust measurements were done at the plant there were no data left. Similarly, there were no personnel records and probably no employee lists left. Bliss and Ankers¹² said that after a series of tests, the plant never operated near capacity due to a variety of circumstances. There was only a low level of intermittent activity during the 17 years of its existence. Because of the poor operational conditions, they noted the UNIDO site was significantly contaminated and this also posed a danger to the adjacent neighborhood. The asbestos waste was put into bags and then thrown into the river which ultimately flowed through the city (Figure 3F) (Ramirez, personal communication, 2009).

Duralit Chrysotile plant

This plant is located 7 km outside Cochabamba (Figure 3G). The plant apparently used some Bolivian and Cape South African crocidolite for testing purposes early in its history.

COMACO plant

COMACO is a major producer of concrete cement products. Historically, it purchased Bolivian crocidolite for some of its product lines (Tejada, personal communication, 2011) and one of its plants was located in the city of Cochabamba (Figure 3H). Today, it is based in Santa Cruz.

The major product lines using the Bolivian crocidolite made shingles, tiles and water tanks. However, other products were produced in Cochabamba and distributed through the city and to other parts of Bolivia.

Pipe insulation, general lagging, drilling mud

Medium length fiber was sold to oil refineries, sugar refineries, and other companies for pipes and general lagging on, for example, furnace coating and towers in the petroleum refining industry.²⁹ Bliss and Ankers¹² said that grade “#6 is the remainder/leftover (residue material used for insulation).” YPFB, the national oil company, initially bought crocidolite from Banco Minera. The company used crocidolite to insulate their pipes and tanks and had a department to make pipes exclusively for them. Short fiber was used in the pipes since 1946 (Ramirez, personal communication, 2009) The exact location of the plant in Cochabamba could not be determined. Ramirez said crocidolite may also have been used as drilling mud.

Textiles

Long crocidolite fiber was used for spun thread textiles.²⁹

Filters

Medium length fiber was used in various filter media (also see below under “United States”) by the chemical industry for the purification of different harsh chemicals and gases (“thermic air freshener”²⁹).

Brakes and brake lining

Medium length crocidolite fiber was used in the automotive industry for brakes and brake linings.²⁹

Paper and cardboard foil

Medium length crocidolite fiber was used in the production of thermic coating in fine cardboard foil.

Floor tiles

‘Polyvinyl crocidolite asbestos foil’ was used in some floor tiles.²⁹

Plastic reinforcement, construction and ceiling tiles

Crocidolite was also used in construction, plastic reinforcement, and ceiling tile production (Ramirez, personal communication, 16 April 2009)

Precious metals/artisan work

Bolivian crocidolite was used in “gold or silver work to produce artistic objects in pressed or molded masses”.²⁹ It was also used in sculptures (Tejada, personal communication, 2011).

Distribution to Bolivian Towns Outside of Cochabamba

Sixty percent of all of the Fibrolit crocidolite products have gone to Santa Cruz (Tejada, personal communication, 2011). In addition to shingles, tiles and water tanks, long fiber is used preferentially to line the boilers of the sugar mills commonly found around Santa Cruz.

There were at least 40 distributors in Bolivia of crocidolite containing products. These distributed the products from the factory to the marketplace by private trucks within and outside Bolivia. Fibrolit had a major distribution agency in La Paz. This also made small amounts of crocidolite containing products.

Other, Smaller Deposits of Bolivian Crocidolite

Tarija

Tarija (1905 m) is a city of 132 000 located in the south of Bolivia ca 96 km north of the Argentine border. Founded in 1574, it was formerly established as part of Bolivia in 1825. It is recognized for its beautiful colonial architecture and vineyards.

The crocidolite deposits and mines near Tarija are very small and consist largely of short fiber (Tejada, personal communication, 2011). This made their exploitation economically unfeasible (Ramirez, personal communication, 2009).

Eastern Bolivia ear the Mutun iron deposit

Iron deposit near Mutum in the extreme eastern part of Bolivia along the Brazilian border around 30 km south of Puerto Suarez (Figure 1) is one of the largest in the world. There is a small amount of Bolivian crocidolite near the Mutun iron mining area.^30,31 The area is rather sparsely populated but conceivably workers, their families, certain towns’ folk, and others living along the distribution lines of the ore may incur exposure to crocidolite fiber.

International Distribution

Chile

Bolivian crocidolite was sold to Chile through Arica and Antafagusta and transported by train either through La Paz or Potosi (Ramirez, personal communation, 2009). Sales were made from 1950 to 1980. It was sold to Chile for the production of fibrocement water pipes and tubes^. The use of asbestos cement pipes in the North of Chile was documented by Schull (unpublished) in Putre, San Miguel, Chungara, Arica and Chanaral as part of their Multi-Andean Genetic Health Programme.³²

Bolivian crocidolite was also exported to the United States through Chile. This was discontinued in 1972. The location of the Chilean plants that processed the Bolivian crocidolite is not known. However, review of the historical records of the regions in the north of Chile for diverse cancer types failed to reveal a mesothelioma excess.

Argentina

Argentina used long fiber Bolivian crocidolite to make firefighter's clothes sold under the name ‘Christ Desu’ (Ramirez, personal communication, 2009). The location of the Argentine plants that processed the Bolivian crocidolite is not known. However, we are not aware of reports of mesothelioma clusters in the north of Argentina where these materials would have been processed. No doubt, given the highly fibrous nature of the material, this would have been a very dusty operation (Figure 5).

Brazil

Petrobras initially used Bolivian crocidolite in Brazil (Ramirez, personal communication, 2009).

United States

Bolivian crocidolite was stockpiled for strategic use in the production of filters³³ Appendix 2. Gaensler and Goff³⁴ reported the use of Bolivian crocidolite, in combination with South African, in their study of asbestos related disease in filter paper plant workers in the Boston area. Knudson³⁵ recommended the use of Bolivian crocidolite in cigarette filter papers. Some may also have been used for a short time in school notebook paper as well.

Storage and Transport of the raw asbestos

The crocidolite was carried in paper and jute bags. Some were re-used for other purposes. The risk of developing mesothelioma from the handling of raw asbestos contaminated jute bags is well known.³⁶ Breakage of bags and spillage of crocidolite also took place en route from the mines in the Chapare ca 220 km from Cochabamba. Historically the road was very bad which caused more bags to break particularly since the asbestos was initially transported by mule trains of 100 to 150 animals. Afterwards it was brought by truck (Tejada, personal communication, 2011). The mineral in transport was 85% pure.^12,37

Other Sources of Potential Ascertainment Bias

It could be argued that the individuals at greatest risk outside of the plants were those who installed the tiles, shingles and water tanks from sawing or drilling these materials. It could also be argued that such individuals were largely from the lower classes. However, some residents would also have installed these materials themselves as the instructions for doing so were simple and straightforward.

Clearly, if the attendant risk was so high, clusters of mesothelioma would have been found in these workers after six decades. It could be argued that since such work was done outside the exposures were just too low but if that was the case it would support the notion of a mesothelioma threshold.

MISDIAGNOSIS

The periods of ascertainment for the three cities (La Paz: 19781982; 1988–1992; Santa Cruz: 1998–2008; and Cochabamba: 2003–2009) were contemporaneous with the development and existence of the diagnostic tools presently used to diagnose mesothelioma. Appendix 3 ^38–41 Thus, by 1978 which is the starting date for the case ascertainment done in the present study, the histological, histochemical and immuno-histological tools for the recognition of mesothelioma on small tissue samples had been established in conjunction with necessary radiological diagnostic methods.³⁸ Moreover, the major hospitals in the three largest cities of Bolivia that were the subject of this study were equipped with the radiological and pathological tools needed to diagnose mesothelioma by 1978. The cases were also reviewed by experienced senior pathologists and radiologists.

Seven of the 13 Santa Cruz cases (Table 4) should probably be excluded. Cases 9 and 11 had predominant histological features uncommonly found in mesothelioma that make the diagnosis suspect (giant cell features). Case 2 (‘benign fibrous mesothelioma of the pleura’), case 5 (well differentiated papillary mesothelioma of the peritoneum), and case 6 (tunica vaginalis mesothelioma) are histological variants not causally associated with asbestos exposure.³⁹ Case 12 is also suspect as it is merely listed as “meso-appendix”. Case 13 simply refers to tumor as “primary is unknown with pulmonary metastases”. The very young age and the fact that the patient was a female further suggests it is not a mesothelioma or one not related to asbestos exposure.

Lung Cancer

Mesotheliomas are most commonly confused with carcinomas metastatic to the pleura and the most frequent primary source is the lung. Lung cancer, however, is relatively uncommon in Bolivia due to the comparatively low use of tobacco.¹⁵ Therefore, lung cancers presenting as pleural tumors (at least the so called pseudo-mesotheliomatous adenocarcinomas of the lung⁴⁰ are probably quite uncommon and are thus rather unlikely to present a significant source of diagnostic confounding in this study.

Tuberculosis

Historically, pleural tuberculosis (TB) has been the major source of historical diagnostic confounding for mesothelioma. Indeed, the cases of mesothelioma discovered by Wagner et al.⁴¹ in the Cape crocidolite mine fields were found in miners thought to have resistant pleural TB.⁴² Some of the pathologists that participated in the present study said cases of thickened pleura were frequently biopsied. However, Bolivia has one of the highest rates of TB in the Western hemisphere.⁴³ As TB is not widely screened in Bolivia, pleural TB could be a source of confounding

Nosological classification

The categorization of mesotheliomas by the nosologists did not appear to be problematical. This was done using the standard ICD system (CEI in Spanish) (also see above). There were tumors, nonetheless, classified as ‘primary site undefined’ for 82 men (rate 8.5) and 60 women (rate 6.0) for neoplasms classified from 1978 to 1982 out of a total of 2734 (839 men; 1795 women). Similarly, tumors were also categorized as ‘Primary site undefined’ for 63 men (100.1 rate) and 130 women (160.5 rate) for neoplasms classified from 1988 to 1992 out of a total of 4,597 (1505 men; 3092 women). There is no way to be certain some mesotheliomas were not placed in these categories.

MESOTHELIOMA THRESHOLD, FIBER WIDTH, AND MECHANISTIC CONSIDERATIONS

The apparent failure to see a mesothelioma excess due to Bolivian crocidolite suggests the exposures incurred by the residents in the three major cities of Bolivia contained too few Stanton fibers to reach a mesothelioma threshold. Failure to produce mesotheliomas in animals using Bolivian crocidolite, albeit in only a few studies, is also supportive evidence for a mesothelioma commonly found for example in quarried aggregate stone used for myriad purposes throughout the world. Logic dictates these materials would produce large numbers of mesothelioma clusters if they were as potent as true amphibole asbestos fibers. However, to our knowledge, none has been seen.

Acknowledgements: The authors would like to thank Sr Oscar Tejada Cabrera, mine and plant owner, Dr. Ricardo Ramirez, co-author of this paper and mining engineer who has studied the mine for many years and Sr Jiminez Gallo who was the former Director of the UNIDO plant for their background information to this study.

Disclosure: Some $7,000 of financial support came from RJ Lee which represented about 5% of the total cost of the study; other finance came from personal funds. RJ Lee had no role in the design of the study, data collection, analysis or interpretation of results.

Appendix A: APPENDIX 1

The Milling Plant: “The mill operates all year round and employs four people.. The roofed mill building is open on both sides. Asbestos that arrives from the mine is piled up near the rolling mill and it is fed by manual shoveling. This plant has a preliminary grinding place and material that cannot be ground is separated and piled aside. The milled product is manually separated and transported in wheelbarrows to a hammering mill, where it is again introduced to the mill using shovels. … From this recollection chamber, the material is transported manually towards one of the two sieving machines … The total production reaches on average between 2–3 metric tons per day. Four people operate the plant, working for eight hours a day, five days a week.

Appendix B: APPENDIX 2

“… (blue asbestos) shall conform with National Stockpile Specification P-80-R, dated April 17,1952, which designates that the material purchased shall be Bolivian crocidolite asbestos or its equivalent. Three grades are covered, as follows: Crude No.1, a minimum of 85% (by weight) of which shall be in fibers three-fourths of an inch in length or longer; Crude No. 2, a minimum of 85% of which shall consist of fibers three-eighths of an inch to three-fourths of an inch in length; and Run-of-Mine (crude or milled), a minimum of 90% of lumps and fibers of which shall be retained on a No. 16 sieve. The material shall contain not more that 2% of moisture and not more than 5% of foreign matter. The specification includes items covering methods of test, etc. Details of sampling and inspection are omitted as this material is no longer being purchased for the stockpile.”³³

Appendix C: APPENDIX 3

Historically, diagnoses of mesothelioma were not generally made before 1960 though reports certainly documented the existence of rare examples of these tumors.⁵⁰ This is well exemplified by the discussions of the principal author with Sir Richard Doll in 2003 in Oxford. Thus: “Chris Wagner had recently died and his wife and colleague, Dr. Margaret Wagner, were my dinner guests in Oxford. Margaret recounted the difficulties Chris had in convincing his colleagues in South Africa in 1958 that the tumors he recognized in the crocidolite miners were mesothelioma (as described by Wagner in Henderson³⁸). Sir Richard Doll said he felt there was at least one mesothelioma amongst the ‘lung tumors’ he found in the Rochedale textile asbestos factory workers⁵¹ but pathologists were very reluctant to make the diagnosis. Sir Richard said this was because Rupert Willis, the pre-eminent tumor pathologist at the time held great sway and had taken the view, I believe quite correctly, that such tumors were exceedingly rare and could only be diagnosed with full autopsy. Willis confirmed this to me in person in 1977 when I visited him at his home in the Wirral in the north of England. Things changed after Wagner's 1960 publication⁴¹ on the finding of mesotheliomas in the South African mines and thereafter Chris developed some of the first histochemical stains to further refine the accuracy of the diagnosis. By 1978³⁹ additional histochemical and immuno-histochemical stains had been developed and these constituted a basic staining panel for confirming the diagnosis on tissue biopsies.”

REFERENCES

1. Ilgren E, Browne K. Asbestos-related mesothelioma: evidence for a threshold in humans and animals. Reg Tox Pharm. 1991;13:116–132.
2. Ilgren E. The fiber length of coalinga chrysotile: enhanced clearance due to its short nature in aqueous solution with a brief critique on ‘‘Short Fiber Toxicity’’. Indoor Built Environ. 2008;17:20–24.
3. Eastern Research Group. Report of the expert panel on health effects of asbestos and synthetic vitreous fibers: the influence of fiber length. Prepared for the agency for toxic substances and disease registry division of Health Assessment and Consultation Atlanta, GA (2003).
4. Ilgren E. The fiber width of coalinga chrysotile: reduced respirability due to its thick nature in an aerosol and its ‘‘Ultra-Thin’’ nature in aqueous solution (In Vivo). Indoor Built Environ. 2008;17:20–41.
5. Wylie A, Bailey K, Kelse J, et al. The importance of width in asbestos fibre carcinogenicity and its implications for public policy. Amer Indus Hyg Asso J. 1993;54:239–252.
6. Stanton M, Wrench C. Mechanisms of mesotheliomas induction with asbestos and fibrous glass. J Natl Cancer Inst. 1972;48(3):797–821.
7. Stanton M, Layard A, Tergeris E, et al. Relation of particle dimension to carcinogenicity in amphibole asbestos and other fibrous minerals. J Natl Cancer Inst. 1981;67:965–975.
8. Shedd KB. US Department of the Interior: fiber dimensions of crocidolite from Western Australia, Bolivia, and the Cape and Transvaal Provinces of South Africa. US Bureau of Mines Report of Investigations —8998. Washington, DC: United States Department of the Interior. Bureau of Mines; 1985.
9. Webster I. Asbestos and malignancy. South Africa Med J. 1973;47:165–171.
10. Webster I. Malignancy in relation to crocidolite and amosite biological effects of asbestos. Lyon, France: IARC Scientific Publications (No.81 IARC); 1973. Pp.195–198.
11. Ross M. The geologic occurrences and health hazards of amphibole and serpentine asbestos. Chap.
3. In: Amphiboles and Other hydrous pyriboles – mineralogy, (Veblen D. ed.). Min Soc Am Rev. 1981;9A: 279–323.
12. Bliss C, Ankers W. High level assistance for the evaluation of the experimental plant for asbestos processing [SI/BOL/89/802] 1990.—— 13. Brown S, Angelopoulos M. Evaluation of erosion release and suppression of asbestos fibers from asbestos building products. Am Indust Hyg Assoc J. 1991;52(9):363–371.
14. Campopiano A, Ramires D, Zakrzewska M, et al. Risk assessment of the decay of asbestos cement roofs. Ann Occup Hyg. 2009;53:627–638.
15. Dalenz R. El Cancer en La Paz–Bolivia. Aspectos Epidemiologicos y de Pathologia Geographica. 2008.—— 16. Ilgren E, Wagner J. Background incidence of mesothelioma: animal and human evidence. Reg Tox Pharm. 1991;13:133–149.
17. Karjalainen A, Meurman L, Eukkala E. Four cases of mesothelioma among Finnish anthophyllite miners. Occup Environ Med. 1994;51:212–215.
18. Timbrell V, Griffiths D, Pooley FD. Possible biological importance of fibre diameter of South African amphiboles. Nature. 1971;232:55–56.
19. Timbrell V, Pooley FD, Wagner J. Characteristics of Respirable Asbestos Fibres. In: Pneumoconiosis: Proc Intl Conf Johannesburg. Cape Town: Oxford University Press; 1970: 120–125.
20. Harington J, Gilson J, Wagner J. Asbestos and mesothelioma in Man. Nature. 1971;232:54–55.
21. Dalenz RJ, Correa P, Haenszel W. Morbidity from Cancer in La Paz, Bolivia. Intl J Cancer. 1981;28:397–314.
22. Dalenz R, Montano S, Guerra C, et al. El cancer en la zona Andina de Bolivia. Patologý´a (Mex). 1991;29:123–127.
23. Dalenz R, Casablanca S. Aspectos socioeconómicos del cancer en dos poblaciones andinas de Bolivia. Salud Boliviana. 2002;13:11–14.
24. Dalenz R, Calderón R, Rodrý´guez J, et al. Morbilidad por cancer en La Paz/El Alto y Sucre, Bolivia. Revista Andina de Salud (Sucre). 2004;13:23–30.
25. Ilgren E, Brena M, Larragoita C, et al. A reconnaissance study of a potential emerging Mexican mesothelioma epidemic due to fibrous zeolite exposure. Indoor Built Environ. 2008;17:496–515.
26. Luce D, Brochard P, Quenel P, et al. Malignant pleural mesothelioma associated with exposure to tremolite. Lancet. 1994;344:1777.
27. Baris Y, Sabin A, Ozesmie M. An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain in Anatolia. Thorax. 1978;33:181–192.
28. Baris Y, Simonato L, Artvinli M, et al. Epidemiological and environmental evidence of the health effects of exposure to erionite fibers: a four-year study in the Cappadocian Region of Turkey. Int J Cancer. 1987;39:10–17.
29. Ramirez R. Estudio de Ingeniera Global Esinglo. Los Minerales de Asbesto en El Chapare. Consideraciones Geologicas y Mineralogicas. Doctoral thesis, School of Engineering. 1989. —— 30. Arce Burgoa O. Guia a los Yacimientos Metaliferos de Bolivia. SPC Impresores SA. ISBN 978-99954-0-143-6. 2007.
31. Redwood S. Crocidolite and magnesite associated with Lake Superior type banded iron formation in Chapare Group of eastern Andes, Bolivia. Trans Inst Min Metal. 1993;102:114–123.
32. Mueller W, Schull V, Schull W, et al. A multinational Andean Genetic and Health Program: growth and development in an hypoxic environment. Ann Human Biol. 1978;5:329–352.
33. Bowles O. The Asbestos Industry. US Bureau of Mines, Bulletin 552. Washington, DC: US Govt. Print Office; 1955.—— 34. Gaensler E, Goff AM. Asbestos-related disease in crocidolite and chrysotile filter paper plants. VIIth International Pneumoconioses Conference (NIOSHILO), DHHS (NIOSH) Publication No. 90–108, Part I. 1990; Sept.: 397–401.
35. Knudson H. Filter for Tobacco Smoke. Patent 276j/798 United States Patent Office September 4, 1956.
36. Ascoli V, Carnovale-Scalzo C, Nardi F, et al. A one-generation cluster of malignant mesothelioma within a family reveals exposure to asbestoscontaminated jute bags in Naples, Italy. European J Epidemiol. 2003;18: 171–174.
37. Ankers B. Report of UNIDO investigation findings to McKenna, C. National Occupational Hygiene Service Ltd., Manchester. Ref. SI/BOL/89/802/ NOHS (1990)—— 38. Henderson DW. In: Henderson DW, Shilkin KB, Langlois SLeP, Whitaker D, eds. Discovery of mesothelioma. Malignant Mesothelioma. Washington, DC: Taylor and Francis Hemisphere Publishing Corp; 1991.
39. Churg A, Cagle PT, Roggli VL. Tumours of the Serosal Membranes. Armed Forces Institute of Pathology Atlas of Tumour Pathology, Fourth Series, Fascicle 3. Churg A, Cagle PT, Roggli VL, eds. Washington DC:, 2006 40. Colby TV, Koss MN, Travis WD. Tumors of the lower respiratory system. In: Rosai J, Rosai JS, eds. Atlas of tumor pathology, 3rd series, Fascicle 13. Washington, DC: Armed Forces Institute of Pathology; 1995:465–471.
41. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Brit J Ind Med. 1960;17:260–271.
42. Wagner J In: Henderson DW, Shilkin KB, Langlois SLeP, Whitaker D, eds. Discovery of Mesothelioma. Washington, DC: Taylor and Francis Hemisphere Publishing Corp; 1991.
43. US AID for Bolivia Tuberculosis Profile. 2009. www.usaid.gov/our_work/ global_health/.../tuberculosis/.../bolivia.pdf.
44. Ilgren E. Mesotheliomas of animals: a comprehensive, tabular compendium of the world’s literature. CRC press. 356 pp. ISBN 0-8493-4308-9. 1993.
45. Browne K. Asbestos related malignancy and the Cairns Hypothesis. Brit J Indust Med. 1991;48:73–76.
46. Oberdörster G, Morrow P, Spurny K. Size dependent lymphatic short term clearance of amosite fibers in the lung. Ann Occup Hyg. 1988;32(S1):149–156.
47. NIOSH. Asbestos fibers and other elongated mineral particles: state of the science and roadmap for research. June 2008. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. 2008.
48. Aust A, Cook P, Dodson R. Morphological and chemical mechanisms of elongated mineral particle toxicity’s. J Toxicol Environ Health. 2011;14(1–4):40–75.
49. Ilgren E. Coalinga fibre—a short, amphibole—free chrysotile. Part 6 Lack of amphibole asbestos contamination. Indoor Built Environ. 2004;13:325– 341.
50. Wagner J. The discovery of the association between blue asbestos and mesotheliomas and the aftermath. Br J Indust Med. 1991;48:399–403.
51. Doll R. Mortality from lung cancer in asbestos workers. Brit J Indust Med. 1955;12:81–86.

** Available on request from the authors.

The respiratory tract including the nasal cavity, the ears, and conjunctiva are in contact with the environment and are the first line of defense against viral invasion. Normal healthy individuals respond to, contain, and clear invading viruses by many means including physical barriers as well as the actions of the innate and acquired immune systems. Infection is a principle cause of morbidity and mortality in immunocompromised patients and the respiratory system is especially vulnerable. When caring for immunodeficient patients an understanding of the mechanisms of host defense and immunity as well as the predisposing factors, causes, and complications of infection and the optimal use of anti-infective therapy is all critical in optimizing outcome.

Host defense against pathogens includes both innate and acquired immunity. The innate immune system comprises cellular components; phagocytes, monocytes, and neutrophils; natural killer (NK) cells; as well as soluble components, complement and lysozyme. It is present prior to exposure to a microorganism, does not discriminate between the various types of microorganism, and is not enhanced by exposure to invading pathogens. The innate immune system is very effective in dealing with many microorganisms via pattern recognition receptors (toll-like receptors) that recognize pathogen-associated molecular patterns or conserved structures of invading microorganisms.¹

In contrast, the acquired immune system has two defining characteristics: the first is its antigen specificity and the second is memory. The acquired immune system is composed of both the cellular and humoral immune systems. The cellular acquired immune system is comprised of T-cells of two major categories. The first, CD8 positive cytotoxic T-cells are cells that detect and lyse other cells infected with intracellular pathogens such as virus, fungi, or mycobacteria. The second category, CD4 positive helper T-cells assist in orchestrating the immune response. The other branch of the acquired immune system is the humoral immune system, which is mediated by antibodies, proteins that can specifically recognize antigens and lead to the removal of the invading microorganism. B-cells proliferate and differentiate into antibody secreting plasma cells. The humoral immune system is responsible for clearing extracellular pathogens, most notably bacteria.²

It is important to develop a conceptual framework of the elements of host defense and immunity as this understanding provides a framework with which to approach diagnosis and management of the patient. Knowledge of the type of infection and infecting organism may indicate which arm of the host's defenses are defective and, reciprocally, an understanding of the immune deficiency will provide information about likely pathogens. As all viral pathogens are obligate intracellular pathogens and must replicate within a cell, T-cells are critical for control of these infections. Defects in T-cell immunity are of major factor in the morbidity and mortality from these respiratory infections (see Table 1).

DIAGNOSIS AND INVESTIGATION OF IMMUNODEFICIENCIES

A careful medical history and full physical examination are essential to direct further investigation of children in whom the diagnosis of an immunodeficiency is suspected and should precede any laboratory or radiological investigations.

In the medical history, pregnancy and birth history may give information about possible congenital infections, intrauterine growth retardation, or prematurity, any of which may indicate an immune deficiency. Delayed separation of the umbilical cord may suggest a defect in neutrophil migration and these children usually present later with a pyogenic infectious problem. In the history, the age of onset of infections, proven or suspected causative organisms, the site of infection, the duration of illness, and time to recovery with adequate treatment all contribute to identification of immunodeficiency. Other issues in the history that should be sought when investigating immunodeficiency are failure to thrive, chronic diarrhea, and evidence of respiratory system damage such as a productive cough suggesting bronchiectasis or clubbing. In addition, a careful family history of other children or relatives that may suggest an autosomal recessive or X-linked pattern of inheritance is also important. A tactful inquiry of the parents to determine if there is consanguinity or any risk factors for infection with a human immunodeficiency virus (HIV) should also be made.

An immunodeficient child is more likely to have infections that take longer to resolve on appropriate therapy, for example, bacterial pneumonia failing to respond to appropriate antibiotic therapy or have an atypical course, severe hemorrhagic chicken pox or an unusual type of organism, Pneumocystis jirovecii pneumonia. It should be noted, however, the occurrence of frequent viral upper respiratory tract infections in a young child with no other significant infectious illnesses is not indicative of an underlying immune defect as up to 8–10 upper respiratory tract infections per year is normal in preschool children.

The physical examination should be directed toward finding evidence of adequate growth; that is, height and weight percentiles, evidence of chronic infection in the ears, sinuses or throat, as well as examination of the oral cavity and napkin area for candidiasis. In addition, a respiratory examination and full physical examination of the other body systems must be performed. The presence of lymphoid tissue or rashes should also be noted.

Diagnostic imaging

Findings from history and examination may guide radiological evaluation of the respiratory tract with X-ray, computerized tomography (CT), magnetic resonance imaging (MRI), or ultrasound indicated in specific clinical circumstances.

Laboratory investigations

Diagnosis

Epidemiological features such as seizures or exposure history and clinical features such as systemic signs or symptoms or a rash may be significant in establishing the viral etiology of pneumonitis. However, the clinical presentation is rarely distinctive and diagnosis generally depends upon detection of the viral agent in an appropriate respiratory specimen. Upper respiratory tract samples can be used as many viruses can be isolated from these specimens, but lower respiratory tract samples may have a higher yield or greater specificity, particularly in immunocompromised hosts. Rapid antigen detection tests are available for respiratory syncytial virus (RSV) influenza, parainfluenza virus (PIV), and adenovirus and human metapneumovirus (hMPV), but these are not as sensitive as polymerase chain reaction (PCR) based assays. However, where viruses replicate and are shed in the upper respiratory tract—such as herpes simplex virus (HSV) and rhinovirus—detection of these viruses in the lower rather than upper respiratory tract is much more specific in the diagnosis of an invasive disease.³

Primary immunodeficiencies

Primary immunodeficiencies are uncommon but serious disorders that can effect one or more arms of the immune system including physical barrier, humoral (antibody class or subclass production) or cell-mediated immunity, or the complement cascade, NK cells or phagocytic cells. The nature of the immunodeficiency dictates the pattern of infection seen in the affected individual.^4,5

Secondary immunodeficiencies

Secondary immunodeficiency is more common than primary disorders and increasing in frequency due to our success with solid organ transplantation and in treating cancer where immunosuppressive drugs are widely used. Secondary immunodeficiency can also occur in children with autoimmune disease who receive immunosuppressive therapy and the biological reactive agents (eg, against tumor necrosis factor [TNF] function). In addition, viral infections can depress immune function (eg, measles), immunoglobulin deficiency secondary to protein losing states may result in decreased humoral immune function, and complement consumption states also cause immunodeficiency.

Immunodeficiency due to drugs and radiation

In medical care today there is increasing use of biological agents to manipulate immune function. Examples are antibodies to human lymphocytes or specific T-lymphocyte subpopulations (antilymphocyte globulin) that can be used to treat aplastic anemia, graft vs host disease, and graft rejection. These agents induce a prolonged and profound lymphopenia and depress antibody production. Monoclonal antibodies directed against B-lymphocytes have been used in the treatment of lymphoproliferative disease in transplant patients but result in depletion of B-lymphocyte populations for many months with resultant hypogammaglobulinemia.

Other monoclonal antibodies such as etanercept, soluble TNF receptor, infliximab, anti-TNF, basiliximab, and anti-interleukin-2 receptor are used in both transplant settings and in autoimmune disorders such as juvenile idiopathic arthritis and Crohn's disease.

Cyclosporin and tacrolimus are reversible agents that affect predominately T-lymphocyte but also B-lymphocyte numbers and function. Other cytotoxic drugs used in the treatment of leukemia and solid tumors can have significant immunosuppressive effects. Examples include cyclophosphamide, azathioprine, mycophenolate mofetil, and 6-mercaptopurine, all of which affect B-lymphocyte function and antibody production but also decrease T-cell numbers and function. Methotrexate may suppress antibody responses at higher doses. Radiation therapy, either total body irradiation or lymphoid irradiation, has a profound and long lasting effect on lymphocyte mediated immune function and antibody responses.

Corticosteroids are less specific in their action but they are potent immunosuppressive drugs. The degree of immunosuppression is related to the dose and duration of therapy and probably varies amongst individuals. As a general rule, a dose of prednisone or equivalent corticosteroid of 2 mg per kg per day for more than week or 1 mg per kg per day for more than a month is considered immunosuppressive. Corticosteroids can also affect monocytes and polymorphs.

There are other drugs that also have side effects that affect immune function. Phenytoin affects IgA production and may result in functional IgA deficiency. Depression of neutrophil function and numbers can be a side effect of a large number of drugs including antibiotics such as the sulphonamides, penicillins, and ganciclovir.

Malnutrition

Severe protein malnutrition can have profound effects on immune function including changes in lymphocyte numbers and functions, phagocytosis, or antibody and complement production. These patients are at increased risk of tuberculosis, measles, pneumocystis, and staphylococcal pneumonia.

RESPIRATORY INFECTIONS

Respiratory infections have a major impact in health and are a major cause of morbidity and mortality globally with acute viral respiratory illness being the most common illness. Viruses cause respiratory illness with different clinical syndromes depending on the age and immune status of the host. In addition, each of the respiratory syndromes may be caused by a variety of specific pathogens.

Seasonal pattern

There is a significant variation of the incidence of specific viral respiratory disease particularly in temperate climates and in the wet season in tropical climates.⁶ Influenza and RSV epidemics occur predominately in the winter or wet season with PIV type 3 showing predominance in the spring and PIVs 1 and 2 showing predominance in autumn and early winter. Rhinoviruses cause infections throughout the year but with an increased frequency in autumn and spring. Enterovirus infections have peak prevalence in late summer and early autumn and adenoviruses are isolated throughout the year. Varicella zoster virus infection occurs throughout the year but with a peak more common in the late winter and early spring.

CLINICAL SYNDROMES

Upper respiratory tract infections

Patients who are immunosuppressed are more susceptible to infections causing the common cold, a syndrome caused by more than 200 viruses with variable degrees of rhinitis and pharyngitis. They can also acquire pharyngitis and croup (acute laryngotracheobronchitis) and all these upper respiratory tract infections can have a prolonged and more severe course in the immunosuppressed. These infections do not lead to increased mortality unless the infection spreads into the lung parenchyma and respiratory function is severely compromised. Early recognition of these illnesses and identification of the causative virus may indicate the need for specific antiviral therapy to prevent spread to the lower respiratory tract.

Bronchiolitis

Bronchiolitis is a characteristic syndrome in infants and young children with obstruction to expiratory air flow being the major pathophysiological event. It may be preceded with rhinitis or nasal congestion and rhinorrhea and there may be history of exposure to an adult or sibling with a minor cold or respiratory illness. The major infectious cause of bronchiolitis is RSV. hMPV is a more newly recognized cause of bronchiolitis with clinical features indistinguishable from that of RSV. Adenovirus can also cause bronchiolitis in infants and is often quite severe, particularly in the immunosuppressed. Bronchiolitis can be progressive in immunosuppressed patients, particularly those with T-cell defects leading to hypoxia, the major abnormality of gas exchange, due to ventilation perfusion imbalance that can proceed to death.

Viral pneumonia

Pneumonia is defined by inflammation of lung parenchyma with development of abnormalities of alveolar gas exchange and often associated visual changes on imaging studies. There is no distinctive radiographic pattern that differentiates viral from bacterial pneumonia; however, diffuse bilateral interstitial changes are more suggestive of a viral etiology. Children usually present with prodromal symptoms of upper respiratory infection including pharyngitis and progress to develop fever; lower respiratory tract symptoms; and signs with tachypnea, nonproductive cough, wheezing, or increased breath sounds. Very young infants may have apneic episodes with minimal fever. There may frequently be associated croup or bronchiolitis.

Bacterial superinfection is a common complication of viral lower respiratory tract infection particularly following influenza and measles. Typically, the bacterial superinfection occurs after almost complete recovery from the viral infection, usually 2–14 days later, with recurrence of fever and development of cough and dyspnea. Chest X-ray changes may show lung infiltrates.

Bacterial superinfection following viral pneumonitis can be caused by many bacteria, most commonly Streptococcus pneumoniae but also Staphylococcus aureus including community-acquired methicillin resistant organisms and Haemophilus influenzae.

Differentiation between viral and bacterial causes of pneumonia on clinical grounds can often be difficult, particularly in young children, and radiological criteria do not always distinguish these entities clearly. Mixed viral and bacterial pneumonia may be present.

Viral pneumonia is an important cause of morbidity and mortality in immunocompromised individuals, and individuals with depressed cellular immunity may develop severe life threatening pulmonary infections with a broader spectrum of viral agents including those that typically cause lower respiratory tract disease but also more unusual opportunistic viral pathogens. The most common agent is influenza, but other viruses include respiratory syncitial virus (RSV), hMPV, coronaviruses, PIVs, and rhinoviruses. Adenoviruses are a significant cause of severe disseminated infection with high mortality in the immunosuppressed patient.

Varicella can occasionally cause pneumonitis and chest X-rays may show a nodular infiltrate with a peribronchial distribution involving both lungs. Measles can be complicated by clinically severe pneumonitis with subsequent bacterial superinfection being common.

THE PATHOGENS

Respiratory syncitial virus (RSV)

The RSV has been associated with the largest proportion of viral pneumonia in young children, particularly associated with bronchiolitis, where bronchiolitis and pneumonia represent a spectrum of lower respiratory tract involvement that are not clearly distinguishable clinically.⁷

The RSV is a well-recognized cause of pneumonitis in bone marrow and solid transplants and nosocomial transmission has been well documented. It typically presents with nondescriptive upper respiratory symptoms that progress over several days to severe life threatening lower respiratory tract involvement with mortality rates of up to 50%.

Children with severe combined immune deficiency (SCID) usually have severe and devastating infections due to RSV and develop persistent viral shedding and progressive pneumonia. Children who acquire RSV during chemotherapy for malignancy may develop severe life threatening disease and children with HIV infection have a decreased likelihood of wheezing, but prolonged viral carriage with a higher rate of pneumonitis and increased morbidity. In HIV-positive children, when there is good supportive care and antiretroviral therapy, RSV is generally not severe but in resource poor settings, the overall mortality from these infections is quite significant ranging from 10% to 65%.⁸

Hemopoietic stem cell transplant (HCT) recipients acquiring RSV infection, especially around the time of transplantation, often have a fulminant clinical course.^9,10 There is a significant risk of fatal RSV infection in children with profound immunosuppression due to chemotherapy for malignancy or in children who have solid organ transplantation, particularly lung and heart recipients. The RSV infection in immunosuppressed children are initially similar to those of the immunocompetent child with low grade fever, cough, rhinorrhea, nasal congestion, and sore throat; however, other common findings in immunocompromised older children are sinusitis, otitis media, nausea, and tachypnea. Upper respiratory tract disease can then progress to lower respiratory tract disease over 1–2 weeks with the progression and lack of engraftment in HCT recipients, decreased lymphocytes counts, and an older age at the time of transplantation as risk factors for progression.¹¹ In patients with severe leukopenia, pulmonary infiltrates, and chest X-ray changes may be delayed or absent. Either CT or MRI scanning may be useful in documentation of lower tract disease, although the findings are usually nonspecific. Lower respiratory tract involvement is often manifested by increasing respiratory distress, worsening hypoxia, and a need for assisted ventilation. Recovery from RSV pneumonitis following assisted ventilation is possible but uncommon.

Human metapneumovirus (hMPV)

hMPV, first described in 2001,¹² can cause severe infections in immunocompromised infants and children and is clinically very similar to RSV. However, the potential severity and clinical course of hMPV infections is still unclear and further long-term prospective studies are needed to understand the severity of disease due to hMPV in immunocompromised infants and children.¹³

Parainfluenza viruses (PIVs)

PIVs are a significant cause of viral pneumonia in infants and young children, most commonly PIV-3.¹⁴ The PIVs are also a cause of lower respiratory tract infection in both solid organ and bone marrow transplants, with type 3 being the most common but all 4 serotypes have been implicated.

The PIV infection may initially present as a mild upper respiratory tract disease and unlike RSV and hMPV it tends to only progress to lower respiratory tract disease in severely immunocompromised patients such as SCID, HIV, or allogeneic HCT recipients.¹⁵ Clinical signs of PIV lower respiratory tract disease are cough, tachypnea, hypoxia, and infiltrates on chest X-ray and the progressive disease may require respiratory support.

Influenza

Influenza viruses A and B have two surface proteins hemagglutinin (H) that enables the attachment of the virus to cells and the initiation of infection, and neuraminidase (N) that mediates release of newly formed virions from the cells. These two surface proteins, H and N, exhibit substantial antigenic variation among influenza A viruses with 16 H subtypes and 9 N subtypes while influenza B has only one type of H and N. The occurrence of annual global influenza epidemics is due to antigenic drift, a process of antigenic variation due to stepwise mutation of the H and/or N genes and reflected in variations of the antigenic characteristics of these proteins (and thus escape from immune memory).This antigenic drift results in the recurrent annual influenza epidemics seen each winter. Additionally, the segmented nature of the influenza genome allows for antigenic shift—the reassortment of genome segments from two different influenza A viruses with major changes in the H or N proteins or both.¹⁶ It was this antigenic shift that resulted in the recent H1N1 swine influenza 2009 global pandemic.

The clinical course of influenza in patients with cellular immune deficiency such as HIV, primary immunodeficiencies, or treatment for malignancy or immunosuppression following transplantation may be more prolonged with viral shedding for months observed in some patients. In influenza patients with progression to severe viral pneumonia, bacterial superinfection may also occur. There is significant morbidity and mortality and this is related to the degree of immunosuppression with those who are more severely immunosuppressed having greater severity.

Adenoviruses

Adenoviruses are frequently isolated from children with respiratory disease and are implicated in about 10% of childhood pneumonias; however, this is difficult to assess because of the long and intermittent asymptomatic respiratory shedding of adenoviruses in children.¹⁷

Adenoviruses are a significant cause of morbidity and mortality in immunocompromised patients, particularly in those receiving matched unrelated donor or T-cell depleted bone marrow grafts. Infection tends to be disseminated, with isolation of the virus from multiple body sites including lungs, liver, gastrointestinal tract, and urine with adenovirus infection caused by adenovirus serotypes rarely found causing respiratory disease in immunologically normal subjects.¹⁸

Rhinoviruses

Rhinoviruses have been associated with community-acquired pneumonias in a significant proportion of children.¹⁹ In immunocompromised patients, rhinovirus has been isolated from the lower respiratory tract, but the significance of this has been difficult to interpret due to the prevalence of rhinoviruses in the upper respiratory tract and the risk of contamination when collecting lower respiratory tract samples. However, there is now definitive evidence for rhinovirus causing lower respiratory tract illness following lung transplantation.²⁰ Thus the prevalence and severity of the rhinovirus lower respiratory tract disease in an immunosuppressed patient is yet to be fully defined.

Measles

Pneumonia is the most frequent and serious complication of measles, most commonly bacterial pneumonia; however, measles giant cell pneumonia is a severe and often fatal form of pneumonia in immunosuppressed individuals, those with hematological or other malignancy, or AIDS.²¹

Children with deficient cell-mediated immunity may develop severe progressive and often fatal measles virus infection often without typical rash or characteristic prodrome as these patients do not mount a cellular immune response involved in the pathogenesis of rash seen in immune competent individuals and a high index of suspicion must be maintained. In immunosuppressed patients, giant cell pneumonia is the most frequent manifestation characterized by increasing respiratory insufficiency. Chest X-rays often show diffuse interstitial alveolar infiltrates and the case fatality rate is estimated to be about 70% in patients with malignancy and 40% in HIV-infected patients.²¹

Measles is often very severe in malnourished children, frequently resulting in secondary infections causing pneumonia and diarrhea with a case fatality rate exceeding 10%. Contributing factors that increase morbidity and mortality for measles include early age of infection, rapid loss of maternal antibody, vitamin A deficiency, and concurrent infection with other pathogens.

Cytomegalovirus (CMV)

CMV is a frequent cause of severe pneumonitis in immunosuppressed individuals, particularly transplant recipients. The highest risk of CMV pneumonitis in transplant population is in 1–3 months posttransplant with a peak incidence at 2 months. Diffuse interstitial pneumonitis is the most frequent radiological manifestation but nodular infiltrates can also occur. Severe CMV infection can present with multiple clinical findings, most notably, fever, neutropenia, abnormal liver function tests, and mucosal ulcerations and these may be clues to diagnosis.

Fever is common. Pneumonitis, often with pulmonary infiltrates occurs especially in recipients of lung or heart-lung transplants and despite prolonged antiviral treatment they often develop obliterative bronchiolitis indicating that CMV plays an important role in the etiology of chronic rejection.^22,23 Pneumonitis is often a major life threatening infection in bone marrow allograft patients; however, this illness is now becoming less frequent due to the use of prophylactic antiviral agents. Patients will often present with fever and hypoxia associated with interstitial infiltrates on a chest X-ray. The CMV pneumonitis is much less frequent in autograft recipients, strongly supporting the immunopathological process for disease manifestation. The CMV pneumonitis is often associated with graft vs host diseases (GVHD) and it is unclear whether CMV precipitates GVHD or whether the immunosuppressive nature of GVHD facilitates CMV reactivation and disease. In patients with AIDS, CMV causes a wide variety of disease syndromes but CMV pneumonitis is quite uncommon.

Herpes simplex virus (HSV) type 1 and type 2

Herpes simplex pneumonitis occurs largely in immunocompromised individuals or newborn infants. Mucocutaneous disease may be present in a vast majority of immunosuppressed patients prior to presentation and they may develop a focal pneumonia as a result of spread from the upper respiratory tract or a diffuse interstitial disease resulting from hematogenous spread.²⁴

Varicella zoster virus (VZV)

Immunocompromised children including those with NK cell deficiencies; those being treated for malignancy, congenital, or acquired defects of cell-mediated immunity such as those undergoing organ transplantation or those with HIV infection; and individuals receiving high dose steroids may be susceptible to severe or fatal varicella infection.²⁵ Rarely patients may develop an acute systemic disease with disseminated intravascular coagulation. Children with HIV infection often have mild to moderate disease but this is not universal and severe disease can occur in those patients with AIDS. These patients may develop progressive varicella with ongoing fever and development of new vesicular lesion often up to 2–3 weeks. These skin lesions are often large, umbilicated, and hemorrhagic but in some patients they may be “wart-like” hyperkerototic lesions that can be present for months.²⁶ Primary varicella pneumonia is a frequent complication and accounts for much of the mortality ascribed to varicella. Pneumonia usually occurs within several days after onset of the rash but this interval may be longer with more than 70% of patients having fever, cough, and often dyspnea. Other features may be rales, hemoptysis, and chest pain. The chest X-ray typically shows a diffuse nodular or miliary pattern that is more pronounced in the perihilar regions.²⁷ Treatment with antiviral agents has greatly improved morbidity and mortality in this infection.

Severe acute respiratory syndrome (SARS)

The novel human coronavirus, severe acute respiratory syndrome (SARS), caused epidemics of severe respiratory disease in healthy adults in 2003.²⁸ This illness has not been seen again, but if it were to return, it would be predicted to cause severe disease in immunocompromised patients.²⁹

DISCUSSION

Acute viral respiratory infections are a very common infection in infants and children and in most cases cause limited morbidity for a short and defined period. However in immunocompromised infants and children, especially those with a primary of secondary deficiency in T-cell-mediated immunity, respiratory virus infections can be much more severe resulting in increased morbidity and mortality. Rapid sensitive and specific diagnosis allows for early intervention with appropriate infection control measures to prevent spread of infection to other vulnerable patients. Early recognition and diagnosis will facilitate antiviral therapy, where this is available. The early treatment of respiratory viral infections may significantly improve outcome in both the duration and severity of the infection; however, the therapy should be commenced as soon as is practical to optimize outcomes.

Disclosure: There are no conflicts of interest.

REFERENCES

1. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–787.
2. Tosi MF. Normal and impaired immunological responses to infection. In: Feigin R, Cherry JD, Demmler-Harrison GJ, Kaplan SL, eds. Feigin and Cherry’s Textbook of Pediatric Infectious Diseases. 6th ed. Philadelphia, PA: Saunders; 2009:21–64.
3. Kesson AM. Viral respiratory infections. Paediatr Respir Rev. 2007;8:240– 248.
4. Kesson AM, Kakakios A. Immunocompromised children: conditions and infectious agents. Paediatric Respiratory Reviews. 2007;8:231–239.
5. Cant AJ, Davies G, Cale C, Gennery AR. Immunodeficiency. In: McIntosh N, Helms P, Smyth R, Logan S, eds. Forfar and Arneil’s Textbook of Pediatrics. 7th ed. Edinburgh: Churchill Livingston; 2008:1139–1176.
6. White DO, Fenner F. Epidemiology of viral infections. In: Medical Virology. 4th ed. San Diego, CA: Academic Press; 1994:233–255.
7. Hall CB, Hall WJ, Speers DM. Clinical and physiological manifestations of bronchiolitis and pneumonia: outcome of respiratory syncytial virus. Am J Dis Child. 1979;133:798–802.
8. King JC Jr, Burke AR, Clemens JD, et al. Respiratory syncitial virus illness in human immunodeficiency virus infected and non-infected children. Pediatr Infect Dis J. 1993;12:733–739.
9. Hertz MI, Englund JA, Snover D, Bitterman PB, McGlave PB. Respiratory syncitial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine (Baltimore). 1989;68:269–281.
10. Hall CB, Powell KR, Schnabel KC, Gala CL, Pincus PH. Risk of secondary bacterial infection in infants hospitalised with respiratory syncitial virus infection. J Pediatr. 1988;113:266–271.
11. Hall CB, Powell KR, McDonald NE, et al. Respiratory syncitial virus infection in children with compromised immune function. N Engl J Med. 1986;315:77–81.
12. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nature Med. 2001;7:719–724.
13. Madhi SA, Ludewick AH, Abed Y, Klugman KP, Boivon G. Human metapneumovirus associated lower respiratory tract infections among hospitalized human immunodeficiency virus type 1 (HIV-1)-infected African infants. Clin Infect Dis. 2003;37:1705–1710.
14. Iwane MK, Edwards KM, Szilagyi PG, et al. New Vaccine Surveillance Network. Population based surveillance for hospitalisations associated with respiratory syncitial virus, influenza virus and parainfluenza viruses among young children. Pediatrics. 2004;113:1758–1764.
15. Frank JA Jr, Warren RW, Tucker JA, Zeller J, Wilfert C. Disseminated parainfluenza virus infection in a child with severe combined immunodeficiency. Am J Dis Child. 1983;137:1172–1174.
16. Hayden FG, Palese P. Influenza. In: Richmond DD, Whitley RJ, Hayden FG, eds. Clinica Virology. 3rd ed. Washington, DC: ASM Press; 2009:943– 976.
17. Juven T, Mertsola J, Waris M, et al. Etiology of community-acquired pneumonias in 254 hospitalised children. Pediatr Infect Dis J. 2000;19:293– 298.
18. Becroft DMO. Brochiolitis obliterans, bronchiolitis, and other sequelae of adenovirus type 21 infection in young children. J Clin Pathol. 1971;24:72–81 19. McMillan JA, Weiner LB, Higgins AM, MacKnight K. Rhinovirus infection associated with serious illness among pediatric patients. Pediatr Infect Dis J. 1993;12:321–325.
20. Kaiser L, Aubert JD, Pache JC, et al. Chronic rhinoviral infection in transplant recipients. Am J Resp Crit Care Med. 2006;174:1932–1399.
21. Kaplan LJ, Daum RS, Smaron M, Mccarthy CA. Severe measles in immunocompromised patients. JAMA. 1992;267:1237–1241.
22. Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev. 2000;13:83–121.
23. Duncan SR, Grgurich WF, Iacono AT, et al. A comparison of ganciclovir with aciclovir to prevent cytomegalovirus after lung transplantation. Am J Respir Crit Care Med. 1994;150:146–152.
24. Nash G. Necrotising tracheobronchitis and bronchopneumonia consistent with herpetic infection. Hum Pathol. 1972;5:339–345.
25. Gershon A, Silverstein SJ. Varicella zoster virus. In: Richmond DD, Whitley RJ, Hayden FG, eds. Clinica Virology. 3rd ed. Washington, DC: ASM Press; 2009:451–474.
26. Aaonson J, McCherry G, Hoyt L, et al. Varicella does not appear to be a cofactor for human immunodeficiency virus infection in children. Pediatr Infect Dis J. 1992;11:1004–1008.
27. Triebwasser JH, Harris JE, Bryant RE, Rhoades ER. Varicella pneumonia in adults. Report of seven cases and a review of the literature. Medicine (Baltimore). 1967;42:409–423.
28. Kuiken T, Fouchier RA, Schutten M, et al. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet. 2003;362:263–270.
29. Hon KLE, Leung CW, Cheng WTF, et al. Clinical presentations and outcome of severe acute respiratory syndrome in children [research letters]. Lancet. 2003;361:1701–1703.
30. Geha RS, Norarangelo LD, Cassanova J-L, et al. The International Union of Immunological Societies (IUIS) Primary Immunodeficiency Diseases (PID) Classification Committee. J Allergy Clin Immunol. 2007;120:776–794.

Pregnancy results in many changes in female body, which make it more susceptible to respiratory complications.^{1, 2} On the other hand, acute respiratory diseases are associated with many maternal complications during pregnancy like spontaneous premature rupture of membranes,³ placental abruption,⁴ preterm delivery,⁵ placenta previa, preeclampsia, cesarean delivery, and increased length of hospital stay.⁶ Also, they are associated with fetal morbidities such as prematurity, low birth weight, small-for gestational age, and congenital anomalies.⁶

The most commonly studied respiratory emergency recorded during pregnancy is the poorly controlled asthma, which has a definite adverse effect on both baby and mother, while most asthma medications have little or no adverse effect. The most common maternal and fetal morbidities are preterm labor,⁷ preeclampsia,⁸ transient tachypnea in newborn,⁹ oligohydramnious,¹⁰ and increased risk of cesarean section.⁶

Pulmonary embolism (PE) is a leading cause of maternal mortality during pregnancy and up to 6 weeks postpartum compared with non-pregnant women. Women who are pregnant have a 5-fold increased risk for venous thromboembolism (VTE).¹¹ The incidence of PE in pregnancy varies between 1 per 1000 and 1 per 3000 deliveries.¹² Within the antenatal period, thromboembolism occurs equally within each trimester, and the postnatal period is the most dangerous time in terms of deaths per week but no period of pregnancy is without risk.¹³ The major risk of heparin use is maternal hemorrhage especially in uteroplacental junction.^{14, 15}

Pneumonia is the most common frequent cause of non-obstetric infection in pregnant subjects and the third most frequent cause of non-obstetric death.¹⁶ It poses a special hazard for pregnant women possibly due to changes in a pregnant woman's immune system. Many complications can lead to premature labor, intrauterine growth retardation (IUGR), and perinatal death and increase the risk of maternal death during pregnancy. Extensive pneumonia with severe hypoxia may cause intrauterine fetal death. ^17–19

Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does the treatment of the disease. Maternal tuberculosis has been associated with an increased risk of spontaneous abortion, perinatal mortality, and low birth weight in some studies, and the outcome is unfavorably influenced by delays in diagnosis or treatment.^{20, 21}

Primary pulmonary hypertension (PPH) is a rare, progressive condition aggravated by the physiologic changes occurring during pregnancy and surgery. The maternal mortality rate associated with pregnancy and pulmonary hypertension range from 30% to 50%.²²

Acute respiratory failure during pregnancy, although relatively uncommon, continues to be a prominent cause of maternal mortality, accounting for 30% of maternal deaths,²³ and is the most common reason for admission to the intensive care unit (ICU) of critically ill obstetric patients.²⁴

The aim of this study was to assess the maternal and fetal perinatal complications related to respiratory diseases requiring hospitalization among pregnant women and to describe and quantify the impact of respiratory diseases during pregnancy on maternal and fetal health.

PATIENTS AND METHODS

This prospective, hospital-based, observational, case-control study included 34 pregnant women admitted with respiratory diseases in Chest Department, Assiut University Hospital and Assiut Women Health Hospital during the period from June 2010 to June 2011 as well as 34 pregnant women attending in outpatient Maternity Clinic with no respiratory complaint selected randomly by cross over 1:1 from computer data base, as controls. All ladies were followed up every month during their pregnancy and 1 week after delivery. The detailed demographic data including age, medical, gynecological, and obstetric histories were reported. Complete physical and gynecological examinations were done, as well as the following investigations to confirm their gestational and pulmonary diagnosis: abdominal and pelvic ultrasonography, plain x-ray chest if needed, transthoracic ultrasonography, compression Doppler of lower limbs, echocardiography, sputum gram stain, direct smear for acid-fast bacilli, PCR for H₁N₁ surface antigen, and D-Dimer. These data were collected, and any associated complications in both the mother and her infant were recorded.

Maternal outcomes were defined as follows: preterm labor (pregnancies with 34 or less completed weeks of gestation), gestational diabetes, membrane-related disorders (premature rupture of membranes, infection of amniotic cavity, oligohydramnios, and polyhydramnios), hypertensive disorders of pregnancy (preeclampsia, transient hypertension, and gestational hypertension), antepartum hemorrhage (placenta previa and premature separation of placenta), mode of delivery (normal or cesarean), postpartum hemorrhage, and increased length of hospital stay >3 days.

Fetal and Infant outcomes were low birth weight (<2500 g), high birth weight (>4000 g), preterm birth (gestational age < 37 completed weeks), post-term birth (gestational age > 42 weeks), IUGR (small for gestational age, fetal growth ratio < 0.85), large for gestational age (>1.15), intrauterine fetal death, any congenital anomalies, and increased length of hospital stay >3 days.

Exclusion criteria were maternal smoking, previously diagnosed medical diseases such as hypertension, DM, rheumatic heart, chronic hepatic, collagen vascular, hematologic diseases before pregnancy, maternal age > 40 years old, or mothers on anticoagulant therapy.This study was approved by the Ethical Committee of Assiut University.

Statistical Analysis

The data were analyzed using the statistical package Version 11; SPSS AG, USA. For multiple comparisons between the parametric variables, one-way analysis of variance (ANOVA) tests was done, and p value <.05 was considered significant. Estimation of relative risk (odds ratio, OD) was done by logistic regression using multivariate analysis and presented with 95% confidence interval (CI).

RESULTS

The study included 34 pregnant ladies with respiratory diseases hospitalized in Assiut University Hospitals and 34 ladies with normal pregnancy as controls. Seventeen patients (50%) in the diseased group were <25 years old, mean age 24.8±3.9, and range from 19 to 39 years old. House wives accounted for 76.5% and 79.4%, respectively, and were from Assiut Governorate. There was no statistical difference of medical importance between this group and controls (Table 1).

In the diseased group, 44.1% were primigravida and 55.9% multigravida, 29.4% had two or more children, 41.1% had previous cesarean sections. The duration of last delivery was <1 year in 63.2%. Also, there was not any statistical difference between both group except in the number and indications of previous cesarean sections (Table 2).

The indications of hospital admission were uncontrolled asthma in 32.4%, PE (20.6%), acute bronchitis, tuberculosis, interstitial pulmonary fibrosis (8.8% each), acute respiratory distress syndrome (ARDS), swine flu (H₁N₁), and bacterial pneumonia in 5.9%, and one lady had primary pulmonary hypertension (Table 3).

All asthmatic patients were treated with inhaled bronchodilators and inhaled steroids, short-acting B2 agonist, theophylline, and systemic steroids if indicated. Patients with PE were treated with low molecular weight heparin. Tuberculous ladies were treated by Isoniazid (INH), rifampicin (RIF), and Ethambutol for 2 months and then with INH and RIF for 7 months. Patients with H1N1 were treated with the antiviral oseltamivir (Tamiflu®) for 1 week.

The maternal and fetal complications in pregnant ladies with respiratory diseases and controls were recorded in Table 4. The most common maternal complications were premature rupture of membranes (PROM, 17.6%), antepartum hemorrhage (placenta previa and placental abruption, 11.7% and 2.9%, respectively), gestational diabetes mellitus (11.7%), gestational hypertension, and preeclampsia (5.8% each). Four patients required mechanical ventilation and similar number needed prolonged hospital stay after delivery. All maternal complications were statistically more frequent in patients than controls except gestational DM and hypertension. As regard, the recorded fetal complications were as follows: 14.6% were low birth weight, 8.8% had IUGR, 5.8% intrauterine fetal death, and 11.7% required hospital stay >3 days. These were all significantly higher than recorded in controls.

Figure 1 showed that maternal and fetal complications were more significantly recorded in patients with asthma (31.2% and 61.5%, respectively) and PE (21.8 and 15.4%, respectively). Tuberculosis was associated with 12.5% of maternal complications, and ARDS was associated with 15.4% of fetal complications.

Univariate analysis of the maternal respiratory diseases during pregnancy as risk factors of bad maternal or fetal outcomes showed that acute bronchitis, H₁N₁, IPF, and pulmonary hypertension were not significant. Further multivariate analysis with logistic regression showed that asthma and PEs are significantly important risk factors for maternal and fetal morbidities. Tuberculosis and pneumonia were significantly risky for mothers and ARDS for the fetus (Table 5).

DISCUSSION

In this study, we found that pregnant women admitted with respiratory diseases had increased risk of adverse maternal and fetal outcomes. Maternal asthma and PE were the most common recorded causes of hospitalization and associated with higher risk of maternal and fetal complications.

As recorded in this study, asthma is the most common medical condition that can complicate pregnancy (32.4% in this group). The prevalence of asthma in USA is estimated to be 3.7%–8.4% and it affects 200 000–376 000 pregnancies annually. Episodes of acute asthma requiring emergency department visit or hospitalization have been reported in 9%–11% of pregnant subjects managed by asthma specialists.⁹

Few studies found no significant difference in birth outcomes between asthmatic and non-asthmatic females.^{25, 26} However, initial observations of the relationship between maternal asthma and maternal and fetal outcomes, taken from the Norwegian Birth Registry in 1972, suggested increased risks from bronchial asthma of preterm birth, low birth weight, preeclampsia, and neonatal death.²⁷ Subsequently, Bertrand et al.²⁸ proposed that the hyperreactivity of smooth muscle characteristic of asthma might lead to both bronchial and uterine complications. Liu et al. suggested that the more common sequelae in pregnancies complicated by asthma or asthma medication include preterm delivery and low birth weight.²⁹ The most common maternal and fetal morbidities are preterm labor,⁷ preeclampsia,^{8, 30} transient tachypnea in newborn,⁹ oligohydramnious,¹⁰and increased risk of cesarean section.⁶ Increasing asthma severity and symptoms appeared to significantly decrease fetal growth, particularly when they occurred in the absence of an asthma diagnosis. A possible causal effect on these outcomes is due to a hypoxic effect from chronic reduced pulmonary function in the asthmatic pregnant mother has been suggested. These results are in agreement with the finding in the included group.

It is difficult to disentangle the influence of asthma from the effect of medications in many studies of treated women. Greenberger and Patterson,³¹ reported that avoiding acute asthma attacks by use of steroids and theophylline resulted in low birth weight rates equal to the normal population. Schatz et al.³² reported that inhaled or oral steroid therapy had no effect on birth weight. In a later article, Schatz et al.³³ found that actively managed patients (which included the use of oral prednisone for the most severe cases) had no increased risk of IUGR, low birth weight, or preterm delivery. Moreover, Stenius-Arniala et al.³⁴ reported no increased risk of preterm delivery in patients managed with β₂ agonists and theophylline for acute episodes. Olesen et al.³⁵ reported that Danish women who received prescription drugs for asthma during pregnancy had newborns with birth weight and birth length within expected ranges, but both outcomes worsened when the intensity of asthma therapy was reduced.

However, Corchia et al.³⁶ reported a low birth weight rate of 5.6% in asthmatic women treated with β₂ agonists and 18.2% in untreated women. Interestingly, they did observe increased likelihood of preterm delivery with greater medication use, which appeared to be restricted to theophylline and oral steroids.³⁷ The effect of the asthma medications was not recorded in the present study.

The second most recorded maternal illness in this study was PE. PE is the leading cause of maternal death.³⁸ The rate of PE in pregnancy is five times greater than that for non-pregnant women of the same age and is about 1 in 1500 deliveries; the risks are even higher in the puerperium. The physiological changes during pregnancy, maternal age, parity, obesity, operative delivery, and hypercoagulable state further increase the risk of VTE during pregnancy.^{1, 11,39–41}

Pregnant women with pulmonary embolus are usually otherwise healthy. They either die suddenly and unexpectedly or they have an illness that lasts several days or weeks where the diagnosis has not been considered. This emphasizes the need for prophylaxis in some cases and above all for correct diagnosis.⁴² There were no recorded maternal deaths due to PE in the present study and this may be explained by the early diagnosis and treatment of PE.

In this study, 21.8% of maternal complications and 15.4% of fetal complications were recorded in patients with PE. The main cause of maternal morbidity was antepartum hemorrhage. Ginsberg and Bates¹⁵ stated that although heparin (the mainstay of therapy for acute VTE in pregnancy) does not cross the placenta and so does not carry risks of teratogenesis, fetal hemorrhage, and bleeding at the uteroplacental junction is a possibility.

The rate of major bleeding with various doses of unfractionated heparin (UFH) was 2%.⁴³ Also, therapeutic doses of subcutaneous UFH (adjusted-dose UFH) can cause a persistent anticoagulant effect at the time of delivery, which can complicate its use prior to labor.^{44, 45} The mechanism for this prolonged effect is unclear. Bleeding complications appear to be very uncommon with low molecular weight heparin (LMWH). ^46–48

As regard fetal complications, there are two potential fetal complications of maternal anticoagulant therapy: teratogenicity and bleeding.^{16, 49} IUFD was recorded in 5.8% of the studied group and in patients with PE. So, it seems that anticoagulation therapy rather than the PE itself is the cause of both maternal and fetal outcomes.

We recorded 9.3% of maternal complications and 15.4% of fetal complications in pregnant patients admitted with pneumonia (preterm labor and low birth weight). These results were in agreement with many studies. Munn et al.⁵⁰ stated that there is persuasive evidence to indicate that maternal and fetal outcomes are affected by maternal pneumonia. Mothers with pneumonia are significantly more likely to deliver before 34 weeks gestation, with preterm delivery occurring in up to 43% of cases. Prostaglandin production or the host's inflammatory response to infection may be responsible. In addition, infants born to mothers with pneumonia weigh significantly less.⁵⁰ A difference of 150 g in the birth weight of infants born to mothers with pneumonia compared with controls was recorded and the frequency of low birth weight infants (2500 g or less) was higher in cases than in controls (16% vs. 8%).⁵¹ Mothers with pneumonia are more likely to deliver early and have infants of lower birth weight than other pregnant women.⁵²

The most common complication of H₁N₁ influenza (swine-flu) is pneumonia. Other reported complications noted in pregnant women include disseminated intravascular coagulation, cognitive impairment postviremia/encephalitis, psychological effects after the recovery phase, requiring appropriate support, VTE and PE.⁵² There are no previous records of maternal and fetal morbidities in pregnant women with H₁N₁ pneumonia. During this study, two pregnant ladies were admitted with H₁N₁ pneumonia, one of them required mechanical ventilation but weaned within 3 days without any fetal complications.

The effects of TB on pregnancy depend upon various factors such as type, site and extent of the disease, stage of pregnancy when management gets instituted, nutritional status of mother, presence of concomitant disease, immune status and co-existence of HIV infection, availability of facilities for early diagnosis and treatment, and so on.⁵³ If antituberculosis treatment (ATT) is started early in pregnancy, the outcome is the same as that in non-pregnant patients, whereas late diagnosis and care is associated with 4-fold increase in obstetric morbidity and 9-fold increase in preterm labor.²⁰ Poor nutritional states, hypoproteinemia, anemia, and associated medical conditions add to maternal morbidity and mortality. Co-existing HIV infection is known to augment progression of TB and worsen the immunosuppression.⁵⁴

Maternal tuberculosis has been associated with an increased risk of spontaneous abortion, perinatal mortality, and low birth weight in some studies, and the outcome is unfavorably influenced by delays in diagnosis or treatment.^{20, 21} In agreement, it was found that TB was associated with increased relative risk of maternal complications in pregnant tuberculous mother (specially spontaneous abortion).

A fetus can get TB infection either by hematogenous spread through umbilical vein to fetal liver or by ingestion or aspiration of infected amniotic fluid.⁵⁵ True congenital TB is believed to be rare. The risk to neonate of getting TB infection shortly after the birth is greater.⁵⁶ No recorded cases of congenital TB were found in this study.

Primary pulmonary hypertension (PPH) is a rare, progressive condition aggravated by the physiologic changes occurring during pregnancy. The maternal mortality rate associated with pregnancy and pulmonary hypertension ranges from 30% to 50%.²² Pulmonary hypertension has always been considered to be an indicator of poor prognosis in pregnancy⁵⁷ and is said to carry high morbidity and mortality to both the mother and the fetus. Also, pulmonary hypertension has always been a feature of cardiac disorders in which early termination of pregnancy is traditionally recommended. In certain instances, the severity of maternal pulmonary hypertension in rheumatic heart diseases can be higher than in congenital heart diseases.⁵⁸ Only one patient with PPH was included in this study and was associated with oligohydramnios.

Although less than 1% of women require admission to an ICU during pregnancy or the peripartum period (the last month of gestation and the first few weeks after delivery), both maternal and fetal mortality are high when such care is required.⁵⁹

Mirghani et al. have found that only 0.11% to 0.89% of deliveries require maternal ICU admission.⁶⁰ The most common indications for ICU admission are postpartum hemorrhage and the hypertensive disorders (severe preeclampsia or eclampsia). Maternal mortality is high when critical care is required, with estimates ranging from 5% to 30%.⁶¹ In the present study, 11.7% needed ICU admission and mechanical ventilation. This is higher than the recorded results as the included mothers had already respiratory diseases requiring hospitalization.

Fetal mortality is also high when critical care is required. Early gestational age, severe maternal illness, the need for maternal blood transfusions, and the absence of prenatal care are associated with fetal mortality.⁶² Only four patients were admitted to ICU in the studied group and 50% had IUFD.

The effect of maternal ARDS on neonatal outcomes is not well studied, but high rates of fetal death, spontaneous preterm labor, and fetal heart rate abnormalities are reported. A high rate of perinatal asphyxia among surviving infants is also reported. In one series of 13 patients with ARDS who reached viability (>24 weeks), the perinatal fetal death rate was 23%.⁶³ More recently, in a series of 10 antepartum patients in the third trimester ventilated for ARDS, only five of the neonates survived intact after delivery, data were not available for one infant.²³ This study supported that ARDS is a relative risk factor of fetal morbidities and was associated with 15.4% of fetal complications.

The mortality and morbidity rates of ARDS in the general population are high, with reported mortality ranging from 35% to 60%.⁶⁴ In a series of 83 obstetric patients with ARDS, the antepartum mortality rate was 23% and the postpartum mortality rate was 50%.⁶⁵ Similarly, in another series of 28 obstetric patients with ARDS, the mortality rate was 39% and three of the 17 survivors had long-term sequelae.⁶³ Multiple organ dysfunction syndrome has been reported as the most common cause of maternal death.^{23, 66} No maternal morbidities or mortalities due to ARDS were recorded in the present study.

The limitations of this study were in the small number of included subjects, lack of some databases concerning the detailed therapeutic regimens especially for asthmatic patients, arterial blood gas analysis, pulmonary function tests monitoring specially in those patients admitted in the Women Health Hospitals. It is recommended to do similar observational studies with larger study population.

CONCLUSIONS

The key of successful management of respiratory diseases during pregnancy is early identification and treatment, stabilizing hemodynamics and oxygenation, and close monitoring of both mother and fetus. Knowledge of normal maternal and fetal physiology and implementing strategy to maintain fetal oxygenation is important. A multidisciplinary team approach is required to ensure a successful outcome for both mother and fetus specially asthma and PE.

Disclosure: The authors declare no conflict of interest.

REFERENCES

1. Rizk NW, Kalassian KG, Gilligan T, Druzin MI, Daniel DL. Obstetric complications in pulmonary and critical care medicine. Chest. 1996;110: 791–809.
2. Al-Suleiman SA, Qutub HO, Rahman J, Rahman MS. Obstetric admissions to the intensive care unit: a 12-year review. Arch Gynecol Obstet. 2006;274:4.
3. Getahun D, Ananth CV, Oyelese Y, Peltier MR, Smulian JC, Vintzileos AM. Acute and chronic respiratory diseases in pregnancy: association with spontaneous premature rupture of membranes. J Matern Fetal Neonatal Med. 2007;20:669–675.
4. Getahun D, Ananth CV, Peltier MR, Smulian JC, Vintzileos AM. Acute and chronic respiratory diseases in pregnancy: association with placental abruption. Am J Obstet Gynecol. 2006;195(4):1180–1184.
5. Sorensen TK, Dempsey JC, Xiao R, Frederick IO, Luthy DA, Williams MA. Maternal asthma and risk of preterm delivery. Ann Epidemiol. 2003;13: 267–272.
6. Dimissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med. 1998;158:1091–1095.
7. Juniper EF, Newhouse MT. Effect of pregnancy on asthma: a systematic review and meta-analysis. In: Schatz M, Zeiger RS, Claman HC, eds. Asthma and Immunological Diseases in Pregnancy and Early Infancy. New York: Marcel Dekker; 1993:401–427.
8. Schatz M. Asthma during pregnancy: interrelationships and management. Ann Allergy. 1992;68:123–133.
9. Barken MB, Triche EW, Belanger K, Saftlas A, Beckett WS, Leaderer BP. Asthma symptoms, severity, and drug therapy: a prospective study of effects on 2205 pregnancies. Obstet Gynecol. 2003;102:739–752.
10. Lao TT, Huengsburg M. Labour and delivery in mothers with asthma. Eur J Obstet Gynecol Reprod Biol. 1990;35:183–190.
11. Pereira A, Krieger BP. Pulmonary complications of pregnancy. Clin Chest Med. 2004;25:299–310.
12. Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scott Med J. 1996;41:83–86.
13. Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost. 1992;67:519–520.
14. Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest. 2001;119:122S–131S.
15. Ginsberg JS, Bates SM. Management of venous thromboembolism during pregnancy. J Thromb Haemost. 2003;1:1435–1442.
16. Ramsey PS, Ramin KD. Pneumonia in pregnancy. Obstet Gynecol Clin North Am. 2001;28:553–569.
17. Maccato M. Respiratory insufficiency due to pneumonia during pregnancy. Obstet Gynecolol Clin North Am. 1991;18:289–299.
18. Lim WS, Macfeerlane JT, Colthorpe CL. Pneumonia and pregnancy. Thorax. 2001;56:398–405.
19. Lim WS, Macfeerlane JT, Colthorpe CL. Treatment of community acquired lower respiratory tract infection during pregnancy. Am J Respir Med. 2003;2:221–233.
20. Figueroa-Damien R, Arredondo-Garcia JL. Pregnancy and tuberculosis: influence of treatment on perinatal outcome. Am J Perinatol. 1998;15: 303–306.
21. Ormerod P. Tuberculosis and pregnancy and the puerperium. Thorax. 2001;56:494–499.
22. Weiss B, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systemic overview from 1978 through 1996. J Am Coll Cardiol. 1998;31:1650–1657.
23. Catanzarite V, Willms D, Wong D, Landers C, Cousins L, Schrimmer D. Acute respiratory distress syndrome in pregnancy and the puerperium: causes, courses, and outcomes. Obstet Gynecol. 2001;97:760–764.
24. Afessa B, Green B, Delke I, Koch K. Systemic inflammatory response syndrome, organ failure, and outcome in critically ill obstetric patients treated in an ICU. Chest. 2001;120:1271–1277.
25. Jana N, Vasishta K, Saha SC, Khunnu B. Effect of bronchial asthma on the course of pregnancy, labour and perinatal outcome. J Obstet Gynaecol. 1995;21:227–232.
26. Dombrowski MP, Schatz M, Wise R, et al. Asthma during pregnancy. Obstet Gynecol. 2004;103:5–12.
27. Bahna S, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol. 1972;27:397–406.
28. Bertrand J, Riley S, Popkin J, Coates A. The long term pulmonary sequelae of prematurity: the role of familial airway hyperreactivity and the respiratory disease syndrome. N Eng J Med. 1985;312:742–745.
29. Liu S, Wen S, Demissie K, Marcoux S, Kramer M. Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am J Obstet Gynecol. 2001;184:90–96.
30. Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol. 2003;112:283–288.
31. Greenberger P, Patterson R. The outcome of pregnancy complicated by severe asthma. Allergy Proc. 1988;9:539–543.
32. Schatz M, Zeiger R, Hoffman C. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Chest. 1990;98:389–392.
33. Schatz M, Zeiger R, Hoffman C, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am J Respir Crit Care Med. 1995;151:1170–1174.
34. Stenius-Aarniala B, Piirila P, Teramo K. Asthma and pregnancy: a prospective study of 198 pregnancies. Thorax. 1988;43:12–18.
35. Olesen C, Thrane N, Nielsen G, Sorensen H, Olsen J. A population-based prescription study of asthma drugs during pregnancy: changing the intensity of asthma therapy and perinatal outcomes. Respiration. 2001;68:256–261.
36. Corchia C, Bertollini R, Forastiere F, Pistelli R, Perucci C. Is maternal asthma a risk factor for low birth weight? Results of an epidemiologic survey. Eur J Epidemiol. 1995;11:627–631.
37. Wen S, Demissie K, Liu S. Adverse outcomes in pregnancies of asthmatic women: Results from a Canadian population. Ann Epidemiol. 2001;11:7–12.
38. Pabinger I, Grafenhofer H. Thrombosis during pregnancy: risk factors, diagnosis and treatment. Pathophysiol Haemost Thromb. 2002;32:322–324.
39. Rubio ER, Alper B, Szerlip HM. Respiratory complications of pregnancy. Obstet Gynecol Surv. 2002;57:39–46.
40. Stone SE, Morris TA. Pulmonary embolism and pregnancy. Crit Care Clin. 2004;20:661–677.
41. Tan LK, De Swiet M. Management of thromboembolic disease in pregnancy. Ann Acad Med Singapore. 2002;31:311.
42. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med. 1992;326:1240–1245.
43. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R. Heparin therapy during pregnancy: risks to the fetus and mother. Arch Intern Med. 1989;149:2233–2236.
44. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119:108s–121s.
45. Anderson DR, Ginsberg JS, Burrows R, Brill-Edwards P. Subcutaneous heparin therapy during pregnancy: a need for concern at the time of delivery. Thromb Haemost. 1991;65:248–250.
46. Greer IA, Thomson AJ. Management of venous thromboembolism in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2001;15:583–603.
47. Devendra G, Morris T. Pulmonary embolism and deep venous thrombosis treated with either low molecular weight heparin or unfractionated heparin have the same incidence of thrombocytopenia. Chest. 2000;118: 262s.
48. Lindhoff-Last E, Nakov R, Misselwitz F, Breddin HK, Bauersachs R. Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecularweight heparin. Br J Haematol. 2002;118:1137–1142.
49. Ginsberg JS, Kowalchuk G, Hirsh J, et al. Heparin therapy during pregnancy: risks to the fetus and mother. Arch Intern Med. 1998;149: 2233–2236.
50. Munn MB, Groome LJ, Atterbury JL, Baker SL, Hoff C. Pneumonia as a complication of pregnancy. J Matern Fetal Med. 1999;8:151–154.
51. Yost NP, Bloom SL, Richey SD, Ramin SM, Cunningham FG. An appraisal of treatment guidelines for antepartum community-acquired pneumonia. Am J Obstet Gynecol. 2000;183:131–135.
52. Lim BH, Mahmood TA. Pandemic H1N1 2009 (swine flu) and pregnancy. Obstet Gynaecol Reprod Med. 2010;20(4):101–106.
53. Good JT, Iseman MD, Davidson PT, Lakshminarayan S, Sahn SA. Tuberculosis in association with pregnancy. Am J Obstet Gynecol. 1981;140: 492–498.
54. Saade GR. Human immunodeficiency virus (HIV) related pulmonary complications in pregnancy. Semin Perinatol. 1997;21(4):336–350.
55. Hamadeh MA, Glassroth J. Tuberculosis and pregnancy. Chest. 1992;101: 1114–1120.
56. Starke JR. Tuberculosis. An old disease but a new threat to the mother, fetus, and neonate. Clin Perinatol. 1997;24(1):107–127.
57. Ducey JP, Ellsworth SM. The hemodynamic effects of severe mitral stenosis and pulmonary hypertension during labor and delivery. Intensive Care Med. 1989;3:192–195.
58. Lin JH, Zhao WX, Su Y, Shi J, Jiang GJ, Wu ZM. Perinatal management and pregnancy outcome in pregnant women with pulmonary hypertension complicating cardiac disease. Zhonghua Fu Chan Ke Za Zhi. 2006;41: 99–102.
59. Keizer JL, Zwart JJ, Meerman RH, Harinck BI, Feuth HD, van Roosmalen J. Obstetric intensive care admissions: a 12-year review in a tertiary care centre. Eur J Obstet Gynecol Reprod Biol. 2006;128:152–156.
60. Mirghani HM, Hamed M, Ezimokhai M, Weerasinghe DS. Pregnancyrelated admissions to the intensive care unit. Int J Obstet Anesth. 2004;13: 82–85.
61. Zwart JJ, Dupuis JR, Richters A, Ory F, van Roosmalen J. Obstetric intensive care unit admission: a 2-year nationwide population-based cohort study. Intensive Care Med. 2010;36:256–263.
62. Leung NY, Lau AC, Chan KC, Yan W. Clinical characteristics and outcomes of obstetric patients admitted to the intensive care unit: a 10-year retrospective review. Hong Kong Med J. 2010;16:18–25.
63. Mabie WC, Barton JR, Sibai BM. Adult respiratory distress syndrome in pregnancy. Am J Obstet Gynecol. 1992;167(4 Pt 1):950–957.
64. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349.
65. Catanzarite VA, Willms D. Adult respiratory distress syndrome in pregnancy: report of three cases and review of the literature. Obstet Gynecol Surv. 1997;52:381–392.
66. Perry KG Jr, Martin RW, Blake PG, Roberts WE, Martin JN Jr. Maternal mortality associated with adult respiratory distress syndrome. South Med J. 1998;91:441–444.
67. Clark SL, Belfort MA, Dildy GA et al. Maternal death in the 21st century: causes, prevention, and relationship to cesarean delivery. Am J Obstet Gynecol. 2008;199:36.e1–36.e5.

In the event of acute respiratory failure (ARF), invasive mechanical ventilation (IMV) is a required practice to support gas exchanges and to unload respiratory muscles. Even if it is a life-saving procedure, it is not lacking from complications that actually make worse morbidity and mortality in intubated patients. Firstly, nosocomial infections, and in particular ventilator-associated pneumonia (VAP), are associated with a longer hospital stay and an increased risk of death.¹ In fact, it is well known that an endotracheal tube can predispose to the development of pneumonia by impairing cough and mucociliary clearance because contaminated secretions can accumulate above the cuff and leak around the cuff or because bacterial binding to the surface of bronchial epithelium is increased. Invasive ventilatory support also increases the risk of feeding aspiration that can be shown in almost 50% of patients receiving prolonged ventilation.² Gastrointestinal hemorrhages³ and generalized myopathy⁴ are other important possible complications. Heavy sedation or curarization during the first days of ventilation as well as sepsis and multiple organ failure (MOF) is an important risk factor for the development of both myopathy and neuropathy.⁵ The evidence of all these complications may, per se, explain why trying to reduce the duration of invasive ventilation, when it is not possible to avoid it, should be the most important goal in patients needing for prolonged invasive mechanical ventilation. Weaning is defined as the process of gradual removal of mechanical ventilation support toward spontaneous ventilation. In more than 70% of patients needing invasive mechanical ventilation, if accurately monitored about the readiness for a spontaneous breathing trial (SBT), weaning is possible in a few days (a median of 1 and 3 days in the intervention and control group, respectively).⁶ However, there is a group of ventilated patients requiring a gradual and longer withdrawal of respiratory support.⁷ There are no differences between the two most popular weaning methods, either the gradual progressive reduction of pressure support level or T-piece breathing. In fact, they result to be equally effective, and the operator confidence with one or the other technique should be the criteria of choice.⁸

In this review, we will analyze the use of noninvasive ventilation (NIV) throughout the period of extubation, where the different timings of application correspond to different “philosophy ” of use, such as NIV as a tool to shorten the weaning time, to avoid the occurrence of post extubation failure, and to treat overt respiratory distress or failure in the first 48 hours after extubation.

We searched Medline, EmBase, and the Cochrane database, using the keywords “non-invasive” or “noninvasive (mechanical) ventilation” and “weaning ” or “ post-extubation failure” or “post-extubation distress” for all reports of adults, published until March, 2011. Our search was limited to publications in English. We selected relevant reports and comprehensive reviews. We also searched the reference lists of identified publications, selecting relevant articles with an emphasis on research of acute respiratory failure.

NIV AS A WEANING TECHNIQUE

One-third of IMV time is devoted to weaning⁹ and it becomes close to 50% in patients affected by chronic obstructive pulmonary disease (COPD), cardiac failure, and neurological problems. When the weaning fails, it is usually associated with an increased risk of death, prolonged intensive care unit (ICU) stay, and transfer to long-term facilities.¹⁰

Many investigators examined the possibility to wean patients ventilated invasively using NIV to shorten the intubation time and to avoid the above-mentioned complications.

From a physiological point of view, NIV is similar to IMV, in fact, it reduces the breathing work and frequency, decreases the negative deflections of intrathoracic pressure, improves gas exchange, and rests respiratory muscles.¹¹ For the same reasons, NIV could be able to counteract physiological mechanisms associated with weaning failure or difficulties: imbalance between respiratory muscle capacity and load, left ventricular dysfunction due to the large negative deflection of intrathoracic pressure, and a sudden increase in the resistive load due to an upper airway obstruction.

By the light of this knowledge, the first application of NIV in the weaning process was to substitute at one point in time the endotracheal tube with NIV by face or nasal masks with the aim to shorten the duration of intubation.

Udwadia et al.¹² in 1992 published the first report describing use of NIV to facilitate liberation from IMV in 22 consecutive patients referred to their hospital for weaning difficulties. Most of the patients had hypercapnic respiratory insufficiency due to different underlying pathologies (chest wall defects, neuromuscular disorders, and primary cardiac disease). All of them had undergone and failed at least one conventional weaning attempt. Twenty of the 22 patients were successfully stabilized on NIV and all of these were transferred from the ICU to a step-down unit or a general ward. Only two patients did not tolerate NIV, and it is noteworthy that both were affected by “pure” hypoxemic respiratory failure due to pulmonary fibrosis after ARDS and cryptogenic pulmonary fibrosis. Afterward, other noncontrolled studies also encouraged the use of NIV as a weaning technique.^13–15 Particularly, one of them¹⁴ enrolling 14 patients (8 COPD and 4 with restrictive disease) showed that 13 of 14 patients were successfully weaned with NIV, whereas only one patient died in the ICU. The most striking result of this paper was that in 5 of 14 patients trials with NIV were started within a week of intubation, and that in three of them were performed within the first 24 hours. This experience introduced the idea that the switch from intubation to NIV could be carried out early than normal even in patients considered by the attending physician “as individuals in whom weaning from ventilation was predicted to be difficult.” All these studies were clinically very promising, but in the era of the evidence-based medicine only randomized, controlled trials could change the attitude of physicians toward the controversial problem of weaning.

Some years later, two randomized controlled studies were performed in Europe and were conducted on patients intubated for an episode of acute hypercapnic respiratory failure.^{16, 17} The first was a multicentric study¹⁶ that enrolled only severe COPD patients. Forty-eight hours after intubation, if hemodynamically stable, with a normal temperature, with an acceptable neurological status and no signs of pneumonia, 68 patients underwent T-piece trial. Only patients who failed this trial (a total of 50) were randomized either to extubation with immediate application of NIV or to continued weaning process using conventional weaning methods. By 60 days, 88% of patients ventilated noninvasively had been successfully weaned vs 68% patients ventilated invasively. Mean duration of mechanical ventilation was significantly higher in the control group (16 + 11 vs 10 + 6 days). The probability of success (survival and weaning) during ventilation was found to be significantly higher in the noninvasively ventilated group and ICU stay significantly shorter in this group. Survival rates at 60 days were also statistically different. None of the patients weaned noninvasively developed nosocomial pneumonia, whereas 7 (28%) of those treated invasively did. The other randomized and controlled study, performed by a French group in a single ICU (17), was conducted on patients intubated for an episode of ARF due to COPD or other restrictive disease. In a similar study design enrolling 33 patients, authors confirmed the finding of shorter duration of invasive mechanical ventilation in the groups weaned noninvasively. However, no differences were found in term of ICU and hospital stays as well as the 3-month survival in the two groups. Moreover, even if the mean period of daily ventilatory support in the NIV group was significantly shorter than in the conventional group, total duration of mechanical ventilation was found to be longer. This apparently contradictory result may be explained by the different definition of weaning during NIV in the two studies. In the Italian study, it was defined as an “all or none phenomenon,” whereas the French study reflected a more clinical attitude to ventilate patient, once extubated, for a few hours a day, even in the absence of any sign of post extubation failure. Some years later, Ferrer et al.¹⁸ published a study in which they compared, in a randomized controlled trial, NIV with conventional weaning strategy in patients with “persistent” weaning failure defined as a failure of a SBT for three consecutive days. The study was stopped after having included 50% (43 patients) of the estimated patients because a planned interim analysis showed a significant reduction of duration of mechanical ventilation in the NIV group (9.5±8.3 vs 20.1±13.1 for the NIV group and the conventional weaning group, respectively). ICU stay and hospital stay were also significantly reduced in the NIV group. There were no significant differences in the incidence of reintubation between the two groups. However, patients treated by NIV had a minor incidence of serious complications (nosocomial pneumonia and septic shock) and a better ICU and 90 days survival. It is interesting to note that even if this study was planned to enroll difficult-to-wean patients regardless of the underlying disease, almost 80% of recruited patients were affected by chronic pulmonary disorders, so one more time, the study didn't contribute to assess the benefits of NIV for weaning in other forms of respiratory failure, such as ARDS, post surgical complications, or cardiac impairment. Some small and not randomized trials have been performed using NIV for weaning trauma patients with hypoxemic respiratory failure¹⁵ and nonCOPD patients with persistent ARF after early extubation.¹⁹ However, based on these studies, we cannot recommend NIV as a weaning strategy in severe hypoxic patients. Afterward, randomized controlled studies that enrolled adults with respiratory failure who required invasive mechanical ventilation for at least 24 hours, and weaned either using NIV or conventional methods, were also object of two meta-analysis.^{20, 21} The most recent one²¹ showed that noninvasive weaning was significantly associated with reduced mortality (relative risk 0.55, 95% confidence interval (CI) 0.38–0.79), VAP (0.29, 95% CI 0.19–0.45), length of stay in intensive care unit (weighted mean difference 6.27 days, 8.77 to 3.78) and hospital ( 7.19 days, 10.80 to 3.58), total duration of ventilation, and duration of invasive ventilation. However, as already underlined, most studies included in the review enrolled predominantly or exclusively patients with chronic obstructive pulmonary disease. Even if a subgroup analysis suggested greater benefits of noninvasive weaning in patients with COPD, the results of analyses of subgroup effects were predominantly nonsignificant. This could be explained on the one hand by the contamination of mixed populations with patients with COPD and on the other hand the small number of studies evaluating noninvasive weaning in patients with other causes of respiratory failure, so that the latter population was probably underpowered to detect significant interactions. More recently, Trevisan and her group in Brasil²² performed another similar study in invasively ventilated patients for different causes. A heterogeneous group of 65 patients treated with IMV from more than 48 hours who failed a SBT, were randomly assigned to the NIV group or to the IMV group. Comparison between the two groups showed that the percentage of complications was lower in the NIV group (28.6% vs 75.5%), with a lower incidence of pneumonia and tracheotomy. The length of stay in the ICU and mortality rate were not statistically different. One important limitation of this study was the relatively small sample size and the heterogeneity of population that prevented the possibility to perform a stratified analysis per subgroup of patients. In the meantime, Prasad and coworkers leaded in India a similar randomized controlled trial,²³ evaluating the role of NIV for weaning from IMV in a selected group of COPD patients. Patients after a SBT failure were randomized into two groups to receive either NIV or continued weaning with IMV in pressure support mode. However, in this study no statistically significant differences were found between the two groups in terms of duration of MV, hours of weaning, ICU stay, incidence of VAP, and number of deaths at discharge from ICU at 30 days. A possible explanation for these results could be related to the small number of patients recruited in the trial. Girault et al.²⁴ recently completed a randomized controlled trial with a large number of patients needing IMV for different reasons, in 17 centers in France. Data were presented so far in an abstract form. Inclusion criteria were the same reported in the previous study. Patients were randomized into three groups either to continue intubation in IMV or to start NIV or to receive standard medical therapy after extubation. There were no differences in weaning failure, complications, ICU or hospital stay, or hospital survival. Interestingly, NIV was used effectively as rescue therapy in patients weaned invasively and also in patients extubated with oxygen alone. Furthermore, larger studies will be needed to assess the real impact of NIV on heterogeneous population of ICU patients. The bad tolerance of facial interfaces and the possible difficulties fitting masks has been considered as possible causes for failure of NIV in the weaning process.²⁵ Lately, the helmet has been considered as a potential alternative for NIV. In a recent case report, Klein et al.²⁶ described the possibility to rapidly wean COPD patients intubated for an ARF by using helmet during NIV. They showed a good patient's compliance, lower costs, and nurse workload and mostly, fewer complications related to sedation and infections compared to invasive ventilation. Further studies will be needed to assess the role of routine helmet NIV from IMV weaning.

The main results from the studies reported in this section are shown in Table 1.

In conclusion, through all these studies, strong support to NIV as a weaning strategy in the subgroup of COPD patients who experienced a failure of a SBT was provided, with the effect of reducing mortality, minimizing ventilator-associated pneumonia, and shortening length of hospital stay.

NIV AND POST EXTUBATION FAILURE

Prevention

Post extubation failure is a major clinical problem in ICUs. It is usually defined when respiratory distress (ie, increased breathing frequency and indirect signs of incipient fatigue such as massive activation of accessory muscles and/or inward movements of the lower rib cage), worsening of Arterial Blood Gases (ie, PaCO2> 10 mm Hg and decrease in pH < 0.10; PaO2< 60 mm Hg or SaO2 < 90% while receiving FIO2 >0.50–1.0) or inability to protect the airway because of upper airway obstruction or excess pulmonary secretion, occurs within the first 72 hours after extubation.

Post extubation failure requiring reintubation occurs on average in 13% of patients.²⁷ The prognosis of these patients is very poor because their hospital mortality exceeds 30%–40%, with the cause of extubation failure (ie, nonairway problems) and the time to reintubation, being independent predictors of outcome.^{28, 29} Moreover, reintubation represents “per-se” an independent risk factor for nosocomial pneumonia, as assessed by Torres in a case-control study.³⁰

Few studies have evaluated the use of NIV as a mean to prevent the development of a post extubation respiratory failure. Jiang et al. ³¹ conducted a prospective study on 93 patients randomized to receive NIV or oxygen therapy after planned or unplanned extubation. They found no difference in the reintubation rate between the two groups; however, in this study, NIV was used indiscriminately in all the patients being extubated. On the other hand, Epstein et al. ²⁹ showed that there is a certain subset of patients whose clinical characteristics at the time of extubation may predict reintubation. Therefore, it was suggested that the application of NIV in this selected population of at risk patients may avoid the occurrence of post extubation failure and consequently the possibility of reintubation.

Based on this hypothesis, two randomized trials from Nava and Ferrer^{32, 33} were, therefore, performed to assess whether NIV is effective in preventing the occurrence of post- extubation failure in patients at “highest risk” when compared to standard medical treatment. The two trials adopted similar criteria to define the category of patients at potential risk (ie, persistent weaning failure, post extubation hypercapnia, age, weak cough reflex, or a preexisting cardiac disease) and similar design (ie, sequential use of NIV in the first 48 hrs). In the first trial,³² 97 patients were randomly assigned to receive SMT or NIV. The use of NIV determined a 16% reduction in the risk for reintubation (p=.027), whereas the protective effect on ICU mortality (−12%) was close to achieving a statistical significance (p=.064). Moreover, the need for reintubation was associated with a 60% increase in the risk of ICU mortality (p<.01). Patients needing reintubation had a statistically higher ICU length of stay compared with those who did not (23.89 29.51 vs. 8.64 5.19, p<.001). Authors concluded that the preventive application of NIV in a subset of patients at risk of post extubation failure after having passed a spontaneous breathing trial may reduce the need for reintubation. The latter was associated with a higher risk of ICU mortality, and the use of NIV resulted in a reduction of risk of ICU mortality, mediated by the reduction for the need of reintubation.

Similar results were found in the second randomized trial³³ by Ferrer et al. Differently from the previous study, in this trial NIV was also used as rescue therapy in patients from the two groups in case of respiratory failure after extubation without needing immediate reintubation. Authors found in 162 patients that NIV significantly reduced the incidence of respiratory failure after extubation, but the differences between the two groups in the reintubation rate failed to be significant. This was due to the efficacy of NIV as rescue therapy to avoid reintubation in 9 out of 19 patients in the SMT group and 4 out of 4 patients in the NIV group. Moreover, although reintubation after rescue therapy with NIV occurred later than direct reintubation, the time from extubation to reintubation did not influence mortality. However, the beneficial effects of NIV on survival appear restricted to patients with chronic respiratory disorders and hypercapnia during the spontaneous breathing trial. To confirm the result found in this subgroup of patients, Ferrer and colleagues³⁴ performed a multicentre randomized controlled trial specifically designed for patients who developed hypercapnia during an SBT. They were randomly divided to receive NIV or conventional oxygen therapy after a successful SBT. Primary end point was to avoid respiratory failure within 72 hours after extubation. They found that respiratory failure was less frequent in the NIV arm then in the other one (15% vs 25%). NIV was also independently associated with a lower risk of respiratory failure after extubation and in patients with respiratory failure, NIV as a rescue therapy, avoided reintubation. The overall 90 days mortality was significantly lower in the group of NIV (11% vs 31%).

Obesity represents another important risk factor for post extubation respiratory failure. El Sohl and colleagues³⁵ looked at NIV immediately after extubation in morbidly obese patients who had been ventilated for more than 48 hours. Compared to matched control patients treated with conventional medical therapy, they found a 16% absolute risk reduction of post extubation respiratory failure and a less need for reintubation in the NIV group (10 in the NIV group vs 26% in controls). A shorter length of ICU stay and a reduced mortality were found only in the subgroup of hypercapnic patients treated by NIV. In summary, routine use of NIV immediately after extubation is not recommended, except for patients at high risk for extubation failure, and particularly for those with persistent hypercapnia after extubation, where the application of a mechanical aid may support the respiratory pump, that in these patients is prone to develop fatigue.

The main results from the studies reported in this section are shown in Table 2.

Treatment

The use of NIV has been suggested in attempt to avoid reintubation in patients who show signs of “incipient” or even overt respiratory failure following extubation.

Hilbert and coworkers³⁶ demonstrated that NIV improved the outcome of patients with COPD and post extubation hypercapnic respiratory failure when compared to conventional treatment of matched subjects, by reducing the need for endotracheal intubation, the mean duration of ventilatory assistance, and the duration of ICU stay.

In a randomized controlled trial,³⁷ patients developing ARF within 48 hours after extubation were randomized to receive standard medical therapy alone or NIV. The authors did not find any difference in reintubation rate, hospital mortality rate, ICU, and hospital stay, despite there was a trend of a shorter duration of hospital stay in the NIV group. It is, therefore, important to underline few comments to the present study. Patients were considered eligible for the study when developing respiratory distress defined, in the present study, as a respiratory rate greater than 30 minutes, presence of increased respiratory rate greater than 50% from baseline rate, use of respiratory accessory muscles, or abdominal paradox. These criteria could be not necessarily related to a post extubation failure. Moreover, after the first year, patients with an acute exacerbation of COPD were excluded from this study even if the randomized trial and strong evidences supported the use of NIV for this class of patients. Esteban et al. ³⁸ conducted a large multicenter, randomized trial to evaluate the effect of NIV on mortality of patients who had respiratory failure. Within the subsequent 48 hours of IMV, they were randomly assigned to either NIV or standard medical therapy. The study was stopped prematurely during an interim analysis because the authors found a higher mortality rate in the NIV group compared to the standard therapy (25% vs 14% respectively, p=.048). However, the dissimilarity appeared to be due to differences in the rate of death among the patients who required reintubation (38% in NIV group vs 22% in SMT group, p=.06). This could correlate with the result of a longer interval between the onset of ARF and re-intubation in NIV group (p=.02). This study was performed in an unselected group of patients, consequently the authors concluded that there was the potential that selected patients (ie, those with COPD) may still benefit from NIV, but the sample was too small to allow meaningful conclusions. As a result, the authors concluded that NIV does not improve survival and may in fact be harmful. Although selected patients in specialized centers may benefit from this therapy, specific hypothesis needs to be tested prospectively. What remains unclear is a result not discussed in the paper of the 114 patients assigned to SMT, 28 received NIV as rescue therapy; of these only 7 (25%) were subsequently intubated and 3 (11%) died. This means that patients who perform NIV as rescue therapy had a lower rate of failure and a lower rate of death than patients who performed NIV as first attempt (failure rate = 48%, rate of death =25%). In summary, until now literature does not support the routine use of NIV to treat an incipient post extubation respiratory failure.

The main results from the studies reported in this section are shown in Table 3.

In general, NIV is not presently indicated for the treatment of patients showing respiratory distress or failure after extubation, but future studies are certainly needed in selected population of patients, such as those of a chronic respiratory disorder or signs of respiratory pump failure.

CONCLUSIONS

Weaning process is crucial and a recent review by Epstein et al.³⁹ underlines that the majority of studies focused on this topic found NIV superior to IMV. Until now, if the weaning criteria are met, confirmed evidences of real NIV efficacy have been proved only in selected population of patients such as people with acute-on-chronic respiratory failure (COPD exacerbation) to shorten the length of invasive mechanical ventilation, the ICU stay, and to avoid intubation-related complications such as VAP. The role of NIV in all the other conditions (ie, hypoxic patients, post surgical patients) remains unclear. Randomized controlled studies have demonstrated that NIV may be even harmful to treat an over episode of post extubation respiratory failure, whereas promising results were obtained using NIV to prevent reintubation in patients considered at risk. In the event of unplanned extubations, during the weaning period, NIV could also be considered as a good option to prevent reintubation.

Acknowledgements: Annalisa Carlucci is the principal investigator for this report.

Disclosure: The authors declare no conflict of interest.

REFERENCES

1. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541–548.
2. Elpern EH, Scott MG, Petro L, Ries MH. Pulmonary aspiration in mechanically ventilated patients with tracheostomies. Chest. 1994;105:563–566.
3. Mutlu GM, Mutlu EA, Factor P. GI Complications in patients receiving echanical ventilation. Chest. 2001;119(4):1222–1241.
4. Berek K, Margreiter J, Willeit J, Berek A, Schmutzard E, Mutz NJ. Polyneuropathies in critically ill patients: a prospective evaluation. Intensive Care Med. 1996;22:849–855.
5. Latronico N, Fenzi F, Recupero D, et al. Critical illness myopathy and neuropathy. Lancet. 1996;347:1579–1582.
6. Ely WE, Baker AM, Dunagan DP, et al. Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N.Engl.J. Med. 1996;335:1864–1869.
7. Brochard L, Rauss A, Benito S, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am.J.Respir.Crit. Care Med. 1994;150:896–903.
8. Esteban A, Alia I, Ibanez J, Bonito S, Tobin MJ. Modes of mechanical ventilation and weaning: a national survey of Spanish hospitals. Chest. 1994;106:1188–1193.
9. Ely EW. Challenges encountered in changing physicians’ practice styles: the ventilator weaning experience. Intensive Care Med. 1998;24:539–541.
10. Epstein SK, Ciubataru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest. 1997;112:186–192.
11. Vitacca M, Ambrosino N, Clini E, et al. Physiological response to pressure support ventilation delivered before and after extubation in patients not capable of totally spontaneous autonomous breathing. Am J Respir Crit Care Med. 20011;164(4):638–641.
12. Udwadia ZF, Santis GK, Steven MH, Simonds AK. Nasal ventilation to facilitate weaning in patients with chronic respiratory insufficiency. Thorax. 1992;47:715–718.
13. Goodenberger DM, Couser JI Jr, May JJ. Successful discontinuation of ventilation via tracheostomy by substitution of nasal positive pressure ventilation. Chest. 1992;102:1277–1279.
14. Restrick LJ, Scott AD, Ward EM, French Ro, Cornwell WE, Wedjicha JA. Nasal intermittent positive-pressure ventilation in weaning intubated patients with chronic respiratory disease from assisted intermittent positive pressure ventilation. Respir Med. 1993;87:199–204.
15. Gregoretti C, Beltrame F, Lucangelo U, et al. Physiologic evaluation of non-invasive pressure support ventilation in trauma patients with acute respiratory failure. Intensive Care Med. 1998;24:785–790.
16. Nava S, Ambrosino N, Clini E, et al. Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease. A randomized, controlled trial. Ann Intern Med. 1998;128(9):721–728.
17. Girault C, Daudenthun I, Chevron V, Tamion F, Leroy J, Bonmarchand G. Noninvasive ventilation as a systematic extubation and weaning technique in acute-on-chronic respiratory failure. A prospective, randomized controlled study. Am J Respir Crit Care Med. 1999;160:86–92.
18. Ferrer M, Esqinas A, Arancibia F, et al. Non invasive ventilation during persistent weaning failure. Am J Respir Crit Care Med. 2003;168:70–76.
19. Kilger E, Briegel J, Haller M, et al. Effects of noninvasive positive pressure ventilatory support in non-COPD patients with acute respiratory insufficiency after early extubation. Intensive Care Med. 1999;25:1374–1380.
20. Burns KE, Adhikari NK, Meade MO. A meta-analysis of noninvasive weaning to facilitate liberation from mechanical ventilation. Can J Anesth. 2006;53:305–315.
21. Burns KE, Adhikari NK, Keenan SP, Meade M. Use of non-invasive ventilation to wean critically ill adults off invasive ventilation: metaanalysis and systematic review. BMJ. 2009;338:b1574.
22. Trevisan CE, Vieira SR. Research group in mechanical ventilation weaning. Noninvasive mechanical ventilation may be useful in treating patients who fail weaning from invasive mechanical ventilation: a randomized clinical trial. Crit Care. 2008;12(2):R51. Epub 2008 Apr 17.
23. Prasad SB, Chaudhry D, Khanna R. Role of noninvasive ventilation in weaning from mechanical ventilation in patients of chronic obstructive pulmonary disease: an Indian experience. Indian J Crit Care Med. 2009;13(4):207–212.
24. Girault C, Bubenheim M, Benichou J, Bonmarchand G. Non Invasive ventilation and weaning from mechanical ventilation in chronic respiratory failure patients: the venise study: preliminary results. Proc Am Thorax Soc. 2009; A2165 (abstract).
25. Carlucci A, Richard JC, Wysocki M, Lepage E, Brochard L. SRLF collaborative group on mechanical ventilation. Noninvasive versus conventional mechanical ventilation. An epidemiologic survey. Am J Respir Crit Care Med. 2001;163(4):874–880.
26. Klein M, Weksler N, Bartal C, Gurman GM. Helmet noninvasive ventilation for weaning from mechanical ventilation. Respir Care. 2004;49(9):1035–1037.
27. Boles J-M, Bion J, Connors A, et al. Task force: weaning from mechanical ventilation. Eur Respir J. 2007;29:1033–1056.
28. Epstein SK, Ciubotaru RL, Wong JB. Effect of failed extubation on the outcome of mechanical ventilation. Chest. 1997;112:186–192.
29. Espstein SK, Ciubotaru RL. Independent effects of etiology of failure and time to reintubation on outcome for patients failing extubation. Am J Respir Crit Care Med. 1998;158:489–493.
30. Torres A, Gatell JM, Aznar E, et al. Re-intubation increases the risk of nosocomial pneumonia in patients needing mechanical ventilation. Am J Respir Crit Care Med. 1995;152:137–141.
31. Jiang JS, Kao SJ, Wang SN. Effect of early application of biphasic positive airway pressure on the outcome of extubation in ventilator weaning. Respirol. 1999;4:161–165.
32. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients. Crit Care Med. 2005;33:2465–2470.
33. Ferrer M, Valencia M, Nicolas JM, et al. Early noninvasive ventilation averts extubation failure in patients at risk: a randomized trial. Am J Respir Crit Care Med. 2006;173:164–170.
34. Ferrer M, Sellarés J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with chronic respiratory disorders: randomised controlled trial. Lancet. 2009;374(9695):1082–1088. Epub 2009 Aug 12.
35. El Sohl AA, Aquilina A, Pineda L, Dhanvantri V, Grant B, Bouquin P. Non invasive ventilation for prevention of post-extubation respiratory failure in obese patients. Eur Respir J. 2006;28:588–595.
36. Hilbert G, Gruson D, Portel L, Gbikpi-Benissan G, Cardinaud JP. Noninvasive pressure support ventilation in COPD patients with postextubation hypercapnic respiratory insufficiency. Eur Respir J. 1998;11(6):1349–1353.
37. Keenan SP, Powers C, McCormack DG, Block G. Noninvasive positivepressure ventilation for postextubation respiratory distress. JAMA. 2002;287:3238–3244.
38. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Non-invasive positive pressure ventilation for respiratory failure after extubation. NEJM. 2004;350:2462–2460.
39. Epstein SK, Durbin CG. Should a patient be extubated and placed on noninvasive ventilation after failing a spontaneous breathing trial? Jr. Respir Care. 2010;55(2):198–206; discussion 207–208.

Chronic obstructive pulmonary disease (COPD) is characterized by not fully reversible airflow limitation and a range of pathology changes in the lung, consisting of a mixture of inflammation in the small airways and parenchyma destruction ¹. In the past years, it was usually considered a smoking-related disease ². Based on this consideration, most researches focused on COPD with smoking. As the result, COPD has not been well characterized among those nonsmokers. However, increasing evidence showed that some patients with COPD were nonsmokers, indicating that factors other than smoking may be involved in the development of COPD ^3–7 . Here we review on the burdens, clinical characteristics, and the risk factors of COPD among nonsmokers who have never smoked during their lifetime, especially in China and to acquire more research interest..

PREVALENCE AND PROPORTION OF COPD IN NONSMOKERS

The prevalence of COPD among nonsmokers varied across countries and areas due to variations in studied population and the definition of COPD. Based on self-reported physician diagnosis, the prevalence of COPD was 5.1% among nonsmokers in the United States according to pooled results from studies of the First National Health and Nutrition Examination Survey (NHANES I), NHANES II, and HHANES ⁸. According to GOLD spirometry criteria, 6.6% of nonsmokers were diagnosed with COPD in the NHANES III study ⁹, with 9.1% of COPD prevalence among nonsmokers aged 30 to 80 years. The results were similar to the COPD prevalence among nonsmokers in Korea (8.8% among subjects aged ≥45 years) ¹⁰. Among Chinese nonsmokers aged ≥40 years, COPD patients account for 5.2% of the whole, including 1.4% in Global Obstructive Lung Disease (GOLD) stage I (FEV1/FVC > 70% and FEV1 ≥ 80% predicted values) and 3.7% in GOLD stages II-IV (FEV1/FVC >70% and FEV1 > 80% predicted values) ¹¹. The result was close to that in five Colombian cities (8.9%) ¹², Mexico City (6.2%), and Caracas (6.6%), and lower than that in three other Latin American cities (Sao Paulo 12.5%, Montevideo 15.3%, and Santiago 15.9%) ⁶, using the same diagnostic criteria among populations of the same age.

A recent review from Salvi and Barnes ¹³ showed that the proportion of nonsmoking COPD patients in all COPD patients ranged from 17.0% in Venezuela to 68.6% in India, depending on variations of studied population and the definition of COPD, with a higher proportion in developing countries and a lower one in the developed countries (Fig. 1). For instance, 47.6% of patients with COPD identified by a respiratory questionnaire in South Africa ¹⁴ are nonsmokers and the proportion goes to 68.6% in India ¹³, but decreases to 17.0% in 16 developed counties ¹⁵, 20.0% in Sweden ¹⁶, and 20.2% in Finland ¹⁷, respectively. Based on the GOLD spirometry criteria, an estimated 17.0%-38.8% of patients with COPD were nonsmokers worldwide, with 23% in USA ⁹, 22.9% in UK ¹⁸, and 23.4% in Spain ¹⁹. In China, nonsmokers account for 38.6% of all COPD patients ¹¹. These results suggest that the burden caused by nonsmoking COPD patients is much higher than previously expected in both developed and developing countries ²⁰, and risk factors other than smoking may contribute to the higher prevalence of nonsmoking COPD patients in developing countries than that in developed countries.

RISK FACTORS OF COPD IN NONSMOKERS

Smoking is well established as the predominant risk factor for COPD ^{1 2}. However, as mentioned above, more than 17% of the cases occur among nonsmokers ^9–19 , indicating the involvement of other risk factors.

Indoor air pollution

Coal and biomass fuel such as wood, charcoal, crops, twigs, dried grass, and dung largely used for cooking or heating in low-income countries and produces a large amount of combustion (ie, respirable particulates (PM10), carbon monoxide, nitrogen dioxide, sulfur oxides, formaldehyde, polycyclic organic matter, and other toxic elements) contributes a significant part to indoor air pollution ^21–29 . According to the World Health Organization (WHO) estimation, approximately 50% of all households and 90% of rural households utilize biomass or coal fuels for cooking and heating in the world. About three billion people worldwide are exposed to smoke produced from biomass or coal fuel burning ^{22, 23, 29}. More than 80% of the households in India and sub-Saharan Africa use biomass or coal fuel for cooking, and in rural areas of Latin America the proportion ranges from 30% to 75% ^23–26 .

In China, approximately 60% of rural households use biomass fuel for cooking and 31% use coal fuel ²⁷. The detailed distribution of households by cooking fuel category in China is shown in Fig. 2. In recent investigations involving 13 urban and rural areas in China, 44.6% and 73.2% of nonsmokers had been reported to be exposed to biomass and coal smoke, respectively, and 40% had poor ventilation in the kitchen ¹¹. Even in some developed countries, such as Canada, Australia, and western partsof the United States, the persistent rise in cost for modern sources of energy has prompted an increase in wood or other biomass products consumption for heating maintenance ^{25, 26, 29}. For example, a study in New Mexico reported that 26% of participants had been exposed to smoke from a biomass fuel ²⁸.

Many epidemiologic studies have pointed out that indoor air pollutants from the combustion of biomass and coal fuels are related to respiratory symptoms, COPD, a greater decline in lung functions and significantly increase the morbidity and the burden of COPD-related lung diseases, which is particularly obvious in nonsmoking women ^{21–25,26, 28–34} . A meta-analysis of 36 studies showed that exposure to biomass smoke was a factor of the much higher risk for COPD (odds ratio 2.3, 95% CI: 1.5-3.5) ³⁴. Another review showed that the people exposed to biomass have an odds ratio (OR) of 2.44 (95% CI: 1.9-3.33) for developing COPD, relative to those who are not exposed to biomass smoke, 2.73 (95% CI: 2.28-3.28) among women and 4.30 (95% CI: 1.85-10.01) among men, as well as 2.55 (95% CI: 2.06-3.15) among nonsmokers ³⁵, consistent with the report by Kurmi et al ³⁶, which suggested there was a positive correlation between the use of solid fuels and COPD (OR = 2.80, 95% CI: 1.85-4.0) and chronic bronchitis (OR = 2.32, 95% CI: 1.92-2.80).

Among Chinese nonsmokers, those who cooked with biomass fuel had higher odds in developing COPD than those who did not (OR was 1.31; 95% CI: 1.08-1.58). The odds of COPD occurrence increased by 1.48 times (95% CI: 1.07-2.05) among nonsmokers who use coal for heating and 1.27 times (95% CI:1.04-1.55) among those nonsmokers whose ventilation in the kitchen was poor. Moreover, a dose-response pattern between COPD and years of exposure to biomass for cooking and coal for heating were observed as well ¹¹. These results were consistent with those from Turkey, India, and other developing counties ^{24, 25}. A 16-year retrospective cohort study in Xuwei County in China showed that installation of a chimney for household coal stoves significantly reduced the incidence of COPD ³⁷. Recently, two randomized controlled trials showed that the use of a chimney woodstove significantly reduced indoor air pollution from household biomass burning and may relieve symptoms and reduce the rate of a FEV₁ decline ^{38, 39}. Even in some developed countries such as the United States, exposure to wood smoke was also reported to increase the risk of developing COPD by 70% (95% CI: 30-220) ²⁸. It is estimated by WHO that an average of 22% COPD worldwide was attributed to biomass and coal smoke and that was 34% for female and 12% for male ^{23, 26}. Globally, close to 50% of the deaths from COPD in developing countries could be attributed to biomass and about 75% of these are in women ⁴⁰. Indoor air pollution was globally ranked 10th among preventable risk factors causing the burden of disease and fourth in developing countries ⁴¹.

Environmental tobacco smoke (ETS) is another major contributor to indoor air pollution apart from biomass and coal smoke. In China, the prevalence of ETS is much higher ^{11, 42, 43} since there is little restriction on smoking in public indoor places. Gu et al ⁴² reported that 49.2% of nonsmokers aged 35-74 years had been exposed to ETS at home or in the workplace, with 12.1% of men and 51.3% of women at home, and 26.7% of men and 26.2% of women in their workplaces. A study in Guangzhou ⁴³ reported that 28% of women had ETS exposure 40 h per week in more than 5 years. In our recent national surveys ¹¹, 78.2% of nonsmokers at the age of 40 years or older had ETS exposure.

The role of ETS in respiratory disease is being recognized ^44–51 . Previous literatures also indicated that ETS was associated with an increase in the risk of both acute respiratory illness among children and chronic respiratory disease among adults ^45–47 . ETS was also shown to contribute to higher bronchial responsiveness and a declined pulmonary function. Exposure to parental smoking in childhood potentially had an effect on the adult onset of obstructive lung diseases and chronic respiratory symptoms ^48–50 . In addition, ETS was associated with a bigger risk of COPD exacerbation and a worse health status ⁵¹.

However, information available for correlation between ETS and COPD is rather limited, especially in China. Most previous studies included small samples and smokers in the analysis ^52–54 , and less was from China ^{55, 56}. Law ⁵² examined eight studies and estimated that ETS increased the risk of COPD in adults by 25% (95% confidence interval 10%-43%). But a comprehensive review of 23 published studies ⁵⁷ and further studies published subsequently ^{58, 59} showed conflicting results. In China, Yin et al ⁴³ showed a link between ETS exposure and the risk of COPD among nonsmokers. As Yin et al ⁴³reported, there was an association between the risk of COPD and self-reported exposure to ETS at home and the work place with 1.48 (95% CI: 1.18-1.85) of an adjusted odds ratio for high level exposure (equivalent to 40 h a week for more than 5 years) and there were significant associations between reported respiratory symptoms and increasing ETS exposure (1.16, 1.07-1.25 for any symptom). These observations were similar to those observed in other countries ^{53, 54}. In addition, in investigations with India, a combined exposure to both ETS and solid fuel combustion caused a higher OR for chronic bronchitis than exposure alone ⁶⁰.

In China, over 60% of the adults are nonsmokers ⁶¹ and according to an investigation by Yin et al ,⁴³ about 1.9 million deaths of nonsmoking COPD patients could be attributed to ETS in the current population in China. Thus, legislations or regulations preventing passive smoking are urgent in China.

Occupational exposure

Up to now, exposure to toxic gases ⁶², grain dust in farms ⁶³, dust and fumes ⁶⁴, ammonia, hydrogen sulfide, and inorganic and organic dusts ⁶⁵, diesel exhaust (eg, garages and mines), and other irritant gases and vapors ⁶⁶ have been shown to be associated with bronchitis or COPD (defined as postbronchodilator FEV1/FVC <0.70) in cross-sectional studies. Some exposure showed a dose-dependent response; that is, as shown in a Norwegian study ⁶⁵, livestock farmers have a 40% (95% CI: 10-70) higher risk of developing COPD than crop farmers do, which is strongly correlated with concentrations of ammonia. Furthermore, farmers rearing more than one type of livestock (eg, sheep, goats, and poultry) had a significantly greater risk of having COPD than those rearing only one type of livestock ⁶⁵.

In china, there is little information regarding the relationship between COPD and occupational exposure among nonsmokers, as it is common for the coexistence of occupational exposure and smoking. As shown in our recent national survey, prevalence of occupational exposure to dusts/gases/fumes was 20.5% among total population and 20.1% among nonsmokers ^{11, 67, 68}. Occupational exposure to dusts/fumes/gases (OR was 1.20, 95% CI: 1.04-1.39) and dusts of grain (OR was 1.48, 95% CI: 1.18-1.86) increased the risk of COPD diagnosed by the GOLD criteria among total population. Occupational exposure to dusts/fumes/gases (OR was 1.37, 95% CI: 1.25-1.49), hard-rock mining (OR was 2.31, 95% CI: 1.67-3.20), coal mining (OR was 1.71, 95% CI: 1.09-2.70), dusts of cement (OR was 1.92, 95% CI: 1.47-2.52), chemical or plastics manufacturing (OR was 1.58, 95% CI: 1.37-1.83), spray painting (OR was 1.46, 95% CI: 1.16-1.84), and other dusts or fumes (OR was 1.46, 95% CI: 1.29-1.64) significantly increased the occurrence of respiratory symptoms after adjustment for smoking.

Outdoor air pollution

Historic air pollution events provide clear evidence that exposure to high levels of outdoor air pollutants is associated with increased mortality and morbidity due to COPD and related cardiorespiratory diseases ⁶⁹. The association between high concentrations of outdoor air pollutants and COPD exacerbations and worsening of preexisting COPD is supported by strong evidence ⁷⁰. In a recent 4-year study in China, the data suggested that subjects with an improvement on outdoor air pollution had less decline of FEV1 than those living in a relatively worse environment ⁷¹. However, more evidence to support such a correlation is not yet available, and large-scale, multinational, prospective epidemiological studies are needed to address this important issue.

Age and gender

The study in China showed that advanced age was the factor that shows strong effects on the prevalence of COPD among nonsmokers ¹¹, consistent with other studies ^{1, 4–10}. But Kojima et al ⁷² reported that the proportion of COPD cases increased with age in male nonsmokers but not in female nonsmokers. The impact of age on COPD may result from the accumulative effects of other risk factors such as occupational exposure, indoor and outdoor air pollution, and so on. In addition, aging may weaken the respiratory muscles, resulting in decreased PEF and FEV1/FVC ⁷³.

In a Chinese epidemiology study, it was found that females accounted for the majority of nonsmoking COPD subjects. The male nonsmokers were more likely than female nonsmokers to have COPD (8.8% vs. 4.4%), which is consistent with findings from Germany and Norway ⁷⁴, but is contradictory with the findings from Australia, Iceland, and Poland, which showed a greater prevalence of GOLD stage II or higher COPD among female nonsmokers than in male nonsmokers ⁷⁵. A higher prevalence of COPD in female vs. male nonsmokers (2.1% vs. 0.8%, respectively) was also noted in the Canadian National Population Health Survey, which employed the physician diagnosis of COPD ⁷⁶. Since COPD is a disease involving inflammation, it is also possible that sexual dimorphism of the human immune response may also be responsible for gender differences in the disease ⁷⁷. But up to now, the gender correlation with COPD has not yet been confirmed.

Genetic factors

COPD is considered a disease that is caused by chronic exposure of genetically susceptible individuals to harmful environmental factors. Family history of respiratory diseases is also associated with the higher prevalence of COPD in the study of China ^{11, 67}, and an interesting fact was observed in this study; subjects with their mothers rather than their fathers suffering from respiratory diseases appeared to be comparatively more liable to develop COPD. Moreover, there seemed to be a trend that the risk for COPD increased with the number of patients with respiratory disease in their families. However, the link of family history of respiratory disease to COPD can't exclude the confounding effects of environmental factors. In addition, α1-antitrypsin deficiency, which is still the only genetic factor definitively identified to date, only accounts for 1% of COPD cases and has not been found in the Chinese. Accordingly, the possible genetic or environmental effects are yet to be further recognized.

Others

As indicated by the study in Chinese nonsmokers, factors other than smoking and those mentioned above that have been shown to be associated with COPD include chronic cough during childhood, low BMI, and poor socioeconomic status, which is in agreement with other literatures and reports ^78–80 . Poor socioeconomic status is likely to be indicative of other factors such as intrauterine growth retardation, poor nutrition and housing conditions, independently being associated with COPD and lung function. Low BMI was reportedly strongly associated with COPD in cross-sectional and cohort studies even after adjusting for other potential risk factors ^{79, 80}; however, the causality between BMI and COPD remains unclear and needed to be elucidated. For instance, Harik-Khan et al ⁸⁰ demonstrated that the incidence of obstructive airway disease, defined as FEV1 percentage predicted <65%, was highest in lean men and lowest in overweight men. Poor nutritional status at birth or during early infancy was associated with the impaired lung function and the development of COPD in adulthood ⁸¹. However, the malnutrition reducing respiratory muscle and resulting in pulmonary function decline were found even in those subjects without lung diseases and pulmonary inflammation or tissue hypoxia presented in COPD contributed to the low BMI ^{82, 83}.

With regard to chronic asthma and tuberculosis, currently some cross-sectional studies ⁶ showed that asthma was associated with COPD. The association was further provided by some longitudinal studies, which showed that the patients with asthma had lower initial values of lung function and a greater rate of FEV1 decline ⁸⁴, more likely to develop chronic bronchitis, emphysema, and COPD than those without asthma ⁸⁵. The association might be explained by the hypothesis that chronic airway inflammation and airway hyperresponsiveness in individuals with asthma might increase irreversible and progressive lung damage from the environmental factors ⁸⁶. Pulmonary tuberculosis is also shown to be associated with COPD in some studies ^87–90 . Up to now, however, there was no study in terms of the role of asthma and tuberculosis in nonsmoking Chinese COPD.

Altitude was hypothesized to be associated with COPD in the PLANTINO study ⁶. Cold, windless, humid, and foggy climates were also regarded as risk factors for COPD in some papers ⁹¹; however, the result was not supported by further evidence ¹².

CLINICAL FEATURES, PROGNOSTIC AND PHENOTYPE

COPD consists of small airway diseases and parenchyma destruction, and there exist different phenotypes. It could be possible that the nonsmoking COPD has a distinct phenotype from that of the smoking COPD. But very few studies have systemic investigations about it. Birring et al ¹⁸[AQ renumber] found that COPD in nonsmokers predominantly affected females and could be divided into at least two pathologic subgroups according to the number of sputum eosinophilia. Shavelle et al ⁹² showed that the reduction in life expectancy was less for those who had never smoked than for those with COPD due to smoking. Moran-Mendoza et al ⁹³ reported that women with COPD due to exposure to biomass smoke had more lung fibrosis, greater pigment deposition, and thicker pulmonary artery intimae than did those with COPD due to tobacco smoking, who had greater emphysema and epithelial damage. Ozbay et al ⁹⁴ investigated nonsmoking women with COPD and biomass fuel exposure, and found that the most common HRCT findings were increased lung volume or diffuse emphysema, thickening of interlobular septae, focal emphysematous areas, increased cardiothoracic ratio, and increased bronchovascular arborization. The results suggested that biomass fuel has deleterious effects on pulmonary function and structure leading to obstructive and restrictive pathologies. However, Ramírez-Venegas et al ⁹⁵ reported that Mexican women, who had COPD and had been exposed to smoke from biomass fuel, had similar clinical characteristics, quality of life, and mortality to those with COPD due to tobacco smoking.

The study in China ¹¹ also indicated that nonsmoking COPD may have different profiles from smoking COPD. Unlike those with smoking-related COPD, nonsmoking COPD patients were less likely to have the following respiratory symptoms, including chronic cough and expectoration, lower BMI, lower FEV1/FVC ratio, and FEV1 percentage predicted values and previous medical records of chronic bronchitis or COPD, while were more likely to have asthma diagnosed by a physician and most had suffered respiratory diseases in their childhood.

FUTURE RESEARCH DIRECTIONS

In conclusion, more than one-third of patients with COPD in China have never smoked and over 60% of the population are nonsmokers. Indoor air pollution resulting from solid fuel and ETS, outdoor air pollution, occupational exposures, and so on are important risk factors for COPD development. However, up to now, information available on nonsmoking COPD in China is very limited. Further investigations are required to elucidate the involved factors and their shared contributions to COPD to achieve better estimation and reduction of the burden of nonsmoking COPD in different countries. Further investigations should also help to address the similarities and differences between smoking and nonsmoking COPD in clinic features including phenotypes, radiographic features, prognostic, and comorbidities. Of course, more efforts should be taken to explore the underlying cellular and molecular mechanisms regarding the pathogenesis and development of smoking and nonsmoking COPD, which could provide useful information for the treatment of smoking COPD and nonsmoking COPD. Furthermore, we need to adopt health policy measures and reduce the burden of nonsmoking COPD.

Disclosure: The authors declare no conflict of interest.

Funding: The study was funded by Chinese central government key research projects of the 10^th National Five-year Development Plan grant 2001BA703B03(A) (Dr. P. Ran) and in part by Guangdong Key Research Project grant B30301 (Dr. P. Ran).

REFERENCES

1. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532–555.
2. Anderson D, Ferris BG Jr. Role of tobacco smoking in the causation of chronic respiratory disease. N Engl J Med. 1962;267:787–794.
3. Mannino DM. Looking beyond the cigarette in COPD. Chest. 2008; 133:333–334.
4. Fukuchi Y, Nishimura M, Ichinose M, et al. COPD in Japan: the Nippon COPD epidemiology study. Respirology. 2004;9:458–465.
5. Ezzati M, Kammen DM. Indoor air pollution from biomass combustion and acute respiratory infections in Kenya: an exposure-response study. Lancet. 2001;358:619–624.
6. Menezes AM, Perez-Padilla R, Jardim JR, et al. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet. 2005;366:1875–1881.
7. Ekici A, Ekici M, Kurtipek E, et al. Obstructive airway diseases in women exposed to biomass smoke. Environ Res. 2005;99:93–98.
8. Whittemore AS, Perlin SA, DiCiccio Y. Chronic obstructive pulmonary disease in lifelong nonsmokers: results from NHANES. Am J Public Health. 1995;85:702–706.
9. Celli BR, Halbert RJ, Nordyke RJ, Schau B. Airway obstruction in never smokers: results from the Third National Health and Nutrition Examination Survey. Am J Med. 2005;118:1364–1372.
10. Kim DS, Kim YS, Jung KS, et al. Prevalence of chronic obstructive pulmonary disease in Korea: a population based spirometry survey. Am J Respir Crit Care Med. 2005;172:842–847.
11. Zhou Y, Wang C, Yao W, et al. COPD in Chinese nonsmokers. Eur Respir J. 2009;33:509–518.
12. Caballero A, Torres-Duque CA, Jaramillo C, et al. Prevalence of COPD in five Colombian cities situated at low, medium, and high altitude (PREPOCOL study). Chest. 2008;133:343–349.
13. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in nonsmokers. Lancet. 2009;374:733–743.
14. Ehrlich RI, White N, Norman R, et al. Predictors of chronic bronchitis in South African adults. Int J Tuberc Lung Dis. 2004;8:369–376.
15. Cerveri I, Accordini S, Verlato G, et al. European Community Respiratory Health Survey (ECRHS) Study Group. Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults. Eur Respir J. 2001;18:85–89.
16. Lindberg A, Jonsson A-C, Ronmark E, et al. Prevalence of chronic obstructive pulmonary disease according to BTS, ERS, GOLD and ATS criteria in relation to doctor’s diagnosis, symptoms, age, gender, and smoking habits. Respiration. 2005;72:471–479.
17. von Hertzen L, Reunanen A, Impivaara O, et al. Airway obstruction in relation to symptoms in chronic respiratory disease—a nationally representative population study. Respir Med. 2000;94:356–363.
18. Birring SS, Brightling CE, Bradding P, et al. Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study. Am J Respir Crit Care Med. 2002;166: 1078-1083.
19. Pen˜a VS, Miravitlles M, Gabriel R, et al. Geographic variations in prevalence and underdiagnosis of COPD: results of the IBERPOC multicentre epidemiological study. Chest. 2000;118:981–989.
20. Regional COPD Working Group. COPD prevalence in 12 Asia-Pacific countries and regions: projections based on the COPD prevalence estimation model. Respirology. 2003;8:192–198.
21. Liu S, Zhou Y, Wang X, et al. Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural south China. Thorax. 2007;62:889–897.
22. Smith KR. Indoor air pollution in developing countries: recommendations for research. Indoor Air. 2002;12:198–207.
23. Bruce N, Perez-Padilla R, Albalak R. Indoor air pollution in developing countries: a major environmental and public health challenge. Bull World Health Organ. 2000;78:1078–1092.
24. Ezzati M, Kammen DM. The health impacts of exposure to indoor air pollution from solid fuels in developing countries: knowledge, gaps, and data needs. Environ Health Perspect. 2002;110:1057–1068.
25. Desai MA, Mehta S, Smith KR. Indoor Smoke from Solid Fuels: Assessing the Environmental Burden of Disease at National and Local Levels. Geneva: World Health Organization; 2004. (WHO Environmental Burden of Disease Series, No. 4) 26. Torres-Duque C, Maldonado D, Pérez-Padilla R, et al.; Forum of International Respiratory Studies (FIRS) Task Force on Health Effects of Biomass Exposure. Biomass fuels and respiratory diseases: a review of the evidence. Proc Am Thorac Soc. 2008;5:577–590.
27. Mestl HE, Aunan K, Seip HM, et al. Urban and rural exposure to indoor air pollution from domestic biomass and coal burning across China. Sci Total Environ. 2007;377:12–26.
28. Sood A, Petersen H, Blanchette C, et al. Wood smoke-associated chronic obstructive pulmonary disease (COPD)—underappreciated in the United States? Am J Respir Crit Care Med. 2009;179:A4742.
29. Liu Y, Lee K, Perez-Padilla R, et al. Outdoor and indoor air pollution and COPD-related diseases in high- and low-income countries. Int J Tuberc Lung Dis. 2008;12:115–127.
30. Fullerton DG, Bruce N, Gordon SB. Indoor air pollution from biomass fuel smoke is a major health concern in the developing world. Trans R Soc Trop Med Hyg. 2008;102:843–851.
31. Ekici A, Ekici M, Kurtipek E, et al. Obstructive airway diseases in women exposed to biomass smoke. Environ Res. 2005;99:93–98.
32. Ran PX, Wang C, Yao WZ, et al. The risk factors for chronic obstructive pulmonary disease in women in Chinese rural areas. Zhonghua Nei Ke Za Zhi. 2006;45:974–979.
33. Sezer H, Akkurt I, Guler N, et al. A case-control study on the effect of exposure to different substances on the development of COPD. Ann Epidemiol. 2006;16:59–62.
34. Po JYT, Shahidi N, Fitzgerald J, et al. Respiratory disease associated with solid biomass fuel exposure in rural women and children: a systematic review and meta-analysis. Am J Respir Crit Care Med. 2009;179:A4740.
35. Hu G, Zhou Y, Tian J, et al. Risk of COPD from exposure to biomass smoke: a metaanalysis. Chest. 2010;138:20–31.
36. Kurmi OP, Semple S, Simkhada P, et al. COPD and chronic bronchitis risk of indoor air pollution from solid fuel: a systematic review and metaanalysis. Thorax. 2010;65:221–228.
37. Chapman RS, He X, Blair AE, et al. Improvement in household stoves and risk of chronic obstructive pulmonary disease in Xuanwei, China: retrospective cohort study. BMJ. 2005;331:1050–1055.
38. Smith-Sivertsen T, Diaz E, Pope D, et al. Effect of reducing indoor air pollution on women’s respiratory symptoms and lung function: the RESPIRE randomized trial, Guatemala. Am J Epidemiol. 2009;170:211–220.
39. Romieu I, Riojas-Rodriguez H, Marron-Mares AT, et al. Improved biomass stove intervention in rural Mexico: impact on the respiratory health of women. Am J Respir Crit Care Med. 2009;180:649–656.
40. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global Burden of Disease and Risk Factors. Washington, DC: World Bank Publications; 2006.
41. World Health Organization. The World Health Report 2002: Reducing Risks, Promoting Healthy Life. Geneva: World Health Organization; 2002.
42. Gu D, Wu X, Reynolds K, et al. Cigarette smoking and exposure to environmental tobacco smoke in China: the international collaborative study of cardiovascular disease in Asia. Am J Public Health. 2004;94: 1972–1976.
43. Yin P, Jiang CQ, Cheng KK, et al. Passive smoking exposure and risk of COPD among adults in China: the Guangzhou Biobank Cohort Study. Lancet. 2007;370:751–757.
44. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan. BMJ. 1981;282:183–185.
45. Kurukulaaratchy RJ, Matthews S, Arshad SH. Does environment mediate the earlier onset of the persistent childhood asthma phenotype? Pediatrics. 2004;113:345–350.
46. David GL, Koh WP, Lee HP, et al. Childhood exposure to environmental tobacco smoke and chronic respiratory symptoms in non-smoking adults: the Singapore Chinese Health Study. Thorax. 2005;60:1052–1058.
47. Svanes C, Omenaas E, Jarvis D, et al. Parental smoking in childhood and adult obstructive lung disease: results from the European Community Respiratory Health Survey. Thorax. 2004;59:295–302.
48. Janson C, Chinn S, Jarvis D, et al. Effect of passive smoking on respiratory symptoms, bronchial responsiveness, lung function, and total serum IgE in the European Community Respiratory Health Survey: a cross-sectional study. Lancet. 2001;358:2103–2109.
49. Chen R, Tunstall-Pedoe H, Tavendale R. Environmental tobacco smoke and lung function in employees who never smoked: the Scottish MONICA study. Occup Environ Med. 2001;58:563–568.
50. Gerbase MW, Schindler C, Zellweger JP, et al. Respiratory effects of environmental tobacco exposure are enhanced by bronchial hyperreactivity. Am J Respir Crit Care Med. 2006;174:1125–1131.
51. Eisner MD, Iribarren C, Yelin EH, et al. The impact of SHS exposure on health status and exacerbations among patients with COPD. Int J Chron Obstruct Pulmon Dis. 2009;4:169–176.
52. Law MR, Hackshaw AK. Environmental tobacco smoke. Br Med Bull. 1996;52:22–34.
53. Radon K, Büsching K, Heinrich J, et al. Passive smoking exposure: a risk factor for chronic bronchitis and asthma in adults? Chest. 2002;122: 1086–1090.
54. Evans J, Chen Y. The association between home and vehicle environmental tobacco smoke (ETS) and chronic bronchitis in a Canadian population: the Canadian Community Health Survey, 2005. Inhal Toxicol. 2009;21:244–249.
55. Lam TH, Ho LM, Hedley AJ, et al. Environmental tobacco smoke exposure among police officers in Hong Kong. JAMA. 2000;284:756–763.
56. Zhang Hong, Cai Baiqiang. The impact of tobacco on lung health in China. Respirology. 2003;8:17–21.
57. Jaakkola MS, Jaakkola JJ. Effects of environmental tobacco smoke on the respiratory health of adults. Scand J Work Environ Health. 2002;28 (suppl 2):52–70.
58. Eisner MD. Environmental tobacco smoke exposure and pulmonary function among adults in NHANES III: impact on the general population and adults with current asthma. Environ Health Perspect. 2002;110:765–770.
59. Fidan F, Cimrin AH, Ergor G, et al. Airway disease risk from environmental tobacco smoke among coffeehouse workers in Turkey. Tob Control. 2004;13:161–166.
60. Jindal SK, Aggarwal AN, Chaudhry K, et al.; Asthma Epidemiology Study Group. A multicentric study on epidemiology of chronic obstructive pulmonary disease and its relationship with tobacco smoking and environmental tobacco smoke exposure. Indian J Chest Dis Allied Sci. 2006;48:23–29.
61. Yang G, Ma J, Chen A, et al. Smoking cessation in China: findings from the 1996 national prevalence survey. Tob Control. 2001;10:170–174.
62. Chester EH, Gillespie DG, Krause FD. The prevalence of chronic obstructive pulmonary disease in chlorine gas workers. Am Rev Respir Dis. 1969;99:365–373.
63. Husman K, Koskenvuo M, Kaprio J, Terho EO. Vohlonen I. Role of environment in the development of chronic bronchitis. Eur J Respir Dis Suppl. 1987;152:57–63.
64. Becklake MR. Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1989;140:S85–S91.
65. Eduard W, Pearce N, Douwes J. Chronic bronchitis, COPD, and lung function in farmers: the role of biological agents. Chest. 2009;136: 716–725.
66. Weinmann S, Vollmer WM, Breen V, et al. COPD and occupational exposures: a case-control study. J Occup Environ Med. 2008;50:561–569.
67. Zhong N, Wang C, Yao W, et al. Prevalence of chronic obstructive pulmonary disease in China: a large, population-based survey. Am J Respir Crit Care Med. 2007;176:753–760.
68. Zhou Y, Wang C, Yao W, et al. Occupational Exposure to Dusts/Gases/ Fumes Is Contributed to Chronic Obstructive Pulmonary Disease and Respiratory Symptoms. Chin J Respir Crit Care Med. 2009;8:6–11.
69. Sunyer J. Urban air pollution and chronic obstructive pulmonary disease: a review. Eur Respir J. 2001;17:1024–1033.
70. Arbex MA, de Souza Conceic¸a˜o GM, Cendon SP, et al. Urban air pollution and chronic obstructive pulmonary disease-related emergency department visits. J Epidemiol Community Health. 2009;63:777–783.
71. Zhou Y, Hu G, Wang D, et al. Community based integrated intervention for prevention and management of chronic obstructive pulmonary disease (COPD) in Guangdong, China: cluster randomised controlled trial. BMJ. 2010;341:c6387.
72. Kojima S, Sakakibara H, Motani S, et al. Effects of smoking and age on chronic obstructive pulmonary disease in Japan. J Epidemiol. 2005;15: 113–117.
73. Wilson D, Adams R, Appleton S, et al. Difficulties identifying and targeting COPD and population-attributable risk of smoking for COPD: a population study. Chest. 2005;128:2035–2042.
74. Celli BR, Halbert RJ, Isonaka S, Schau B. Population impact of different definitions of airway obstruction. Eur Respir J. 2003;22:268–273.
75. Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet. 2007;370:741–750.
76. Chen Y, Breithaupt K, Muhajarine N. Occurrence of chronic obstructive pulmonary disease among Canadians and sex-related risk factors. J Clin Epidemiol. 2000;53:755–761.
77. Han MK, Postma D, Mannino DM, et al. Gender and chronic obstructive pulmonary disease: why it matters. Am J Respir Crit Care Med. 2007;176:1179–1184.
78. Edwards CA, Osman LM, Godden DJ, Douglas JG. Wheezy bronchitis in childhood: a distinct clinical entity with lifelong significance? Chest. 2003;124:18–24.
79. Guerra S, Sherrill DL, Bobadilla A, et al. The relation of body mass index to asthma, chronic bronchitis, and emphysema. Chest. 2002;122: 1256–1263.
80. Harik-Khan RI, Fleg JL, Wise RA. Body mass index and the risk of COPD. Chest. 2002;121:370–376.
81. Lechner AJ. Perinatal age determines the severity of retarded lung development induced by starvation. Am Rev Respir Dis. 1985;131:638–643.
82. Donahoe M, Rogers RM, Wilson DO, et al. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1989;140:385–391.
83. Creutzberg EC, Schols AM, Bothmer-Quaedvleig FC, et al. Prevalence of an elevated resting energy expenditure in patients with chronic obstructive pulmonary disease in relation to body composition and lung function. Eur J Clin Nutr. 1998;52:396–401.
84. Lange P, Parner J, Vestbo J, et al. A 15-year followup study of ventilatory function in adults with asthma. N Engl J Med. 1998;339:1194–1200.
85. Silva GE, Sherrill DL, Guerra S, et al. Asthma as a risk factor for COPD in a longitudinal study. Chest. 2004;126:59–65.
86. Vignola AM, Kips J, Bousquet J. Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol. 2000;105(pt 1):1041–1053.
87. Lancaster JF, Tomashefski JF. Tuberculosis: a cause of emphysema. Am Rev Respir Dis. 1963;87:435–457.
88. Birath G, Caro J, Malmberg R, et al. Airways obstruction in pulmonary tuberculosis. Scand J Respir Dis. 1966;47:27–36.
89. Snider GL, Doctor L, Demas TA, et al. Obstructive airway disease in patients with treated pulmonary tuberculosis. Am Rev Respir Dis. 1971;103:625–640.
90. Plit ML, Anderson R, Van Rensburg CE, et al. Influence of antimicrobial chemotherapy on spirometric parameters and pro-inflammatory indices in severe pulmonary tuberculosis. Eur Respir J. 1998;12:351–356.
91. Avino P, De Lisio V, Grassi M, et al. Influence of air pollution on chronic obstructive respiratory diseases: comparison between city (Rome) and hill country environments and climates. Ann Chim. 2004;94:629–635.
92. Shavelle RM, Paculdo DR, Kush SJ, et al. Life expectancy and years of life lost in chronic obstructive pulmonary disease: findings from the NHANES III follow-up study. Int J Chron Obstruct Pulmon Dis. 2009;4:137–148.
93. Moran-Mendoza O, Perez-Padilla JR, Salazar-Flores M, et al. Wood smoke-associated lung disease: a clinical, functional, radiological and pathological description. Int J Tuberc Lung Dis. 2008;12:1092–1098.
94. Ozbay B, Uzun K, Arslan H, et al. Functional and radiological impairment in women highly exposed to indoor biomass fuels. Respirology. 2001;6:255–258.
95. Ramý´rez-Venegas A, Sansores RH, Pérez-Padilla R, et al. Survival of patients with chronic obstructive pulmonary disease due to biomass smoke and tobacco. Am J Respir Crit Care Med. 2006;173:393–397.

Pneumomediastinum is a radiologic finding identified as the presence of air spreading through the tissue planes inside the mediastinum. It was originally reported by Laennec in 1819 and was at first discovered as a result of thoracic trauma ¹. Pneumomedistinum, in its classical form, results from a laceration of the esophagus or the tracheobronchial structures and portends a poor prognosis, especially if a delay in diagnosis occurs; therefore, it is commonly viewed by the medical community as an ominous finding suspicious for the disruption of the upper aerodigestive or tracheobronchial systems.

The presence of pneumomediastinum can be clustered in two major categories: primary (also referred to as spontaneous pneumomediastinum) and secondary pneumomediastinum. Spontaneous pneumomediastinum commonly occurs from a sudden increase in the intrathoracic pressure, which subsequently leads to the leakage of tracheobronchial air into the pulmonary interstitium and further migration into the mediastinum. This condition is commonly associated with episodes of emesis, persistent cough, asthma exacerbation, excessive physical activity, drug inhalation, defecation, and so on, or may frequently be unrelated to any specific triggering event. These definitions are in agreement with prior case series reported ^2–12. In contrast, secondary pneumomediastinum results from a specific injury or pathology such as blunt thoracic trauma ¹³, high-pressure mechanical ventilation ¹⁴, intrathoracic infections—especially pneumocystis carinii pneumonia (PCP) ¹⁵, cavitary pulmonary disease ¹⁶, surgical procedures, and esophageal or tracheobronchial disruptions ¹⁷. Furthermore, patients with primary or secondary pneumomediastinum commonly present with a negative plain radiograph (CXR) and a positive computed tomogram (CT scan) of the chest. This group of patients, commonly referred to as CXR-occult-pneumomediastinum, has progressively increased in recent years due to the widespread use of computed tomography.

This report presents a systematic review of the etiologies, radiographic presentations, associated pathologies, risk factors, and outcomes of patients with secondary pneumomediastinum and reviews the relevance for the presence of CXR-occult pneumomediastinum.

SECONDARY PNEUMOMEDIASTINUM

Secondary pneumomediastinum results primarily from two major conditions: blunt thoracic trauma and ventilator-induced pulmonary barotrauma. Pneumocystis carinii infections, an opportunistic infection that has become prevalent following the identification of the human immunodeficiency virus (HIV), has also emerged as an underlying etiology of pneumomediastinum. Patients with this infection frequently develop cystic pulmonary lesions and interstitial pulmonary emphysema that progressively extend into the formation of a pneumothorax, pneumomediastinum, or both, especially in the setting of respiratory failure requiring mechanical ventilation ¹⁸.

Blunt thoracic trauma

Pneumomediastinum in the presence or absence of pneumothorax may occur in up to 10% of patients suffering from severe blunt thoracic trauma ¹⁹. In the majority of cases it follows a benign course and commonly results from the extension of a pneumothorax through a pleural disruption, the central migration of air from a peripheral intraparenchymal leak, or a clinically silent esophageal microperforation. Despite the benign course of this finding, there is a small but objective occurrence of injuries to the tracheobronchial tree and, rarely, the upper aerodigestive systems. This finding is likely to increase with the recent widespread use of routine CT scanning in trauma patients; hence, there is discrepancy regarding its significance and the need for further testing to confirm the integrity of the larynx, trachea, bronchi, and esophagus.

We found only one descriptive study addressing the relevance of pneumomediastinum in the setting of blunt thoracic trauma. Dissanaike reported on 136 patients with pneumomediastinum identified on a CT scan following blunt thoracic trauma. In this report, pneumomediastinum was also detected on a CXR in only 15% of the patients. The overall mortality in this study was 3% ¹³.

Wintermark reported on 51 cases of pneumomediastinum following blunt thoracic trauma and found five tracheobronchial injuries (10%) and no esophageal injuries. The majority of cases resulted from alveolar disruption and dissection along the bronchovascular sheaths with subsequent migration of air into the mediastinum. Five patients presented with tracheobronchial injuries and the mortality rate in the entire group was 11%. This study was not designed to evaluate the importance of pneumomediastinum in the setting of severe blunt thoracic trauma ²⁰.

In a previous report of secondary pneumomediastinum we compared the two major responsible etiologies for this condition, blunt thoracic trauma and ventilator-induced barotrauma. The CXR-occult pneumomediastinum was preferentially seen following blunt thoracic trauma, as compared to patients developing ventilator-induced pneumomediastinum (83% vs 19%, P<.001). The mortality rates were also significantly different: 6% vs 81%, respectively (P<.001) ²¹.

Pneumomediastinum in the setting of blunt thoracic trauma is commonly benign and has a low mortality. Tracheobronchial injuries are infrequent and esophageal injuries are rarely seen. The CT scan assessment has a very high sensitivity and missed injuries are nil in large series reported; thus, the use of contrast esophagram, esophagoscopy, and bronchoscopy should be individualized and restricted to patients with a high radiologic suspicion of esophageal or tracheobronchial injuries, without compromising the welfare of the patients. The CT scan of the chest is the gold standard to detect mediastinal air and CXR has a very low sensitivity in this patient population, thus, presenting with a high rate of CXR-occult pneumomediastinum. In contrast, CXR has a high sensitivity to detect mediastinal air in ventilator-induced pneumomediastinum, thus, the presence of CXR-occult pneumomediastinum is considerably less predominant.

Ventilator-induced pneumomediastinum

There are no studies specifically reporting on the independent significance of pneumomediastinum in the setting of ventilator-induced pulmonary barotrauma. The few reports in the literature only describe a mixed series of patients with ventilator-induced pulmonary barotrauma and cluster subcutaneous emphysema, pneumothorax, and pneumomediastinum under this category ^{14 22–26} . Several reports have associated positive-pressure ventilation—with or without positive end expiratory pressure (PEEP)—with pulmonary barotrauma. The rates reported a range from 4% to 18% ²². Downs reported the presence of pneumothorax in 7%, pneumomediastinum in 35%, and subcutaneous emphysema in 39% of patients requiring positive end expiratory pressures greater than 20 torr ²⁷.

Gammon studied 139 patients on mechanical ventilation and analyzed the risk factors and radiographic patterns associated with ventilator-induced barotrauma. Pneumomediastinum occurred in 21% and pneumothorax in 14%. The highest rate of pulmonary barotrauma was seen in patients with adult respiratory distress syndrome (ARDS) and an intermediate risk was seen in patients with COPD and pneumonia. Pneumomediastinum and pneumothorax developed in 62% and 38% of patients with ARDS, in contrast with 6% and 8% in patients without ARDS, respectively (P<.05). The presence of either pneumothorax or pneumomediastinum carried an increased risk of mortality: 55% for pneumomediastinum and 65% for pneumothorax. These elevated rates may be confounded by the frequent occurrence of ARDS—over 60%—in patients who develop pulmonary barotrauma. According to this report, patients developing pulmonary barotrauma carried a higher mortality in the non-ARDS but not in the ARDS population ¹⁴.

The presence of pneumomediastinum in the setting of mechanical ventilation is a marker for a higher mortality; however, it may have a variable prognostic value in the setting of different underlying conditions. The high prevalence of ARDS and the high severity of illness may be confounding variables for this higher mortality. There are no reports in the literature that adjust outcomes according to the severity of illness to determine the independent significance of pneumomediastinum in patients on mechanical ventilation.

CXR-occult pneumomediastinum

The widespread use of CT scans of the chest is expected to increase the detection of pneumomediastinum not evident on a CXR. The significance of this finding is unclear and evidence in the literature is lacking in this regard.

We studied 69 patients with pneumomediastinum and found CXR-positive pneumomediastinum in 56% and CXR-occult pneumomediastinum in 44%. Both groups were compared for age, gender, etiology, subcutaneous emphysema, pneumothorax, pleural effusion, thoracostomy tube placement, mortality, and length of hospital stay. There was significantly less subcutaneous emphysema (P<.05) and a nearly significant lower mortality in the population with CXR-occult pneumomediastinum (13% vs 33%, P=.056). The presence of mediastinal air in both radiologic tests (CXR-positive pneumomediastinum) may appear to suggest a higher severity of illness with an increased mortality; however, as reported above, the sensitivity of CXR is lower to detect pneumomediastinum following blunt thoracic trauma as opposed to ventilator-induced barotrauma (17% vs 75%). This differential sensitivity translates into the clustering of the lower mortality blunt thoracic trauma patients primarily in the CXR-occult pneumomediastinum group, and the higher mortality ventilator-induced barotrauma patients in the CXR-positive group (P<.05, data unpublished). We believe this preferential distribution of etiologies into CXR-positive or CXR-occult pneumomediastinum reflects on a lower mortality rate in the latter group, since trauma patients are commonly younger and have a more favorable physical condition as compared to patients on respiratory failure. To determine more precisely the significance of CXR-occult pneumomediastinum, a difference in outcomes needs to be analyzed by conducting this comparison within each responsible etiology; unfortunately, the low frequency of this occurrence does not allow accruing a patient sample with adequate power for this analysis.

In summary, pneumomediastinum is a radiologic finding that can develop as a result of a variety of etiologies. With the widespread use of computed tomography, CXR-occult pneumomediastinum has progressively increased. The CXR-occult pneumomediastinum primarily comprises patients suffering from spontaneous pneumomediastinum or following blunt thoracic trauma, both conditions with a more favorable prognosis. The primary determinant of outcomes appears to be the underlying etiology and not the radiologic findings.

CONCLUSIONS

Pneumomediastinum is an unusual finding in daily practice commonly viewed by the medical community as a potentially ominous radiographic sign. Unlike spontaneous pneumomediastinum, secondary pneumomediastinum has a defined responsible etiology and can result from a variety of conditions, including in decreasing frequency, severe blunt thoracic trauma, ventilator-induced pulmonary barotrauma, pulmonary cavitary lesions, surgical interventions, esophageal perforations, and PCP among others. Blunt thoracic trauma carries a distinctly more favorable prognosis as compared to patients suffering from ventilator-induced pneumomediastinum. The CXR-occult pneumomediastinum is preferentially seen following blunt thoracic trauma. Ventilator-induced barotrauma commonly presents as CXR-positive pneumomediastinum. Secondary pneumomediastinum could merely be a marker of a higher severity of disease or could be directly related with a less favorable outcome. The infrequent occurrence of this finding makes it difficult to design studies with adequate power to determine the independent prognostic value of the presence of pneumomediastinum in a variety of etiologies.

Disclosure: Dr. Manuel Caceres is the principal investigator for this report.

REFERENCES

1. Laennec RTH. A Treatise on Diseases of the Chest and On Mediate Auscultation. 2nd ed. Translated by John Forbes. London: T and G Underwood; 1827.
2. Caceres M, Ali SZ, Braud R, Weiman D, Garrett HE. Spontaneous pneumomediastinum: a comparative study and review of the literature. Ann Thorac Surg. 2008;86:962–966.
3. Mondello B, Pavia R, Ruggeri P, Barone M, Barresi P, Monaco M. Spontaneous pneumomediastinum: experience in 18 adult patients. Lung. 2007;185:9–14.
4. Campillo-Soto A, Coll-Salinas A, Soria-Aledo V, et al. Spontaneous pneumomediastinum: descriptive study of our experience with 36 cases. Arch Bronconeumol. 2005;41:528–531.
5. Newcomb AE, Clarke CP. Spontaneous pneumomediastinum: a benign curiosity or a significant problem? Chest. 2005;128:3298–3302.
6. Koullias GJ, Korkolis DP, Wang XJ, Hammond GL. Current assessment and management of spontaneous pneumomediastinum: experience in 24 adult patients. Eur J Cardiothorac Surg. 2004;25:852–855.
7. Miura H, Taira O, Hiraguri S, Ohtani K, Kato H. Clinical features of medical pneumomediastinum. Ann Thorac Cardiovasc Surg. 2003;9:188–191.
8. Jougon JB, Ballester M, Delcambre F, Mac Bride T, Dromer CE, Velly JF. Assessment of spontaneous pneumomediastinum: experience with 12 patients. Ann Thorac Surg. 2003;75:1711–1714.
9. Abolnik I, Lossos IS, Breuer R. Spontaneous pneumomediastinum. A report of 25 cases. Chest. 1991;100:93–95.
10. Yellin A, Gapany-Gapanavicius M, Lieberman Y. Spontaneous pneumomediastinum: is it a rare cause of chest pain? Thorax. 1983;38:383–385.
11. Halperin AK, Deichmann RE. Spontaneous pneumomediastinum: a report of 10 cases and review of the literature. NCMJ. 1985;46:21–23.
12. Vidal MF, Gonzalez OJ, Nualart BL, et al. Spontaneous pneumomediastinum in the adult. Presentation of 13 cases and review of the literature. Med Clin. 1984;82:797–802.
13. Dissanaike S, Shalhub S, Jurkovich GJ. The evaluation of pneumomediastinum in blunt trauma patients. J Trauma. 2008;65:1340–1345.
14. Gammon RB, Shin MS, Buchalter SE. Pulmonary barotrauma in mechanical ventilation. Patterns and risk factors. Chest. 1992;102: 568–572.
15. Moss S, Carey PB, Hind CR. Pneumocystis carinii pneumonia presenting with pneumomediastinum in an HIV-positive patient. Postgrad Med J. 1995;71:96–97.
16. Qureshi SA. Spontaneous pneumomediastinum associated with pulmonary cavitation. Postgrad Med J. 1980;56:48–49.
17. Huh J, Milliken JC, Chen JC. Management of tracheobronchial injuries following blunt and penetrating trauma. Am Surg. 1997;63:896–899.
18. Rumbak MJ, Winer-Muram HT, Beals DH, Fry P. Tension pneumomediastinum complicating pneumocystis carinii pneumonia in acquired immunodeficiency syndrome. Crit Care Med. 1992;20:1492–1494.
19. Bejvan SM, Godwin JD. Pneumomediastinum: old signs and new signs. Am J Roentgenol. 1996;166:1041–1048.
20. Wintermark M, Schnyder P. The Macklin effect: a frequent etiology for pneumomediastinum in severe blunt chest trauma. Chest. 2001;120: 543–547.
21. Caceres M, Braud RL, Maekawa R, Weiman DS, Garrett HE Jr. Secondary pneumomediastinum: a retrospective comparative analysis. Lung. 2009;187:341–346.
22. Cullen DJ, Caldera DL. The incidence of ventilator-induced pulmonary barotrauma in critically ill patients. Anesthesiology. 1979;50:185–190.
23. De Latorre FJ, Tomasa A, Klamburg J, Leon C, Soler M, Rius J. Incidence of pneumothorax and pneumomediastinum in patients with aspiration pneumonia requiring ventilatory support. Chest. 1977;72:141–144.
24. Johnson TH, Altman AR. Pulmonary interstitial gas: first sign of barotrauma due to PEEP therapy. Crit Care Med. 1979;7:532–535.
25. Petersen GW, Baier H. Incidence of pulmonary barotrauma in a medical ICU. Crit Care Med. 1983;11:67–69.
26. Reines HD. Manifestations of barotrauma in acute respiratory failure. Am Surg. 1981;47:421–425.
27. Downs JB, Chapman RL. Treatment of bronchopleural fistula during continuous positive pressure ventilation. Chest. 1976;63:363–366.

Immunotherapy has gained worldwide acceptance as a treatment option for allergic diseases since it was first introduced in 1911.¹ The initial route of administration of immunotherapy was via the subcutaneous route (SCIT). In the past century other modes of administration have been investigated to improve patient safety and comfort. Oral immunotherapy was first proposed in the early 1900s.² During the 1950s, local bronchial desensitization was suggested and investigated,^{4, 5} whereas sublingual immunotherapy (SLIT) appeared in 1986.⁶ That same year 26 deaths caused by SCIT were reported by the British Committee for the Safety of Medicines⁷ and raised serious concerns about the safety and the risk-benefit ratio of SCIT. This prompted the search for safer and more convenient modalities of immunotherapy.

Since 1990 when Tari et al¹⁰ published the first randomized controlled study results including pediatric patients, multiple double-blind, placebo-controlled trials have been undertaken. In 2001 the Allergic Rhinitis and its Impact on Asthma (ARIA) position paper accepted the use of SLIT in adults and children as a valid alternative to SCIT¹¹ and this was confirmed by the ARIA update in 2008.¹²

In 2009 the World Allergy Organization (WAO) published a position paper with goals to advise global constituents on the current State of the Art on SLIT, to offer consensus on its use based on currently available evidence and expert opinion and to develop practice parameters. Unmet needs were identified by analysis of recent and ongoing SLIT clinical trials, then recommendations for further studies needed, and suggestions for the appropriate methodology to conduct them were offered.¹³ In this position paper, indications, contraindications, risks, and benefits of SLIT were clearly stated, and SLIT was affirmed as an effective treatment.

To date more than 70 double-blind placebo-controlled trials have been published, in addition to postmarketing surveillance studies and meta-analyses. In July 2010, the WAO published a position paper to identify the indications, contraindications, and practical aspects of the treatment.¹⁴

There are still several aspects of SLIT that remain to be further investigated such as optimal dose, duration of treatment, the long-lasting effect, the preventive action, and the exact mechanisms of action (Fig. 1).

DEFINITION

Allergen-specific immunotherapy (SIT), or allergen vaccination is the practice of administering increasing amounts of allergen(s) (the allergenic extract or vaccine) to allergic subjects in order to achieve hyposensitization, which is to reduce the symptoms occurring during the natural exposure to the allergen(s) itself.

In SLIT, the allergen extract (prepared as drops or tablets) is kept under the tongue for 1–2 minutes and then swallowed: thus this route is also called sublingual-swallow, although some investigators have also used the sublingual-spit modality.¹³

INDICATIONS

High-dose SLIT may be indicated in the following cases:

• Selected patients with rhinitis, conjunctivitis, and/or asthma caused by allergy to pollens or house dust mites.

• Patients who are inadequately controlled with conventional pharmacotherapy.

• Patients who have had systemic reactions during specific immunotherapy by injection.

• Patients who have compliance problems with or refuse immunotherapy by injection.^{12, 15, 16}

Sublingual immunotherapy has been shown to be effective for allergic rhinitis due to both seasonal and perennial allergens in adults and children.¹⁷ In addition, it can potentially modify the disease and the clinical benefits may be sustained years after discontinuation of treatment. The SLIT is effective in allergic rhinitis in children older than 5 years and may be safe in allergic rhinitis in children older than 3 years. This is supported by four meta-analyses ^18–21 and further by five large recent phase III trials. ^22–27 Whether SLIT would be safe to use in children younger than 3 years of age has been assessed by two observational and one post-marketing survey SLIT studies. ^28–30 One study involved the use of monomeric allergoid SLIT in children 23 months to 46 months with intermittent or mild persistent asthma or persistent rhinitis. Two cases of adverse events were reported, both abdominal.²⁸

Another study involving children aged 38–80 months treated with SLIT to pollens and house dust mite also reported the incidence of adverse events, urticaria, gastrointestinal, and orolabial itch.²⁹

The postmarketing survey assessed 126 children aged 3 to 5 years with allergic rhinitis and/or asthma that were treated with SLIT to various allergens. Nine adverse events were reported in seven children, two local with oral itching and seven systemic reactions in the form of abdominal pain and diarrhea. It should be noted that all of these events occurred during the induction phase.³⁰

With regards to asthma, the results have been conflicting. When asthmatic subjects with no active symptoms have been studied, little or no clinical effect of SLIT was found. ^31–33 When subjects with current asthma symptoms were studied, improvement from SLIT were seen.^{14 34–39}

Sublingual immunotherapy should be considered if asthma symptoms are persistent despite pharmacological and nonpharmacological measures, or when medications cause unacceptable side effects or patients refuse to use inhaled corticosteroid. The SLIT should only be considered if there is a clear connection between the patient's symptoms and exposure to a particular allergen. If the patient has severe/uncontrolled asthma, SLIT is a contraindication. Other indications for SLIT that still are on an experimental basis include latex allergy, food allergy, atopic dermatitis, and venom allergy.^{40, 41} Most of the studies that have been done so far have mainly addressed the use of monotherapy SLIT, or occasionally the use of two allergens. This is in contrast to the US practice of SCIT where multiple allergens are typically mixed and used together. Two postmarketing surveys assessing the incidence of adverse events in multiple allergen SLIT failed to show a significant increase in adverse events if the treatment is correctly prescribed and standardized extracts are used.^{42, 43} There are a few isolated case reports of anaphylaxis from multiple allergen SLIT.^{44, 45} It should be noted that in both of these cases more than five different allergens were used, which is not standard of care in Europe. Further studies are needed to address what should be the optimal number of allergens that can be mixed together and prove to be safe and effective.

DOSING ISSUES

Is SLIT dose-dependent? Two large trials conducted with grass pollen extracts did show that the efficacy of SLIT versus placebo ranged from 25% to 50% with the cutoff for efficacy being 20%.^{46, 47} They also showed that the efficacy was dose-dependent and that the optimal dose for grass SLIT was 30 times that of SCIT. The amount of allergen given during a course of SLIT is higher than in an equivalent SCIT; therefore, the treatment is often termed high-dose SLIT.⁴⁸

There are, however, challenges when evaluating the dose-dependent efficacy of SLIT. First of all, not all clinical trials that are available reveal the exact microgram of allergen that was used and, if they do, the amount has been empirically chosen (ie, not based on published dose-response studies). Also when comparing the dose ratio of SLIT/SCIT, the data you are faced with might not be reliable as the preparations are from different manufacturers.⁴⁹ The current recommendation of the minimum daily dose is approximately 5 micrograms per day.⁵⁰ There is still need for dose-ranging studies for all relevant allergens.

Regimens of administration are a debated aspect of SLIT. It has been given daily or every other day, but the differences in efficacy between these regimens have not been systematically studied. On the basis of convenience for the patient, a daily regimen has been suggested. Studies have shown that there does not need to be a build-up phase, as starting directly with maintenance has not been shown to pose a higher risk of adverse reactions. ^50–52 Pollen allergy poses another question with regards to dosing regimens. When should you start SLIT in regards to onset of pollen season? SLIT can be administered preseasonally (stop at the beginning of the season), precoseasonally (stop at the end of the season), or continuously. Precoseasonal schedules are commonly chosen for pollen allergy, whereas for perennial allergens continuous treatments are preferred (Table 1).

IMMUNOLOGIC EFFECTS

The goal of allergen-specific immunotherapy is to induce tolerance to allergens. ^53–58 Our knowledge of how this is achieved is better established in SCIT, which includes (1) changing the IgE/IgG ratio, with an increase of particularly IgG4 that acts as a blocking antibody, (2) involvement of regulatory T-cells, (3) release of inhibitory cytokines (IL-10 and TGFβ), and (4) skewing of cytokine profile in favor of TH1 responses.^{48 58–60}

The oral mucosa is exposed to various antigenic stimuli from the environment primarily from foods and bacterial colonization. Because of oral tolerance, the mucosa remains uninflamed.⁶¹

Dendritic cells (DCs) play a crucial role in responding to pathogens and triggering the adaptive immune system. In the oral mucosa the predominant DCs are the oral mucosal Langerhans cells (oLCs) located in the suprabasal epithelium layer, which constitutively express high affinity receptors for IgE (FcɛRI).⁶² During SLIT, the allergen is captured locally within the oral mucosa by these oCLs and they subsequently mature and migrate to local lymph nodes where the production of blocking IgG antibodies and induction of T-cells with suppressive function occur.^{63, 64} They also stimulate production of IL-10, TGFβ, and upregulate indoleamine 2 dioxygenase (IDO), which is a rate-limiting enzyme in the metabolism of tryptophan, resulting in decreased T-cell proliferation (Fig. 2).^{65, 66}

TREATMENT EFFECTS IN ALLERGIC RHINITIS (ADULTS AND CHILDREN) AND ALLERGIC ASTHMA

Sublingual immunotherapy is effective in treatment of allergic rhinitis, both in children and adults. This is based on the results from four meta-analyses ^18–21 and later confirmed by large phase III trials on SLIT in grass pollen allergic rhinitis. ^{22– 27} Quality of life has been shown to be improved based on symptom scores.^{27, 67}

Several controlled trials have assessed the use of SLIT in patients with asthma and have also observed a protective effect from development of bronchial symptoms.^{68, 69, 10, 70} Bousquet et al³⁴ demonstrated in their article from the late 1990s that SLIT with house dust mite (HDM) causes a reduction in asthma symptoms in adults and children proven to be sensitized to HDM. They also found an improvement in lung function parameters and overall quality of life.

The importance of utilizing immunotherapy in patients with respiratory allergies is twofold. First, it improves the patient's quality of life, and second, it has a protective effect on progression to asthma and the development of new sensitizations, which is especially true in children (Table 2).⁷¹

DATA ON SLIT TO PREVENT ASTHMA AND NEW SENSITIZATIONS

Allergic rhinitis is a risk factor for the development of asthma. Over 80% of asthmatics have rhinitis, and 10–40% of patients with rhinitis have asthma.⁷² It has also been observed that in patients with respiratory allergies new sensitizations develop over time.

Allergen specific immunotherapy may alter the natural history of respiratory allergy by preventing the onset of new sensitizations and/or reducing the risk of asthma onset. Studies investigating the use of SCIT in these type of patients have shown that immunotherapy will not only prevent the development of asthma, but will also have long-lasting beneficial effects after discontinuation of SCIT.^{73, 74} To date several studies have shown the ability of SLIT to prevent the onset of asthma and new sensitizations as well. ^75–77 A recent double-blind, placebo-controlled trial reported improvement of both clinical and immunological markers after treatment with SLIT tablets for a course of 3 years. In addition, the patients showed improvement up to 1 year after discontinuation of SLIT.⁷⁸ Additional studies have confirmed a long lasting effect with patients treated for 4 years showing sustained benefits for up to 15 years in one study.⁷⁷

EXPERIMENTAL USES OF SLIT

Sublingual immunotherapyhas been primarily approved for the treatment of allergic rhinoconjunctivitis and allergic asthma. SLIT has also been tried in several other allergic diseases including: venom hypersensitivity, atopic dermatitis, food allergy, and latex allergy.

Latex

There are two small double-blind, placebo-controlled studies about the use of SLIT in latex allergy that have shown benefit.^{79, 40} In the Nettis et al⁷⁹ study, a small group of subjects were enrolled to receive latex extract or placebo. The subjects were followed over 12 months and both the symptom scores and medication scores improved in all subjects. The SLIT group also had improved objective parameters including bronchial and glove provocation tests.

Food allergy

Currently there are no curative interventions for food allergy. The use of SLIT in food allergy has been looked at and there are some positive reports regarding the efficacy of oral immunotherapy and SLIT for various food allergies including egg, milk, hazelnut, and peanut.⁸¹ However, some authors suggest that SLIT is not ready for clinical practice in food allergies because of the potential for adverse reactions and side effects that have been seen with a high frequency in some studies. ^82–84 In addition, there are still many unanswered questions including appropriate dosing regimens, patient selection, and postdesensitization care.^{85, 86} Further studies are needed to address these issues in order for this treatment to be recommended for food allergy.

Atopic dermatitis

Atopic dermatitis is considered an allergic inflammatory disease. Therefore, it would seem rational that immunotherapy could be beneficial for some patients in whom a defined allergen has been demonstrated to be important. Patient with atopic dermatitis and sensitization to house dust mite have shown benefit from HDM SCIT in some studies.⁸⁷ One study by Pajno et al⁸⁸ demonstrated clinical benefit of SLIT when using standardized mite extract in children with mild–moderate allergic atopic dermatitis, whereas the benefit was variable in the severe form. Another cohort study by Mastrandrea⁸⁹ analyzed a 6-year follow-up of 35 patients with AD, one group with concomitant mild asthma or rhinitis and another group without respiratory allergic symptoms. Patients with eczema scores of 1–3 were started on allergen-specific SLIT for 36 months and they then attended 3-yearly follow-up visits to evaluate the long-term effect of the treatment. The outcomes were favorable for the use of SLIT in patients with atopic dermatitis and no serious adverse reactions were noted. However, much more information is needed before SLIT can be recommended for AD.

Venom

Subcutaneous route is the cornerstone in treatment of hymenoptera venom allergy. The use of SLIT in honeybee hypersensitivity has been shown to decrease the extent of large local reactions, which in itself is not an indication for immunotherapy.⁴¹ Further studies are needed to evaluate the efficacy of SLIT in preventing systemic reactions.

APPROPRIATE DESIGN OF SLIT STUDIES

There are deficiencies and considerable heterogeneity in both design and data interpretation of SLIT studies, making it difficult to assess the true value of SLIT in all circumstances.

A recent review of double-blind, placebo-controlled trials of SLIT indicates that many of the studies have a duration of less than 12 months (38/58) and involve small numbers of subjects (<100 in 40/58).⁴⁷ Performing studies with a small number of subjects could result in Type II errors and in having insufficient information about the safety of the treatment. To avoid these and other pitfalls it is recommended that all confirmatory trials on SLIT should be performed by using a randomized, placebo-controlled, double-blind design,⁴⁷ and all studies should be reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement.⁸⁹ The CONSORT statement provides recommendations for conducting and reporting RCTs. It offers a standard way for authors to prepare reports of trial findings, facilitating their complete and transparent reporting, and aiding their critical appraisal and interpretation.^{90, 91} It is also recommended having a detailed description of participant inclusion and exclusion criteria; identification of primary, secondary, and exploratory outcomes; to use standardized allergens; and to report adverse events in an ICH guidelines-based fashion.^{47, 92, 93}

There may be a significant amount of local side effects from SLIT allergens and this has made it difficult to come up with a suitable placebo. Optimally a placebo should have the same taste, appearance, and consistency as the active allergen and should cause local symptoms consistent with a standardized allergen extract.⁴⁹

FUTURE DIRECTIONS OF SLIT

Immunotherapy is a lengthy process and requires a great deal of commitment from the patient. The immunological responses are favorable and the long-lasting effects make specific immunotherapy an optimal choice for treatment of many allergic disorders. There is now data available to support the use of immunological adjuvants in SLIT in order to shorten the treatment time and maintain the immunological benefits of SLIT. Pfaar et al⁹⁴ evaluated the use of toll-like receptor 4 agonist monophosphoryl lipid A (MPL) in combination with SLIT grass pollen extracts. This was a double-blind, placebo-controlled, dose-escalating phase I/IIa study involved 80 grass pollen-sensitive subjects that were randomized into four groups of 20 subjects to receive daily treatment for 8 weeks. Sixteen patients per group received SLIT and four received placebo. The formulation given to each group varied with respect to grass pollen extract and MPL content. The tolerability and immunological response were measured by grass allergen nasal challenge tests (NCTs) performed prior to dosing and in weeks 4 and 10. Grass pollen-specific immunoglobulin G (IgG) and IgE antibodies were measured at baseline and prior to dosing in weeks 2, 3, 4, 5, and 10. No significant adverse reactions were noted. Patients in the two groups given SLIT containing the highest amount of MPL experienced the highest proportion of negative NCTs after 10 weeks (47% and 44%, vs 20% with placebo). The same patients also showed earlier median increases in specific IgG and smaller increases in IgE levels than those receiving other formulations.⁹⁴ There are other adjuvants that are being explored, but MPL has shown the most promising data to date and further larger studies are encouraged in this area.

Recently, the use of monomeric allergoids for SLIT has been studied. In a study with HDM, this treatment was shown to be safe and effective for perennial allergic rhinitis.⁹⁵

CONCLUSION

It is clear from the data that are available that SLIT has efficacy in the treatment of allergic rhinitis and asthma in both adults and children. However, there is a great deal of heterogeneity in the studies that have been reported to date and standardized ways on how to perform and report clinical trials with SLIT need to be put in place. Nonetheless, the convenience and added safety of this form of SIT make it an attractive addition to the therapeutic armamentarium for allergic respiratory diseases (Table 3).

Disclosures of potential conflicts of interest: P. Jonsson-Razdan has nothing to disclose. T. B. Casale, Principal Investigator on studies funded to Creighton University by Schering-Plough and Stallergenes; Advisory Board for Stallergenes.

REFERENCES

1. Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;1:1572– 1573.
2. Black JH. The oral administration of pollen. J Lab Clin Med. 1927;12:1156.
3. Herxeimer H. Bronchial hypersensitization and hyposensitization in man. Int Arch Allergy Appl Immunol. 1951;40:40–57.
4. Herxeimer H, Prior EN. Further observations in induced asthma and bronchial hyposensitization. Int Arch Allergy Appl Immunol. 1952;3:159–161.
5. Scadding K, Brostoff J. Low dose sublingual therapy in patients with allergic rhinitis due to dust mite. Clin Allergy. 1986;16:483–491.
6. Committee on the Safety of Medicines. CSM update: desensitizing vaccines. BMJ. 1986;293:948.
7. Tari MG, Mancino M, Monti G. Efficacy of sublingual immunotherapy in patients with rhinitis and asthma due to house dust mite. A double-blind study. Allergol Immunopathol. 1990;18:277–284.
8. Bousquet J, Van Cauwenberge P, Khaltaev N. Aria Workshop Group. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108(suppl 5):S147–S334.
9. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(suppl 86):8– 160.
10. Canonica GW, Bousquet J, Casale T, et al. Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy. 2009;64(suppl 91):1–59.
11. Passalacqua G, Compalati E, Canonica GW. Sublingual immunotherapy: clinical indications in the WAO-SLIT Position Paper. World Allergy Org J. 2010;3(7):216–219.
12. Bousquet J, Lockey R, Malling HJ. WHO Panel Members. Allergen immunotherapy: therapeutic vaccines for allergic diseases: a WHO position paper. J Allergy Clin Immunol. 1998;102:558–562.
13. Malling H. Immunotherapy. Position paper of the EAACI. Allergy. 1988; 43(suppl 6):9–33.
14. Wilson DR, Torres L, Durham SR. Sublingual immunotherapy for allergic rhinitis. Allergy. 2005;60:3–8.
15. Wilson DR, Lima MT, Durham ST. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005; 60:4–12.
16. Penagos M, Compalati E, Tarantini F, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol. 2006;97:141–148.
17. Olaguý´bel JM, Alvarez Puebla MJ. Efficacy of sublingual allergen vaccination for respiratory allergy in children: conclusions from one meta-analysis. J Investig Allergol Clin Immunol. 2005;15:9–16.
18. Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy. 2009;64:1570–1579.
19. Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118:434–440.
20. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117:802–809.
21. Didier A, Malling HJ, Worm M, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol. 2007;120:1338–1345.
22. Bufe A, Eberle P, Franke-Beckmann E, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol. 2009;123:167–173.
23. Wahn U, Tabar A, Kuna P, et al. Efficacy and safety of 5-grasspollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2009;123:160–166.
24. Didier A, Melac M, Montagut A, Lhéritier-Barrand M, Tabar A, Worm M. Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy. Allergy. 2009;64:166–171.
25. Fiocchi A, Pajno G, Grutta S. Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol. 2005;95: 254–358.
26. Agostinis F, Tellarini L, Canonica GW, et al. Safety of sublingual immunotherapy with a monomeric allergoid in very young children. Allergy. 2005;60:133.
27. Di Rienzo V, Minelli M, Musarra A, Sambugaro R, Pecora S, Canonica GW. Post-marketing survey of sublingual immunotherapy in children below the age of 5 years. Clin Exp Allergy. 2005;35:560–564.
28. Dahl R, Stender A, Rak S. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy. 2006;61:185–190.
29. Pham Pham-Thi N, Scheinmann P, Fadel R, Combebias A, Andre C. Assessment of sublingual immunotherapy efficacy in children with house dust mite-induced allergic asthma optimally controlled by pharmacologic treatment and mite-avoidance measures. Pediatr Allergy Immunol. 2007;18: 47–57.
30. Pajno GB, Vita D, Parmiani S, Caminiti L, La Grutta S, Barberio G. Impact of sublingual immunotherapy on seasonal asthma and skin reactivity in children allergic to Parietaria pollen treated with inhaled fluticasone propionate. Clin Exp Allergy. 2003;33:1641–1647.
31. Bousquet J, Scheinmann P, Guinnepain MT, et al. Sublingual swallow immunotherapy (SLIT) in patients with asthma due to house dust mites: a double blind placebo controlled study. Allergy. 1999;54:249–260.
32. Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacy of sublingual immunotherapy with high-dose mite extracts in asthma: a multicenter, double-blind, randomized, and placebo-controlled study in Taiwan. Respir Med. 2006;100:1374–1383.
33. Lue KH, Lin YH, Sun HL, Lu KH, Hsieh JC, Chou MC. Clinical and immunologic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, randomized, placebo-controlled study. Pediatr Allergy Immunol. 2006;17(6):408–415.
34. Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical and immunologic effects of long-term sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy. 2000;55(9):842–849.
35. Stelmach I, Kaczmarek-Wozniak J, Majak P, Olszowiec-Chlebna M, Jerzynska J. Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen. Clin Exp Allergy. 2009;39:401–408.
36. Pajno GB, Passalacqua G, Vita D, Caminiti L, Parmiani S, Barberio G. Sublingual immunotherapy abrogates seasonal bronchial hyperresponsiveness in children with Parietaria-induced respiratory allergy: a randomized controlled trial. Allergy. 2004;59:883–887.
37. Bernardini R, Campodonico P, Burastero S, et al. Sublingual immunotherapy with a latex extract in paediatric patients: a double-blind, placebo-controlled study. Curr Med Res Opin. 2006;22:1515–1522.
38. Severino MG, Cortellini G, Bonadonna P, et al. Sublingual immunotherapy for large local reactions caused by honeybee sting: a double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2008;122(1):44–48.
39. Agostinis F, Foglia C, Landi M, et al. The safety of sublingual immunotherapy with one or multiple pollen allergens in children. Allergy. 2008;63:1637–1639.
40. Lombardi C, Gargioni S, Cottini M, Canonica GW, Passalacqua G. The safety of sublingual immunotherapy with one or more allergens in adults. Allergy. 2008;63(3):375–376.
41. Eifan AO, Keles S, Bahceciler NN, Barlan IB. Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Allergy. 2007;62:567–568. doi: 10.1111/j.1398-9995.2006.01301.x 42. Dunsky E, Goldstein MF, Dvorin DJ, Belecanech G. Anaphylaxis to sublingual immunotherapy. Allergy. 2006;61:1235.
43. Canonica GW, chair. Sub-lingual immunotherapy. World Allergy Organization Position Paper 2009. WAO J. 2009;2:233–281.
44. Canonica GW, Baena-Cagnani C, Bousquet J, et al. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62:317–324.
45. Nouri-Aria KT, Wachholz PA, Francis JN, et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol. 2004;172:3252–3259.
46. Casale TB, Canonica GW, Bousquet J, et al. Recommendations for appropriate sublingual immunotherapy clinical trials. J Allergy Clin Immunol. 2009;124(4):665–670.
47. Lombardi C, Incorvaia C, Braga M, Senna G, Canonica GW, Passalacqua G. Administration regimens for sublingual immunotherapy to pollen allergens: what do we do now? Allergy. 2009;64:849–854.
48. Guerra L, Compalati E, Rogkakou A, Pecora S, Passalacqua G, Canonica GW. Randomized open comparison of the safety of SLIT in a no updosing and traditional updosing schedule in patients with Parietaria allergy. Allergol Immunopathol. 2006;34:823.
49. Rodriguez F, Boquete M, Ibanez MD, de la Torre-Martinez F, Tabar AI. Once daily sublingual immunotherapy without updosing—a new treatment schedule. Int Arch Allergy Immunol. 2006;140:321–326.
50. Akdis CA, Akdis M, Blesken T, et al. Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. J Clin Invest. 1996;98:1676–1683.
51. Akdis CA, Blesken T, Akdis M, Wüthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest. 1998;102:98–106.
52. Francis JN, Till SJ, Durham SR. Induction of IL-10
CD4
CD25
T cells by grass pollen immunotherapy. J Allergy Clin Immunol. 2003;111: 1255–1261.
53. Jutel M, Akdis M, Budak F, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003;33:1205–1214.
54. Akdis M, Verhagen J, Taylor A, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergenspecific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199:1567– 1575.
55. Ling EM, Smith T, Nguyen XD, et al. Relation of CD4
CD25
regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet. 2004;363:608– 615.
56. Niederberger V, Horak F, Vrtala S, et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci USA. 2004;101(suppl 2):14677–14682.
57. Akdis CA, Joss A, Akdis M, Faith A, Blaser K. A molecular basis for T-cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. FASEB J. 2000;14(12):1666–1668.
58. Novak N, Haberstok J, Bieber T, Allam J-P. The immune privilege of the oral mucosa. Trends Mol Med. 2008;14:191–198.
59. Akkoc T, Akdis M, Akdis CA. Update in the mechanisms of allergenspecific immunotherapy. Allergy Asthma Immunol Res. 2011;3(1):11–20.
60. Aoyama-Kondo T, Yoshida T, Tsobe K, et al. Characterization of antibody responses of local lymph nodes to antigen given under the oral submucosa. Immunobiology. 1992;184:372–383.
61. Van Helvoort JM, Samsom J, Chantry D, et al. Preferential expression of IgG2b in nose draining cervical lymph nodes and its putative role in mucosal tolerance induction. Allergy. 2004;59:1211–1218.
62. Allam JP, Novak N, Fuchs C, et al. Characterization of dendritic cells from human oral mucosa: a new Langerhans cell type with high constitutive FC epsilon RI expression. J Allergy Clin Immunol. 2003;112:141–148.
63. Von Bubnoff D, Fimmers R, Bogdanov M, Matz H, Koch S, Bieber T. Asymptomatic atopy is associated with increased indoleamine 2,3- dioxygenase activity and interleukin 10 production during seasonal allergen exposure. Clin Exp Allergy. 2004;34:1056–1063.
64. Rak S, Yang WH, Pedersen MR, Durham SR. Once-daily sublingual allergen specific immunotherapy improves quality of life in patients with grass pollen induced allergic rhinoconjunctivitis: a double-blind, randomised study. Qual Life Res. 2007;16:191–201.
65. Casanovas M, Guerra F, Moreno C, Miguel R, Maranon F, Daza JC. Double-blind, placebo-controlled clinical trial of preseasonal treatment with allergenic extracts of Olea europaea pollen administered sublingually. J Investig Allergol Clin Immunol. 1994;4:305–314.
66. Feliziani V, Lattuada G, Partmiani S, Dall’aglio PP. Safety and efficacy of sublingual rush immunotherapy with grass allergen extracts. A doubleblind study. Allergol Immunopathol (Madr). 1995;23:224–230.
67. Vourdas D, Syrigou E, Potamianou P, et al. Double-blind placebocontrolled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization. Allergy. 1998;53:662– 672.
68. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109:251–256.
69. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children—a 14-year study. Pediatrics. 1968;42:793– 802.
70. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy. 2001;31:1392–1397.
71. Purello-D’Ambrosio F, Gangemi S, Merendino RA, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy. 2001;31: 1295–1302.
72. Novembre E, Galli E, Landi F, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2004;114:851–857.
73. Marogna M, Tomassetti D, Bernasconi A, et al. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol. 2008;101:206–211.
74. Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Longlasting effects of sublingual immunotherapy according to its duration: a 15-year prospective study [published online ahead of print October 12, 2010]. J Allergy Clin Immunol. 2010;126(5):969–975.
75. Durham SR, Emminger W, Kapp A, et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol. 2010;125:131–138.
76. Nettis E, Colanardi MC, Soccio AL, et al. Double-blind, placebocontrolled study of sublingual immunotherapy in patients with latexinduced urticaria: a 12-month study. Br J Dermatol. 2007;156(4):674–681.
77. Pajno GB, Caminiti L, Ruggeri P, et al. Oral immunotherapy for cow’s milk allergy with a weekly up-dosing regimen: a randomized single-blind controlled study. Ann Allergy Asthma Immunol. 2010;105(5):376–381.
78. Skripak JM, Nash SD, Rowley H, et al. A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy. J Allergy Clin Immunol. 2008;122:1154–1160.
79. Blumchen K, Ulbricht H, Staden U, et al. Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy Clin Immunol. 2010;126:83–91.
80. Buchanan AD, Green TD, Jones SM, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol. 2007;119:199–205.
81. Scurlock AM, Burks AW, Jones SM. Oral immunotherapy for food allergy. Curr Allergy Asthma Rep. 2009;9:186–193.
82. Thyagarajan A, Varshney P, Jones S, et al. Peanut oral immunotherapy is not ready for clinical use. J Allergy Clin Immunol. 2010;126:31–32.
83. Werfel T, Breuer K, Ruéff F, et al. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study. Allergy. 2006;61: 202–205.
84. Pajno G, Caminiti L, Vita D, et al. Sublingual immunotherapy in mitesensitized children with atopic dermatitis: a randomized double-blind placebo-controlled study. J Allergy Clin Immunol. 2007;120:164–170.
85. Mastrandrea F, Serio G, Minelli M, et al. Specific sublingual immunotherapy in atopic dermatitis. Results of a 6-year follow-up of 35 consecutive patients. Allergol Immunopathol (Madr). 2000;28(2):54–62.
86. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;134(8):657–662.
87. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
88. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332.
89. ICH Expert Working Group. Structure and content of clinical study reports. E3: ICH harmonized tripartite guidelines. November 30, 1995. Available at: http://www.ich.org/cache/compo/276-254-1.html [Accessed August 8, 2010].
90. Bousquet PJ, Brozek J, Bachert C, et al. The CONSORT statement checklist in allergen-specific immunotherapy—a GA2LEN paper. Allergy. 2009;69:1737–1745.
91. Pfaar O, Barth C, Jashke C, Hormann K, Klimek L. Sublingual allergenspecific immunotherapy adjuvanted with monophosphoryl lipid A: a phase I/IIa study. Int Arch Allergy Immunol. 2011;154:336–344. doi: 10.1159/ 000321826 92. Marogna M, Colombo F, Cerra C, et al. The clinical efficacy of a sublingual monomeric allergoid at different maintenance doses: a randomized controlled trial. Int J Immunopathol Pharmacol. 2010;23(3): 937–945.
93. Calderon M, Casale TB, Togias A, Bousquet J, Durham S, Demoly P. Allergen-specific immunotherapy for respiratory allergies: From metaanalysis to registration and beyond. J Allergy Clin Immunol. 2011; 127(1): 30–38.

Since its introduction by Professor Shigeto Ikeda in 1964, the use of flexible fiberoptic bronchoscopy (FOB) is expanding, and it is considered to be one the most important breakthrough in diagnostic pulmonology.

Bronchoalveolar lavage (BAL) is a specialized technique, described by Reynolds and Newball in 1974, which consists instillation of small quantity of saline directly into distal airways and recovering the aspirate through FOB. This technique allows recovery of cells, inhaled particles, infectious organisms, and solutes from the lower respiratory tract and in particular from the alveolar spaces of the lung, which are representative of inflammatory and immune system of the entire lower respiratory tract.

Since its introduction BAL has been extensively used for evaluation of various pulmonary conditions including infectious, inflammatory, and malignant diseases.¹ Localized disease naturally requires lavage of the radiographically involved area, in its choice High Resolution Computer Tomography (HRCT) is essential.

In diffuse lung disease, the middle or lingular lobe is recommended as a standard site for BAL. The procedure is only minimally invasive and usually well tolerated (its side effects are more or less comparable with those of routine FOB under local anesthesia). The procedure is associated with practically no mortality and carries a low complication rate between 0% and 2.3% compared with 7% with transbronchial biopsy and 13% with surgical lung biopsy. There are no absolute contraindications for the performance of BAL beyond those noted for bronchoscopy.

Detailed recommendations and guidelines both for technique of bronchoscopy, and analysis of BAL fluid have been developed and published to standardize the procedure so that limitations related to different methods followed by various bronchoscopists all over the world can be minimized²; in fact one of the most commonly encountered problems with interpreting BAL results has been variability between centres.

BAL has gained widespread acceptance as a powerful investigative tool in the field of pulmonary medicine. It has become a standard diagnostic procedure in patients with ILD. Routine processing of BAL fluid cellular analyses for patients with ILD includes total and differential cell counts and the determination of lymphocyte subsets as well as the morphological appearances of cells, besides cultures and special stains for infection in appropriate clinical setting.³

It is thought that alterations in lavage fluid and cells reflect pathologic changes in the corresponding parenchymal constituents. A number of studies have shown a good correlation between the type and number of inflammatory cells obtained by BAL and those observed in histologic lung biopsy sections or derived from mechanically dispensed lung tissue in several ILDs such as idiopathic pulmonary fibrosis (IPF), sarcoidosis, and hypersensitivity pneumonitis (HP).

Also BAL collects samples from a much larger area of the lungs than can be obtained by the small tissue fragments of transbronchial biopsy or even by surgical biopsy, thereby giving a more representative picture of inflammatory and immunologic changes. Thus, this technique serves as a “window to the lung.”⁴

IDIOPATHIC PULMONARY FIBROSIS (IPF)

Interstitial lung diseases (ILDs) represent a very broad and heterogeneous group of acute and chronic infiltrative lung disorders; idiopathic interstitial pneumonias (IIP) (IPF, Nonspecific Interstitial Pneumonia (NSIP), Desquamative Interstitial Pneumonia (DIP), Cryptogenic Organizing Pneumonia (COP), Respiratory Bronchiolitis associated interstitial lung disease (RB-ILD), Lymphocytic Interstitial pneumonia (LIP), Acute Interstitial Pneumonia (AIP) is a group of ILD formed by respiratory tract disorders whose etiology is unknown, the clinical course differs, and the prognosis varies.⁵

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease with poor prognosis and no proven effective treatment (5-year survival rate: between 20% and 40%). Symptoms and signs are usually nonspecific. Nonproductive cough and progressive dyspnea on exertion are typical, with variable onset and progression. Common signs include tachypnea, reduced chest expansion, and bibasilar end-inspiratory dry crackles. Pulmonary function tests typically reveal a restrictive pattern and reduction in diffusing capacity for carbon monoxide (DLCO). Arterial blood gas (ABGs) shows hypoxemia, which is often exaggerated or elicited by exercise and low CO₂ levels. Chest X-ray typically shows diffuse reticular opacities in the lower and peripheral lung zones. Small cystic lesions (honeycombing) and dilated airways due to traction bronchiectasis are additional findings. HRCT shows diffuse, patchy, subpleural, bibasilar, reticular opacities with irregularly thickened interlobular septa and intralobular lines; subpleural honeycombing; and traction bronchiectasis. Typically ground-glass is scanty and ground glass opacities affecting more than 30% of the lung suggest an alternative diagnosis.

BAL IN IPF

Clinical Use

BAL fluid examination is one of the initial procedures in the diagnosis of ILD. In the majority of cases, it provides only additional information and cannot be the basis for a definite diagnosis. However, this relatively noninvasive procedure is very useful in the differential diagnosis of ILD: a normal BAL fluid cell profile, in fact, excludes an active inflammation.

Bronchoalveolar lavage and/or transbronchial biopsy, one of four major criteria in the 2000 ATS/ERS IPF Statement,⁶ was no more essential in the diagnostic algorithm of 2002 ATS/ERS Consensus Classification. According to the 2002 ATS/ERS Consensus Classification,⁷ a confident diagnosis of IPF without surgical lung biopsy is made with consistent clinical/physiological findings and the typical features on high-resolution computed tomography (HRCT).

However the addition of BAL to the diagnostic procedures is useful in patients suspected of having IPF with a no-confident CT diagnosis and/or no-consistent clinical features, in the absence of a surgical biopsy. BAL cell differentials are of additional diagnostic benefit in this clinical setting.

Research Tool

BAL sampling of the lower airways and alveoli has become a common tool of research to obtain cells and proteinaceous materials and to describe the milieu of the airways in animal and human. For this reason BAL is also of value to study immune and inflammatory mechanisms in IPF, and in many other diseases.

Idiopathic pulmonary fibrosis (IPF) pathogenesis is still unknown. Currently IPF seems to be characterized by fibroblast proliferation, remodeling and extracellular matrix (ECM) accumulation, and histopathologic signature of usual interstitial pneumonia (UIP). Moreover, IPF has been shown to be associated with oxidative/nitrosative stress: the elevated oxidant burden in turn triggers the activation of growth factors and metalloproteases and evokes an imbalance in the acetylases/deacetylases and disruptions of the transcription of several inflammatory genes in the lung. We report some recent studies where BAL was used as a research tool in IPF.

Recently it was shown that in IPF tissue infiltrating CD8+ T lymphocytes (TLs) are associated with breathlessness and physiological indices of disease severity, as well as that CD8+ TLs recovered by BAL relate to those infiltrating lung tissue, implicating that they might play a role in its pathogenesis.⁸ The exact mechanisms through which CD8+ TLs contribute to lung injury and pulmonary fibrosis are not yet clear. The current hypothesis on the development of IPF conceptualizes ongoing, multiple, small focal episodes of epithelial lung injury followed by a pathologic fibrotic repair mechanism and an imbalance in the expression of T-helper type 1 (Th1) and Th2 cytokines. CD8+ TLs are known to produce type 2 cytokines such as interleukin-4 and interleukin-5. Recently, it has been hypothesized that in patients with IPF an excessive recruitment of CD8+ TLs may occur in response to repeated viral infections and this excessive response may play a role in the development of lung damage through multiple mechanisms (nuclear factor κB, tumor necrosis factor κ) of epithelial cells activation, production of chemokines by the alveolar cells, which may in turn amplify inflammatory responses in the lung.

In a recent study by Papiris et al ⁹ evaluated the relationships between BAL cells and physiologic and clinical parameters of disease severity in IPF patients. Among the different inflammatory cells studied, CD8+ TLs correlated positively with the Medical Research Council (MRC) chronic dyspnea grade and negatively with Residual Volume, while the CD4 + /CD8+ ratio correlated negatively with the MRC chronic dyspnea grade. Activated CD8 + /38+ TLs correlated negatively with the Forced expiratory volume in the 1st second (FEV1) and Forced Vital Capacity (FVC). Furthermore, neutrophils correlated positively with the MRC dyspnea grade and negatively with DLCO, PaO2, and PaCO2. BAL CD8+ TLs associations with physiological and clinical indices seem to confirm their implication in IPF pathogenesis.

Several studies have demonstrated the presence of CC chemokines in human ILDs; for example augmented production of macrophage chemoattractant protein-1 (CCL2) by metaplastic epithelial cells and its increase in parallel with disease activity were reported in IPF.

Moreover others studies have found various cytokine and chemokine levels to be increased in BAL fluid in IPF and levels of several CC chemokines, CCL2, CCL 17, CCL 22 suggested a poor outcome in IPF patients. However remains to be determined whether CC chemokines influence really the prognosis of IPF.¹⁰

Genetics defects in surfactant protein A2 can be found in IPF and also in lung cancer; blood biomarkers metalloproteases MPP7 and MPP1 in patients with IPF are revealing, in fact BAL fluid concentrations and gene expression for these two metalloproteases to be significantly overexpressed in IPF.¹¹

In a recent study by Ishikawa et al ¹² unbiased proteomics and subsequent Mass Spectrometry (MS) and Western blot analyses indicated reduced levels of Hb (α,β) monomers and complexes in lung specimens from patients with IPF compared to the controls. According to the immunohistochemistry, normal human lung expressed Hbα and Hbβ most prominently in the alveolar epithelial cells while in the IPF lung, the levels of both Hb monomers were very low or even undetectable. This is the first study showing the expression of Hb in human lung. Examination of BAL via gene microarray technology or proteomic analyses may allow BAL to assume a more prominent role in diagnosis, discovery of the pathogenesis and management of lung disease in the near future.

Idiopathic pulmonary fibrosis (IPF) is characterized by the insidious onset of dyspnea or cough in a large proportion of patient; however, a subset of patients has a short duration of symptoms with rapid progression to end-stage disease.

Finally in one study by Selman et al ¹³ they evaluated clinical and molecular features of “rapid” and “slow” progressors with IPF: a subgroup of IPF patients, in fact, predominantly smoking males, display an accelerated clinical course and have a gene expression pattern that is different from those with slower progression and longer survival (increased adenosine A_2B receptor gene, immunoreactive A_2BAR, prominin-1/CD133). Moreover, two genes associated with the Hermansky-Pudlak syndrome, HPS3 and Rab38, a small GTPase of the Rab family expressed in bronchial and alveolar epithelial cells, were increased in the “rapid” progressors group. These findings highlight the variability in the progression of IPF, and may explain, in part, the difficulty in obtaining significant and reproducible results in studies of therapeutic interventions in patients with IPF.

BAL CELL COUNT IN IPF

In IPF, the characteristic BAL pattern is an increase in the total number of cells, an increase in neutrophils, usually to a moderate degree (10–30% of total cells), with or without an additional increase in eosinophils. Usually, the neutrophils are twice as high as the eosinophils. Such increase in neutrophils is noted in 70–90% of patients, and associated increase in eosinophils in 40–60% of patients. An additional increase in lymphocytes is recorded in 10–20% of patients.

A finding of raised neutrophils (>3–4%) and raised eosinophils (>2%) is characteristic of IPF, but not diagnostic. A lone increase in BAL lymphocytes or eosinophils is uncommon and these observations may influence diagnostic confidence.

However, these findings are seen in a wide variety of fibrosing lung conditions other than IPF.¹⁴

DIFFERENTIAL DIAGNOSIS BETWEEN IPF AND OTHER IIP

A great challenge in BAL cytology interpretation is to distinguish other IIP from IPF.^{1, 3, 4, 15} In BAL there is marked difference between DIP-pattern and UIP and NSIP: the latter (UIP, NSIP) is characterized by a much higher percentage of neutrophils and lymphocytes.

The differentiation between fibrotic-NSIP and UIP, in absence of surgical lung biopsy, is a difficult challenge for physicians. After the first description of NSIP in 1994, BAL lymphocytosis is more likely suggestive of NSIP rather than UIP. A few recent studies have also shown that BAL could provide substantial diagnostic information on UIP and NSIP. ^3–5 An isolated and marked increase in lymphocytes is uncommon in IPF (<10% of patients), so when present, other disorders should be excluded (eg, granulomatous diseases, sarcoidosis, extrinsic allergic alveolitis, LIP, COP, NSIP…).

In some reports,¹⁶ BAL lymphocytosis is higher in NSIP than UIP. In a series of 122 patients with histologically confirmed UIP and NSIP, Ryu et al ¹⁷ found a significant difference in the BAL lymphocyte proportion between NSIP and UIP (mean, 29% versus 5.5%, respectively).

Ohshimo et al ¹⁸ showed that the absolute number and the percentage of lymphocytes was significantly higher in the non-IPF group (NSIP and HP) than in the IPF group. The percentage of macrophages was significantly lower in the non-IPF group than in the IPF group. No significant differences were found between groups regarding the numbers of neutrophils and eosinophils. In this study BAL lymphocytosis changed diagnostic perception in six of 74 patients who would have been misdiagnosed as having IPF without BAL.

However, Veeraraghavan et al ¹⁹ studied retrospectively 54 patients with histologically proven idiopathic UIP (n=35) or fibrotic NSIP (n=19), all presenting clinically as IPF. These findings were also compared with the BAL profile of patients with other categories of IIP. The authors conclude that BAL findings do not discriminate between UIP and NSIP in patients presenting with clinical features of IPF.

No exact cut-off level has been evaluated for the lymphocytosis in BAL; for this reason distinguishing IPF from the NSIP solely based on the BAL cellular profile is difficult.

Ultimately the BAL cell count does not differentiate between fibrotic NSIP and UIP, even if an increase in BAL lymphocytes is in favor of NSIP (idiopathic or secondary).

COMORBIDITY AND/OR COMPLICATIONS

The role of BAL in IPF diagnosis remains controversial, in contrast it is essential in the diagnosis of complications of the disease, such as infections, lung malignancy, drug injury, and accelerated phase.

Infections

Microscopic analysis after May-Grünwald Giemsa and Gram staining allows a rapid evaluation of differential cell count, percentage of cells containing intracellular organisms (ICO), and direct visualization of organisms, including Pneumocystis jirovecii.²⁰ Papanicolaou staining may show intranuclear or intracytoplasmic inclusion on epithelial cells as effect of viral cytopathic action (adenovirus, herpesvirus, cytomegalovirus); finally, specific stain as silver metenamine may show the presence of fungi (aspergillus, mucor, etc.). The morphology and Gram staining of organisms identified by BAL have correlated closely with the results of culture, allowing early and appropriate antibiotic selection. The microscopic analysis of BAL, during an infection disease, shows a significant increase in the total count and percentage of neutrophils, generally more than 50%.

In one study the absence of BAL neutrophilia predicted the absence of pneumonia within 2 days of specimen collection in 97% of patients, while the finding of less than 50% neutrophils in BAL fluid had a negative predicted value of 100% in another.²¹ The percentage of cells that contain ICO more than 5% may be considered diagnostic of infectious pneumonia, however, the sensitivity of the test has varied widely in different reports (37–100%).^{22, 23}

The BAL also allows to perform quantitative bacterial cultures. When pulmonary infiltrates are associated with immunosuppressive therapy BAL makes a crucial contribution to the detection of opportunistic infection.²⁴

The BAL facilitates the differentiation between colonization and infection. The currently accepted threshold for defining infection is ≥10⁴ colony forming units (cfu) per mL^–1. Counts >10³ cfu/mL could be considered significant in treated patients with a compatible clinical picture. The routine culture concerns bacteria and fungi²⁵ but other pathogens can be investigated (ie, Mycobacterium tuberculosis, P. jirovecii, CMV, Chlamydia pneumoniae, L. pneumophila).

Acute Exacerbation with Diffuse Alveolar Damage (DAD) Superimposed on UIP

BAL fluid cytological findings in DAD are characterized by a marked predominance of neutrophils (>50%) in the early phase and a recruitment of macrophages, lymphocytes, and eosinophils in the late phase. The presence of reactive type II pneumocytes has been described and their atypia may be severe enough to mimic carcinoma. Some remnants of hyaline membranes inglobed in balls of type II reactive pneumocytes were also described.^{17 26–}

Lung Cancer

Lung cancer may complicate clinical course of IPF in 10% of patients. BAL is a useful diagnostic tool in diffuse or disseminated lung malignancies that do not involve the bronchial structures visible by endoscopy.²⁹ The neoplastic histotype and the intraparenchymal neoplastic growth pattern are good predictors for diagnostic yield; adenocarcinoma, particularly bronchoalveolar carcinoma pattern, and tumors with lymphangitic growth patterns are more easily diagnosed by BAL³⁰; in these cases the diagnostic yield reported is higher than 80%. Morphological analysis may be implemented by immunocytochemical or molecular tests to identify the cell lineage and the presence of monoclonality. Disorders in which bronchioloalveolar cell hyperplasia/dysplasia is a significant morphological component may have cytological features in BAL fluid that mimic lung neoplasms: acute respiratory distress syndrome (ARDS), AIP, and acute exacerbation of IPF are the most important clinical entities in this group.

PROGNOSIS AND FOLLOW UP

Although the factors and indices suggestive of a poor prognosis in IPF include decreased FVC and diffusion capacity of the lung for carbon monoxide (DLCO), the degree of desaturation during a 6-min walk test, and a negative response to corticosteroid therapy, no definite consensus has been reached on the factors influencing survival in this disease. The prognostic role of BAL has been the subject of some clinical studies.

Old studies, performed before the IPF statement¹⁰ showed that marked increase in neutrophils and/or eosinophils were related to negative prognosis, whereas elevated lymphocyte counts were more likely associated with a good response to corticosteroid treatment.

In the study by Veeraraghavan et al ¹⁹ BAL findings have no prognostic value, once the distinction between the two has been made histologically. They studied 35 IPF/UIP and 19 NSIP: the median follow-up time was 3.4 years, 29 (83%) of the UIP patients and 11 (58%) of the NSIP patients died during follow-up. Thus none of the constituents of BAL cell counts predicted survival.

Instead, for Ryu et al ¹⁷ BAL can be useful to predict the prognosis in the absence of the histopathologic diagnosis, in fact, in this paper, higher BAL lymphocyte count was the only independent predictor of a longer survival.

A recent study by Kinder et al ³¹ shows that BAL fluid neutrophil percentage obtained at the time of initial diagnosis is an independent predictor of time to death or transplant. The impact was most dramatic in the first year of follow-up and attenuated with time. There was no association between mortality and BAL fluid lymphocyte and eosinophil percentages.

It is not proven if serial BAL have a role in monitoring the course of disease and guiding therapy better than other functional indices of change. Use of BAL to monitor therapy has not been widely used in pulmonary fibrosis.

CONCLUSIONS

• BAL is not required as a diagnostic tool in patients with clinical features and HRCT appearances typical of IPF.

• In patients with uncertain diagnosis, typical BAL cellular profiles may allow an alternative diagnosis (ie, HP, sarcoidosis, etc.).

• BAL should be considered in all patients with suspected infection, malignancy or acute exacerbations. In such cases, BAL may be diagnostic.

The clinical utility of BAL at the time of diagnosis of IPF should be reconsidered.

Disclosure: The authors declare no conflict of interest.

REFERENCES

1. Costabel U, Guzman J. Bronchoalveolar lavage. In: Schwarz MI, King Jr TE, eds. Interstitial Lung Disease. Hamilton-London: BC Decker Inc; 2003:114–133.
2. Technical recommendations and guidelines for bronchoalveolar lavage (BAL). Report of the European Society of Pneumology Task Group. Eur Respir J. 1989;2:561–585.
3. Meyer KC. Bronchoalveolar lavage as a diagnostic tool. Semin Respir Crit Care Med. 2007;28:456–460.
4. Spagnolo P, Richeldi L, Raghu G. The role of bronchoalveolar lavage cellular analysis in the diagnosis of interstitial lung diseases. Eur Respir Mon. 2009;46:36–46.
5. Nagai S, Handa T, Ito Y, Takeuchi M, Izumi T. Bronchoalveolar lavage in idiopathic interstitial lung diseases. Semin Respir Crit Care Med. 2007;28(5):496–503.
6. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646–664.
7. Demedts M, Costabel U. ATS/ERS international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Eur Respir J. 2002;19:794–796.
8. Daniil Z, Kitsanta P, Kapotsis G, et al. CD8
T lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosis. Respir Res. 2005;6:81–89.
9. Papiris SA, Kollintza A, Karatza M, et al. CD8
T lymphocytes in bronchoalveolar lavage in idiopathic pulmonary fibrosis. J Inflam. 2007;4:14.
10. Reynolds HY. Present status of bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulm Med. 2009;15:479–485.
11. Shinoda H, Tasaka S, Fujishima S, et al. Elevated CC chemokine level in bronchoalveolar lavage fluid is predictive of a poor outcome of idiopathic pulmonary fibrosis. Respiration. 2009;78:285–292.
12. Ishikawa N, Ohlmeier S, Salmenkivi K, et al. Hemoglobin a and b are ubiquitous in the human lung, decline in idiopathic pulmonary fibrosis but not in COPD. Respir Res. 2010;11:123–136.
13. Selman M, Carrello G, Estrada A, et al. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern. PLoS ONE. 2007;2:e482.
14. Pesci A, Ricchiuti E, Ruggiero R, De Micheli A. Bronchoalveolar lavage in idiopathic pulmonary fibrosis: what does it tell us? Respir Med. 2010;104:570–573.
15. Domagala-Kulawik J. BAL in the diagnosis of smoking-related interstitial lung diseases: review of literature and analysis of our experience. Diagn Cytopathol. 2008;36:909–915.
16. Tabuena RP, Nagai S, Tsutsumi T, et al. Cell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese patients. Respiration. 2005;72:490–498.
17. Ryu J, Chung MP, Han J, et al. Bronchoalveolar lavage in fibrotic idiopathic interstitial pneumonias. Respir Med. 2007;101(3):655–660.
18. Ohshimo S, Bonella F, Cui A, et al. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:1043–1047.
19. Veeraraghavan S, Latsi PI, Wells AU, et al. BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia. Eur Respir J. 2003;22:239–244.
20. Pesci A, Majori M, Caminati A. Bronchoalveolar lavage in intensive care units. Monaldi Arch Chest Dis. 2004;61(1):39–43.
21. Garrard CS, A’Court CD. The diagnosis of pneumonia in the critical ill. Chest. 1995;108:17S–25S.
22. Sole-Violan J, Rodriguez de Castro F, Rey A, Martý´n-González JC, Cabrera-Navarro P. Usefulness of microscopic examination of intracellular organism in lavage fluid in ventilator – associated pneumonia. Chest. 1994;106:889–894.
23. Valles J, Rello J, Fernández R, et al. Role of bronchoalveolar lavage in mechanically ventilated patients with suspected pneumonia. Eur J Clin Microbiol Infect Dis. 1994;13:549–558.
24. Agusti C, Rano A, Rovina M, et al. Inflammatory response associated with pulmonary complications in non-HIV immunocompromised patients. Thorax. 2004;59:1081–1088.
25. Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid. A tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med. 2008;177:27–34.
26. Grotte D, Stanley MW, Swansone PE, Henry-Stanley MJ, Davies S. Reactive type II pneumocytes in bronchoalveolar lavage fluid from adult respiratory distress syndrome can be mistaken for cells of adenocarcinoma. Diagn Cytopathol. 1990;6:317–322.
27. Biyoudi-Vouenze R, Tazi A, Hance AJ, Chastre J, Basset F, Soler P. Abnormal epithelial cells recovered by bronchoalveolar lavage: are they malignant? Am Rev Respir Dis. 1990;142(3):686–690.
28. Nakos G, Kitsiouli EL, Sangaris T, Lekka ME. Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Inten Care Med. 1988;24:296–303.
29. Poletti V, Poletti G, Murer B, Paragoni L, Chilosi M. Bronchoalveolar lavage in malignancy. Semin Respir Crit Care Med. 2007;28:534–545.
30. Poletti V, Romagna M, Allen KA, Gasponi A, Spiga L. Bronchoalveolar lavage in the diagnosis of disseminated lung tumors. Acta Cytologica. 1995;39(3):472–477.
31. Kinder BW, Brown KK, Schwarz MI, Ix JH, Kervitsky A, King TE Jr. Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest. 2008;133:226–232.

Emphysema is defined histologically as a permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of the alveolar walls ¹. There are three major subcategories of emphysema described (Fig. 1). Centrilobular (or centriacinar) disease is the most common type and represents destruction of the acinar walls in the central or core region of the acinus in the initial stages. With time and increased disease severity the whole acinus is involved and the distinction from panlobular disease becomes blurred. Centrilobular emphysema is closely related to cigarette smoking and dust inhalation and is usually more prominent in the upper lung zones. Panlobular (panacinar) emphysema involves destruction of all portions of the acinus from the outset of disease and is more commonly found in the lower lung zones. The most common cause of panlobular emphysema is a deficiency in alpha-1 antitrypsin. Paraseptal emphysema indicates disease in the periphery of the acini (ie, near the septa) and is usually mild and asymptomatic although it can coexist with other types of emphysema ^2–4 .

Clinically these different forms of emphysema are indistinguishable from one another and even from significant airways disease—the other major pathological player in the chronic obstructive pulmonary disease (COPD) spectrum. Traditional techniques for assessing disease severity, such as pulmonary function tests, are similarly unable to discriminate the different forms of emphysema or its severity, nor whether a patient has significant concomitant airways disease since both bronchiolitis and emphysema independently cause a reduction in lung function ⁵. Distinction between the different types of emphysema relies on qualitative visual assessment. Pathological studies in relatively small groups of subjects have determined the traditional view that centrilobular emphysema, particularly in the upper lung zones, is predominant in smoking related COPD, whereas panlobular emphysema with a lower zone predominance is the main type in alpha-1 antitrypsin deficiency. However, it is clear that both types of emphysema can be present in both of these groups of patients ^{6, 7}. Unfortunately there is a paucity of prevalence data for the emphysema subtypes as assessed by computed tomography (CT) in large patient cohorts and the relationship with functional outcomes in COPD. Such distinctions were previously only of academic interest, since treatment was administered for COPD as a single entity rather than for its individual pathological subtypes. Recent work has shown however that CT imaging has a role to play in defining the pathological phenotypes in cases of COPD, whether as an emphysema or airways predominant subgroup ^{8, 9}. With the prospect of targeted therapies on the horizon, the ability to accurately differentiate the pathological subtypes of emphysema in vivo may soon be clinically warranted. Indeed the extent and distribution of emphysema is already used to determine the suitability of patients for lung volume reduction surgery (LVRS) ¹⁰.

In this paper we assess the ability of CT scanning to assess the distribution of emphysematous change within the lung parenchyma and the clinical relevance of these pathological phenotypes of COPD.

COMPUTED TOMOGRAPHY (CT)

A CT scanner measures the density of tissues by assessing the degree of x-ray attenuation. The CT units (Hounsfield units, HU) are arranged around the density of water (HU = 0) and the CT scanner is also calibrated to air (HU-1000). The upper limit of the scale is usually around +3000 HU, which allows a CT scan to demonstrate approximately 4000 gradations of density represented as shades of gray with air displayed as black and highly dense materials (eg, cortical bone, metallic implants) displayed in white. As the human eye can only differentiate approximately 50 shades of gray, the CT data are usually displayed on much smaller scales within the density spectrum (known as windowing). For example, lungs may be viewed with a window width of 600 HU (rather than the full 4000) centered on perhaps −600 HU. These settings would display only the range −900 to −300 HU; anything less dense would automatically appear black, while all tissues of greater density than the lung parenchyma would appear white. Such an arrangement enables users to make more sense of the data by accentuating the natural differences in density between neighboring structures and excluding scanned areas of less interest.

COMPUTED TOMOGRAPHY (CT) ASSESSMENT OF EMPHYSEMA

The CT is therefore an ideal tool for assessing emphysema as it can easily display density differences in the lung parenchyma that are characteristic of the disease. In areas where there has been parenchymal destruction, air will replace soft tissue and the HU moves toward −1000 HU; emphysema is therefore characterized by areas of low density on the CT. Early CT studies of emphysema demonstrated that measurements of lung density correlated with morphometric assessment of distal airspace enlargement in resected lung tissue ^11–14 . Subsequent work has also shown correlations between CT measured emphysema and pulmonary function; indeed CT has been shown to be more accurately related to the extent of emphysema than pulmonary function, as the latter makes no allowance for the effect of coincident airways disease ^15–17 .

The extent and distribution of emphysema can be subjectively assessed through visual inspection of the scanned images by a trained observer ^{11, 13, 18}. Such techniques, however, have been shown to underestimate disease extent when compared with quantitative pathological assessment ^{18, 19} and are subject to both intra- and interobserver variability. Such limitations are overcome by the application of a quantitative method for the assessment of emphysema on a CT and current research takes advantage of this increased accuracy. Hayhurst and colleagues were the first to utilize such a method by displaying frequency distribution of the attenuation values within the lung. They demonstrated that patients with emphysema had more pixels in the range −900 to −1000 HU than patients without emphysema ¹².

There are two common methods for determining the extent of emphysema quantitatively; the percentile point analysis and the threshold cut-off point. The percentile method defines a specific point on the frequency distribution of X-ray attenuation values. Different cut-off points have been suggested for the best representation of emphysema such as the 5th or 15th percentile ^20–22 . The second approach is the threshold method first described by Müller et al ²³. The threshold method uses a predefined cut-off value in HU to differentiate “normal” from emphysematous lung. The percentage of pixels in the scanned lung volume below this threshold can be assessed. The benefit of this technique is that the percentage of lung volume within the defined density range (known as the pixel or voxel index) is closely representative of the percentage of emphysema within the lungs. In addition, the distribution of these low attenuation areas can be delineated (Fig. 2). Initial studies using CT scans with 10 mm lung slices showed that −910 HU provided the best correlation with histologically defined emphysema ²³. Subsequent work by Gevenois et al ^{24, 25} used 1 mm CT sections (more in keeping with current technology) and showed that the optimal threshold in this scenario is −950 HU. A recent workshop on CT scanning assessed these different techniques and suggested that both threshold and percentile analysis were suitable techniques to assess emphysema in cross-sectional studies but that the15th percentile method was more suitable for longitudinal work ²⁶.

Various other techniques have been developed to investigate emphysema on the CT, although so far they been less widely utilized. The size of emphysematous lesions can be estimated by plotting the number of low attenuation voxels that are connected to neighboring low attenuation voxels (ie, clusters of voxels) against the cumulative size of this cluster ²⁷. This parameter has been shown to relate to exercise tolerance ²⁷ and survival ²⁸, although it does not relate well to pathological measurements of emphysema ²⁹. Mishima et al ³⁰ evaluated the distribution and development of low attenuation clusters in emphysema and showed that with progressive disease, the clusters increase in size but decrease in number. This relationship was expressed as a fractal dimension (D) and may be a useful indicator of early emphysematous change ³⁰. Coxson et al ³¹ have used prediction equations to quantify the lung surface area and surface area to volume ratios based on CT assessment of volume and histologic estimates of the surface area. They showed that mild emphysema is associated with increased lung volume while severe disease leads to a decrease in surface area ³¹. Other authors have developed textural analysis of the lung parenchyma where a large number of textural features from high resolution imaging are utilized to classify a tissue pattern. This has been shown to compare well with both the voxel index −950 and qualitative visual assessments of emphysema, particularly in identifying early changes in asymptomatic smokers ^32–34 .

The advent of spiral CT techniques allowed the entire lung volume to be sequentially scanned in a single breath hold for the first time. This enables an accurate, whole lung emphysema assessment to be made. In addition, on modern multidetector row scanners, slice thickness (z axis) and pixel dimensions (x and y axes) are equal meaning the CT units of volume (voxels) are cubic—also known as isotropic voxels. The benefit of voxel isotropy is that the image data are obtained with the same high resolution in all three dimensions. This is clearly an important feature when assessing the distribution of emphysema. Nonisotropic voxels suffer from image degradation if viewed or analyzed in any plane other than the traditional cross section. A comparison of 3-dimensional datasets with traditional high resolution CT showed no difference in emphysema detection or correlation with pulmonary function tests, but analysis was found to be more time efficient when analyzed in 3-D ³⁵. Another benefit of modern spiral scanning is the rapidity with which the dataset can be acquired. With a 16 cm detector row, 320 slice CT—the current industry standard—the entire thorax can be scanned in only a few seconds ³⁶, meaning even a breathless patient can be scanned within a single breath hold.

EFFECT OF RESPIRATION ON COMPUTED TOMOGRAPHY (CT) ASSESSMENT

There has been much debate over the best means to control for and display lung volume changes in relation to respiration. To achieve repeatability of the scanned lung volume, some authors advocate respiratory gating, which can ensure that scanning is always performed at the same lung volume ^{37, 38}. This is thought to be of particular importance in longitudinal studies to minimize volume and hence density changes in the same patient over time ³⁹. However, other studies have shown no benefit in the use of respiratory gating ⁴⁰. Given that emphysema progression may result in changes in lung volume, most research is currently simply performed during a breath hold; patients receive coaching on the breath hold technique and variation is found to be low using this protocol ^{41, 42}.

Other studies have investigated whether the quantification of emphysema is more optimally assessed during inspiration or expiration. Several authors have shown better correlations with pulmonary function tests using expiratory scans ^{43, 44}. Unfortunately, air trapping—which is a feature of small airways disease—is found maximally during full expiration ^45–47 and therefore will complicate emphysema analysis in cases of a mixed disease phenotype. As discussed above, pulmonary function tests are not discriminatory for emphysema and airways disease; this probably accounts for the better correlations found on some expiratory studies. Many authors therefore prefer to perform emphysema analysis during inspiration.

EMPHYSEMA DISTRIBUTION AND PULMONARY FUNCTION

Numerous studies have investigated the relationships between the CT estimated distribution of smoking related emphysema and pulmonary function tests. Initial work compared patients with either an upper or lower zone predominance of disease. Gurney et al ⁴⁸ found in 59 unselected smokers that there was a predominance of upper zone emphysema and postulated that this was related to the known association of the centrilobular pathological subtype in smokers. Despite the predominantly upper zone distribution Gurney and colleagues demonstrated that lower zone emphysema correlated better with pulmonary function. They concluded that the upper zones are a silent region where extensive parenchymal destruction can occur before it becomes clinically or functionally apparent; since there is less functional lung in the upper zones, the lower zones may be more important in preserving function. This theory was supported by similar results in studies by Nakano and colleagues and Saitoh and colleagues ^{49, 50}. Both of these authors showed more airflow limitation in patients with lower zone predominant emphysema, while upper zone predominant disease correlated better with reduced carbon monoxide gas transfer ^{49, 50}. Haraguchi et al ⁵¹ further divided the lungs into core and rind segments—the core segment is defined as the central 50% of lung tissue when viewed on a traditional axial CT slice (Fig. 2). Both studies found that the core lung segment was most strongly related to pulmonary function ^{49, 51}. Nakano et al also found a predominance of core emphysema in their cohort of 73 COPD patients. A similar argument was provided by Haraguchi to explain the functional importance of the lung core as has been described for the lower zones in previous studies; with less ventilation and perfusion it was postulated that the lung peripheries are less functionally important and therefore overall lung fuction is not as severely impeded by peripheral lung disease. Some limitations of these studies include the relatively small patient numbers and, excepting Nakano and Saitoh, the others used a qualitative assessment of emphysema. In addition, none of these studies make an assessment of airways disease in the cohort; Haraguchi and colleagues did however attempt to exclude patients with obvious airways disease from their study.

More recent studies with larger patient numbers have failed to demonstrate the same relationships between upper and lower zone predominant emphysema and pulmonary function. Aziz and colleagues tried to quantify the impact of airways disease by subjective assessment in their cohort of 101 patients. They found that the bronchial wall thickness and emphysema both independently determined FEV₁, while core predominant disease and worsening emphysema were both independently related to carbon monoxide gas transfer. They found no correlation between cranio-caudal emphysema distribution and gas transfer and also no correlation between emphysema distribution (cranio-caudal or core-rind) and FEV₁ ⁵². Similarly, in a study carried out by the present authors, emphysema distribution in 129 patients with smoking related emphysema was not independently associated with pulmonary function. In these patients with a predominance of upper zone/core disease distribution, core disease correlated with FEV₁ and FEV₁/FVC ratio but this relationship was shown to be confounded by emphysema severity following subsequent multiple linear regression analysis. No significant association with pulmonary function was found when emphysema distribution was analyzed comparing upper and lower zones ⁵³. Further work from a proportion of the same cohort of patients analyzing both airways and emphysema using quantitative analysis showed a negative correlation between advancing airways disease and emphysema and no correlation between airways disease and pulmonary function. These results indicate that the relationship between emphysema and pulmonary function in this cohort was independent of airways disease ⁵⁴.

Another recent study compared smoking related emphysema distribution and pulmonary function in a large cohort (875) of patients who underwent CT scanning as part of a lung cancer screening program. Gietema et al ⁵⁵ categorized emphysema as either predominantly moderate (−910 to −950 HU) or severe (≤950 HU) and found that moderate disease in the upper lung zones was associated with more airflow limitation and gas exchange impairment than basal disease, while there was no association between disease distribution and pulmonary function in severe emphysema. In contrast to most other cohorts that have been studied, these patients showed a predominance of lower zone disease. The results of Gietema and colleagues may give some insight into the natural history of smoking related emphysema. The cohort were heavy smokers (minimum of 30 pack years) aged 50–75 years. The subjects were, however, relatively healthy at the time of study; those with reported poor health status were excluded and the mean CT measure of severe emphysema (percentage of voxels less than −950) was 0.12%, which compares with a range of 6.4%–44% in the other studies described in this review ^48–54 . Of patients defined as having predominantly moderate emphysema, there was only a 29.2% predominance of upper zone disease. This figure increased to 37.8% in those categorized as having severe disease ⁵⁵. Therefore, differences in disease severity between this and the other study cohorts described may explain the relatively low level of upper zone predominant disease identified by Gietema and colleagues. More work is needed to adequately define the relationships between the natural history of emphysema, its pathological distribution, and pulmonary function.

EMPHYSEMA ASSOCIATED WITH ALPHA-1 ANTITRYPSIN DEFICIENCY

Emphysema related to alpha-1 antitrypsin deficiency shows a distinct pattern of disease distribution. In comparison to the smoking related emphysema, alpha-1 deficient disease was classically described as predominantly affecting the basal regions of the lungs ⁵⁶. Early CT studies utilized densitometry to evaluate the longitudinal progression of emphysema in these patients. Stolk et al ⁵⁷ found changes in voxel indices related better to health status (as assessed by the St. George's Respiratory Questionnaire, SGRQ) than changes in either FEV₁ or transfer factor for carbon monoxide (DL_CO). Dowson et al ⁵⁸ found that over a 2-year period there was a significant deterioration in all measured parameters (CT density, SGRQ, and pulmonary function), but CT lung density measurements and DL_CO were most significantly related to deterioration in health status. Significant changes of emphysema on CT were also found in the upper zones; it was postulated that alpha-1 deficient disease progresses from the predominantly lower zone to involve the upper zones with increased severity of disease. By comparing disease distribution in patients with different patterns of deranged pulmonary function, Holme and Stockley ⁵⁹ found similar results, such that predominantly lower zone disease correlated with an abnormal FEV₁ while upper zone disease was associated with derangement in both DL_CO and FEV₁. In a larger cohort of 119 alpha-1 deficient patients, Parr and colleagues ⁶⁰ found just over one-third of their cohort had predominantly upper zone emphysema. After matching patients from either group for age and total emphysema volume, they also found that a basal predominance was associated with a greater impairment of FEV₁ but less impairment of gas exchange. These findings highlight the importance of evaluating emphysema distribution in addition to assessing pulmonary function for alpha-1 deficient patients. Finally, a study of 256 alpha-1 deficient patients followed up over 5 years found that a decrease in CT lung density was a better predictor of death than either FEV₁ or DL_CO. In particular, decreasing lung density in the upper zones was found to be most predictive of a poor outcome ⁶¹. In summary, emphysema severity in cases of alpha-1 antitrypsin deficiency is only really appreciated through imaging, which takes account of both the volume and distribution of disease.

PREDISPOSITION TO EMPHYSEMA AND ITS DISTRIBUTION

Several recent studies have shown differences in the distribution and clinical phenotype of emphysema between men and women. Martinez et al ⁶² first reported on gender differences in emphysema with data collected from the National Emphysema Treatment Trial (NETT). In a large cohort of 1053 patients referred for assessment for LVRS, they found women had significantly less emphysema than men and that their emphysema was more likely to have a core distribution ⁶². Similar results were subsequently published by Dransfield and colleagues who also demonstrated a higher proportion of emphysema in men in their cohort of 396 patients. This finding was consistent when analysis was divided into upper, middle, and lower lung thirds ⁶³. In the current authors study, we also found a significant association between core emphysema and female sex and that females were more likely to exhibit upper zone predominance. Our findings were independent of overall emphysema severity ⁵³. Two more recent studies also concluded that women had less emphysema than men ^{64, 65}, however in their cohort of 957 patients, Sverzellati et al ⁶⁵ did not find increased disease predominance in the core of the lung. Such differences in disease distribution in men and women have been related to behavioral patterns in smokers, where men are thought more likely to deeply inhale, and also to sex differences in susceptibility to cigarette smoke based on innate immunity. It is likely the causative factors in emphysema are multifactorial, but undoubtedly there will be some form of genetic predisposition that underlies the risk to each individual.

It has long been suspected that there is a genetic predisposition for COPD. It is clear that there is a wide degree of susceptibility among smokers for the development of COPD and it is also clear that the condition is heterogeneous; with the same exposure to smoke, some patients develop airways disease predominantly, while others suffer from a predominance of emphysema with a variety of pathological subtypes and distributions. So far there is only one conclusively proven genetic link to the disease; as discussed above, a deficiency in alpha-1 antitrypsin leads to a severe, familial form of emphysema with a distinct (although seemingly variable) pattern of distribution. Several studies have reported other genetic links for the distribution of emphysema. Ito and colleagues demonstrated a genetic polymorphism that is linked to a predisposition for upper zone predominant emphysema identified using quantitative CT assessment ⁶⁶. More recent work based on data from the NETT used CT analysis to phenotype emphysema distribution patterns in 282 patients and correlated these with known genetic variants within the cohort. They found two polymorphisms that were significantly associated with predominantly upper zone emphysema and postulated that both apical and basal disease might be influenced by different genetic mechanisms ⁶⁷. These results suggest that future treatments for emphysema are likely to be driven by phenotypic differences in the disease, where imaging will have a significant role to play.

LUNG VOLUME REDUCTION SURGERY (LVRS)

One area where treatment of emphysema has lead to improvement in lung function, symptoms, and exercise tolerance is with LVRS. The outcomes of this treatment are critically dependant on the patients’ degree of lung functional impairment but also on the characteristics and distribution of emphysema ^68–71 . In a randomized controlled trial of 1033 patients, there was a high risk of death in patients with homogeneously distributed emphysema ¹⁰ and poorly selected patients achieved only negligible functional gain ⁷². Subsequently, therefore, potential candidates for LVRS are carefully selected based on a number of criteria including severe emphysema with a predominantly upper lobe heterogeneous distribution ⁷³ and it is recommended that the chest CT is used as the primary tool in making this distinction ⁷⁴. Nakano and colleagues ⁷⁵ have also shown that a greater extent of emphysema, in the rind of the upper lung specifically, predicts a more favorable outcome. Data from NETT were also used to determine the value of preoperative CT in predicting postoperative lung function in a large study of 608 subjects and similarly found that CT measures of emphysema and its distribution were predictive of post-LVRS improvement ⁷⁶.

SUMMARY

Thoracic CT scanning provides the means to rapidly and accurately assess both the extent and distribution of emphysema in vivo. Various techniques are available to achieve this but automated quantitative methods have been shown to be superior in their analysis. These measurements have been validated with pathology and pulmonary function and several authors have also begun to show correlations between CT measured emphysema and other clinical outcomes of the disease. The CT assessment of emphysema has the added benefit of allowing simultaneous and accurate measurement of airway dimensions, allowing airways and emphysema predominant phenotypes to be derived.

The distribution of emphysema has been shown to be related to the underlying pathological subtype that is variable among patients. There are some predictable patterns of emphysema distribution described that seem to relate to differing susceptibility to cigarette smoke, but further work is needed to fully understand this markedly heterogeneous disease. Early studies have shown associations between emphysema distribution and disease severity measured with pulmonary function as well as other clinical parameters of the disease. For a small subset of patients, the importance of emphysema distribution in relation to treatment outcome is already described. With increased understanding of the relationships between emphysema distribution and the underlying disease process, it is likely that an analysis of emphysema distribution will become more commonplace. CT scanning currently provides the best and most tested means for the assessment of the extent and distribution of emphysema in vivo.

Disclosure: The authors declare no conflict of interest.

Funding: National Institute of Health (Bethesda, MD, USA: Grant RFA-HL02-005), the Norman Salvesen Emphysema Research Trust (Edinburgh, UK).

REFERENCES

1. The definition of emphysema: report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases workshop. Am Rev Respir Dis. 1985;132:182–185.
2. Thurlbeck WM, Muller NL. Emphysema: definition, imaging, and quantification. AJR. 1994;163:1017–1025.
3. Stern EJ, Frank MS. CT of the lung in patients with pulmonary emphysema: diagnosis, quantification, and correlation with pathologic and physiologic findings. Am J Roentgenol. 1994;162(4):791–798.
4. Takahashi M, Fukuoka J, Nitta N, Takazakura R, Nagatani Y, Murakami Y, Otani H, Murata K. Imaging of pulmonary emphysema: a pictorial review. Int J COPD. 2008;3(2):193–204.
5. Nakano Y, Muro S, Sakai H, et al. Computed tomographic measurements of airway dimensions and emphysema in smokers: correlation with lung function. Am J Respir Crit Care Med. 2000;162:1102–1108.
6. Finkelstein R, Ma HD, Ghezzo H, Whittaker K, Fraser RS, Cosio MG. Morphometry of small airways in smokers and its relationship to emphysema type and hyperresponsiveness. Am J Respir Crit Care Med. 1995;152(1):267–276.
7. Saetta M, Kim WD, Izquierdo JL, Ghezzo H, Cosio MG. Extent of centrilobular and panacinar emphysema in smokers’ lungs: pathological and mechanical implications. Eur Respir J. 1994;7:664–671.
8. Fujimoto K, Kitaguchi Y, Kubo K, Honda T. Clinical analysis of chronic obstructive pulmonary disease phenotypes classified using high-resolution computed tomography. Respirology. 2006;11:731–740.
9. Makita H, Nasuhara Y, Nagai K, et al. Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease. Thorax. 2007;62:932–937.
10. National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung volume reduction surgery. N Engl J Med. 2001;345:1075–1083.
11. Goddard PR, Nicholson EM, Laszlo G, Watt I. Computed tomography in pulmonary emphysema. Clin Radiol. 1982;33:379–387.
12. Hayhurst MD, MacNee W, Flenley DC, et al. Diagnosis of pulmonary emphysema by computerised tomography. Lancet. 1984;2:320–322.
13. Bergin C, Muller N, Nichols DM, et al. The diagnosis of emphysema: a computed tomographic-pathologic correlation. Am Rev Respir Dis. 1986;133:541–546.
14. Foster WL Jr, Gimenez EI, Roubidoux MA, et al. The emphysemas: radiologic-pathologic correlations. RadioGraphics. 1993;13:311–328.
15. Sanders C, Nath PH, Bailey WC. Detection of emphysema with computed tomography: correlation with pulmonary function tests and chest radiography. Invest Radiol. 1988;23:262–266.
16. Kinsella M, Müller NL, Abboud RT, Morrison NJ, DyBuncio A. Quantitation of emphysema by computed tomography using a ‘‘density mask’’ program and correlation with pulmonary function tests. Chest. 1990;97:315–321.
17. Klein JS, Gamsu G, Webb WR, Golden JA, Müller NL. High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity. Radiology. 1992;182:817–821.
18. Foster WL Jr, Pratt PC, Roggli VL, Godwin JD, Halvorsen RA Jr, Putman CE. Centrilobular emphysema: CT-pathologic correlation. Radiology. 1986;159:27–32.
19. Miller RR, Muller NL, Vedal S, Morrison NJ, Staples CA. Limitations of computed tomography in the assessment of emphysema. Am Rev Respir Dis. 1989;139:980–983.
20. Gould GA, Macnee W, McLean A, et al. CT measurements of lung density in life can quantitate distal airspace enlargement: an essential defining feature of human emphysema. Am Rev Resp Dis. 1988;137:380–392.
21. Madani A, Zanen J, de Maertelaer V, Gevenois PA. Pulmonary emphysema: objective quantification at multi-detector row CT-comparison with macroscopic and microscopic morphometry. Radiology. 2006;238:1036– 1043.
22. Dirksen A. Monitoring the progress of emphysema by repeat computed tomography scans with focus on noise reduction. Proc Am Thorac Soc. 2008;5:925–928.
23. Müller NL, Staples CA, Miller RR, Abboud RT. ‘‘Density mask’’: an objective method to quantitate emphysema using computed tomography. Chest. 1988;94:782–787.
24. Gevenois PA, de Maertelaer V, De Vuyst P, Zanen J, Yernault JC. Comparison of computed density and macroscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med. 1995;152:653–657.
25. Gevenois PA, De Vuyst P, de Maertelaer V, et al. Comparison of computed density and microscopic morphometry in pulmonary emphysema. Am J Respir Crit Care Med. 1996;154:187–192.
26. Coxson HO. Quantitative chest tomography in COPD research: chairman’s summary. Proc Am Thorac Soc. 2008;5:874–877.
27. Coxson HO, Whittall KP, Nakano Y, et al. Selection of patients for lung volume reduction surgery. Pulmonary perspective using a power law analysis of the computed tomographic scan. Thorax. 2003;58:510.
28. Martinez FJ, Foster G, Curtis JL, et al. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med. 2006;173:1326–1334.
29. Madani A, Van Muylem A, de Maertelaer V, Zanen J, Gevenois PA. Pulmonary emphysema: size distribution of emphysematous spaces on multidetector CT images—comparison with macroscopic and microscopic morphometry. Radiology. 2008;248:1036–1041.
30. Mishima M, Hirai T, Itoh H, et al. Complexity of terminal airspace geometry assessed by lung computed tomography in normal subjects and patients with chronic obstructive pulmonary disease. Proc Natl Acad Sci. 1999;96:8829–8834.
31. Coxson HO, Rogers RM, Whittall KP, et al. A quantification of the lung surface area in emphysema using computed tomography. Am J Respir Crit Care Med. 1999;159:851–856.
32. Uppaluri R, Mitsa T, Sonka M, Hoffman EA, McLennan G. Quantification of pulmonary emphysema from lung computed tomography images. Am J Respir Crit Care Med. 1997;156:248–254.
33. Uppaluri R, Hoffman EA, Sonka M, Hartley P, Hunninghake GW, McLennan G. Computer recognition of regional lung disease patterns. Am J Respir Crit Care Med. 1999;160:648–654.
34. Xu Y, Sonka M, McLennan G, Guo J, Hoffman EA. MDCT-based 3-D texture classification of emphysema and early smoking related lung pathologies. IEEE Trans Med Imaging. 2006;25:464–475.
35. Park KJ, Bergin CJ, Clausen JL. Quantitation of emphysema with threedimensional CT densitometry: comparison with two-dimensional analysis, visual emphysema scores, and pulmonary function test results. Radiology. 1999;211:541–547.
36. Aquilion ONE: World’s first dynamic volume CT system. Available at: http://www.toshiba-medical.eu/en/Our-Product-Range/CT/Systems/ Aquilion-ONE/. 8 August 2011.
37. Kalender WA, Rienmuller R, Seissler W, Behr J, Welke M, Fichte H. Measurement of pulmonary parenchymal attenuation: use of spirometric gating with quantitative CT. Radiology. 1990;175:265–268.
38. Moroni C, Mascalchi M, Camiciottoli G, et al. Comparison of spirometric-gated and -ungated HRCT in COPD. J Comput Assist Tomogr. 2003;27:375–379.
39. Dirksen A, Friis M, Olesen KP, Skovgaard LT, Sorensen K. Progress of emphysema in severe a1-antitrypsin deficiency as assessed by annual CT. Acta Radiol. 1997;38:826–832.
40. Gierada DS, Yusen RD, Pilgram TK, et al. Repeatability of quantitative CT indexes of emphysema in patients evaluated for lung volume reduction surgery. Radiology. 2001;220:448–454.
41. Friedman PJ. Imaging studies in emphysema. Proc Am Thorac Soc. 2008;5:494–500.
42. Parr DG, Sevenoaks M, Deng CQ, Stoel BC, Stockley RA. Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; methodological advances. Respir Res. 2008;9:21–28.
43. Kauczor HU, Hast J, Heussel CP, Schlegel J, Mildenberger P, Thelen M. CT attenuation of paired HRCT scans obtained at full inspiratory/ expiratory position: comparison with pulmonary function tests. Eur Radiol. 2002;12:2757–2763.
44. Zaporozhan J, Ley S, Eberhardt R, et al. Paired inspiratory/expiratory volumetric thin-slice CT scan for emphysema analysis: comparison of different quantitative evaluations and pulmonary function test. Chest. 2005;128:3212–3220.
45. Newman KB, Lynch DA, Newman LS, Ellegood D, Newell JD Jr. Quantitative computed tomography detects air trapping due to asthma. Chest. 1994;106:105–109.
46. Hansell DM, Rubens MB, Padley SP, Wells AU. Obliterative bronchiolitis: individual CT signs of small airways disease and functional correlation. Radiology. 1997;203:721–726.
47. Lucidarme O, Coche E, Cluzel P, Mourey-Gerosa I, Howarth N, Grenier P. Expiratory CT scans for chronic airway disease: correlation with pulmonary function test results. Am J Roentgenol. 1998;170:301–307.
48. Gurney JW, Jones KK, Robbins RA, et al. Regional distribution of emphysema: correlation of high-resolution CT with pulmonary function tests in unselected smokers. Radiology. 1992;183:457–463.
49. Nakano Y, Sakai H, Muro S, et al. Comparison of low attenuation areas on computed tomographic scans between inner and outer segments of the lung in patients with chronic obstructive pulmonary disease: incidence and contribution to lung function. Thorax. 1999;54:384–389.
50. Saitoh T, Koba H, Shijubo N, Tanaka H, Sugaya F. Lobar distribution of emphysema in computed tomographic densitometric analysis. Invest Radiol. 2000;35:235–243.
51. Haraguchi M, Shimura S, Hida W, Shirato K. Pulmonary function and regional distribution of emphysema as determined by high resolution computed tomography. Respiration. 1998;65:125–129.
52. Aziz ZA, Wells AU, Desai SR, et al. Functional impairment in emphysema: contribution of airway abnormalities and distribution of parenchymal disease. AJR. 2005;185:1509–1515.
53. Mair G, Miller JJ, McAllister D, et al. Computed tomographic emphysema distribution: relationship to clinical features in a cohort of smokers. Eur Respir J. 2009;33:536–542.
54. Mair G, Maclay J, Miller JJ, McAllister D, Connell M, Murchison JT, MacNee W. Airway dimensions in COPD: relationship with clinical variables. Respir Med. 2010;104:1683–1690.
55. Gietema HA, Zanen P, Schilham A, et al. Distribution of emphysema in heavy smokers: impact on pulmonary function. Respir Med. 2010;104: 76–82.
56. Stavngaard T, Shaker SB, Dirksen A. Quantitative assessment of emphysema distribution in smokers and patients with alpha1-antitrypsin deficiency. Respir Med. 2006;100:94–100.
57. Stolk J, Ng WH, Bakker ME, et al. Correlation between annual change in health status and computer tomography derived lung density in subjects with a1-antitrypsin deficiency. Thorax. 2003;58:1027–1030.
58. Dowson LJ, Guest PJ, Stockley RA. Longitudinal changes in physiological, radiological, and health status measurements in alpha(1)-antitrypsin deficiency and factors associated with decline. Am J Respir Crit Care Med. 2001;164:1805–1809.
59. Holme J, Stockley RA. Radiologic and clinical features of COPD patients with discordant pulmonary physiology: lessons from a1-antitrypsin deficiency. Chest. 2007;132:909–915.
60. Parr DG, Stoel BC, Stolk J, Stockley RA. Pattern of emphysema distribution in a1-antitrypsin deficiency influences lung function impairment. Am J Respir Crit Care Med. 2004;170:1172–1178.
61. Dawkins PA, Dowson LJ, Guest PJ, Stockley RA. Predictors of mortality in a1-antitrypsin deficiency. Thorax. 2003;58:1020–1026.
62. Martinez FJ, Curtis JL, Sciurba F, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176:243–252.
63. Dransfield MT, Washko GR, Foreman MG, Estepar RSJ, Reilly J, Bailey WC. Gender differences in the severity of CT emphysema in COPD. Chest. 2007;132:464–470.
64. Camp PG, Coxson HO, Levy RD, et al. Sex differences in emphysema and airway disease in smokers. Chest. 2009;136:1480–1488.
65. Sverzellati N, Calabrò E, Randi G, et al. Sex differences in emphysema phenotype in smokers without airflow obstruction. Eur Respir J. 2009;33:1320–1328.
66. Ito I, Nagai S, Handa T, et al. Matrix metalloproteinase-9 promoter polymorphism associated with Hersh, DeMeo, and Silverman: genetics of emphysema 491 upper lung dominant emphysema. Am J Respir Crit Care Med. 2005;172:1378–1382.
67. Demeo DL, Hersh CP, Hoffman EA, et al. Genetic determinants of emphysema distribution in the national emphysema treatment trial. Am J Respir Crit Care Med. 2007;176:42–48.
68. Sciurba FC, Rogers RM, Keenan RJ, et al. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema. N Engl J Med. 1996;334:1095–1099.
69. Cooper JD, Patterson GA, Sundaresan RS, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg. 1996;112:1319–1329.
70. Geddes D, Davies M, Koyama H, et al. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med. 2000;343: 239–245.
71. Flaherty KR, Kazerooni EA, Curtis JL, et al. Short-term and long-term outcomes after bilateral lung volume reduction surgery: prediction by quantitative CT. Chest. 2001;119:1337–1346.
72. National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume—reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348:2059–2073.
73. DeCamp MM, Lipson D, Krasna M, Minai OA, McKenna RJ, Thomashow BM. The evaluation and preparation of the patient for lung volume reduction surgery. Proc Am Thorac Soc. 2008;5:427–431.
74. Washko GR, Hoffman E, Reilly JJ. Radiographic evaluation of the potential lung volume reduction surgery candidate. Proc Am Thorac Soc. 2008;5:421–426.
75. Nakano Y, Coxson HO, Bosan S, et al. Core to rind distribution of severe emphysema predicts outcome of lung volume reduction surgery. Am J Respir Crit Care Med. 2001;164:2195–2199.
76. Washko GR, Martinez FJ, Hoffman EA, et al. Physiological and computed tomographic predictors of outcome from lung volume reduction surgery. Am J Respir Crit Care Med. 2010;181:494–500.