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Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency., (Copyright 2008 S. Karger AG, Basel.)

Bronchoalveolar lavage (BAL) can provide diagnostic information in cases of primary and metastatic disease to the lung. Diagnostic material can be obtained in about 50% of primary lung cancers, with more accuracy in bronchoalveolar cell carcinoma and adenocarcinoma than in squamous cell carcinoma. The diagnostic yield for cytologic examination is comparable to that of other widely used endoscopic techniques such as transbronchial biopsy. Technical considerations for the performance of BAL for the diagnosis of cancer remain incompletely defined. These include: 1) methods to assure lavage of the appropriate segment, 2) the type of cytologic preparation and stain used, 3) conditions such as viral infections and anti-neoplastic chemotherapy, which can induce changes in airway epithelial cells very difficult to distinguish from malignancy, 4) the optimum technique for the performance of lavage. Lavage may be limited in staging patients with primary lung cancer, but may be useful in staging metastatic lung cancer. In selected clinical situations, BAL will be an important tool for the physician caring for patients in whom malignancy of the lung is suspected.

To assess the utility of bronchoalveolar lavage as a technique for diagnosing lung cancer, 850 lavages from 421 patients were reviewed. Biopsy-proven lung carcinoma was present in 35 cases. Of these, 24 (68.6%) had cells diagnostic of malignancy on cytologic preparations of the bronchoalveolar lavage fluid. Agreement between cancer subtypes determined by lavage and by tissue biopsy was 79.1%; variation usually occurred between large cell undifferentiated carcinoma and adenocarcinoma, not with small cell anaplastic carcinoma. The subtype of tumors was most accurately determined by examination of Papanicolaou-stained slides. Reactive bronchial epithelium often mimicked carcinoma, but could be correctly identified by its characteristic cytomorphology. No false-positive diagnoses of lung cancer occurred in 386 patients. The sensitivity of bronchoalveolar lavage for the diagnosis of lung carcinoma is similar to that of transbronchial biopsy and Wang needle biopsy. Because bronchoalveolar lavage may detect opportunistic infections, interstitial lung diseases and malignant cells with a low morbidity, it is a useful tool to assess patients with pulmonary infiltrates.

Because immunosuppression is required to control rejection, liver allograft recipients are susceptible to a variety of opportunistic pathogens. A total of 191 bronchoalveolar lavage (BAL) specimens from 89 patients (53 adults and 36 children) who underwent orthotopic liver transplantation was reviewed. One case each of cytomegalovirus (CMV), staphylococcal and Enterobacter pneumonia was diagnosed with the aid of pretransplant BAL. The pretransplant BAL in 62 patients showed rare yeasts in 24.2%; these probably represent oropharyngeal contaminants since the patients involved had no symptoms of Candida pneumonia. Among 54 patients who developed respiratory symptoms and underwent posttransplant BAL, 23 (42.6%) were infected with opportunistic pathogens, including Pneumocystis carinii (22.2%), CMV (22.2%) and herpes simplex virus (HSV) (7.4%). Frequently, infection with multiple organisms was present. Adults constituted 100% of the HSV-infected group, 69.2% of the CMV-infected group and 16.6% of the group infected with P carinii. The diagnosis of these infections was aided by a combination of cytology, microbial culture and in situ hybridization techniques. Although BAL permitted the diagnosis and treatment of opportunistic infections, high mortality (62.5%) occurred with CMV and HSV pneumonia. Further studies into methods that permit earlier diagnoses of these infections are necessary.

Two common methods for the preparation of bronchoalveolar lavage (BAL) fluid for cytologic examination, cytocentrifugation and membrane filtration, have been found to yield different results in the quantitation of lymphocytes. To compare these two methods for the quantitation of neutrophils, the differential counts from 640 consecutive clinical specimens were analyzed retrospectively. The percentage of neutrophils resulting from the preparation of the BAL fluids by the two methods were highly correlated (r2 = .72). However, cytocentrifugation yielded consistently higher neutrophil percentages than did membrane filtration (means for all samples: 18.5 +/- 1.0% vs. 14.7 +/- 0.9%; P less than .001). To investigate the source of the variation in neutrophil quantitation by the two methods, two series of mixing experiments were performed in which neutrophil-rich cell suspensions were added to BAL fluids. Determination of the cellular differentials before and after mixing the cell suspensions demonstrated that membrane filtration preparation tends to lose neutrophils while cytocentrifugation accurately recovers neutrophils. Thus, accurate quantitation of the two cells recovered by BAL may require use of both cytocentrifugation and membrane filtration.

Cultured skin fibroblasts from patients with hereditary adenomatosis of the colon and rectum (ACR) have a disorganized cytoskeleton. Since fibronectin has been found to restore normal cytoskeletal and cellular morphology to transformed cells, we investigated the fibronectin pattern in ACR cells. We found that although both fibronectin synthesis and binding to the cell surface were apparently normal, addition of fibronectin did not restore a normal distribution of actin cables to ACR cells. The data suggest that coupling of cell surface-bound fibronectin to the cytoskeleton might be constitutively defective in ACR cells.

Review of the bronchoalveolar lavage specimens from 326 patients resulted in the identification of Alternaria in 28 (8.6%) of the specimens. On Papanicolaou-stained Millipore filters, the most common finding was a yellow-brown-pigmented muriform conidium with characteristic transverse and longitudinal septations. Four of the patients had floccose branched and septated hyphae of Alternaria in addition to conidia. Budding yeast or yeast forms were also present in the lavage fluid of 14 of the patients with Alternaria. Two patients had concurrent Pneumocystis carinii pneumonia, and one patient had cytomegalovirus pneumonitis. No patient developed clinical features of systemic Alternaria infection, and autopsy of four patients did not reveal pneumonia. Alternaria conidia in a bronchoalveolar lavage fluid will usually represent laboratory contaminants or nonpathogenic saprophytes, and their significance lies in distinguishing them from other fungi. However, the expanded use of immunosuppressive therapy and the increasing prevalence of acquired immune deficiency syndrome may render such saprophytes clinically important.

Abnormal chest radiographs in patients with Hodgkin's disease are occasionally due to pulmonary Hodgkin's disease. The fluids recovered from bronchoalveolar lavages (BALs) from 50 patients prior to autologous bone marrow transplantation for advanced Hodgkin's disease were examined. Abnormal chest roentgenograms were present in 24 patients (48%); 4 (17%) of these had Reed-Sternberg cells or their mononucleated variants in the lavage fluid and an alveolar lymphocytosis averaging 31.4% (normal: 11.5%). The lymphocytes were small and monotonous. Of the 20 patients with abnormal chest roentgenograms but no Reed-Sternberg cells in the lavage fluid, the lymphocyte count was 10.88%, with only 3 patients exceeding 17%. Two patients with normal chest roentgenograms had Reed-Sternberg-like cells in their lavage fluids and averaged 23% lymphocytes in their lavage differential count. Eosinophils averaged 1% or less of the lavage differential and were not predictive of pulmonary Hodgkin's disease. This experience suggests that pulmonary Hodgkin's disease can be diagnosed by BAL. Reed-Sternberg cells and their mononucleated variants can be recognized by their characteristic cytomorphologic features, although care must be taken not to misinterpret reactive binucleated macrophages as neoplastic cells. In patients with Hodgkin's disease, Reed-Sternberg cells should be sought when an alveolar lymphocytosis is present.

While bronchoalveolar lavage is frequently performed to evaluate immunocompromised hosts for infection, the significance of rare yeasts found on the cytologic examination of lavage fluid is unclear. This study used the latex agglutination method to test lavage fluids for Candida antigen to assess its usefulness in distinguishing Candida pneumonia from Candida colonization of the respiratory tract or oral contamination of the lavage specimen. Ninety-seven specimens from 87 patients were categorized on the basis of historical, microbiologic, cytologic and serologic data. Bronchoalveolar lavage fluids were positive for Candida antigen in 0 of 20 specimens from normal controls, 0 of 14 specimens from patient controls, 5 (36%) of 14 specimens from patients with Pneumocystis carinii pneumonia, 0 of 5 specimens from patients with gastrointestinal candidiasis, 0 of 9 specimens contaminated by oral-derived yeasts, 2 (10%) of 19 specimens from patients with probable Candida colonization and 15 (94%) of 16 specimens from patients with clinical and laboratory evidence of Candida pneumonia. We conclude that this test assists in the differentiation of Candida pneumonia from other situations in which yeasts are recovered by bronchoalveolar lavage.