Bronchoalveolar lavage fluid characteristics in acute and chronic lung transplant rejection.

BACKGROUND: The detection of graft rejection by bronchoalveolar lavage remains controversial. METHODS: To assess the value of bronchoalveolar lavage fluid in acute and chronic rejection after lung transplantation we analyzed bronchoalveolar lavage fluid cellular differential characteristics, lymphocyte sub-types and interleukin-6 (IL-6) and interleukin-8 (IL-8) cytokine levels in patients with exclusively either acute rejection (n = 37) or bronchiolitis obliterans (BO; n = 48). Both groups were compared with a control group of lung transplantation patients without rejection or infection, matched for the time the lavage was performed after lung transplantation. RESULTS: The bronchiolitis obliterans group showed marked neutrophilia, high IL-8 and higher CD4(+)CD25(+) and CD8(+)CD45(+) bronchoalveolar lavage fluid levels when compared with their stable controls. When using a cut-off point of >3% neutrophils in the lavage, the sensitivity for BO is 87.0%, the specificity 77.6%. The sensitivity of IL-8 for BO when using a cut-off point of >71.4 pg/ml is 74.5%, the specificity 83.3%. Bronchoalveolar lavage fluid in acute rejection was characterized by marked lymphocytosis, but showed no difference when compared with stable controls in any of the lymphocyte sub-types studied. When using a cut-off point of <==1% lymphocytes in the lavage, the sensitivity for acute rejection (AR) is 40.4%, the specificity 95.6%. The marked neutrophilia, high IL-8 cytokine level and more activated lymphocyte population in bronchiolitis obliterans may indicate ongoing local allograft rejection. CONCLUSIONS: In the present study we were not able to show any difference in lymphocyte sub-types when comparing acute rejection and control subjects. Cellular and soluble parameters in bronchoalveolar lavage fluid appear useful for diagnosing bronchiolitis obliterans.     

Bronchoalveolar lavage in talc induced lung disease.

A 65 year old woman with a history of occupational talc inhalation presented with hypoxaemia, cough, and dyspnoea with a normal chest radiograph. Bronchoalveolar lavage showed considerable lymphocytosis, with a predominance of T8+ T lymphocytes, and open lung biopsy showed peribronchiolar granulomas containing talc crystals. Corticosteroid treatment resulted in dramatic improvement. Bronchoalveolar lavage may aid in the diagnosis of talc related lung injury.     

Bronchoalveolar lavage in lung transplantation. State of the art

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) has become a crucial tool in the management of lung transplant recipients. Detection of pulmonary infectious pathogens by culture, cytology, and histology of BAL, protected brush specimens, and transbronchial biopsies (TBB) is highly effective. Morphologic and phenotypological analyses of BAL cells may be suggestive for certain complications after lung transplantation. For interpretation of BAL findings, the natural course of BAL cell morphology and phenotypology after lung transplantation must be considered. During the first 3 months after pulmonary transplantation, elevated total cell count in BAL and neutrophilic alveolitis are common, representing the cellular response to graft injury and interaction of immunocompetent cells of donor and recipient origin. With increasing time after transplantation the CD4/CD8 ratio decreases due to lowered percentages of CD4 cells in BAL. During bacterial pneumonias, the cellular profile of BAL is characterized by a marked granulocytic alveolitis. Lymphocytic alveolitis with a decreased CD4/CD8 ratio is suggestive of acute rejection, but is also found in viral pneumonias and obliterative bronchiolitis. In the case of a combined lymphocytosis and neutrophilia without any evidence of infection, obliterative bronchiolitis should be considered. Functional analyses of BAL cells can give additional information about the immunologic status of the graft, even before histologic changes become evident but have not been established in routine transplant monitoring. However, functional studies suggest an important role of activated, alloreactive and donor-specific T lymphocytes in the pathogenesis of acute and chronic lung rejection. Investigations of soluble components in BAL have given further insight into the immunologic processes after lung transplantation. In this overview, the characteristics of BAL after lung transplantation will be summarized, and its relevance for the detection of pulmonary complications will be discussed.     

Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease.

The reported prevalence of interstitial lung disease in patients with rheumatoid arthritis has varied from 10% to 50%, yet less than 5% of patients with arthritis develop severe fibrosing interstitial lung disease. This suggests that subclinical disease may not always presage progressive disease. Bronchoalveolar lavage fluid from patients with rheumatoid arthritis and either clinically evident interstitial lung disease or subclinical disease was examined for the presence of factors with a putative role in the development of interstitial fibrosis. Patients with subclinical disease were identified by prospective radiographic and lung function screening of 93 patients with rheumatoid arthritis. Fourteen patients were identified in this manner and an association between subclinical disease and smoking history was noted. Eleven patients with established interstitial lung disease had increased neutrophils (p less than 0.05), collagenase, and type III procollagen N terminal peptide levels (p less than 0.01) in the bronchoalveolar lavage fluid. Preliminary characterisation of the bronchoalveolar lavage collagenase suggested that it originated from neutrophils. Ten patients with subclinical interstitial lung disease underwent bronchoalveolar lavage. Of these, one had increased neutrophils and two had increased collagenase concentrations--abnormalities associated with advanced interstitial lung disease and a poor prognosis. These results suggest that in arthritis patients with evidence of subclinical pulmonary interstitial disease bronchoalveolar lavage might be useful in identifying those who may require careful monitoring in the hope that early treatment will prevent severe fibrosis.     

Nocardia infection in lung transplant recipients.

BACKGROUND: Nocardia is responsible for infection in both normal and immunocompromised hosts. Organ transplant recipients are increasingly recognized as a sub-group of immunocompromised patients in whom nocardia is an important pathogen. The frequency of nocardia in organ transplant recipients varies between 0.7% and 3%. Nocardia infection has largely been reported in heart, kidney and liver transplant recipients. Presentations of nocardia in lung transplant recipients have been restricted primarily to case reports. The present study reviews the clinical and epidemiologic characteristics of nocardia infection in lung transplant recipients at our institution. METHODS: A retrospective cohort study of 473 lung transplant recipients from January 1991 to November 2000 was done at a university hospital. Patient demographics, immunosuppressive regimen at the time of isolation of nocardia species, use of trimethoprim-sulfamethoxazole for Pneumocystis carinii prophylaxis, rejection episodes in the preceding 6 months, concurrent pathogens, site of infection, radiologic findings and treatment and outcome were recorded. RESULTS: Nocardia infection was found in 2.1% (10 of 473) of our lung transplant recipients. Median time of onset was 34.1 months after transplantation. Nocardia species included N farcinica in 30% (3 of 10), N nova in 30% (3 of 10), N asteroides complex in 30% (3 of 10) and N brasiliensis in 10% (1 of 10) of patients. Post-transplant diabetes was present in 50% (5 of 10) of patients. The primary indication for lung transplantation was emphysema in 40% (4 of 10). Native lung involvement was noted in 75% (3 of 4) of patients with single lung transplant. Breakthrough nocardia infection were noted in 6 patients who were receiving trimethoprim-sulfamethoxazole prophylaxis for P carinii pneumonia; all breakthrough isolates remained susceptible to trimethoprim-sulfamethoxazole. Overall mortality was 40% (4 of 10). All patients (3 of 3) with infection due to N farcinica, except 1 (1 of 7) with infection due to other nocardia species, died. Seventy-five percent (3 of 4) of deaths were attributable to nocardia infection. CONCLUSIONS: Nocardia infection tended to involve the native lung in single lung transplant recipients. Trimethoprim-sulfamethoxazole for P carinii prophylaxis at the doses given was not protective against nocardiosis in these patients. Infection with N farcinica was associated with poor outcome. Thus, species identification and extended courses of antibiotics based on antimicrobial susceptibility testing are important in management of these patients.     

Cyclosporine nephrotoxicity in lung transplant recipients.

End-stage lung disease has been treated successfully by lung transplantation (LTXP) at our institution since 1983. We report on the renal function of 30 LTXP recipients who were followed for at least 6 months (mean, 39 months; range, 6-60 months). All patients received quadruple immunosuppressive therapy including cyclosporine A, with a trough serum level (RIA) between 150 and 250 ng/ml for the first 6 months between 125 and 150 mg/ml after 6 months. The mean serum creatinine (SeCr) increased from a baseline value of 75 +/- 3.5 to 182 +/- 13.9 microM at the end of the follow-up. The greatest change in SeCr occurred within the first 6 months post LTXP. Fifteen of 30 patients who were initially normotensive required at least one antihypertensive medication post LTXP. By the end of the follow-up, 9 patients had SeCr > 200 microM. Two patients in this institution have progressed to end-stage renal disease requiring dialytic therapy. CsA nephrotoxicity has emerged as a major source of morbidity in the lung transplant population. Nephrotoxicity occurs early, and there does not appear to be any trend toward reversibility despite a lowering of the dose. Renal parenchymal injury may be progressive, despite an apparent plateau of the SeCr in some patients.     

Bronchogenic carcinoma in lung transplant recipients.

Although lung transplant recipients have a higher prevalence of non-melanoma skin cancers and lymphoma than the general population, the same has not been noted for bronchogenic carcinoma. If an increased prevalence of bronchogenic carcinoma exists, contributing factors may include the high rate of previous tobacco use in this population and/or the chronic immunosuppression used to prevent allograft rejection. With time, the incidence of bronchogenic carcinoma in the lung transplant population is likely to parallel the increasing longevity and number of transplanted individuals. We describe 2 cases of bronchogenic carcinoma in lung transplant recipients that demonstrate the morbidity associated with the discovery or development of bronchogenic carcinoma in this population.     

Bronchoalveolar lavage cytokine profile in a cohort of lung transplant recipients: a predictive role of interleukin-12 with respect to onset of bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome is the main long-term complication of lung transplantation that limits survival of lung transplant patients. Its pathophysiologic mechanisms are still poorly understood but it seems to result from a chronic immunologic/inflammatory insult leading to excessive fibroproliferation. The aim of this longitudinal study of 44 lung recipients was to determine whether a number of bronchoalveolar lavage and clinical variables are associated with a higher risk of developing bronchiolitis obliterans syndrome. METHODS: Bronchoalveolar lavage studies involved assessment of several cytokines including: interleukin-8, monocyte chemoattractant protein-1, regulated-upon-activation normal T cell expressed and secreted (RANTES), gamma-interferon, interleukin-12, interleukin-10 and transforming growth factor-beta. RESULTS: The predictivity of bronchoalveolar lavage (BAL) features with respect to onset of bronchiolitis obliterans syndrome was assessed by the Cox regression model. Among clinical variables, bacterial and viral infections were found to significantly predict occurrence of bronchiolitis obliterans syndrome (hazard ratio [HR] for bacterial infection: 13.044, 95% confidence interval [CI] 1.34 to 126.69, p = 0.027; HR for viral infections: 4.88, 95% CI 1.004 to 22.87, p = 0.05). Among BAL variables, only IL-12 was significantly predictive of bronchiolitis obliterans syndrome (HR 0.956, 95% CI 0.901 to 1.01, p = 0.03). In addition, in a sub-group cross-sectional analysis, bronchiolitis obliterans syndrome patients were compared with clinically stable patients, and significant increases in median levels of interleukin-8 and monocyte chemoattractant protein-1 BAL fluid were detected. CONCLUSIONS: These findings support the contention that interleukin-12 plays a role in the modulation of the local pro-/anti-fibrotic balance of allograft airways.     

Pregnancy in lung transplant recipients

Eight female lung transplant recipients, all of whom became pregnant after transplant, were reported to the National Transplantation Pregnancy Registry from US transplant centers. Outcomes of the 8 pregnancies were 4 live births, 3 therapeutic abortions, and 1 spontaneous abortion. Three of the 4 newborns were premature, with low birth weight (< 2500 grams). Rejection during pregnancy occurred in 3 pregnancies (38%). All 8 transplant recipients reported at least 1 complication during pregnancy, including shortness of breath, rejection, and infection. Two of the 4 deliveries were by cesarean section. At follow-up, all children were developing well with no residual problems. Female lung transplant recipients may face higher risks during pregnancy than other solid organ transplant recipients.     

Clinical utility of bronchoalveolar lavage cell phenotype analyses in the postoperative monitoring of lung transplant recipients.

OBJECTIVE: Bronchoalveolar lavage (BAL) fluid provides a crucial tool for investigation of the cellular component of the deep lung spaces and hence to approach the alloreactive response following lung transplantation. This study investigated whether BAL cell profiles can assist for the diagnosis of certain postoperative complications. METHODS: We conducted a retrospective analysis of both transbronchial biopsy and bronchoalveolar lavage materials in a series of 26 consecutive lung transplant recipients (LTR) in relationship with their clinical status at the time of the procedure. BAL fluid was subjected to cell morphology as well as flow cytometric phenotypic analyses. The samples were labeled as follows: normal transplant in clinically stable and healthy recipients, n=58; acute rejection (AR), n=58; infection (INF), n=31; and obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS) n=27. RESULTS: Total BAL cell counts were the highest in INF. Lymphocytic alveolitis was suggestive of both acute allograft rejection and CMV viral infection, with a combined significant increased HLA-DR positive cells in AR. Alveolar neutrophilia with an increased CD4/CD8 ratio was correlated with the diagnosis of OB. The neutrophil percentages, HLA-DR and CD57 positive cells were significantly higher when an infection was present. CONCLUSION: These findings suggest that BAL cell analysis could give complementary information of histological data and further insight into immunologic events after lung allograft. A longitudinal surveillance of BAL cell profiles in an individual patient may be suggestive for a preclinical state of posttransplant acute rejection, bacterial infection and obliterative bronchiolitis.     

Tuberculosis in lung transplant recipients

BACKGROUND: Post-lung transplant infection is one of the leading causes of morbidity and mortality. The cause and incidence are similar in many series; however, infections such as Mycobacterium tuberculosis are influenced by the epidemiologic situation. The authors present a prospective and observational study to define the incidence, clinical presentation, and course of tuberculosis in a cohort of lung transplant patients at a single center in Spain. METHODS: Between 1990 and 2002, cutaneous delayed-type hypersensitivity testing and pathologic and microbiologic study of explanted lungs were conducted in 187 lung transplant patients. Serial bronchoscopies with transbronchial biopsy and bronchioalveolar lavage were performed during follow-up. The diagnosis of tuberculosis was established only when M. tuberculosis was identified in any sample or when histopathologic study was conclusive. RESULTS: Forty-eight patients were classified as anergic (25.6%) and 61 (32.6%) were classified as having a positive tuberculin skin test. Of the 109 patients, 95 received latent tuberculosis infection prophylaxis. Tuberculosis was diagnosed in 12 patients (6.41%); in six of them, diagnosis was determined from the explanted lungs. The remainder were diagnosed during follow-up. Fever and dyspnea were the most common symptoms. Chest radiographic findings presented an alveolar pattern. All patients responded well to antituberculous therapy; no deaths were attributable to tuberculosis. CONCLUSIONS: In the authors' experience, tuberculosis is not rare in lung transplant patients and can be managed successfully with antituberculous therapy without rifampin. A systematic protocol for diagnosing tuberculosis of the explanted lung is useful for reducing tuberculous complications of the implanted lung.     

Hypogammaglobulinemia in lung transplant recipients

BACKGROUND: Infectious complications continue to represent a significant source of morbidity and mortality in lung transplant recipients. Identifying specific, remediable immune defects is of potential value. After one lung transplant patient with recurrent infections was noted to be severely hypogammaglobulinemic, a screening program for humoral immune defects was instituted. The objectives were to define the prevalence of hypogammaglobulinemia in lung transplant recipients, assess levels of antibody to specific pathogens, and correlate infectious disease outcomes and survival with immunoglobulin levels. METHODS: All lung transplant recipients followed at a single center between October 1996 and June 1999 underwent a posttransplant humoral immune status survey as part of routine posttransplant follow-up. This survey consists of total immunoglobulin levels (IgG, IgM, IgA), IgG subclasses (IgG1-4), and antibody titers to Pneumococcus, diphtheria, and tetanus. Since February 1997, this survey has been incorporated into the pretransplant evaluation as well. Humoral survey results for October 1996 through July 1999 were recorded, and clinical information on major infectious disease outcomes was obtained from chart reviews, discharge summaries, the Cleveland Clinic Unified Transplant Database, and review of all microbiological studies and pathology results for each patient. RESULTS: Of 67 patients with humoral immune surveys drawn posttransplant, 47 (70%) had IgG levels less than 600 mg/dl (normal 717-1410 mg/dl), of which 25 (37%) had IgG levels less than 400 mg/dl ("lowest IgG group") and 22 (33%) had IgG levels between 400 and 600 mg/dl ("moderately low IgG group"). A total of 20 patients (30%) had IgG levels of more than 600 mg/dl ("normal IgG group"). Infections that were significantly more common in the lowest IgG group, and more common in the moderately low IgG group than the normal IgG group, included: number of pneumonias (P=0.0006), bacteremias (P=0.02), total bacterial infections (P=0.002), tissue-invasive cytomegalovirus (P=0.01), invasive aspergillosis (P=0.001), total fungal infections (P=0.001), and total infections (P=0.006). Median hospital days per posttransplant year was significantly different in the three groups (11.0 vs. 7.4 vs. 2.8 days, P=0.0003.) Invasive aspergillosis occurred in 44% of the lowest IgG group, 9% of the moderately low IgG group, and 0% of the normal IgG group (P<0.001). Survival was poorest in the lowest IgG group and intermediate in the moderately low IgG group. IgG subclass deficiencies occurred in a variety of patterns. Hypogammaglobulinemic patients lacked protective responses to Pneumococcus in 14/47 (30%), diphtheria in 15%, and tetanus in 19%. In a group of 48 patients screened pretransplant, 90% had normal immunoglobulin levels. CONCLUSIONS: Hypogammaglobulinemia in lung transplant recipients is more common than has been previously recognized. An IgG level of less than 400 mg/dl identifies a group at extremely high risk of bacterial and fungal infections, tissue-invasive cytomegalovirus, and poorer survival. Immunoglobulin monitoring may offer an opportunity for intensive surveillance, tapering of immunosuppression, and preemptive therapy for infection.