Bronchial secretory immunoglobulin a deficiency correlates with airway inflammation and progression of chronic obstructive pulmonary disease.

RATIONALE: Although airway inflammation can persist for years after smoking cessation in patients with chronic obstructive pulmonary disease (COPD), the mechanisms of persistent inflammation are largely unknown. OBJECTIVES: We investigated relationships between bronchial epithelial remodeling, polymeric immunoglobulin receptor (pIgR) expression, secretory IgA (SIgA), airway inflammation, and mural remodeling in COPD. METHODS: Lung tissue specimens and bronchoalveolar lavage were obtained from lifetime nonsmokers and former smokers with or without COPD. Epithelial structural changes were quantified by morphometric analysis. Expression of pIgR was determined by immunostaining and real-time polymerase chain reaction. Immunohistochemistry was performed for IgA, CD4 and CD8 lymphocytes, and cytomegalovirus and Epstein-Barr virus antigens. Total IgA and SIgA were measured by ELISA and IgA transcytosis was studied using cultured human bronchial epithelial cells. MEASUREMENTS AND MAIN RESULTS: Areas of bronchial mucosa covered by normal pseudostratified ciliated epithelium were characterized by pIgR expression with SIgA present on the mucosal surface. In contrast, areas of bronchial epithelial remodeling had reduced pIgR expression, localized SIgA deficiency, and increased CD4(+) and CD8(+) lymphocyte infiltration. In small airways (<2 mm), these changes were associated with presence of herpesvirus antigens, airway wall remodeling, and airflow limitation in patients with COPD. Patients with COPD had reduced SIgA in bronchoalveolar lavage. Air-liquid interface epithelial cell cultures revealed that complete epithelial differentiation was required for normal pIgR expression and IgA transcytosis. CONCLUSIONS: Our findings indicate that epithelial structural abnormalities lead to localized SIgA deficiency in COPD airways. Impaired mucosal immunity may contribute to persistent airway inflammation and progressive airway remodeling in COPD.

Polyomavirus infection and its impact on renal function and long-term outcomes after lung transplantation.

BACKGROUND: Polyomavirus infection causes nephropathy after kidney transplantation but has not been thoroughly investigated in nonrenal organ transplantation. METHODS: Ninety lung transplant recipients were enrolled, and they provided urine samples for over 4.5 years. Samples were analyzed for BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) by conventional and quantitative real-time polymerase chain reaction. RESULTS: Fifty-nine (66%) patients had polyomavirus detected at least once, including 38 patients (42%) for BKV, 25 patients (28%) for JCV, and six patients (7%) for SV40. Frequency of virus shedding in serial urine samples by patients positive at least once varied significantly among viruses: JCV, 64%; BKV, 48%; and SV40, 14%. Urinary viral loads for BKV (10 copies/mL) and JCV (10 copies/mL) were higher than for SV40 (10 copies/mL; P=0.001 and 0.0003, respectively). Polyomavirus infection was associated with a pretransplant diagnosis of chronic obstructive pulmonary disease (odds ratio 6.0; P=0.016) but was less common in patients with a history of acute rejection (odds ratio 0.28; P=0.016). SV40 infection was associated with sirolimus-based immunosuppression (P=0.037). Reduced survival was noted for patients with BKV infection (P=0.03). Patients with polyomavirus infection did not have worse renal function than those without infection, but in patients with BKV infection, creatinine clearances were lower at times when viral shedding was detected (P=0.038). CONCLUSIONS: BKV and JCV were commonly detected in the urine of lung transplant recipients; SV40 was found at low frequency. No definite impact of polyomavirus infection on renal function was documented. BKV infection was associated with poorer survival.

Obstructive sleep apnea is common in idiopathic pulmonary fibrosis.

BACKGROUND: From 1984 to 2006, studies of sleep in patients with interstitial lung disease revealed disturbed sleep, frequent nocturnal desaturations, nocturnal cough, and obstructive sleep apnea (OSA). Our goal was to analyze OSA in an outpatient population of stable patients with idiopathic pulmonary fibrosis (IPF). METHODS: Patients with IPF who had been followed up in the Vanderbilt Pulmonary Clinic were asked to participate. All patients were given a diagnosis of IPF by the 2000 American Thoracic Society consensus statement criteria. Subjects completed an Epworth sleepiness scale (ESS) questionnaire and a sleep apnea scale of sleep disorders questionnaire (SA-SDQ) before undergoing nocturnal polysomnography (NPSG). OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour. RESULTS: Fifty subjects enrolled and completed a NPSG. The mean age was 64.9 years, and the mean BMI was 32.3. OSA was diagnosed in 88% of subjects. Ten subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe OSA (AHI, > 15 events per hour). Only 6 subjects (12%) had a normal AHI. One patient was asymptomatic as determined by ESS and SA-SDQ, but had an AHI of 24 events per hour. The sensitivity of the ESS was 75% with a specificity of 15%, whereas the SA-SDQ had a sensitivity of 88% with a specificity of 50%. BMI did not correlate strongly with AHI (r = 0.30; p = 0.05). CONCLUSIONS: OSA is prevalent in patients with IPF and may be underrecognized by primary care providers and specialists. Neither ESS nor SA-SDQ alone or in combination was a strong screening tool. Given the high prevalence found in our sample, formal sleep evaluation and polysomnography should be considered in patients with IPF.

Long-term outcomes of cytomegalovirus infection and disease after lung or heart-lung transplantation with a delayed ganciclovir regimen.

BACKGROUND: Information is limited on long-term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. METHODS: We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two-wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV-mismatched patients (R-D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. RESULTS: The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R-D+ patients (p < 0.0001). Over 4.3 yr of follow-up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. CONCLUSIONS: The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R-D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.

External-beam radiotherapy for massive hemoptysis complicating mediastinal fibrosis.

Fibrosing mediastinitis with bronchial artery hypervascularity is a rare cause of massive hemoptysis. Conventional therapies for massive hemoptysis include pulmonary or bronchial artery embolization, endobronchial tamponade, or lung resection. A patient with fibrosing mediastinitis presented with refractory massive hemoptysis associated with bronchial hypervascularity and was treated with external-beam radiotherapy (XRT). The application of XRT for massive hemoptysis in malignant and nonmalignant disease of the thorax is discussed.

Chylothoraces after lung transplantation for lymphangioleiomyomatosis: review of the literature and utilization of a pleurovenous shunt.

Chylous effusions are a well-described complication of lymphangioleiomyomatosis (LAM) in both pre- and post-transplant patients. Chylous effusions can cause significant morbidity among patients and most treatment modalities have limitations to complete success. We describe the use of a pleurovenous shunt to treat a refractory chylous effusion in a patient after lung transplant for LAM. After shunt placement, the patient had complete resolution of the chylous effusion and subsequent discharge home after a prolonged hospitalization. The use of a pleurovenous shunt for refractory chylous effusions is a viable option after conventional therapy fails.

Association of progressive structural changes in the bronchial epithelium with subepithelial fibrous remodeling: a potential role for hypoxia.

In airway remodeling that occurs in association with chronic obstructive pulmonary disease (COPD), the relationship between the subepithelium and structural changes of the bronchial epithelium is not well defined. To investigate whether the subepithelium and epithelium undergo remodeling as an integrated unit, we performed morphological examination of 55 bronchial biopsy specimens obtained from explanted or resected lungs from tobacco smokers with COPD. Our results indicate that reticular basement membrane (RBM) thickness is increased and the subepithelial microvascular bed is reduced in association with progression from the normal epithelium to squamous metaplasia. Subsequent bronchial epithelial transformation to dysplasia is characterized by differential subepithelial remodeling with normalization of RBM thickness and subepithelial blood vessel density. Because fibrous remodeling of the subepithelium could limit delivery of nutrients and oxygen to the epithelium, we assessed expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX) as markers of cellular hypoxia. The number of HIF-1alpha-positive epithelial cells increased with progression of epithelial structural changes, RBM thickness, and reduction in blood vessels in the subepithelium. These findings suggest that the HIF-1alpha pathway is activated in response to subepithelial remodeling and contributes to progressive premalignant epithelial lesions in the airways of tobacco smokers with chronic airway inflammation.

A prospective longitudinal study of polyomavirus shedding in lung-transplant recipients.

BACKGROUND: Polyomavirus infection causes renal dysfunction after kidney transplantation, but it has not been thoroughly investigated in nonrenal solid-organ transplantation. METHODS: Fifty lung-transplant recipients provided prospective urine and blood samples over the course of 17 months. Samples were analyzed for BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) using conventional polymerase chain reaction (PCR), sequence analysis, and quantitative real-time PCR. RESULTS: Thirty-one (62%) of 50 patients had polyomavirus detected in at least 1 urine specimen, including 16 (32%) for BKV, 12 (24%) for JCV, and 6 (12%) for SV40. Mean BKV loads (5.0 log(10) copies/mL) did not differ from those of JCV (5.7 log(10) copies/mL; P=.38), but SV40 loads (2.5 log(10) copies/mL) were lower than those of BKV (P=.006) and JCV (P=.002). Blood samples were negative. Infection with individual polyomaviruses or polyomavirus infection in aggregate was not associated with reduced creatinine clearance. Patients not shedding polyomavirus had better survival than patients shedding polyomavirus (P=.049). CONCLUSIONS: Polyomaviruses BKV and JCV were commonly detected in urine from lung-transplant recipients. SV40 was found in 12% of patients but was shed at a lower frequency and with lower viral loads than the other viruses. Polyomavirus infection was not associated with renal dysfunction.

A survey of anti-fungal management in lung transplantation.

BACKGROUND: Fungal infections are an important complication of lung transplantation, but no controlled studies of their management have been performed. Knowledge of actual anti-fungal strategies may aid in the design of future prospective studies. METHODS: Thirty-seven of 69 active lung transplant centers, accounting for 66% of all US lung transplantations, responded to our survey. The survey focused on fungal surveillance, pre- and post-transplant prophylaxis, and approach to fungal colonization. RESULTS: The median number of lung transplantations performed by the centers in 1999 was 14 per year (range, 1-52), and median time that centers were in in operation was 9 years (range, 2-15 years). Seventy percent of centers had a transplant infectious diseases specialist. Pre-transplant fungal surveillance was performed by 81% of centers, with 67% of these surveying all patients and the remainder surveying only sub-sets of patients. Seventy-two percent of all centers started anti-fungal treatment if Aspergillus spp were isolated before transplantation. Itraconazole was the preferred agent (86%). After transplantation, 76% of centers gave anti-fungal prophylaxis, although 24% of these did so only in selected patients. Prophylactic agents in order of preference were inhaled amphotericin B (61%), itraconazole (46%), parenteral amphotericin formulations (25%), and fluconazole (21%); many centers used more than 1 agent. Prophylaxis was initiated within 24 hours by 71% and within 1 week by all centers. Median duration of prophylaxis was 3 months (range, <1 month-lifetime). All 37 centers used anti-fungal therapy if colonization with Aspergillus spp was detected for a median duration of 4.5 months. Itraconazole was the preferred agent. Only 59% of centers treated patients colonized with Candida spp. In a statistical analysis, centers with larger volumes were less likely to treat pre-transplant colonization with Candida spp but more likely to use agents other than itraconazole for post-transplant colonization with Aspergillus spp. Only 14% of centers engaged in any anti-fungal research at the time of the survey. CONCLUSIONS: The majority of surveyed lung transplant programs actively manage fungal infection with prophylaxis or pre-emptive therapy, despite the absence of controlled trials. This survey may provide an impetus and a basis for designing prospective studies.

Acute humoral rejection of human lung allografts and elevation of C4d in bronchoalveolar lavage fluid.

Antibody-mediated rejection is well established for renal allografts but remains controversial for lung allografts. Cardinal features of antibody-mediated rejection in renal allografts include antibodies to donor human leukocyte antigen (HLA) and evidence for antibody action, such as complement activation demonstrated by C4d deposition. We report a lung allograft recipient with circulating antibodies to donor HLA who failed treatment for acute cellular rejection but responded to therapy for humoral rejection. To address the second criteria for antibody-mediated rejection, we determined whether complement activation could be detected by measuring C4d in bronchoalveolar lavage fluid (BALF) by ELISA. Airway allergen challenge of asthmatics activates the complement pathway; therefore, we used BALF from asthmatics pre- and post-allergen challenge to measure C4d. These controls demonstrated that ELISA could detect increases in C4d after allergen challenge. BALF from the index patient had elevated C4d concomitant with graft dysfunction and anti-donor HLA in the absence of infection. Analysis of BALF from 25 additional lung allograft recipients showed that C4d concentrations >100 ng/mL were correlated with anti-HLA antibodies (p = 0.006), but were also observed with infection and in asyptomatic patients. The findings support the occurrence of anti-HLA-mediated lung allograft rejection and suggest that C4d measurement in BALF may be useful in diagnosis.

Chylothorax as a result of chronic lymphocytic leukemia: case report and review of the literature.

Chylothorax occurs when a disruption in the thoracic duct allows chyle to escape into the pleural space. The most commonly reported cause is malignancy, especially lymphoma. However, chylothorax caused by chronic lymphocytic leukemia is rarely reported in the literature. We describe a patient who developed chylothorax secondary to chronic lymphocytic leukemia. In addition, the pathogenesis, diagnosis, and treatment of chylothorax are reviewed.

Miliary tuberculosis as a cause of acute empyema.

Adult respiratory distress syndrome (ARDS) and sepsis are known, life-threatening complications of miliary tuberculosis. This report describes a patient with miliary tuberculosis who rapidly developed an acute tuberculous empyema. She had a fulminant course culminating in ARDS, sepsis and subsequent death. This case highlights the rare association of acute empyema with miliary tuberculosis.

A modified bronchial anastomosis technique for lung transplantation.

BACKGROUND: Low rates of major complications have been reported for the intussuscepting bronchial anastomotic technique but stenosis, malacia, and granulation tissue at the anastomosis may cause clinically important morbidity. We hypothesized that a modification of the telescoping technique that improves bronchial wall apposition might be associated with improved bronchial healing and clinical outcomes. METHODS: The telescoping horizontal mattress "U-stitch" suture technique was modified to incorporate figure-of-eight sutures placed in the cartilaginous wall between each of three intussuscepting U stitches. Serial videotape records of 152 individual anastomoses (99 modified, 53 telescoped) in 118 consecutive operative survivors were retrospectively reviewed by examiners blinded with respect to technique used. Stenosis, airway instability, mucosa quality, and devascularized luminal tissue were graded at 4 to 14 days (initial), 4 to 12 weeks (early), and 6 to 12 months (late) after transplantation. RESULTS: The incidence of anastomotic stenosis was significantly lower using the modified technique at the initial (p = 0.025) and late (p = 0.015) observations. In the initial phase airway instability (p = 0.015) and devascularization grades (p = 0.001) were also significant lower in the modified group. There were no significant differences in mucosal condition between techniques. The modified telescoping technique was associated with significant survival advantage (mean 17.7%; p = 0.029) by multivariate analysis. The incidence of major airway complications (dehiscences and stenoses required stents) tended to be lower (3% versus 6%) in the modified group. CONCLUSIONS: The modified telescoping bronchial anastomosis technique is associated with improved early and late bronchial healing and higher 5-year survival without increased major airway complications.