Analysis of pulmonary non-tuberculous mycobacterial infections after lung transplantation.

PURPOSE: Non-tuberculous mycobacteria (NTM) are important pathogens in lung transplant recipients. This study describes the spectrum of NTM respiratory tract infections and examines the association of NTM infections with lung transplant complications. METHODS: Data from 208 recipients transplanted from November 1990 to November 2005 were analyzed. Follow-up data were available to November 2010. Lung infection was defined by bronchoalveolar lavage, sputum, or blood cultures in the appropriate clinical setting. All identified NTM respiratory tract infections were tabulated. The cohort of patients with NTM lung infections (NTM+) were compared to the cohort without infection (NTM-). Univariate and multivariate analysis was performed to determine characteristics associated with NTM infection. Survival analyses for overall survival and development of bronchiolitis obliterans syndrome (BOS) were also performed. RESULTS: In total, 52 isolates of NTM lung infection were identified in 30 patients. The isolates included Mycobacterium abscessus (46%), Mycobacterium avium complex (MAC) (36%), Mycobacterium gordonae (9%), Mycobacterium chelonae (7%), and Mycobacterium fortuitum (2%), with multiple NTM isolates seen on 3 different occasions. The overall incidence was 14%, whereas cumulative incidences at 1, 3, and 5 years after lung transplantation were 11%, 15%, and 20%, respectively. Comparisons between the NTM+ and NTM- cohorts revealed that NTM+ patients were more likely to be African-American and have cytomegalovirus mismatch. Although no difference was seen in survival, the NTM+ cohort was more likely to develop BOS (80% vs. 58%, P = 0.02). NTM+ infection, however, was not independently associated with development of BOS by multivariate analysis. CONCLUSION: With nearly 20 years of follow-up, 14% of lung recipients develop NTM respiratory tract infections, with M. abscessus and MAC more commonly identified. M. gordonae was considered responsible for nearly 10% of NTM infections. Although survival of patients with NTM infections is similar, a striking difference in BOS rates is present in the NTM+ and NTM- groups.

Airway complication contributing to disseminated fusariosis after lung transplantation.

Fungal infections are common after lung transplantation. However, disseminated fusariosis is rare and we report the first case of airway complications associated with this infectious process. A 77-year-old Caucasian woman, who was status post left single-lung transplant for emphysema, presented to clinic 8 months after lung transplantation with pleurisy, shortness of breath, and declining lung function. Bronchoscopy showed narrowing of the left anastomotic site with dynamic compression during exhalation. An AERO stent was deployed successfully, but 3 weeks later, her symptoms recurred. Bronchoscopy showed total stent occlusion with thick tenacious mucus. Fusarium solani was isolated from cultures, and a new 1.5 cm skin nodule was found on the anteromedial midportion of the patient's left lower leg. Voriconazole and anidulafungin were started. No evidence of mucus accumulation was seen during a follow-up bronchoscopy. It is likely that Fusarium infection contributed to the initial anastomotic complication as well as to obstruction of the stent. Furthermore, the stent may have contributed to establishment and development of disseminated fusariosis. With antifungal therapy, stent patency was maintained and the patient improved clinically.

Probable Phaeoacremonium parasiticum as a cause of cavitary native lung nodules after single lung transplantation.

Lung nodules after lung transplantation most often represent infection or post-transplant lymphoproliferative disorder in the allograft. Conversely, native lung nodules in single lung transplant recipients are more likely to be bronchogenic carcinoma. We present a patient who developed native lung cavitary nodules. Although malignancy was anticipated, evaluation revealed probable Phaeoacremonium parasiticum infection. Phaeoacremonium parasiticum is a dematiaceous fungus first described as a cause of soft tissue infection in a renal transplant patient. Lung nodules have not been previously described and this is the first case, to our knowledge, of P. parasiticum identified after lung transplantation.

Clinical spectrum of gram-positive infections in lung transplantation.

PURPOSE: Gram-positive (GP) organisms are among the most common cause of infections in early postsurgical and immunocompromised populations. Patients recovering from lung transplantation (LT) are particularly susceptible owing to the physiologic stress imposed by surgery and induction with intense immunosuppression. Sites, types, and timing of GP infections following LT are not well documented. This report describes the clinical spectrum of GP infections and their effects on surgical airway complications (SAC) and bronchiolitis obliterans syndrome (BOS) following LT. METHODS AND MATERIALS: Data were collected from 202 patients undergoing 208 LT procedures at a single institution between November 1990 and November 2005. Data were retrospectively analyzed according to timing, location, and causative pathogen. RESULTS: In the median follow-up period of 2.7 years (range, 0-13.6 years), 137 GP infections were confirmed in 72 patients. Sites of infection included respiratory tract (42%), blood (27%), skin, wound and catheter (21%), and other (10%). GP pathogens identified were Staphylococcus species (77%), Enterococcus species (12%), Streptococcus species (6%), Pneumococcus (4%), and Eubacterium lentum (1%). The likelihood of SAC and BOS was increased in lung allograft recipients with GP pneumonia as compared with those without (hazard ratio 2.1; 95% confidence interval=1.5-3.1). CONCLUSIONS: GP organisms were responsible for infections in 40% of lung allograft recipients and most commonly isolated from the respiratory tract and blood stream. Staphylococcal species were most frequently identified, 42% of which were methicillin-resistant Staphylococcus aureus (MRSA). Given the strong association of respiratory tract infections with the development of SAC and BOS, empiric antimicrobial strategies after LT should include agents directed against GP organisms, especially MRSA.

Clostridium difficile colitis in lung transplantation.

PURPOSE: Clostridium difficile colitis (CDC) is the most common nosocomial infection of the gastrointestinal tract in patients with recent antibiotic use or hospitalization. Lung transplant recipients receive aggressive antimicrobial therapy postoperatively for treatment and prophylaxis of respiratory infections. This report describes the epidemiology of CDC in lung recipients from a single center and explores possible associations with bronchiolitis obliterans syndrome (BOS), a surrogate marker of chronic rejection. METHODS: Patients were divided into those with confirmed disease (CDC+) and those without disease (CDC-) based on positive C. difficile toxin assay. Because of a bimodal distribution in the time to develop CDC, the early postoperative CDC+ group was analyzed separately from the late postoperative CDC+ cohort with respect to BOS development. RESULTS: Between 1990 and 2005, 202 consecutive patients underwent 208 lung transplantation procedures. Of these, 15 lung recipients developed 23 episodes of CDC with a median follow-up period of 2.7 years (range, 0-13.6). All patients with confirmed disease had at least 1 of the following 3 risk factors: recent antibiotic use, recent hospitalization, or augmentation of steroid dosage. Of the early CDC+ patients, 100% developed BOS, but only 52% of the late CDC+ patients developed BOS, either preceding or following infection. CONCLUSION: CDC developed in 7.4% of lung transplant patients with identified risk factors, yielding a cumulative incidence of 14.7%. The statistical association of BOS development in early CDC+ patients suggests a relationship between early infections and future chronic lung rejection.

Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.

Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV1 >15%[deltaFEV1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of deltaFEV1 >15%, deltaFEV1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.

Clarithromycin for safe and cost-effective reduction of cyclosporine doses in lung allograft recipients.

BACKGROUND: This study was done to analyze the economic effect of clarithromycin on the daily dosing of cyclosporine in lung transplantation. METHODS: Nine consecutive patients (mean age +/- SEM, 34.6 +/- 5.2 years) had transplantation from June 1995 to June 1996. Median follow-up time was 649 days (range, 431 to 799 days). Preoperative diagnoses were cystic fibrosis (n = 4), idiopathic pulmonary fibrosis (n = 2), emphysema, bronchiectasis, and obliterative bronchiolitis. Median time from transplantation to addition of clarithromycin to a standard immunosuppressive regimen was 86 days (range, 14 to 181 days). RESULTS: Baseline cyclosporine dose (9.9 +/- 2.2 mg/kg/day) was reduced to 5.8 +/- 1.0 mg/kg/day and 4.1 +/- 0.8 mg/kg/day at 1 month and 1 year, respectively, after initiation of clarithromycin therapy. Estimated annual savings were $3,400 per patient. There was no increase in infection or rejection episodes. CONCLUSIONS: Clarithromycin safely reduced the dose and cost of cyclosporine in this series.

Advances in lung transplantation.

Success in lung transplantation (LT) has been attributed to proper patient and donor selection, better preservation and surgical techniques, and experience in postoperative management. In 1995, we refined our perioperative management by implementing newer perioperative strategies with critical pathways and have reduced use of cardio-pulmonary bypass (CPB), thereby improving survival after LT. We compared survival, use of CPB, intubation, intensive care unit (ICU) stay, and hospital times between PRE (prior to 1995) and POST cohorts to analyze our changes in LT. The 1-and 3-year survival rates were 57% and 29% for PRE, and 86% and 62% for POST, p < 0.01. The intubation time and ICU and hospital length of stay were significantly reduced in the POST cohort. Also, the need for CPB was reduced by about 40% in the POST group.

Risk factors for the development of obliterative bronchiolitis after lung transplantation.

BACKGROUND: Acute rejection has emerged as an important risk factor for obliterative bronchiolitis after lung transplantation. We performed a multivariate analysis to assess the impact of additional variables. METHODS: Seventy-four recipients (48 heart-lung, 18 single-lung, and 8 bilateral-lung recipients) who survived longer than 90 days and underwent transplantation more than 15 months before data analysis were included in this study. Several variables were entered into a Cox regression analysis to determine their association with the development of bronchiolitis obliterans syndrome. RESULTS: Bronchiolitis obliterans syndrome developed in 48 (65%) of 74 patients. Significant correlations were detected for acute rejection score, defined as the sum of pathologic grades of each separate acute rejection episode (p = 0.0004, likelihood ratio test value = 12.4) and for lymphocytic bronchiolitis (p = 0.03). In a bivariate model, episodes of organizing pneumonia and bacterial or fungal pneumonia significantly increased the likelihood ratio test value of the acute rejection score. The addition of the cytomegalovirus infection score, reflecting the frequency and severity of infection, to the combination of the acute rejection score and episodes of bacterial or fungal pneumonia resulted in a further significant increase in the likelihood ratio test value. Significant risk factors for moderate to severe stages of airflow limitation were at least one episode of acute rejection of grade > or = 2, younger recipient age, and any acute rejection episode 180 days or longer after transplantation. CONCLUSIONS: Increasing frequency and severity of acute rejection episodes are strongly associated with the development of bronchiolitis obliterans syndrome. Lymphocytic bronchiolitis appeared to be significant by univariate analysis, but in a two-risk factor model, it did not augment the influence of acute rejection. Organizing pneumonia, bacterial or fungal pneumonia, and increasing severity and frequency of cytomegalovirus infections potentiate the effect of acute rejection. Late episodes of acute rejection and younger recipient age increase the risk for development of advanced disease.

Impact of ganciclovir prophylaxis on heart-lung and lung transplant recipients.

BACKGROUND: Cytomegalovirus infection threatens pulmonary allograft survival and function. This retrospective study details the experience of ganciclovir prophylaxis against cytomegalovirus infection and its sequelae. METHODS: Eight-nine lung and heart-lung transplant recipients with positive cytomegalovirus serology were analyzed. The 37 recipients who underwent transplantation before September 1989 received no prophylaxis. The 52 subsequent recipients received ganciclovir prophylaxis. RESULTS: Thirty-six non-prophylaxed versus 42 prophylaxed patients had cytomegalovirus events with cumulative incidences of 100% and 86% (p < < 0.01), and median onsets of 37 +/- 21 versus 85 +/- 35 days, respectively (p < < 0.01); 22 non-prophylaxed versus 27 prophylaxed patients had cytomegalovirus pneumonitis with cumulative incidences of 60% and 55% (p < < 0.01), and median onsets of 34 +/- 14 and 84 +/- 26 days, respectively (p < < 0.01). Respiratory failure caused by cytomegalovirus pneumonitis developed in nine of the non-prophylaxed versus two of the prophylaxed patients (p < < 0.01). The significant estimated survival benefit in patients who received prophylaxis (p = 0.04) was not apparent when reanalysis was performed after exclusion of patients with respiratory failure (p = 0.36). Ganciclovir prophylaxis produced a significant delay in the development of obliterative bronchiolitis with a median time to onset of 1072 +/- 280 days versus 432 +/- 189 days for the non-prophylaxis cohort (p < < 0.01). CONCLUSIONS: Ganciclovir prophylaxis (1) improves recipient survival by reducing the severity of disease and essentially eliminating respiratory failure caused by cytomegalovirus pneumonitis, (2) reduces the incidence and delays the onset of cytomegalovirus events and pneumonitis, and (3) delays the onset of obliterative bronchiolitis.

Pediatric heart-lung transplantation: intermediate-term results.

BACKGROUND: Adult heart-lung transplantation was initiated at Stanford in 1981 and the first pediatric heart-lung transplantation was done in 1986. Intermediate-term results of pediatric heart-lung transplantation at Stanford University are presented. METHODS: A retrospective review of the records of all pediatric heart-lung transplantations done since 1986 was conducted. RESULTS: Nineteen heart-lung transplantations were done in 17 patients. Ages ranged from 2 months to 18 years with a median age of 10 years. At the time of transplantation 5 patients were infants, 7 children, and 7 adolescents. The mean follow-up was 29 +/- 6.2 months (range 1 to 77, median 16) and follow-up was 100% complete. Diagnoses were congenital heart disease in 13, primary pulmonary hypertension in 2, and cystic fibrosis, cystic lymphangiectasia, viral pneumonia, and obliterative bronchiolitis in 1 each. Median wait on the heart-lung transplantation list was 91 days (range 2 to 707). All patients had New York Heart Association class III to IV symptoms, two were receiving ventilator support, and six were receiving oxygen. Fifteen of 19 transplant recipients were discharged from the hospital. The 30-day operative mortality rate was 5.2% (1 of 19). The actuarial survival at 1, 3, and 5 years for all patients was 67%, 51%, and 41%, respectively, and for hospital survivors was 82%, 62%, and 51%. The cause of death was obliterative bronchiolitis in 4, multisystem organ failure in 3, and graft coronary artery disease and chronic airway disease in 1 each. Three patients required retransplantation, 2 because of obliterative bronchiolitis and 1 because of viral pneumonia. Two patients underwent repeat heart-lung transplantation and 1 patient underwent single lung transplantation. Rejection was diagnosed in 73% of recipients, and obliterative bronchiolitis has developed in 32% of recipients. CONCLUSIONS: Survival in pediatric heart-lung transplantation approximates that in the adult procedure at 1, 3, and 5 years. Long-term survival has been achieved but the primary factors limiting further improved survival remain infection and obliterative bronchiolitis.

Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts.

Persistent or recurrent acute allograft rejection (AR) refractory to high-dose steroid therapy can adversely affect long-term outcomes of heart-lung (HLT), bilateral-lung (BLT), and single-lung (SLT) transplantations. The use of total lymphoid irradiation (TLI) for the management of refractory acute AR in six transplant recipients (two men, four women; mean age, 29.8 +/- 3.8 years) is detailed. There are two HLT (primary pulmonary hypertension [PPH], cystic fibrosis [CF]), 1 BLT (pulmonary hypertension postventricular septal defect repair), and 3 SLT (sarcoid, PPH, congenital heart disease with atrial septal defect) recipients. Refractory AR is defined as persistent rejection unresponsive to high-dose steroid therapy in all cases. The BLT and SLT recipients had at least two moderate and one mild AR events per patient. The HLT recipients had at least two moderate acute heart and one severe and one mild asynchronous acute lung rejection events per patient. A total of 800 cGy of total lymphoid irradiation (TLI) was administered over a 5-week period. Mild and transient leukopenia was the only observed side effect. The patient with PPH received TLI 313 days after HLT for recurrent AR at another institution and died of ARDS 4 weeks after completing TLI. The patient with CF received TLI 707 days after HLT and died 457 days after TLI of severe obliterative bronchiolitis (OB) with multiorgan failure. The patient with BLT received TLI 176 days after transplant and died 372 days after TLI of respiratory failure related to severe rejection. One patient with SLT received TLI 78 days after transplant and died 679 days after TLI of severe acute AR. The two remaining patients with SLTs have been free from acute AR for more than 4 years. The patient with sarcoidosis received TLI 37 days after SLT following a clinical rejection event and two severe acute AR events. He is alive with normal lung function 5 years later. The patient with PPH received TLI 108 days after SLT following three moderate acute AR events and is alive with stable OB 4 years later. These limited preliminary results suggest that TLI has merit for the treatment of intractable acute AR following HLT and lung transplantation.

Actuarial survival of heart-lung and bilateral sequential lung transplant recipients with obliterative bronchiolitis.

BACKGROUND: Obliterative bronchiolitis is a progressive form of obstructive airway disease that threatens long-term survival in lung transplant recipients. Its incidence and the long-term survival of lung transplant recipients with obliterative bronchiolitis are unknown. METHODS: The results of 89 heart-lung and 13 bilateral sequential lung transplant survivors beyond 90 days of their operation were analyzed. The date of diagnosis for obliterative bronchiolitis was established histologically (presence of submucosal fibrosis) or physiologically by a persistent reduction in the forced vital capacity to less than 0.7 for greater than 6 weeks. There were 43 patients without obliterative bronchiolitis and 59 patients with obliterative bronchiolitis. RESULTS: No differences were found in the mean age and gender ratios between the two groups. The actuarial 1-, 5-, and 10-year percentage freedom from obliterative bronchiolitis was 72 +/- 4.6, 30 +/- 5.6, and 15 +/- 7.4, respectively, with a median onset of 689 days (range 55 to 3404 days). About half the patients with biopsy-proven obliterative bronchiolitis had a fall in their forced expiratory flow at 50% of forced vital capacity/forced vital capacity nearly 4 months before fulfilling the forced expiratory volume in 1 second criteria established by the Working Group on chronic lung dysfunction. The actuarial 1-, 5-, and 10-year percentage survival of obliterative bronchiolitis negative patients was 90 +/- 4.5, 74 +/- 8.4, and 66 +/- 10.6, respectively, versus 90 +/- 3.9, 49 +/- 6.9, and 27 +/- 10.0, respectively, for obliterative bronchiolitis positive patients (p = 0.38). The actuarial 1-, 3-, 5-, 8-, and 10-year percentage survival of lung transplant recipients after the diagnosis of obliterative bronchiolitis was 74 +/- 5.8, 50 +/- 7.5, 43 +/- 7.8, 23 +/- 8.7, and 11 +/- 9.1, respectively, with a median survival of 1084 days (range 0 to 3442 days). CONCLUSIONS: The forced expiratory flow at 50% of forced vital capacity/forced vital capacity is a more sensitive indicator for the early detection of obliterative bronchiolitis than the forced expiratory volume in 1 second after heart-lung or bilateral sequential lung transplantation. The obliterative bronchiolitis negative group survival tends to be better than the obliterative bronchiolitis positive group. The obliterative bronchiolitis positive lung transplant recipients have reasonable outcomes with a median survival time of nearly 3 years after the diagnosis of obliterative bronchiolitis. Earlier detection of obliterative bronchiolitis and refinements in management may further improve these results.