key: cord-0698555-b7iuemr9 authors: Stjärne Aspelund, Anna; Hammarström, Helena; Inghammar, Malin; Larsson, Hillevi; Hansson, Lennart; Riise, Gerdt C.; Friman, Vanda; Christensson, Bertil; Påhlman, Lisa I. title: Microbiological findings in bronchoalveolar lavage fluid from lung transplant patients in Sweden date: 2018-08-27 journal: Transpl Infect Dis DOI: 10.1111/tid.12973 sha: 0816e748c473f9ddf03d7952738025c7bf22ef33 doc_id: 698555 cord_uid: b7iuemr9 BACKGROUND: Lung transplant patients experience a high risk of airway infections and microbial colonization of the lung due to constant exposure to the environment through inhaled microorganisms, denervation, reduced ciliary transport, and decreased cough. METHODS: In this nationwide prospective study on Swedish lung transplant patients, we evaluated the microbiological panorama of bacteria, fungi, and virus found in bronchoalveolar lavage fluid (BALF) obtained the first year after lung transplantation (LTx). Differences in microbiological findings depending of concomitant signs of infection and background factors were assessed. RESULTS: A total of 470 bronchoscopies from 126 patients were evaluated. Sixty‐two percent (n = 293) of BALF samples had positive microbiological finding(s). Forty‐six percent (n = 217) had bacterial growth, 29% (n = 137) fungal growth, and 9% (n = 43) were positive in viral PCR. In 38% of BALF samples (n = 181), a single microbe was found, whereas a combination of bacteria, fungi or virus was found in 24% (n = 112) of bronchoscopies. The most common microbiological findings were Candida albicans, Pseudomonas aeruginosa and coagulase negative Staphylococcus (in 42 (33%), 36 (29%), and 25 (20%) patients, respectively). Microbiological findings were similar in BALF from patients with and without signs of lung infection and the frequency of multidrug resistant (MDR) bacteria was low. No significant association was found between background factors and time to first lung infection. CONCLUSION: This study gives important epidemiologic insights and reinforces that microbiological findings have to be evaluated in the light of clinical symptoms and endobronchial appearance in the assessment of lung infections in lung transplant patients. Lung transplantation (LTx) increases as a treatment option for end stage lung disease. Although mortality post transplantation has decreased with modern surgical techniques and pharmaceutical regimes, 5-year mortality has been reported to be around 50%, of which infections are the predominant cause of death during the first year post LTx. 1 The constant exposure to the environment through inhaled microorganisms together with denervation, reduced ciliary transport and decreased cough, increase the risk of lung infections. Moreover, heavy immunosuppressive therapy leads to decreased excluded. All patients were followed up for 1 year after transplantation. Written informed consent was obtained from all study participants. The study was approved by the Regional Ethics Committee (Reg nr 433-08) and performed in accordance with the ethical standards of the 1964 declaration of Helsinki and its later amendments. Standard protocol for immunosuppression included induction therapy with ATG (anti-thymocyte globulin), followed by tacrolimus or ciclosporin, mycophenolate mofetil, and steroids. All lung transplant recipients received Pneumocystis prophylaxis with co-trimoxazole. Cytomegalovirus (CMV) prophylaxis with valganciclovir was given to all participants, with the exception of patients in Gothenburg when both donor and recipient were CMV negative. In Lund, patients received fungal prophylaxis with fluconazole for 3-6 months, whereas patients in Gothenburg received oral nystatin for at least 3 weeks. Standard perioperative antibiotic treatment was cefotaxime in Gothenburg and imipenem in Lund. Post-operative modifications or termination of antibiotic treatment was done according to perioperative donor and recipient cultures. During the LTx procedure, bacterial and fungal cultures were obtained from the donor and recipient lungs. The recipients were then followed during the first year after LTx with routine bronchoscopies at 3, 6, and 12 months post transplantation, and additional bronchoscopies were performed in response to clinical symptoms. BAL proce- Bronchoscopies with positive microbiological finding(s) were classified as pneumonia in the presence of at least one of the following clinical criteria; new or increased cough, dyspnea, increased sputa, fever >38°C, worsening gas exchange, or white blood cell count >15 × 10 9 /L, together with new (within 7 days before or after bronchoscopy) infiltrates in chest radiology (x-ray or CT scan). Bronchoscopies with positive microbiological finding(s) were classified as tracheobronchitis in the presence of clinical signs as above with no infiltrates on chest radiology but one or more of the following macroscopic endobronchial abnormalities: inflamed endobronchial Clinical data were recorded at time of bronchoscopy in a study protocol, and retrieved retrospectively from patient records. Time after transplantation was categorized: <1 month, 1-3 months, 3-6 months, 6-9, and 9-12 months after LTx. Microbiological findings were grouped into Gram-negative bacteria (G−), Gram-positive bacteria (G+), yeast, mold, and virus. P. aeruginosa was analyzed separately. Numerical data are presented as median and range. Chi-squared, rank sum, Kruskall-Wallis tests, logistic regression and analysis of variance were used to assess the distribution of background factors among different bacterial groups, lung infections and time periods. Since participants underwent varying numbers of bronchoscopies in the study, and several patients had recurrent findings of the same pathogen in BALF, the frequency of individual microbes is reported as the total number of patients with the actual finding. Grouped microbiological findings during the first year are presented as percent of patients with a bronchoscopy within the specified time period. In contrast to overall microbiological findings, lung infections are presented as number of episodes and not as a proportion of patients. The association between background data (gender, age at LTx, type of LTx and underlying disease, type of immunosuppression, positive or negative donor cultures) and time to first lung infection was estimated with Cox regression. All statistical tests were two-sided, and 95% CIs that did not overlap 1.0 and P-values less than 0.05 were considered statistically significant. Analyses were performed using In total, 135 of 146 (92%) patients eligible for inclusion were consecutively included in the study. Nine patients were unable to give informed consent, one patient declined participation and one patient was not included for unknown reasons. Nine patients died before any bronchoscopy was performed, resulting in 126 patients (97 from Gothenburg and 29 from Lund) prospectively followed up for 1 year after LTx. The participants had a median age of 57 years, 52% were women, 85% underwent double lung transplantation, and chronic obstructive pulmonary disease (COPD) was the most common underlying disease. For detailed patient characteristics, see Table 1 In total, 177 (38%) BALF samples had negative microbiological results, including 75 samples with growth of pharyngeal flora Single n (%) 18 (14) Double n (%) 108 (85) Underlying diagnosis n patients (%) Chronic obstructive pulmonary disease 33 (26) Pulmonary fibrosis 31 (25) Cystic fibrosis 18 (14) Alpha-1 antitrypsin deficiency 17 (13) Pulmonary arterial hypertension 7 (6) Re-transplantation 6 (5) Bronchiolitis obliterans syndrome 2 (2) Other 6 (5) ( Figure 2 ). These were excluded from further analyses. The remain- The proportion of patients with bacterial findings in BALF increased over the first 6 months and then declined ( Figure 3A ). Yeast was most common within the first month after LTx, whereas mold peaked at 3-6 months ( Figure 3B ). The proportion of viral findings increased over time with a maximum of 20% of patients at 6-9 months ( Figure 3C ). During the lung transplantation procedure, bacterial and fungal cul- We wish to thank the staff at the transplantation and bronchoscopy The authors have no conflicts of interest to declare in relation to the material presented. ASA planned the study, compiled data, performed statistical calculations, and wrote the manuscript. In accordance with editorial policies and ethical considerations, all authors revised the material, discussed the results, and contributed to the final manuscript. 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