Extra-pulmonary Nontuberculous Mycobacterial Infections: 16 year retrospective analysis at an academic institution in Cincinnati, Ohio. A thesis submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Master of Science in Clinical & Translational Research In the Department of Environmental Health Division of Epidemiology of the College of Medicine July, 2017 by Kiran Afshan MBBS, University of Karachi, Pakistan, August, 2006 Committee Chair: Erin Haynes, DrPH Abstract Title: Extra-pulmonary Nontuberculous Mycobacterial Infections: 16 year retrospective analysis at an academic institution in Cincinnati, Ohio. Authors: Afshan K, Smulian AG, Jandarov RA, Haglund L. Background: Nontuberculous mycobacterial infections (NTM), once considered a rare cause of human disease, are now increasingly recognized in clinical practice. We have sought to identify clinical and demographic characteristics of the extra-pulmonary NTM infections presenting at our institution during 2000-2015. Methods: Records of patient with culture proven extra-pulmonary NTM infections were reviewed. Demographic information, clinical and microbiologic characteristics and treatment outcomes were captured. Results: 58 cases of extra-pulmonary NTM infections identified were classified into cutaneous 9 (15.52%), soft tissue 38 (65.52%), osteo-articular 9 (15.52%) and disseminated infections 2 (3.45%). 52% of the cases were male. Median age at diagnosis was 52years. All cases were diagnosed based on culture positivity. Among identified mycobacterial species, rapid growing mycobacteria constituted 79% of all cases with following distribution: Mycobacterium fortuitum complex 28 (48.28%), Mycobacterium abscessus/chelonae complex 15 (25.86%), Mycobacterium avium intracellulare complex 3 (5.17%), Mycobacterium marinum 3 (5.17%), Mycobacterium gordonae 2 (3.45%), and one case each of Mycobacterium arupense, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium kansasii, Mycobacterium mageritense, Mycobacterium simiae and Mycobacterium wolinskyi, [combined 7(12.04%)]. Overall cure rate was 84.6%. ii Conclusion: Health care professionals should be aware of increasing significance of the extra- pulmonary NTM infections and should utilize appropriate diagnostic modalities to ensure proper identification and improve treatment outcomes. Key Words: Nontuberculous mycobacteria, extra-pulmonary infections, M fortuitum, M abscessus/chelonae, immunocompromised conditions, treatment outcome. iii iv Table of Contents Introduction----------------------------------------------------------------------------------------------------1 Methods--------------------------------------------------------------------------------------------------------2 Results----------------------------------------------------------------------------------------------------------3-5 Discussion------------------------------------------------------------------------------------------------------5-7 References-----------------------------------------------------------------------------------------------------8-10 Tables and Figures-------------------------------------------------------------------------------------------11-14 v List of Tables & Figures Table 1: Baseline characteristics of the patients with extra-pulmonary nontuberculous Mycobacterial infections during 2000-2015 (n=58). Table 2: Distribution of mycobacterial species causing extra-pulmonary NTM infections (n=58). Figure 1: Antimicrobial susceptibility profile for the extra-pulmonary M. fortuitum isolates. Figure 2: Temporal trends of extra-pulmonary NTM infections, 2000-2015. vi Introduction Nontuberculous mycobacteria (NTM) are ubiquitous environmental agents which are widely distributed in nature1. Belonging to the genus mycobacteria, NTM are acid fast bacilli which exclude Mycobacterium tuberculosis complex and Mycobacterium leprae. There are more than 180 known species of NTM (http://www.bacterio.net/mycobacterium.html) which are traditionally described as rapid growing (RGM) or slow growing (SGM) based on their growth characteristics in the culture media. NTM cause disease states in humans with varied clinical presentation. Nontuberculous mycobacteria, once considered a rare cause of human disease1, have lately emerged as pathogen with increasing clinical significance2, 3, 4. The incidence of NTM infections is on a rise worldwide5-8. NTM have increasingly been implicated in health care related outbreaks9, notably the outbreak of Mycobacterium chimera infections in cardiothoracic surgery patients in centers across Europe and United States10, 11. Nontuberculous mycobacteria are now considered serious pathogen in patients with predisposing conditions such as cystic fibrosis12, 13 and with advanced immunosuppression14-17. NTM cause three major clinical syndromes; pulmonary, extra-pulmonary and disseminated disease18. The majority of pulmonary infections occur in immunocompetent patients19. The disseminated infections are mostly encountered in patients with immunodeficiency states like AIDS, transplant recipients and patients with cancer19-21. The spectrum of extra-pulmonary NTM infections is varied and include skin and soft tissue infections, osteo-articular infections, catheter related and device related infections22. In this retrospective study, we aim to report the clinical features and treatment outcomes of extra-pulmonary NTM infections encountered in our institution over a span of 16 years. 1 Methods We reviewed medical records of the patients with nontuberculous mycobacterial infections at the University of Cincinnati Medical Center (UCMC), Cincinnati Veterans Affairs Medical Center (VAMC) and West Chester Hospital between 2000 and 2015. We utilized mycobacterial culture data from three sources; the microbiology laboratory at the UCMC, VAMC, and a database maintained at the Hamilton County Public Health Tuberculosis Control Unit. The Hamilton County Public Health Department has set up a laboratory surveillance system whereby all laboratories report positive mycobacterial culture results to the Health Department to capture potential tuberculosis cases. We screened these sources to identify patients with positive culture data and performed a retrospective chart review to identify cases of extra-pulmonary NTM infections at our institution. We defined a case of extra-pulmonary NTM infection as a patient demonstrating clinical signs and symptoms of infection, along with a positive culture result for nontuberculous mycobacteria. We excluded all cases of pulmonary NTM infections, cases of active tuberculosis or disseminated mycobacterium avium complex (MAC) infections in patients with HIV. We abstracted data including patients’ demographic information, clinical characteristics, microbiologic data, histopathology findings and radiographic abnormalities. We recorded information pertaining to the treatment modalities utilized, the length of antimicrobial therapy and eventual outcome as defined by clinical cure of infection. We applied descriptive statistics to analyze results using statistical software R. We analyzed categorical variables using Chi-square test and continuous variables using student-T test. This study has been approved by the institutional review board of the University of Cincinnati. 2 Results We identified 58 cases of extra-pulmonary NTM infections, which were classified as cutaneous 9 (15.52%), soft tissue 38 (65.52%), osteo-articular 9 (15.52%) and disseminated infections 2 (3.45%). There were 30 male (52%) and 28 female (48%) cases. Mean age at diagnosis was 51.26 years (median 52.90, range 24.83-84.93). There were 38 Caucasians (66%) and 17 African Americans (29%). The clinical and demographic characteristics of the extra-pulmonary NTM infections are summarized in Table 1. Among comorbid conditions, 11 cases (18.97%) had diabetes mellitus, 8 (13.79%) had cardiovascular disease and 13 (22.41%) had chronic kidney disease. 25 cases (43.1%) reported history of smoking and 14 cases (24.14%) reported alcohol dependence. There were 22 (37.93%) immunocompromised (IC) patients in our study with extra-pulmonary NTM infections. Among these patients, 5 had HIV infection with median CD4 count of 13 cells/µL. There were 4 transplant recipients on immunosuppressive regimen. Rest of the 13 IC cases were on immunosuppressive medications such as corticosteroids and biologics for variety of reasons including Rheumatoid arthritis, Sjogren’s syndrome and Sarcoidosis. The predisposing conditions for the extra-pulmonary NTM infections identified in our study include open trauma in 10 cases (17.24%) and penetrating injuries in 5 cases (8.62%). Injection drug use was identified in 2 cases (3.45%), while another case diagnosed with nasal and maxillary sinusitis had history of intranasal cocaine use. 9 cases (15.52%) occurred post- surgery. Device related infections were identified in 8 cases (13.79%), among which 6 had infected peritoneal dialysis catheters, one patient had ventriculo-peritoneal shunt infection and one with gastric lap band associated abdominal wall infection and intra-abdominal abscess. 6 cases (10.34%) reported history of administration of injectable medications at the infection site prior to acquisition of infections, among which 4 cases received steroid injections and one case received epidural and estrogen injection each. There were 5 (8.62%) extra-pulmonary NTM 3 infections associated with breast augmentation procedures due to infected breast implants.