ARE NONTUBERCULOUS MYCOBACTERIA (NTM) OF CONCERN IN WESTERN PACIFIC REGION? WHO TAG Meeting December 2014 Manila WWYew NTM are ubiquitous organisms present in the environment, notably in water and soil In addition, animal reservoirs are possible Nontuberculous Mycobacteria (NTM) • More than 140 species of NTM can cause infections in human beings and animal, with 20 species representing 95% of all clinical isolates • Pulmonary NTM disease is most frequent and accounts for 65-90% of all clinical NTM diseases. Wolinsky E et al Nontuberculous Mycobacteria and Associated Diseases Am Rev Respir Dis (1979) Colonisation vs Invasion Yew (2009) Environmental Exposure to NTM Contamination Host local defence and systemic immunity ? No progression Transient Colonisation Pathogen virulence ? Host local defence impairment∆ ? Active Colonisation Mycobacterial load ? Other host cofactors* ? Indolent Infection Host susceptibility, local / systemic impairment of immunity ? ∆ e.g. COPD, Pneumoconiosis, Cystic Fibrosis * Bacterial infection, TB, Lung cancer, Tobacco Smoke, Alcohol etc ? Bronchiectasis Overt Disease (PULMONARY) Risk Factors for Pulmonary NTM Disease • Pneumoconiosis • COPD • Cystic fibrosis • BRONCHIECTASIS • HIV • Systemic immunocompromisation • Achalasia and other oesophageal dysmotility • Pulmonary alveolar proteinosis • Alpha-1-antitrypsin deficiency • Body habitus characteristics • Gastroesophageal reflux • Familial • Idiopathic Pathogenicity/ Virulence M. kansasii Lung Disease M. szulgai Lung Disease M abscessus Lung Disease In a Patient with Lung Transplant M abscessus Lung Disease in an Old Patient after His Lately Visit to Hot Spring !! ATS / IDSA Statement: Diagnosis, Treatment and Prevention of NTM Diseases Am J Respir Crit Care Med (2007) Clinical and Microbiologic Criteria for Diagnosing NTM Lung Disease (Adapted)  Clinical and Radiographic (both required) 1. Pulmonary symptoms, nodular or cavitary opacities on CXR, or a HRCT scan that shows multifocal bronchiectasis with multiple small nodules AND 2. Appropriate exclusion of other diagnoses especially TB and mycosis ATS / IDSA Statement: Diagnosis, Treatment and Prevention of NTM Diseases Am J Respir Crit Care Med (2007) Clinical and Microbiologic Criteria for Diagnosing NTM Lung Disease (Adapted)  Microbiologic 1. Positive culture results from at least two separate expectorated sputum samples. If the results from (1) are nondiagnostic, consider repeat sputum AFB smears and cultures OR 2. Positive culture result from at least one bronchial wash or lavage OR 3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM, or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM FIBROCAVITARY MAC Lung Disease In a Middle-Age Male Smoker NODULAR BRONCHIECTASIS due to MAC in an Elderly Woman Koh WJ Clinical Significance of a Single Isolation of Pathogenic NTM from Sputum Specimens Diagn Microbiol Infect Dis (2013) • 120 patients with MAC, 62 patients with M abscessus and 8 patients with M kansassii as a single positive sputum culture were followed up. Bronchiectasis • 26 patients: 16 MAC and 10 M abscessus (14%) had an additional positive culture of the same NTM species and met the ATS diagnostic criteria for NTM lung disease Possible Causes of Rise in Prevalence of NTM Infection / Disease Worldwide Increase in prevalence of HIV infection and other acquired immunocompromised states Increased understanding and organisms as potential pathogens awareness of Increased recognition of association of these mycobacteria with a number of pulmonary and extrapulmonary conditions, as well as pathophysiology of ageing Improvement in methods of detection and recovery Increasing contact of humans with these organisms worldwide Another possible association of increase in prevalence of Pulmonary NTM Infection/Disease? • Decrease of prevalence of TB and/or • Decrease of BCG vaccination Hoefsloot W, van Ingen J, Andrejak C et al The Geographic Diversity of NTM isolated from Pulmonary Samples : A NTM-NET Collaborative Study Eur Respir J (2013) • Worldwide Study in 2008………. Data from 20182 patients (91 NTM species) from 62 laboratories in 30 countries • MAC predominated in most countries, followed by M gordonae and M xenopi • Important differences in geographical distribution of MAC species as well as M xenopi, M kansasii, and Rapidly Growing Mycobacteria Hoefsloot W et al ERJ 2013 • Worldwide, RGM account for 10-20% of all NTM isolates . In USA, M abscessus complex ranks as the second most common cause of NTM lung disease, but its prevalence is even higher in East Asian countries such as Korea and Japan. Proportions of M abscessus, M massiliense and M bolletii in M abscessus complex Koh, Stout, Yew IJTLD (2014) Adapted Author year Country M abscessus M massiliense M bolletii Van Ingen 2009 Netherlands 64% 21% 15% Yoshida 2013 Japan 63% 35% 2% Nakanaga 2014 Japan 60% 37% 3% Koh 2011 Korea 44% 55% 1% Lee 2014 Korea 50% 49% 1% ASIA 39% ASIA 3% 6% ASIA Thomson RM et al Changing Epidemiology of Pulmonary Nontuberculous Mycobacteria Infections Emerg Infect Dis (2010) • The incidence of notified cases of clinically significant pulmonary disease rose from 2.2 per 100,000 in 1999 to 3.2 per 100,000 in 2005 in Queensland • The pattern of disease has changed from predominantly cavitary disease in middle-aged men who smoke to fibronodular disease in elderly women. • Mycobacterium intracellulare is the main pathogen associated with the increase USA Thomson R et al Isolation of NTM from Houshold Water and Shower Aerosols in Patients with Pulmonary Disease Caused by NTM J Clin Microbiol (2013) • The mycobacteria isolated from 20 patients included M avium (5), M intracellulare (12), M abscessus (7), M gordonae (1), M lentiflavum (1), M fortuitum (1), M peregrinum (1), M chelonae (1), M triplex (1) and M kansasii (1) • Pathogenic mycobacteria were isolated from 19 homes. Species identified in the home matched that found in the patient in 7 (35%) cases. M abscessus (3), M avium (1), M gordonae (1), M lentiflavum (1) and M kansasii (1) • NTM from the aerosols included M abscessus (3 homes), M gordonae (2 homes), M kansasii (1 home), M fortuitum complex (4 homes), M mucogenicum (1 home), M wolinsky (1 home). Thomson RM et al Factors Associated with the Isolation of NTM from a Large Municipal Water System in BRISBANE Australia BMC Microbiol (2013) • Species that have been documented to cause disease in humans residing in Brisbane that were also found in water include M gordonae, M kansasii, M abscessus, M chelonae, M fortuitum complex, M intracellulare, M avium, M flavescens, M interjectum, M lentiflavum, M mucogenicum, M simiae, M szulgai, M terrae, with M kansasii frequently isolated . M avium and M intracellulare were only infrequently isolated. • Distance of sampling site from water treatment plant in summer was associated with isolation of NTM. Pathogenic NTM were more likely identified from sites with narrower pipes, predominantly distribution sample points and from sites with asbestos cement or modified PVC pipes. Simons S et al Nontuberculous Mycobacteria in Respiratory Tract Infections, EASTERN ASIA. Emerg Infect Dis (2011) • MAC was most frequently isolated (13%-81%) and was the commonest cause of pulmonary NTM disease (43%-81%). Also pathogenic were the rapidly growing mycobacteria. Among all NTM isolated from pulmonary samples, 31% were considered clinically relevant……most patients were male (79%) and had history of TB (37%)……… Jing H et al Prevalence of Nontuberculous Mycobacteria Infection, China, 2004-2009 (1) Emerg Infect Dis (2012) • In Shanghai, the prevalence of NTM (by isolation among all mycobacteria) increased from 4.26% in 2005 to 6.38% in 2008. • To investigate the NTM prevalence in rural China, the NTM isolation rates, species distribution and drug resistance profiles through a population-based TB sentinel surveillance study in Shandong, the second largest province in China was undertaken. Jing H et al Prevalence of Nontuberculous Mycobacteria Infection, China, 2004-2009 (2) Emerg Infect Dis (2012) • From 2004 through 2009, mycobacteria species were isolated from sputum specimens of 3949 patients with suspected pulmonary TB • The conventional biochemical testing of these specimens identified 68 NTM isolates, of which 64 were confirmed by 16S rRNA gene sequencing : 52 (81.2%) were M intracellulare, 5 (7.8%) were M kansasii, 3 (4.7%) were M fortuitum, 2 (3.1%) were M chelonae and 1 (1.6%) was M gordonae and M scrofulaceum, respectively. Jing H et al Prevalence of Nontuberculous Mycobacteria Infection, China, 2004-2009 (3) Emerg Infect Dis (2012) • NTM isolation rate was lower in the rural area: 1.6% only, and was more stable than that for urban area (e.g. 5.09% in Shanghai) • The NTM strains were found in 30.7% of suspected MDR-TB cases, and 4.0% of retreatment cases were clinically significant NTM infections • Thus the findings suggest that pulmonary NTM colonization/infection pose substantial difficulties in the clinical management of NTM infections and MDR-TB. Lai CC et al Nontuberculous Mycobacteria Infections in Cancer Patients in a Medical Center in Taiwan, 2005-2008 (1) Diagn Microbiol Infect Dis (2012) • A total of 219 cancer patients with NTM infections : 60.7% > 65 years, mostly male • Lung cancer, followed by haematological malignancy and gastrointestinal cancer • Pulmonary NTM infection accounted for 93.6%, followed by skin and soft tissue infections (3.2%), disseminated infections (1.8%) and genitourinary tract infection (1.4%) Lai CC et al Nontuberculous Mycobacteria Infections in Cancer Patients in a Medical Center in Taiwan, 2005-2008 (2) Diagn Microbiol Infect Dis 2012 • Disseminated infections occurred exclusively in patients with haematological malignancy • MAC caused most lung diseases and M abscessus was the most common pathogen for extrapulmonary disease Lai CC et al Clinical Significance of Nontuberculous Mycobacteria Isolates in ELDERLY Taiwanese Patients Eur J Clin Microbiol 2011 • NTM colonization was found in 80.4% (1339 subjects) and only 19.4% had NTM diseases. • The annual incidence rates (per 100,000 inpatients and outpatients) of NTM colonization and disease both increased significantly (P<0.0001) from 10.5 to 15.8 and from 2.1 to 4.3, respectively. • Isolated pulmonary NTM diseases accounted for 90.2 % of NTM cases, with MAC being the most prevalent organisms, followed by M abscessus Khann S et al Linkage of Presumptive MDR-TB Patients to Diagnostic and Treatment Services in Cambodia PLoS One 2013 • Of 19236 patients registered, 2% fufilled the criteria of presumptive MDR-TB , 187 (48%) were examined for culture. This proportion was higher among relapse, failure, return after default and nonconverters at 3 mo of new smear-positive TB patients (>60%) as compared to nonconverters at 2 months of new TB cases (<20%) • Nearly 2/3 (113) of the samples were culture positive; of these, ¾ (85) grew MTB complex and (28) grew NTM. • 21 cases were diagnosed as MDR-TB (all among retreatment TB cases and none from nonconverters) ¼ NTM Research Project in Kampong Cham Preliminary Results MSF* with collaborating organizations • Apparent increase in NTM recovery since introduction of liquid media in laboratories in Cambodia (2009) • Survey of prevalence of NTM appears warranted • Study and treatment of pulmonary NTM diseases would be beneficial to patients and the medical community *Maryline Bonnet [email protected] NTM Research in Kampong Cham (1) • To delineate pulmonary NTM colonization versus disease in PULMONARY TB SUSPECTS • • • • • Assessment of subject comprises Questionnaire on epidemiology and clinical history Physical examination CXR 3 sputum specimens over 2 consecutive days for smear, culture on LJ and MGIT, and back-up storage (for culture) • Speciation of mycobacteria isolated by GenoType Mycobacteium CM/AS • Further speciation and drug susceptibility testing at central reference laboratory NTM Research in Kampong Cham (2) • NTM disease diagnosed by • ATS 2007 Guidelines (clinical, radiological and microbiological criteria) : investigations limited to sputum specimens and also CXR • Consensus of participating experts • NTM colonization, otherwise NTM Research in Kampong Cham (3) • • • • • • • 1186 subjects Mean age 54 yrs Female 51.6% Farmers 43.0% HIV positive 2.3% Current smoker or ex-smoker 37.1% Past TB history 26.0% NTM Research in Kampong Cham (4) • 126 out of 1186 patients (10.6%) had at least one positive culture isolate of NTM • 120/126 NTM isolates were speciated using the alluded molecular technique • 21.7% M fortuitum • 15.8% M intracellulare • 12.5% M abscessus • 10.8% M gordonae • 10.8% M scrofulaceum • 8.3% M simiae • 1.7% M avium NTM Research in Kampong Cham (5) • 11 out of 126 patients (9.0%) were diagnosed to have NTM lung disease • 7 patients had previous TB with severely destroyed lungs • 4 patients had HIV infection (with MAC) Maiga M et al Failure to Recognize Nontuberculous Mycobacteria Leads to Misdiagnosis of Chronic Pulmonary TB PLoS One (2012) • Of 142 TB patients enrolled, 43% were clinically classified as retreatment cases, and 12% of cultured isolates were NTM (8% with NTM disease: 8 MAC, 2 M simiae, and 1 M palustre, with all categorised as retreatment cases); the remaining 4% NTM isolates were in patients who also had TB. These were all new cases. • Among the cases with MAC isolated, only 3 had HIV positivity. Aliyu G et al Prevalence of Nontuberculous Mycobacterial Infections among TB Suspects in Nigeria PLoS One (2013)_ • Of 1603 patients screened, 444 (28%) culture-positive cases of PTB were identified. Of these, 375 (85%) were due to strains of MTB complex and 68 (15%) were due to NTM. • In contrast to TB, NTM cases were more likely to be diagnosed during the calendar months of the Harmattan dust season (OR 2.34, P=0.01) and aged older than 35 years (OR 2.77, P=0.0007) but less likely to have AFB identified on smear (OR 0.06, P<0.0001). Among those with NTM infections, cases 35 years or younger were more likely to have co-infection with HIV (OR 3.76, P=0.0009) McCarthy KD et al Nontuberculous Mycobacterial Disease in Patients with HIV in Southeast Asia. Am J Respir Crit Care Med (2012) • Of 1060 patients enrolled in Thailand and Vietnam, where liquid culture was performed, 124 (12%) had TB and 218 (21%) had NTM. Of 218 subjects with NTM, 66 (30%) were classified as NTM pulmonary disease suspects, 9 (4%) with NTM pulmonary disease, and 10 (5%) with NTM disseminated disease. The prevalence of NTM pulmonary disease was 2% (19/ 1060). • Of 51 patients receiving antiretroviral therapy, none had NTM disease, compared with 19 (2%) of 1009 not receiving ART.