Jennifer Adjemian, PhD Epidemiology Unit, Laboratory of Clinical Infectious Diseases

1. Epidemiology of Pulmonary Nontuberculous Mycobacterial Disease among U.S. Medicare Beneficiaries, 1997-2007 Jennifer Adjemian, PhD Epidemiology Unit, Laboratory of Clinical Infectious Diseases National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH)

2. Nontuberculous Mycobacteria (NTM) • Diverse group of small bacilli • Over 140 species identified • Widely distributed in the environment • Species vary by geographic area • Soil and water (natural and treated) sources • Biofilms lining pipes for drinking water

3. NTM Exposure and Infection • People infected from environmental exposures • Hard to identify exact source of infection • NTM species range greatly in human pathogenicity • Most human infections in U.S. from: • M. aviumcomplex (MAC) (water, soil, animals) • M. kansasii(tap water) • M. abcessus(more common in SE U.S.) • M. chelonae(keratitis cases from contact lenses/LASIK) • M. fortuitum (water, soil; salon whirlpool footbaths)

4. NTM Infection & Disease • Ranges from asymptomatic infection to severe illness • Infection can manifest in the: • Lymphatic system • Skin/soft tissue/bone • Disseminated • Lungs (80%) • Treatment involves multiple antibiotics over extended period of time

5. NTM Lung Disease • Commonly presents as chronic pulmonary disease • Symptoms: • Chronic or recurring cough (with or without blood) • Sputum production • Fatigue • Shortness of breath • Chest pain • Weight loss • Often accompanied by coexisting lung diseases • Bronchiectasis,COPD, and cystic fibrosis

6. PNTM Prevalence Estimates • National prevalence estimates are limited • Not a reportable disease • Estimates vary by location, age and year • 1.8/100,000 to 57/100,000 • Trends observed • Increasing prevalence over time • Older age groups (average age ~70 yrs) • White females (≥ 60%), especially with low BMI

7. Need for National PNTM Prevalence Estimates • National estimates needed: • To determine true public health burden of NTM • To identify most affected segments of US population • To identify risk factors for disease

8. Study Objective • To identify the prevalence and trends of NTM lung disease in adults ≥ 65 yrs throughout US

9. Data Compilation • Data from 5% sample of Medicare Part B enrollees from 1997-2007 • Exclusion criteria: • <65 yrs old, covered by an HMO, enrolled for <1 month, or resided outside US • Data collected on: • Demographics (sex, race/ethnicity, age, location) • ICD-9 codes associated with claims • Scanned for Pulmonary NTM (PNTM) – 031.0

10. Prevalence Estimates • Annual prevalence (AP) for each year and period prevalence (PP) for total time period (1997-2007) • Stratified by sex, race/ethnicity, age group, state of residence, geographic region • Annual percent change (APC) • Poisson regression models used to evaluate significant changes in prevalence over time

11. Risk Factor Analysis • Univariate logistic regression used to evaluate associations between PNTM and demographic factors

12. Results: Population Summary • 2.3 million individuals included from 5% sample • Represents ~4% of all US adults ≥ 65 years old • Demographics similar to general population

13. PNTM Cases • 2,548 PNTM cases identified from 1997-2007 • 65% female, 90% white, and ranged 65-98 yrs old • From all 50 states and DC • 1/3 from the southeastern US • > 50% of cases from 8 states: CA, FL, TX, NY, PA, IL, NC, GA • 13 states averaged < 1 case/yr; ND only reported 1 case

14. U.S. Distribution of NTM Lung Disease Cases in Adults ≥ 65 years of age

15. Period Prevalence (PP) from 1997-2007 • PP was 112 (95% CI: 108-116) cases /100,000 persons • Significantly higher among women than men • 127 vs. 93 cases / 100,000 persons • Varied by geographic location and race/ethnicity

16. PP of PNTM by Sex & Race/Ethnicity(cases/100,000 persons)

17. PP of PNTM by State CA: 191 AZ: 179 LA: 178 MS: 165 FL: 176 HI: 396

18. Annual Prevalence (AP) • Avg AP of 31/100,000 persons per yr • Increased significantly by 8.2% per yr

19. AP by Region & Year

20. Univariate Logistic Regression Analysis

21. Discussion • First study to provide nationally representative estimates of PNTM disease in older adults throughout the US and across various racial/ethnic groups • Prevalence of PNTM is increasing significantly across all regions of the US and among both men and women • ICD-9 codes likely underestimate prevalence

22. Increasing Prevalence of PNTM Disease • Recent shift from middle-aged male smokers to older women without known risk factors • Increasing segment of US population • Improved diagnostics and testing, however increases noted worldwide and throughout various points in time • Greater concentration in drinking water • Resistant to disinfectants and chlorination

23. Race/Ethnicity and PNTM Disease • PNTM cases were predominantly white women, but Asians/Pacific Islander men seem to be at greater risk • Role of race/ethnicity complex and is likely driven by behavioral, cultural, and biological/genetic factors • In Japanese population, PNTM associated with certain alleles of human leukocyte antigen markers • Pacific Islanders more likely than Asian Americans to be smokers, overweight, and have higher chronic disease and mortality rates despite no differences in access to care

24. Geographic Differences in Prevalence • Hawaii had highest prevalence • ~ ½ Asian/Pacific Islander PNTM cases resided in HI, but still had ↑est PP even when they were excluded, suggesting environmental in Hawaii may also contribute • Higher prevalence in SE and West is consistent with prior reports of higher human exposure • ↑ #s of NTM isolated from coastal swamps of SE • NTM most often isolated from CF patients at study sites in southern Louisiana and also California

25. Conclusions • High risk groups and areas likely due to complex interactions among environmental and host factors • With prevalence rising throughout US, clinicians must increase awareness of those at high risk for NTM • More studies needed to better understand complex relationships between host and environment • Prospective epidemiologic case-control studies • Spatial epidemiologic analyses evaluating environmental factors associated with cases on a finer scale

26. Acknowledgements • Support for this study was provided by the LCID, NIAID, NIH, especially: • Kenneth Olivier, MD • Amy E. Seitz, MPH • Steven M. Holland, MD • Rebecca Prevots, PhD, MPH

27. Thank you!

28. Results: PP by Region • Highest in western states (149/100,000 ) • > 1/3 of cases from Southeast (131/100,000) • Lowest PP in Midwest (78/100,000 ) West Midwest Northeast Southwest Southeast

29. Results: COPD by Race/Ethnicity & Sex

30. Results: Bronchiectasis by Race/Ethnicity & Sex

31. Results: Medical Claims Analysis • 16,508 records with pulmonary NTM-related claim • 64% as primary claim • 22% as secondary claim • 11% as tertiary claim • 4% as quaternary claim • 75% had pulmonary NTM as primary claim at least once • 6.5 pulmonary NTM claims submitted on avg per case

32. Results: AP by Sex & Age Group

33. Annual prevalence of PNTM cases among a sample of U.S. Medicare Part B enrollees by sex from 1997-2007

34. Results: Age Distribution of NTM Cases Average Annual % of Enrollees and Cases by Age Group

36. Results: Multivariate Logistic Regression *Significant interaction detected; †Controlled for confounding by COPD and Bronchiectasis

37. Significant Interactions between Sex & Race/Ethnicity

38. Estimating Disease Prevalence through U.S. Medicare Data • Centers for Medicare and Medicaid’s Carrier Standard Analytic File (SAF) • 5% sample of all medical claims submitted for individuals enrolled in Medicare Part B (~44 million) • Final action claims data from non-institutional providers • i.e. physicians, independent clinical laboratories, ambulance providers, and stand-alone ambulatory surgical centers • Claims include primary ICD-9 code and up to 3 additional codes for other conditions associated with the claim • Representative of U.S. population ≥ 65 yrs

39. Mortality Analysis • PNTM cases: • 35% overall all-cause mortality rate • 40% more likely to die than non-cases (OR=1.4 [1.3-1.6]) • Among PNTM cases, risk of death greater in: • Men (OR=1.8 [1.6-2.2]) relative to women • Blacks (OR=2.1 [1.4-3.1]) and Hispanics (OR=2.4 [1.2-4.7]) relative to whites • Those with ≥ 3 comorbidities (OR=1.3 [1.0-1.6]) • Those also diagnosed with lung cancer (OR=1.7 [1.4-2.1], asthma (OR=1.7 [1.1-2.7]) or pneumonia (OR=2.9 [2.3-3.6])

40. AP by Race/Ethnicity & Year

41. Diagnosis with NTM Lung Disease • Clinical/Radiologic • Pulmonary symptoms, nodular/cavitary opacities on chest radiograph,or high-resolution computed tomography (HRCT) scan showing multifocal bronchiectasis with multiplenodules • Appropriate exclusion of other diagnoses. (i.e. TB) • Microbiologic • Pos. culture on ≥ 2 separate sputum samples • Pos. culture on ≥ 1 bronchialwash orlavage • Transbronchial or other lung biopsy withmycobacterial histopathologicfeatures

42. Annual Percent Change (APC) • Overall APC of 8.2% (95% CI: 7.2-9.2) per year

43. Comorbidity Analysis * Prevalence of COPD likely overestimated due to issues associated with Medicare claims coding

44. Prevalence of selected comorbidities among male and female PNTM cases

45. Comorbidities in PNTM Cases • Significantly more likely to be diagnosed with other and greater #s of comorbidities than non-cases • Almost all PNTM cases were diagnosed with at least one other lung-associated condition • All prevalence estimates for PNTM and comorbidities are limited to accuracy of ICD-9 code reporting