Danger in the Water Theodore Marras MD FRCPC University of Toronto & University Health Network

Potential conflicts of interest Financial – none Other – clinical and academic interest in pulmonary NTM disease (especially epidemiology, long term outcomes) Off label use of therapies None of the medications mentioned have a formal indication for the treatment of pulmonary NTM disease Declarations

1.Identify relevant potential infective exposures 2.Review management of pMAC: –Recommended drug treatment –Approach to comprehensive management 3.Review data on treatment outcomes 4.Combining knowledge of: –Environment / interventions (relevance, uncertainty) –Treatment outcomes … to better inform clinical decisions Objectives - Pulmonary Mycobacterium avium complex (pMAC)

Background

Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly Diagnosis

Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly DiagnosisMicro +Micro

Pulmonary NTM - Microbiology NTMM.tb. Where they liveEnvironment (water, soil) Infected host InfectionEnvironmental exposure / inoculation Infective aerosols Spread person- person? NoYes PathogenicWeaklyStrongly DiagnosisMicro / Clin / RadMicro

“Disease” Criteria ClinicalPulmonary symptoms, or Nodules or cavities on CXR, or Multifocal bronchiectasis & multiple small nodules on HRCT (and exclusion of other diagnoses) MicroWith > 2 sputa  2 cultures + With 1 BAL/wash  1 BAL/wash + With biopsy  1 biopsy culture +, or 1 culture + and bx evidence of disease Pulmonary NTM Disease - ATS / IDSA 2007

Age and sex distribution

Increasingly common disease of the elderly in Ontario

Where does it come from?

Moist environments –Natural and treated water –Soils Very disinfectant resistant The Water we Drink - MAC

Hot Tub Lung: Hypersensitivity Pneumonitis to NTM Embil et al.Chest Kahana et al.Chest Mangione et al.Emerg Inf Dis Case recordNEJM Khoor et al.Am J Clin Pathol Rickman et al.Mayo Clin Proc Cappelluti et al.Arch Intern Med Pham et al.J Thoracic Imaging Grimes et al.Respiration AksamitRespir Infect Lumb et al.Appl Environ Micro Systrom & WittramNEJM TOTAL41

Study Design Pulmonary NTM Source of infection … Multiple respiratory samples and shower and bathtub specimens grew MAC, with matching PFGE patterns… Hypersensitivity Pneumonitis Reaction to Mycobacterium avium in Household Water* Theodore K. Marras, MD; Richard J. Wallace, Jr., MD, FCCP; Laura L. Koth, MD; Michael S. Stulbarg, MD;† Clayton T. Cowl, MD, FCCP; and Charles L. Daley, MD (CHEST 2005; 127:664–671)

Pulmonary NTM Source of infection … M. avium isolated from showerhead water and biofilm in the home of a woman with M. avium disease. DNA fingerprinting demonstrated identical M. avium isolates from showerhead and patient … Mycobacterium avium in a shower linked to pulmonary disease Joseph O. Falkinham III, Michael D. Iseman, Petra de Haas and Dick van Soolingen J Water Health 06(2):209–213

Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure

Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure StudyPopulationRisk Factor Odds Ratio (95% CI) P value Reed Am J Epi 2006 Random sample, West Palm Beach FL (N=447) Soil occupation (> 6 years) 2.7 ( ) 0.01 Khan AJRCCM 2007 Representative sample, USA (N=7,384) Farming / Construction 1.43 ( ) 0.02

Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure StudyPopulationRisk Factor Odds Ratio (95% CI) P value Reed Am J Epi 2006 Random sample, West Palm Beach FL (N=447) Soil occupation (> 6 years) 2.7 ( ) 0.01 Khan AJRCCM 2007 Representative sample, USA (N=7,384) Farming / Construction 1.43 ( ) 0.02

Study Design Occupational soil exposure - risk factor for MAC skin test reactivity MAC skin testing - Soil exposure StudyPopulationRisk Factor Odds Ratio (95% CI) P value Reed Am J Epi 2006 Random sample, West Palm Beach FL (N=447) Soil occupation (> 6 years) 2.7 ( ) 0.01 Khan AJRCCM 2007 Representative sample, USA (N=7,384) Farming / Construction 1.43 ( ) 0.02

High numbers of … M. avium, M. intracellulare, and M. chelonae, recovered from aerosols produced by pouring commercial potting soil and potting soil samples provided by patients with pulmonary mycobacterial infections. Dominant mycobacteria in soil samples corresponded to dominant species implicated clinically. Pulsed-field gel electrophoresis demonstrated a closely related pair of M. avium isolates recovered from a patient and from that patient’s own potting soil. App Env Microbiol 2006; 72: Pulmonary NTM Source of infection

Management of pMAC

“Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients” - ATS / IDSA 2007 ATS / IDSA guidelines - Diagnosis  Treatment Symptoms + Imaging + Cultures = NTM Disease

“Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients” - ATS / IDSA 2007 ATS / IDSA guidelines - Diagnosis  Treatment Symptoms + Imaging + Cultures = NTM Disease

When to treat? Micro – R epeated isolates / AFB smear + Symptoms –Systemic* – fatigue, fever/sweat, weight loss –Local – cough, sputum, hemoptysis, dyspnea Significant burden on imaging –Consolidation, nodules, cavities … –Progression Pulmonary NTM - Diagnosis  Treatment

Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

Non-destructive infection Cure Localized destruction Cure (?) Diffuse destruction Suppress Severe drug intolerance Suppress Recurrence Cure or Suppress? Pulmonary MAC - Goals of treatment

ATS / IDSA guidelines - Drug treatment – MAC Drug / class Disease type FibronodularCavitary or Advanced / recurrent MACROLIDE Clari 1000 tiw or Azi tiw Clari qd or Azi qd Ethambutol20-25 mg/kg tiw15 mg/kg/d RifamycinRMP 600 tiw RMP qd or RFB qd Amikacin (SM, KM) Not recommended Consider / recommended (10-15 mg/kg/d)

ATS / IDSA guidelines - Drug treatment – MAC Drug / class Disease type FibronodularCavitary or Advanced / recurrent MACROLIDE Clari 1000 tiw or Azi tiw Clari qd or Azi qd Ethambutol20-25 mg/kg tiw15 mg/kg/d RifamycinRMP 600 tiw RMP qd or RFB qd Amikacin (SM, KM) Not recommended Consider / recommended (10-15 mg/kg/d) Other agents - Fluoroquinolones, clofazimine, linezolid

When to stop? Sputum cultures negative for 12 months Pulmonary NTM - Treatment duration

Comprehensive management

Start with guidelines Expect drug intolerance (staggered start) Macrolides whenever possible Amikacin for advanced cases* Fluoroquinolones, clofazimine, linezolid as needed / tolerated Aim for >3 drugs* –More drugs, higher doses  greater efficacy Tailor therapy –Switch drugs to minimize AE’s –Re-evaluate objectives based on response, toxicity * When treating intensively Pulmonary MAC - Drugs

Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery Avoid exposure –Hot tubs –Shower? Pulmonary MAC - Treatment – Other

Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery Avoid exposure –Hot tubs –Shower? Pulmonary MAC - Treatment – Other

Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery Avoid exposure –Hot tubs –Shower? Pulmonary MAC - Treatment – Other

Other interventions Nutrition Bronchodilators / Inhaled steroids? Pulmonary hygiene Surgery (?) Pulmonary MAC - Treatment – Other

Pulmonary MAC - Following patients on therapy Assess response Microbiologic – sputum q 2-4 months Clinical – periodic Radiographic – LDCT scan 4-6 mo, then q 6-12 mo Follow for drug toxicities Education  important toxicity stop drugs Clinical Rifamycin  CBC, liver tests Ethambutol  visual acuity, colour etc. Amikacin  ‘lytes, creatinine, serum level, audiograms

Outcomes

Clinical practice (geographic region) Leeds, UK; MAC % disease recurrence or mortality at 2 years post treatment Henry, ERJ 2004 pNTM – a chronic disease? - Clinical practice

Clinical practice (specialty clinic) 50% didn’t achieve sputum culture conversion 60% didn’t tolerate initial antibiotics 85% remain symptomatic Huang, Chest 1999 pNTM – a chronic disease? - Clinical practice

StudyRx (months) NSputum convert (%)Success (%) PPITTPPITT Dautzenberg ’ Wallace ’96> Roussel ‘ Griffith ’98> Tanaka ’ Huang ’99> Griffith ‘00> Griffith ‘ Field ’02> Kobashi ‘ Fujikane ’05> Lam ’ Kobashi ’ Kobashi ’ Jenkins ’ Total (weighted)-1,13772%62%50%43% pNTM – a chronic disease? - Clinical studies

Study Follow-up (months) N Recurrence N% Huang ’99<72273/1030 Kobashi ’ /3757 Kobashi ’ /8933 Total (weighted)-24653/13639% pNTM – a chronic disease? - Recurrence

Treatment –Poorly tolerated –Suboptimal efficacy Pulmonary MAC (NTM) - Chronicity

Treatment –Poorly tolerated –Suboptimal efficacy Cause(s) not identified or reversible –Host defect –Exposure remains… Pulmonary MAC (NTM) - Chronicity

Am J Resp Crit Care Med 2007, 175: Canadian Tuberculosis Standards, 6 th ed