Mycobacterium Avium Complex (MAC) (Mycobacterium Avium-Intracellulare = MAI)

Epidemiology

Incidence

  • Mycobacterium Avium Complex is the Most Common of the Non-Tuberculous Mycobacteria to Cause Disease in Humans

Peak Geographic Area

  • Southeast USA

Sites of Clinical Disease

  • Prior to HIV-AIDS Epidemic, 85-90% of all Mycobacterium Avium Complex Isolates were from the Lungs

Microbiology

General Comments

  • Serotypes 4 and 8 Cause Most Cases of HIV-Associated Mycobacterium Avium Complex Disease

Animal Mycobacterium Avium Complex Disease

  • Mycobacterium Avium Complex Causes Disease in Chickens, Birds, Swine, Cattle, and Non-Human Primates
    • Animals May Serve as Reservoirs, But There is No Known Link Between Animal and Human Cases

Environmental Sources of Mycobacterium Avium Complex

  • Animal Bedding
  • Plants
  • Salt Water
  • Soil
  • Standing Fresh Water

Physiology

Primary Acquisition of Mycobacterium Avium Complex Probably Occurs Via the Gastrointestinal Tract (and Occasionally Via the Lungs)

  • Infection is Not Believed to Result from Reactivation
  • Source of MAC Infection in AIDS: given observation that airway and gastrointestinal tract colonization increase the future risk of MAC bacteremia in AIDS (with CD4 <50), it is likely that organism is already present and gains access to bloodstream with progressive decline in immune function (suggests that environmental acquisition of MAC is less likely)

Mechanisms Which May Increase the Risk of Pulmonary Non-Tuberculous Mycobacteria (Am J Respir Crit Care Med, 2013) [MEDLINE]

  • Impaired Nasal NO Production
  • Impaired Ciliary Beat Frequency
  • Impaired Toll-Like Receptor (TLR) Responses

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count)

Sputum Culture (see Sputum Culture)

  • Susceptibility Testing (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]
    • Susceptibility Testing for MAC Isolates: recommended for clarithromycin alone
    • Susceptibility Testing for Mycobacterium Kansasii Isolates: recommended for rifampin alone
    • Susceptibility Testing for Rapidly Growing Mycobacterium (Mycobacterium Chelonae, Mycobacterium Fortuitum, Mycobacterium Abscessus) Isolates: recommended for amikacin, imipenem (Mycobacterium Fortuitum only), doxycycline, fluoroquinolones, sulfonamide or trimethoprim-sulfamethoxazole, cefoxitin, clarithromycin, linezolid, and tobramycin (Mycobacterium Chelonae only)

Serum Immunoglobulin (see xxxx)

  • Hypergammaglobulinemia

Bone Marrow Biopsy (see Bone Marrow Biopsy

  • Cultures may be positive
  • AFB are often found within foamy macrophages/histiocytes
  • Usually absent or poorly formed granulomas

Lymph Node Biopsy (see Lymph Node Biopsy)

  • Cultures may be positive

Liver Biopsy (see Liver Biopsy)

  • Cultures may be positive

Blood Culture (see Blood Culture)

  • May be positive
  • Preferred method of obtaining diagnosis in AIDS-related cases
  • Most frequent source of positive cultures in AIDS cases

Stool Mycobacterium Avium Complex Smears and Cultures

  • Frequently positive in AIDS cases

Intestinal Biopsy

  • Macrophages packed with MAC (may resemble Whipple’s disease)

Criteria for the Diagnosis of Non-Tuberculous Mycobacterial Disease (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]

General Comments

  • Criteria Fit Best for Mycobacterium Abscessus, Mycobacterium Kansasii, Mycobacterium Avium Complex (MAC)
    • There is Not Adequate Data Regarding Other Mycobacteria to Be Certain That These Diagnostic Criteria are Universally Applicable for All Non-Tuberculous Mycobacterial Respiratory Pathogens

Clinical Criteria

  • Compatible Symptoms
  • Appropriate Exclusion of Other Diagnoses (Selected Diagnoses Listed)

Radiographic Criteria

Microbiologic Criteria (At Least One of the Following)

  • Positive Culture Results from at Least Two Separate Expectorated Sputum Samples (see Sputum Culture)
    • If the Results from the Initial Sputum Samples are Non-Diagnostic, Consider Repeat Sputum AFB Smears and Cultures
  • Positive Culture Results from at Least One Bronchial Wash or Bronchoalveolar Lavage (see Bronchoscopy)
  • Lung Biopsy (Transbronchial Biopsy or Other Lung Biopsy) with Mycobacterial Histologic Features (Granulomatous Inflammation or AFB) and Positive Culture for Non-Tuberculous Mycobacteria or Lung Biopsy (Transbronchial Biopsy or Other Lung Biopsy) with Mycobacterial Histologic Features (Granulomatous Inflammation or AFB) and ≥1 Sputum or Bronchial Wash Cultures Positive for Non-Tuberculous Mycobacteria (see Bronchoscopy)

Prevention of Non-Tuberculous Mycobacteria (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]

  • Surgical Wounds, Injection Sites, and iIntravenous Catheters Should Not Be Exposed to Tap Water or Tap Water–Derived Fluids
  • Endoscopes Should Not Be Cleaned in Tap Water
  • Clinical Specimens Should Not Be Contaminated with Tap Water or Ice

Clinical Presentation-Hot Tub Lung/Swimming Pool Lung (Variants of Hypersensitivity Pneumonitis, HP) (see Hypersensitivity Pneumonitis)

Epidemiology

  • Typically Immunocompetent Patient

Diagnosis

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Clinical

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Treatment


Clinical Presentation-Pulmonary Mycobacterium Avium Complex (Non-Immunocompromised Patient)

Epidemiology

Diagnosis

  • CXR/Chest CT
    • Multifocal nodular disease: female predominance
    • Upper lobe cavitary disease: male predominance
    • Bronchiectasis with/without centrilobular nodules (around ectatic bronchi)
  • Sputum Culture/Sensitivity positive MAC cultures
    • The more cultures that are positive, the more likely it is responsible for disease
  • Bronchoscopy
    • Bronchoalveolar Lavage (BAL): cultures may be positive for MAC (does not indicate invasive or disseminated disease)
      • Organism grow slowly and can be identified by the fact that it is non-pigmented and niacin-negative
    • Endobronchial MAC: appears as submucosal “pearls”
    • Endobronchial Biopsy (EBB): positive

Clinical

  • Cavitary/Non-Cavitary Pneumonia (see Pneumonia and Cystic-Cavitary Lung Lesions)
    • Cough (see Cough)
    • Low-Grade Fever (see Fever)
    • Malaise
    • Hemoptysis (see Hemoptysis)
    • Lady Windermere Syndrome (from Oscar Wilde’s Victoria Era Play “Lady Windermere’s Fan”): MAC occurring in typical location of lingula or RML in a middle-aged female (see Middle Lobe Syndrome)
      • In 1992, the “Lady Windermere Syndrome” was Described in a Series of Female Patients (n = 29) with MAC Infection Initially in Middle Lobe or Lingular Distributions (in the Absence of Airway Obstruction or Predisposing Pulmonary Disease) (Chest, 1992) [MEDLINE]
        • Lady Windermere was a Fastidious Female Character in the Victorian-Era (1892) Oscar Wilde Play, “Lady Windermere’s Fan”
        • The Authors Hypothesized that Voluntary Suppression of Cough May Have Led to the Development of Nonspecific Inflammation in the Poorly-Draining Middle Lobe or Lingula, Upon Which MAC Infection then Occurred
  • Cavitary/Non-Cavitary Lung Nodules (see Lung Nodule or Mass and Cystic-Cavitary Lung Lesions)
  • Endobronchial MAC (see Obstructive Lung Disease)
    • Uncommon Presentation in Immunocompetent Hosts, But Cases Have Been Reported (Infect Chemother, 2013) [MEDLINE]
    • Submucosal “Pearls”
  • Extrapulmonary Dissemination: uncommon

Treatment

Medical Therapy (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]

  • 3-Drug Regimen (Macrolide Agent + Rifamycin Agent + Ethambutol)
    • Macrolide (see Macrolides)
    • Rifamycin Group Antibiotic (see Rifamycins)
      • Rifabutin (see Rifabutin): 150-300 mg PO qday
        • Monitor patients receiving both clarithromycin + rifabutin for uveitis and with LFT’s/platelet count/WBC count
      • Rifampin (see Rifampin): 600 mg PO qday
    • Ethambutol (see Ethambutol): 25 mg/kg PO qday
      • Monitor Patient for Visual Loss During Therapy
  • Administration
    • Frequency
      • Most Patients with Nodular/Bronchiectatic Disease: administer 3-drug regimen (Clarithromycin/Azithromycin + Rifampin + Ethambutol) 3x/wk
      • Patients with Severe Nodular/Bronchiectatic Disease or Fibrocavitary Disease: administer 3-drug regimen (Clarithromycin/Azithromycin + Rifabutin/Rifampin + Ethambutol) daily with consideration of either amikacin or streptomycin given 3x/wk early in the course
    • Duration: until culture-negative on therapy for 1 year
  • Clinical Efficacy
    • Retrospective Single-Center Review Examining Clinical Efficacy of 3-Drug Regimen in Nodular/Bronchiectatic MAC (Chest, 2014) [MEDLINE]
      • Macrolide-Based Regimens Demonstrate Favorable Microbiologic Outcomes Without Promotion of Macrolide Resistance
      • Intermittent (3x/wk) Macrolide-Based Regimens are Effective and are Better Tolerated Than Daily Therapy: no difference in sputum conversion or need to discontinue therapy

Surgical Lung Resection

  • Indications: good surgical candidates with localized MAC who do not respond to antibiotics alone
    • Ideally, sputum should be converted to negative prior to surgery
    • If sputum does not convert by 4 mo, (or if by 2-3 mo there is no decrease in the number of organisms), surgery should be carried out

Clinical Presentation-Pulmonary Mycobacterium Avium Complex (Immunocompromised Patient)

Epidemiology

Clinical

Treatment

Medical Therapy

  • 3-Drug Regimen (Macrolide Agent + Rifamycin agent + Ethambutol)
    • Macrolide (see Macrolides)
    • Rifamycin Group Antibiotic
      • Rifabutin (see Rifabutin)
        • Monitor patients receiving both clarithromycin + rifabutin for uveitis and with LFT’s/platelet count/WBC count
      • Rifampin (see Rifampin)
    • Ethambutol (see Ethambutol)
      • Monitor patient for visual loss during therapy
  • Clinical Efficacy in Nodular/Bronchiectatic MAC [MEDLINE]
    • Macrolide-Based Regimens Demonstrate Favorable Microbiologic Outcomes Without Promotion of Macrolide Resistance
    • Intermittent (3x/wk) Macrolide-Based Regimens are Effective and are Better Tolerated Than Daily Therapy: no difference in sputum conversion or the need to discontinue therapy

Surgical Lung Resection

  • Indications: good surgical candidates with localized MAC who do not respond to antibiotics alone
    • Ideally, sputum should be converted to negative prior to surgery
    • If sputum does not convert by 4 mo, (or if by 2-3 mo there is no decrease in the number of organisms), surgery should be carried out

Clinical Presentation-Pulmonary Mycobacterium Avium Complex (HIV-AIDS Patient)

Epidemiology

  • MAC in AIDS is usually a systemic disease that does not involve the lungs
  • In AIDS, source of infection is not clear, no clear environmental sources have been identified
  • MAC occurs in 15-24% of AIDS cases
  • On average, MAC occurs 7-15 months after AIDS diagnosis is made
  • Risk Factor in AIDS: CD4 <200/µL

Physiology

  • Significance of Airway Colonization: presence of airway colonization (with negative blood cultures) increases risk of future dissemination in AIDS with CD4 <50 (83% developed MAC bacteremia within 10 months)
    • Suggests that lungs are a portal for entry

Clinical Manifestations

Treatment

  • Preferred Regimen: Macrolide + Ethambutol + Rifabutin +/- Streptomycin for 15-24 months
    • Single agent therapy with Macrolide leads to resistance (usually several months into therapy) and recurrent symptoms within 8-12 weeks
    • These agents decrease blood colony counts and systemic symptoms
    • Monitor patients receiving both Clarithro + Rifabutin for uveitis, LFT s, platelet counts, and WBC counts
    • Monitor patients on Ethambutol for visual loss
  • Surgical Lung Resection: can be considered for good surgical candidates with localized MAC who do not respond to antibiotics alone
    • Ideally, sputum should be converted to negative prior to surgery
    • If sputum does not convert by 4 months, (or if by 2-3 months there is no decrease in the number of organisms), surgery should be carried out

Clinical Presentation-Mycobacterium Avium Complex Lymphadenitis

Epidemiology

  • Age Group: occurs almost exclusively in children between 1-5 y/o
  • The Majority of Cervical Lymphadenitis Due to Non-Tuberculous Mycobacteria are Due to MAC

Diagnosis

  • Lymph Node Biopsy/Aspiration of Soft Node: best diagnostic procedure

Clinical

  • Painless Swelling of Single or Grouped Lymph Nodes: similar to tuberculous lymphadenitis
    • Most commonly in high anterior cervical chain
    • May produce fistulas
  • Systemic Symptoms/Signs are Uncommon

Treatment (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]

  • Surgical Resection of Affected Nodes: primary treatment
    • Over 90% Cure Rate
  • Macrolide-Based Regimen: should be considered for patients with extensive MAC lymphadenitis or poor response to surgical therapy

Clinical Presentation-Disseminated Mycobacterium Avium Complex

Epidemiology

  • Disseminated MAC was rare prior to AIDS epidemic
  • Presence of MAC in AIDS significantly decreases life expectancy and quality of life
  • Risk Factors for Dissemination
    • AIDS (see Human Immunodeficiency Virus)
      • MAC disease occurs in 19% of AIDS patients with CD4 <250
      • MAC occurs in 50% of AIDS cases at 30 months of follow-up (almost all had CD4 <60 at time of study entry)
      • Airway or GI tract colonization increases the risk of future MAC bacteremia (in AIDS with CD4 <50)
      • HAART and MAC prophylaxis (with clarithromycin, azithromycin, or rifabutin) decrease the incidence of MAC in AIDS
    • Immunocompromised Hosts: steroids are commonly associated
    • Children

Diagnosis

  • Sputum Culture: may be positive (positivity does not indicate invasive/disseminated disease)

Clinical

Prophylaxis (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]

  • Indications
    • HIV/AIDS with CD4 <50 Cells/μl
  • Regimen
    • Azithromycin (see Azithromycin): 1,200 mg PO wk has proven efficacy
    • Clarithromycin (see Clarithromycin): 1,000 mg PO qday has proven efficacy
    • Rifabutin (see Rifabutin): 300 mg PO qday is also effective, but less well tolerated

Treatment

Medical Therapy (ATS Guidelines for Non-Tuberculous Mycobacterial Disease, 2007) (Am J Respir Crit Care Med, 2007) [MEDLINE]

  • Treatment of Disseminated MAC in AIDS: treatment improves survival and decreases symptoms
  • 3-Drug Regimen (Macrolide Agent + Rifamycin Agent + Ethambutol)
    • Macrolide (see Macrolides)
    • Rifamycin Group Antibiotic (see Rifamycins)
      • Rifabutin (ses Rifabutin): 150-350 mg PO qday
        • Monitor patients receiving both clarithromycin + rifabutin for uveitis and with LFT’s/platelet count/WBC count
    • Ethambutol (see Ethambutol): 15 mg/kg PO qday
      • Monitor Patient for Visual Loss During Therapy
  • Administration
    • Frequency: daily 2-3 drug regimen (Clarithromycin/Azithromycin + Ethambutol and Optional Rifabutin)
    • Duration: therapy can be discontinued with resolution of symptoms and reconstitution of cell-mediated immune function

Effect of Immune Reconstitution Inflammatory Syndrome (IRIS) (see Immune Reconstitution Inflammatory Syndrome)

  • Immune reconstitution usually occurs within 6 months after start of HAART therapy and may paradoxically worsen disease, worsen disease from prior clinically latent infection, or result in an exaggerated inflammatory response
    • Disease may appear to worsen with tissue biopsies demonstrating necrosis (with sterile cultures)
    • NSAIDS may decrease the paradoxical inflammatory response

References

  • Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med. 1989 Sep 28;321(13):863-8 [MEDLINE]
  • Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome. Chest. 1992 Jun;101(6):1605-9 [MEDLINE]
  • Mycobacterium avium complex spinal epidural abscess in an HIV patient. Australas Radiol. 1999 Nov;43(4):554-7 [MEDLINE]
  • An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416 [MEDLINE]
  • Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease. Am J Respir Crit Care Med 2010;182:977-982 [MEDLINE]
  • Abnormal nasal nitric oxide production, ciliary beat frequency, and toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium. Am J Respir Crit Care Med 2013;187:1374-1381 [MEDLINE]
  • Endobronchial Mycobacterium avium Infection in an Immunocompetent Patient. Infect Chemother. 2013 Mar;45(1):99-104. doi: 10.3947/ic.2013.45.1.99 [MEDLINE]
  • Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease. Chest 2014;146:276-282 [MEDLINE]
  • Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis. Semin Respir Crit Care Med. 2015 Apr;36(2):217-24. doi: 10.1055/s-0035-1546751. Epub 2015 Mar 31 [MEDLINE]