What are the clinical manifestations of nontuberculous mycobacterial (NTM) infection, including pulmonary and extrapulmonary presentations and how they vary with the patient’s immune status?

Clinical Manifestations of Nontuberculous Mycobacterial (NTM) Infections

NTM infections present with distinct clinical patterns that vary dramatically based on immune status: immunocompetent patients typically develop pulmonary disease with chronic cough and bronchiectasis, while severely immunocompromised patients (CD4 <50 cells/µL) develop disseminated disease with fever, night sweats, and multi-organ involvement. 1

Pulmonary Manifestations in Immunocompetent Patients

Classic Symptoms

• Chronic or recurring cough is present in virtually all patients with NTM pulmonary disease 1
• Sputum production, fatigue, malaise, and dyspnea occur variably 1
• Hemoptysis, chest pain, and weight loss develop with advancing disease 1
• Constitutional symptoms (fever, night sweats, weight loss) become progressively more prevalent as disease advances 1

Two Distinct Radiographic Patterns

Fibrocavitary Disease:

• Thin-walled cavities with less surrounding parenchymal opacity compared to tuberculosis 1
• Less bronchogenic spread but more contiguous disease spread 1
• Marked pleural involvement over affected lung areas 1
• Predominantly affects patients with preexisting structural lung disease (COPD, bronchiectasis, prior TB, pneumoconiosis) 1, 2

Nodular/Bronchiectatic Disease:

• Mid- and lower lung field abnormalities 1
• Up to 90% have associated multifocal bronchiectasis on HRCT 1
• Predominantly affects postmenopausal women with characteristic thin body habitus 1
• Associated morphotype may include scoliosis, pectus excavatum, and mitral valve prolapse 1

Physical Examination Findings

• Nonspecific findings reflecting underlying pulmonary pathology 1
• Chest auscultation may reveal rhonchi, crackles, wheezes, and squeaks 1

Disseminated Disease in Severely Immunocompromised Patients

Critical Risk Factors

• Disseminated NTM occurs almost exclusively when CD4 count falls below 50 cells/µL 1, 3
• Average CD4 count at presentation is typically <25 cells/µL 1, 3
• In the pre-antiretroviral era, nearly 40% of patients with <10 CD4 cells/µL developed disseminated NTM within one year 1, 3
• MAC accounts for 90% of disseminated NTM cases in AIDS patients 1, 4

Classic Clinical Presentation

Constitutional Symptoms (in order of frequency):

• Fever occurs in 80% of patients 1, 3
• Night sweats in 35% 1, 3
• Weight loss in 25% 1, 3
• Abdominal pain or diarrhea is common 1

Physical Findings:

• Abdominal tenderness or hepatosplenomegaly 1
• Palpable lymphadenopathy is NOT common in disseminated MAC 1

Laboratory Abnormalities:

• Severe anemia with hematocrit <25% 1
• Elevated alkaline phosphatase 1
• Elevated lactate dehydrogenase 1
• These abnormalities typically occur 1-2 months before onset of bacteremia 1

Organ Involvement Patterns

• Autopsy studies demonstrate involvement of most internal organs even without localizing symptoms 1, 3
• Pulmonary involvement is rare in AIDS patients with disseminated MAC, occurring in only 2.5% of cases 1, 3
• MAC isolated from respiratory samples in HIV patients usually represents colonization or early dissemination rather than active lung disease 1, 3

Immune Reconstitution Syndrome

• Occurs in patients who recently started antiretroviral therapy 1
• Suppurative lymphadenopathy with swollen, painful cervical, axillary, or inguinal nodes is the most common manifestation 1
• Other manifestations include pulmonary infiltrates, soft tissue abscesses, or skin lesions 1
• Patients have fever but lack other components of MAC bacteremia syndrome 1

Disseminated Disease in Non-AIDS Immunocompromised Patients

Risk Populations

• Renal or cardiac transplant recipients 1
• Chronic corticosteroid use 1
• Leukemia patients 1
• Rare genetic disorders affecting IFN-γ/IL-12 pathway 1

Clinical Presentation Differs by Species

• MAC typically presents as fever of unknown origin 1
• M. kansasii, M. chelonae, M. abscessus, and M. haemophilum present as multiple subcutaneous nodules or abscesses that may spontaneously drain 1, 5
• Rapidly growing mycobacteria (M. chelonae, M. abscessus) are most commonly involved 1

Extrapulmonary Localized Infections

Cervical Lymphadenitis

• Most common form of NTM disease in children aged 1-5 years 1
• Affects submandibular, submaxillary, cervical, or preauricular lymph nodes 1
• Approximately 80% of culture-proven cases are due to MAC 1
• Rarely affects adults in the absence of HIV infection 1

Skin and Soft Tissue Infections

• Occur at puncture wound sites, surgical sites, or traumatic injuries 5, 6
• M. chelonae is the most frequently reported agent in LASIK-associated keratitis 5
• Present as localized infections, nodules, or abscesses 5, 6

Other Extrapulmonary Sites

• Musculoskeletal infections 6
• Gastrointestinal involvement (34.1% in one series) 7
• Genitourinary tract infection (2.4%) 7
• Central nervous system infection (2.4%) 7
• Keratitis (1.2%) 7

Critical Diagnostic Pitfalls

Common Errors to Avoid

• Do not confuse disseminated MAC with tuberculosis - the clinical presentation mimics numerous other infections 3
• MAC isolation from respiratory samples in HIV patients does NOT equal pulmonary disease - it usually represents colonization or early dissemination 1, 3
• In HIV patients with MAC in sputum, investigate for disseminated disease rather than treating as pulmonary infection 1
• Prospective screening of respiratory samples is not recommended 1

Diagnostic Approach for Disseminated Disease

• Blood cultures are diagnostic in >90% of disseminated MAC cases 1, 3
• One positive blood culture is sufficient for diagnosis 3
• For symptomatic patients with two negative blood cultures, consider bone marrow or liver biopsy and culture 1, 3
• For lymphadenopathy without bacteremia, excise accessible nodes for histopathology and culture 1
• Fine needle aspiration may be required for intrathoracic, intraabdominal, or retroperitoneal adenopathy 1

Species-Specific Considerations

Most Common Pathogens by Site

Pulmonary disease: MAC > M. kansasii > M. abscessus 1, 4

Disseminated disease in AIDS: M. avium (>90% of MAC cases) > M. kansasii 1, 4

Disseminated disease in non-AIDS immunocompromised: M. chelonae and M. abscessus most common 1

Cervical lymphadenitis: MAC (80%) > M. scrofulaceum 1

Important Species Distinctions

• M. intracellulare causes most MAC lung disease in the United States, but M. avium causes most disseminated MAC in AIDS 1
• M. abscessus causes lung disease but is NOT associated with disseminated infection in AIDS patients 1
• Species-level identification is essential because treatment regimens, drug susceptibility patterns, and prognosis vary significantly 4