What are the potential complications of untreated or inadequately managed tuberculosis (TB) in patients, particularly those with pulmonary or extrapulmonary TB, and those with comorbidities such as Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)?

Complications of Tuberculosis

Life-Threatening Nature of Untreated Disease

Untreated tuberculosis at most sites is universally fatal, with disseminated TB carrying 100% mortality if left untreated, while appropriate treatment reduces mortality to less than 5% in drug-susceptible cases. 1

• This dramatic mortality reduction represents one of the most significant therapeutic advances in tuberculosis management, emphasizing that treatment initiation should never be delayed regardless of concerns about drug toxicity 2, 1
• The critical window for intervention makes early diagnosis paramount, as delays in diagnosis and treatment initiation have resulted in extended periods of infectiousness, additional transmission cases, and preventable deaths 2

Pulmonary Complications

Acute Structural Damage

• Cavitary disease develops in postprimary tuberculosis, beginning with patchy, ill-defined segmental consolidation that can progress to permanent lung damage 3
• Lobar or segmental atelectasis occurs in primary pulmonary TB, along with parenchymal disease, lymphadenopathy, and pleural effusion 3
• Miliary disease represents hematogenous dissemination with widespread small nodular infiltrates throughout both lungs 3

Chronic Post-TB Sequelae

• Mycetomas (fungal balls) can develop within residual TB cavities after successful treatment, requiring ongoing monitoring 4
• Impaired pulmonary function persists as a chronic complication from anatomic alterations at disease sites, even after microbiologic cure 4
• These chronic complications arise from permanent structural damage despite adequate treatment completion 4

Extrapulmonary Complications

Central Nervous System

• Tuberculous meningitis (TBM) is a critical diagnosis requiring immediate evaluation in any TB patient presenting with altered sensorium 5
• TBM requires extended treatment duration of 9-12 months (versus standard 6 months) and immediate addition of corticosteroids to reduce mortality and severe disability 5
• Focal neurologic deficits from tuberculomas can persist as chronic complications even after successful treatment 4
• CT and MR imaging findings vary depending on disease stage and lesion character 3

Musculoskeletal

• Tuberculous spondylitis and tuberculous arthritis are best diagnosed using CT and MR imaging 3
• These represent structural complications requiring both medical and sometimes surgical management 3

Gastrointestinal and Genitourinary

• CT is especially useful in depicting gastrointestinal tuberculosis and genitourinary tuberculosis, which can affect virtually any organ system 3

Disseminated Disease

• TB can affect virtually any organ system and can be devastating if left untreated, with a known propensity for dissemination from its primary site 3

Complications in HIV-Coinfected Patients

Increased Mortality and Atypical Presentations

• Mortality is significantly higher in HIV-positive patients with TB compared to HIV-negative patients, particularly in those with very low CD4+ cell counts who present with disseminated disease 2
• HIV-infected patients frequently present with extrapulmonary disease and atypical radiographic patterns (hilar adenopathy, middle- and lower-zone noncavitating infiltrates) rather than classical upper zone infiltration with cavitation 2
• Those with CD4+ counts below 50 cells/μL commonly present with disseminated TB 2

Treatment Complications

• Adverse effects of TB medications are more frequent in HIV-positive patients 2
• Drug-resistant TB outbreaks in HIV-positive patients have been documented, requiring specialized regimens when resistance is suspected 2
• Drug-drug interactions between rifamycins and antiretrovirals (particularly protease inhibitors and NNRTIs) complicate management, as rifampin induces P450 enzymes and reduces protease inhibitor levels to negligible concentrations 2

Immune Reconstitution Inflammatory Syndrome (IRIS)

• TB-IRIS can occur when starting antiretroviral therapy, manifesting as paradoxical worsening despite appropriate TB treatment 6
• Severe IRIS requires prednisone 1.25 mg/kg/day (50-80 mg/day) for 2-4 weeks with gradual tapering over 6-12 weeks or longer 6
• For tuberculous meningitis or CNS TB, avoid early ART initiation (within first 8 weeks) due to increased risk of severe IRIS 6

Metabolic and Systemic Complications

Hepatotoxicity

• Drug-induced hepatotoxicity from hepatitic drugs (isoniazid, rifampin, pyrazinamide) requires stopping all hepatotoxic agents if ALT exceeds 5 times the upper limit of normal, or if the patient becomes icteric 2
• Once liver function normalizes, drugs may be restarted sequentially in the presence of two non-hepatitic drugs (streptomycin and ethambutol) 2
• Monthly liver function monitoring is recommended, with testing at baseline, 2 weeks, monthly intervals, and whenever symptoms suggest hepatotoxicity 5

TB-Related Sepsis

• TB-related sepsis is a life-threatening acute complication for which current diagnostic and management approaches are likely inadequate 4
• This represents a critical gap in TB care requiring additional research and resources 4

Complications in Special Populations

Diabetes Mellitus

• Diabetic patients are at major risk of TB, though standard regimens are adequate 2
• Rifampin reduces serum levels of oral hypoglycemic drugs (particularly sulphonylureas), requiring dose adjustments 2

Silicosis

• Standard 6-month short-course chemotherapy may be inadequate in silico-TB due to difficulties in drug penetration into fibrotic lung and impaired macrophage function 2
• Treatment duration should be extended to 8 months (or 12 months if pyrazinamide is not included in the initial intensive phase) 2

Transmission and Public Health Complications

Infectiousness Factors

• Infectiousness correlates with: presence of cough, AFB-positive sputum smear, pulmonary cavitation on chest radiograph, and lack of adequate chemotherapy 2
• Patients with pulmonary or laryngeal TB are most infectious; extrapulmonary TB is usually not infectious except for respiratory tract involvement or open abscesses with extensive drainage 2
• Effective chemotherapy reduces infectiousness, but the timeline varies—some patients remain infectious for weeks or months with unrecognized drug-resistant disease 2

Delayed Diagnosis Consequences

• A single delayed diagnosis resulted in 21 additional TB cases among contacts, with 697 (7.0%) of 9,898 investigated persons developing new latent TB infections 2
• Another delayed diagnosis in a high school student led to 12 additional cases and 292 (23%) of 1,263 students testing positive for TB infection 2

Pediatric Complications

• TB in children indicates failure of the public health system to prevent disease transmission 2
• In one study, 37% of pediatric TB cases had an identifiable adult source-case, and 10% of cases could have been prevented with improved contact investigations 2

Treatment Failure and Relapse

Consequences of Incomplete Treatment

• Failure to complete standard treatment results in treatment failure, relapse, increased TB transmission, and emergence of drug-resistant TB 2
• Poor adherence stems from access difficulties, cultural factors, homelessness, substance abuse, lack of social support, rapid symptom clearing, or forgetfulness 2
• These adverse outcomes are preventable through case-management strategies including directly observed therapy (DOT) 2

Drug Resistance

• Drug-resistant TB requires immediate consultation with a TB specialist and drug susceptibility testing for both first-line and second-line drugs 5
• Mixed mycobacterial infections (simultaneous or sequential) may obscure recognition of M. tuberculosis clinically and in the laboratory 2

Paradoxical Reactions

• Paradoxical worsening during TB treatment represents an immune reconstitution phenomenon rather than treatment failure 5
• Anti-TB therapy should be continued unchanged, with corticosteroids (prednisone 1-2 mg/kg/day) considered for severe reactions with significant clinical impact 5

Critical Monitoring Requirements

• Monthly clinical evaluations should assess treatment response, adherence, and adverse effects 5
• Repeat liver function tests at baseline, 2 weeks, monthly, and whenever symptoms suggest hepatotoxicity 5
• Assessment for signs of increased intracranial pressure, renal function, and medication adherence history during initial evaluation 5