Tuberkulosis Dewasa

01Pathophysiology

Tuberculosis begins when a susceptible host inhales aerosolized droplet nuclei containing Mycobacterium tuberculosis. These particles, measuring 1 to 5 micrometers, are small enough to bypass the mucociliary apparatus and reach the terminal alveoli, where they are engulfed by alveolar macrophages. However, M. tuberculosis has evolved a critical survival mechanism: its mycolic acid-rich cell wall resists phagolysosome fusion, allowing the organism to replicate intracellularly within the macrophage. This is the reason why TB cannot be easily cleared by the innate immune system alone.

Over 2 to 8 weeks, the host mounts a cell-mediated (Type IV) immune response driven by CD4+ T-helper cells and macrophages. Activated macrophages surround the infected cells and form a granuloma, the histopathological hallmark of TB. The center of this granuloma undergoes caseating necrosis (cheese-like, pale yellow material), a finding that distinguishes TB granulomas from those of sarcoidosis (non-caseating). Within this granuloma, multi-nucleated Langhans giant cells and epithelioid cells are characteristic findings on histopathology.

In immunocompetent hosts, this immune containment results in latent TB infection (LTBI), where the bacilli remain dormant. Approximately 5 to 10% of individuals with LTBI will progress to active disease in their lifetime, and the majority of those who do will reactivate within the first 2 years. This probability jumps dramatically in immunocompromised patients: HIV-positive individuals have an annual risk of 5 to 15% of reactivation, compared to 5 to 10% over a lifetime in healthy individuals.

Reactivation TB preferentially occurs in the apical and posterior segments of the upper lobes and the superior segments of the lower lobes. The reason is aerobic: these zones have the highest ventilation-to-perfusion ratio, providing the oxygen-rich environment that M. tuberculosis requires. This anatomic predilection is why classic CXR findings localize to the upper lung zones, and why lower-lobe TB should prompt you to consider HIV or other immunosuppression on an exam vignette.

When the immune system fails to contain the infection, cavitation occurs. The liquefied caseous center drains into an airway, creating a cavity. This cavity provides an aerobic, nutrient-rich niche where bacilli multiply to enormous numbers (up to ${10}^{7}10^\{7\}$ to ${10}^{9}10^\{9\}$), making the patient highly infectious. This is also why large cavities are associated with slower sputum conversion and higher risk of treatment failure.

In the context of TB-HIV coinfection, the depleted CD4 count impairs granuloma formation. Consequently, HIV-positive patients present atypically: lower-lobe disease, miliary patterns, extrapulmonary TB, adenopathy without cavitation, and sometimes a normal CXR altogether. The lower the CD4 count, the more atypical the presentation. This is a frequently tested concept.

02Classification and Clinical Manifestation

Extrapulmonary TB by severity:

03Diagnostic Workup

Step 1: Identify the suspect. Any adult presenting with cough lasting ≥2 weeks, or any cough accompanied by weight loss, intermittent fever, or night sweats, should be classified as a TB suspect. For HIV-positive individuals, any single symptom (cough, fever, weight loss, or night sweats) is sufficient.

Step 2: Obtain sputum specimens. Collect two sputum samples (Spot-Spot, Spot-Morning, or Morning-Spot). The second spot specimen must be taken at least one hour after the first. Quality standard: volume 1-4 mL, mucopurulent.

Step 3: Rapid Molecular Testing (Best Initial Test). The preferred initial diagnostic test is the Xpert MTB/RIF Ultra, a nucleic acid amplification test (NAAT) that simultaneously detects M. tuberculosis DNA and rifampicin resistance mutations in the rpoB gene within approximately 2 hours. Only one quality specimen is needed for this test. If Xpert is unavailable, alternative molecular tests include Truenat MTB-RIF Dx or BD MAX MDR-TB.

Step 4: Interpret results.

If the test detects Mtb and rifampicin is sensitive, initiate DS-TB treatment. For patients with a history of prior TB treatment, order additional isoniazid resistance testing (e.g., Xpert MTB/XDR).

If the test detects Mtb and rifampicin is resistant, close the DS-TB case and transfer to the DR-TB treatment pathway.

If Mtb is not detected, consider CXR and/or a trial of broad-spectrum antibiotics. The clinician may diagnose TB clinically if the clinical picture is strongly suggestive.

Step 5: Radiographic findings (supportive, not confirmatory).

Findings supporting active TB: upper-lobe infiltrates or nodules (apical-posterior segments), cavitation, miliary pattern, unilateral pleural effusion. Findings more consistent with inactive TB: fibrosis, calcification, pleural thickening. Note that CAD-interpreted CXR may be used for screening but cannot serve as a basis for diagnosis.

Critical distinction: A previously "cured" patient who relapses within <6 months of treatment completion must NOT be tested initially with molecular tests (residual DNA may cause false positives). Instead, sputum AFB smear is done first. Only if the smear is positive should molecular testing with resistance detection follow.

Step 6: Culture (Gold Standard). Culture on Lowenstein-Jensen (solid) or MGIT (liquid) media is the most accurate test. It is reserved for confirmation, drug susceptibility testing, and discordant results. This test is not routinely ordered for every patient in primary care settings due to turnaround time and infrastructure requirements.

04Management and Treatment

Dosing by Body Weight

Before starting treatment: Confirm HIV status (mandatory for all TB patients). Screen for diabetes, hepatitis, renal function, and nutritional status. Measure weight and height. Identify household contacts. Assign a treatment supporter (PMO).

Intensive phase (months 1-2): Give HRZE daily. OAT should be taken on an empty stomach (1 hour before or 2 hours after meals) for optimal rifampicin absorption. After 2 weeks of regular therapy, infectiousness drops substantially. Sputum AFB smear is checked at the end of month 2. If the month-2 smear is still positive (non-conversion), evaluate for poor adherence, incorrect dosing, comorbidities, or drug resistance. Order molecular testing for rifampicin resistance at this point, not earlier.

If month-2 smear is still positive: Do NOT extend the intensive phase (no more "extension/sisipan"). Continue the regimen and recheck BTA monthly. If BTA remains positive, the patient can be declared treatment failure at the earliest at the end of month 5 (1-AP).

Continuation phase (months 3-6): Give HR daily. Sputum AFB is checked at 1 month before end of treatment (1-AP) and at end of treatment (AP).

Treatment outcome determination: "Cured" requires documented negative BTA at end of treatment. "Treatment completed" is assigned when the full course is finished but BTA results are missing. "Failed" is declared if BTA is positive at month 5 or later. If a BTA turns positive after a prior negative result (reversal), repeat BTA within 7 days before declaring failure.

Molecular testing must NOT be used for treatment monitoring. Only sputum AFB microscopy is permitted for follow-up.

TB-HIV Coinfection Management

TB with Diabetes Mellitus

Standard 6-month regimen is used. DM increases risk of treatment failure, relapse, and death. Rifampicin induces CYP enzymes that reduce the effectiveness of sulfonylureas, so tighter glucose monitoring or a switch to insulin is recommended. Supplement vitamin B6 at 20 mg/day (isoniazid worsens diabetic neuropathy). Ethambutol requires cautious use due to additive risk of optic neuropathy.

TB with Chronic Kidney Disease

The standard regimen 2HRZE/4HR is used, but dose adjustments are needed for severe CKD (CC <30 mL/min):

$$CC(mL\mathrm{/}min)=\frac{Weight(kg)\times (140-Age)}{72\times SerumCreatinine(mg\mathrm{/}dL)}CC\backslash \; (mL/min)\; =\; \backslash frac\{Weight\backslash \; (kg)\; \backslash times\; (140\; -\; Age)\}\{72\; \backslash times\; Serum\backslash \; Creatinine\backslash \; (mg/dL)\}$$

For females, multiply by 0.85. Isoniazid and rifampicin need no adjustment (biliary excretion). Pyrazinamide and ethambutol require dose spacing: 25-35 mg/kg and 15-25 mg/kg respectively, given 3 times per week after dialysis.

TB in Pregnancy

Standard 6-month regimen (2HRZE/4HR) is safe. Add vitamin B6 throughout. Check baseline liver function. The 4-month regimen (HPMZ) is contraindicated in pregnancy and breastfeeding. Chest X-ray can be performed with abdominal shielding. Breastfeeding should continue; no need to separate mother and infant after 2 weeks of treatment. If TB active is excluded in the infant, give TPT with 6H followed by BCG vaccination.

05Drug-Induced Liver Injury (DILI) and Side Effect Monitoring

Side Effects

DILI Management Protocol

The three hepatotoxic first-line drugs in order of greatest risk are pyrazinamide > isoniazid > rifampicin. Ethambutol is not hepatotoxic and is considered safe.

When to stop OAT:

SGOT/SGPT >5x upper limit of normal (with or without symptoms): stop all OAT, hospitalize.

SGOT/SGPT >3x ULN with symptoms (nausea, vomiting, jaundice): stop all OAT, hospitalize.

SGOT/SGPT >3-5x ULN without symptoms: stop OAT, outpatient monitoring with SGOT/SGPT every 3-5 days.

Total bilirubin ≥2 mg/dL: stop all OAT, hospitalize.

Rechallenge protocol (done at referral hospital only):

Begin rechallenge only when ALT falls to ≤2x ULN, bilirubin normalizes, and symptoms resolve. Reintroduce drugs one at a time, every 2-3 days, starting with the least suspected drug and ending with the most suspected. The recommended order is: ethambutol first, then rifampicin, then isoniazid, then pyrazinamide (because PZA is most hepatotoxic). Check LFTs before each new drug addition. If hepatotoxicity recurs, the last drug added is identified as the culprit and permanently discontinued. Full rechallenge should be completed within a maximum of 21 days.

If pyrazinamide cannot be reintroduced: Extend the continuation phase by 3 months (total treatment: 9 months).

If recurrent hepatotoxicity occurs despite rechallenge: Switch to a non-hepatotoxic regimen using ethambutol, levofloxacin, and/or streptomycin. Plan for a minimum total treatment duration of 9 months with regular liver function monitoring.

Rechallenge is absolutely contraindicated in SJS, TEN, and anaphylaxis. In these cases, desensitization may be considered under strict inpatient monitoring only for essential drugs like rifampicin, and only when alternative regimens cannot meet the minimum of 2 bactericidal agents.

TB with Pre-existing Liver Disease

Managed by Child-Turcotte-Pugh (CTP) score:

Monitoring Schedule

TB Preventive Therapy (TPT) Overview

Priority recipients: household contacts of index cases, people living with HIV, immunocompromised individuals. All TPT recipients must have active TB excluded first. Vitamin B6 10-25 mg/day is mandatory with any isoniazid-containing TPT regimen.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common trap on TB questions is confusing the screening/initial test with the monitoring test and the confirmatory test. Students must remember that Xpert MTB/RIF Ultra is the best initial diagnostic test but must NEVER be used for treatment monitoring (residual DNA causes false positives). Sputum AFB microscopy is the monitoring test, done at months 2, 5 (1-AP), and 6 (AP). Culture remains the gold standard for confirmation and resistance profiling.

A second frequent error involves TB-HIV. When the vignette describes an HIV-positive patient with lower-lobe infiltrates, no cavitation, and lymphadenopathy, students often dismiss TB in favor of pneumonia or lymphoma. The lesson: in advanced HIV, TB does not look like "classic TB." Any single symptom (even just a fever) in an ODHIV qualifies that person as a TB suspect, and LF-LAM urine testing is a valid point-of-care diagnostic tool in this group.

The hepatotoxicity rechallenge sequence is another testing target. Remember to reintroduce drugs from least to most hepatotoxic: E first, then R, then H, then Z. If a student starts the rechallenge with isoniazid or pyrazinamide (the most hepatotoxic agents), that is the wrong answer. Also, if rifampicin causes thrombocytopenic purpura, it is permanently discontinued and never rechallenged.

For TB in pregnancy, the trap is stopping ethambutol out of unwarranted fear. All four first-line drugs (HRZE) are considered safe in pregnancy. Streptomycin, however, is contraindicated (ototoxicity to the fetus). The 4-month regimen (HPMZ) is also contraindicated in pregnancy and lactation.

Finally, do not confuse LTBI testing (TST/IGRA) with active TB diagnosis. TST and IGRA cannot distinguish latent from active disease. A positive TST in a patient with symptoms does not confirm active TB. The diagnosis still requires bacteriological confirmation. Conversely, a negative TST in an HIV-positive patient with a low CD4 count does not rule out TB (anergy).

The core competency being tested across TB questions is this: can you correctly sequence the diagnostic workup (molecular test before culture, never the reverse), identify the right monitoring tool (AFB, not Xpert), and manage drug toxicity using a stepwise rechallenge protocol? Mastering this sequence is what separates a correct from an incorrect answer on exam day.