Tuberculosis

1. History

• Duration of cough: Persistent cough ≥2–3 weeks is the cardinal screening symptom; productive, may be blood-tinged [4-5]
• Constitutional symptoms: Fever (often low-grade, afternoon/evening), drenching night sweats, unintentional weight loss, anorexia, fatigue [6-7]
• Hemoptysis: Ranges from blood-streaked sputum to massive hemoptysis (suggests cavitary disease)
• Chest pain: Pleuritic pain may indicate pleural involvement
• Timing/progression: Insidious onset over weeks to months; subacute trajectory distinguishes TB from typical bacterial pneumonia [4]
• Exposure history: Close contact with known or suspected TB case, duration and setting of exposure
• Travel/residence: Birth in or travel to high-prevalence countries (sub-Saharan Africa, Southeast Asia, South Asia, Eastern Europe) [5]
• Prior TB history: Previous LTBI diagnosis, prior TB treatment, prior positive TST/IGRA
• Immunosuppression: HIV status, TNF-α inhibitor use, organ transplant, corticosteroid use, diabetes, chronic renal failure [8-9]
• Congregate settings: Incarceration, homeless shelters, long-term care facilities [4]
• Important negatives: Absence of cough does not exclude TB, especially in HIV-positive patients; up to 10% of HIV-associated TB cases are subclinical [2]

2. Alarm Features

• Massive hemoptysis (>300 mL/24 hours) — risk of airway compromise and hemorrhagic shock
• Altered mental status, neck stiffness, focal neurological deficits — suspect TB meningitis, the most severe form of extrapulmonary TB [10-11]
• Acute respiratory distress — miliary TB can progress to ARDS with mortality rates of 47–58% in adults [12-13]
• Signs of disseminated/miliary disease: Diffuse miliary pattern on CXR, hepatosplenomegaly, pancytopenia, choroid tubercles on fundoscopy (pathognomonic) [12]
• Hemodynamic instability with pericardial effusion — TB pericarditis with tamponade physiology [14]
• Failure to improve on standard antibiotics for community-acquired pneumonia after 7 days in a high-risk patient [4]
• Severely immunocompromised patients (CD4 <200): Atypical presentations with lower lobe infiltrates, hilar adenopathy, or normal CXR; disseminated disease with mycobacteremia [2]

3. Medications

Standard Treatment (Drug-Susceptible TB) per ATS/CDC/IDSA guidelines: [15-16]

• Intensive phase (2 months): Isoniazid (INH) + Rifampin (RIF) + Pyrazinamide (PZA) + Ethambutol (EMB) — daily dosing preferred
• Continuation phase (4 months): INH + RIF daily (or thrice weekly under DOT)
• Pyridoxine (vitamin B6) 25–50 mg/day: Given with INH to all patients to prevent peripheral neuropathy [16]
• EMB can be discontinued once susceptibility to INH and RIF is confirmed [15]

Key dosing: [17-18]

• INH: 5 mg/kg/day (max 300 mg)
• RIF: 10 mg/kg/day (max 600 mg)
• PZA: 25–35 mg/kg/day (max 2,000 mg)
• EMB: 15–25 mg/kg/day

Newer 4-month regimen (alternative): Rifapentine + moxifloxacin + INH + PZA for 8 weeks, then rifapentine + moxifloxacin + INH for 9 weeks — shown non-inferior to standard 6-month regimen [19]

Critical drug interactions (rifampin is a potent CYP450 inducer): [5][20]

• Reduces levels of: warfarin, oral contraceptives, methadone, protease inhibitors, NNRTIs, dolutegravir (dose adjustment needed), corticosteroids, azole antifungals, many others
• Rifabutin is preferred over rifampin in patients on certain antiretroviral regimens [19]

Contraindicated/caution medications:

• Avoid monotherapy with any single anti-TB drug (promotes resistance)
• Fluoroquinolones: QTc prolongation risk, especially with bedaquiline or clofazimine [21-22]

The following table from an NEJM review summarizes TB drug dosing and key considerations:

4. Diet

• Nutritional optimization is critical — malnutrition is both a risk factor for TB and a consequence of active disease; undernutrition accounts for an estimated 26.9% of attributable risk [23]
• High-protein, calorie-dense diet to support recovery and weight regain
• Avoid alcohol: Increases hepatotoxicity risk with INH, RIF, and PZA [15][19]
• Avoid milk, antacids, and divalent cations within 2 hours of fluoroquinolone or EMB dosing (impairs absorption) [16]
• Administer medications with food to reduce GI side effects [16]

5. Review of Systems

• Pulmonary: Cough (productive/dry), hemoptysis, dyspnea, pleuritic chest pain
• Constitutional: Fever, night sweats, weight loss, fatigue, anorexia
• Neurological: Headache, confusion, neck stiffness, focal deficits (TB meningitis) [10]
• Musculoskeletal: Back pain (Pott disease/spinal TB), joint pain [24]
• GI: Abdominal pain, diarrhea, ascites (peritoneal TB)
• GU: Dysuria, hematuria, flank pain (renal TB — can present years after primary infection) [24]
• Lymphatic: Painless lymphadenopathy, especially cervical (scrofula)
• Dermatologic: Erythema nodosum (hypersensitivity reaction)
• Cardiac: Chest pain, dyspnea, orthopnea (pericardial TB) [14]

6. Collateral History and Family History

• Household contacts: Any known TB cases, duration and proximity of exposure; household contact infection is more likely with smear-positive index cases [25]
• Immigration history: Country of origin, time since arrival, TB prevalence in home country
• Occupational exposure: Healthcare workers, correctional facility staff, laboratory workers
• Social context: Homelessness, substance use, incarceration history, crowded living conditions
• Family history: Congenital immunodeficiencies (chronic granulomatous disease, common variable immunodeficiency) increase susceptibility [8]
• HIV status of household members: Impacts contact investigation urgency

7. Risk Factors

• HIV infection — strongest individual risk factor; 8–10% annual progression rate without ART [1][9]
• Close contact with active pulmonary TB case [26]
• Immigration from high-prevalence countries [5]
• Diabetes mellitus — 7.5% attributable risk [23]
• Immunosuppressive therapy: TNF-α inhibitors, corticosteroids, post-transplant immunosuppression [9][27]
• Chronic kidney disease/dialysis [8]
• Silicosis [8]
• Active smoking — 15.8% attributable risk [23]
• Alcohol misuse — 9.8% attributable risk [23]
• Malnutrition/low BMI — 26.9% attributable risk [23]
• Congregate settings: Prisons, homeless shelters, nursing homes [4]
• Extremes of age: Infants (<1 year) and elderly [11]
• Chronic lung disease/COPD/bronchiectasis — 1.44–3.14-fold increased risk [27]
• Prior untreated LTBI: Greatest risk of progression in first 2 years [9]

8. Differential Diagnosis

• Lung cancer/lymphoma: Especially with upper lobe mass, weight loss, hemoptysis — biopsy may be needed to distinguish
• Community-acquired pneumonia: Shorter duration, acute onset; consider TB if no improvement after 7 days of antibiotics in high-risk patients [4]
• Non-tuberculous mycobacterial (NTM) infection: Similar CXR findings; AFB smear cannot distinguish from TB (requires NAAT or culture) [1]
• Lung abscess/aspergilloma: Cavitary lesions; aspergilloma can colonize old TB cavities
• Sarcoidosis: Bilateral hilar lymphadenopathy, non-caseating granulomas; can mimic TB clinically and radiographically
• Fungal infections: Histoplasmosis, coccidioidomycosis, blastomycosis — geographic exposure history is key
• HIV-associated opportunistic infections: PCP, MAC, CMV — especially at low CD4 counts
• Melioidosis: In endemic areas (Southeast Asia, Northern Australia)
• Empyema: Pleural TB can mimic bacterial empyema

9. Past Medical History

• Prior TB disease or LTBI (treated or untreated)
• HIV/AIDS status and CD4 count, ART regimen
• Diabetes mellitus (increases risk and may alter presentation)
• Chronic liver disease (impacts drug selection and monitoring)
• Chronic kidney disease (dose adjustments for EMB, PZA)
• History of organ transplantation or immunosuppressive therapy
• Silicosis or other occupite lung disease
• Prior BCG vaccination (affects TST interpretation, not IGRA)
• Substance use history (alcohol, IV drugs)
• Pregnancy status (affects drug selection; PZA avoided in some guidelines)

10. Physical Exam

• Vital signs: Low-grade fever, tachycardia, tachypnea; may be afebrile
• General: Cachexia, wasting, diaphoresis
• Pulmonary: Crackles/rales (especially apical), bronchial breath sounds, amphoric breathing over cavities; exam may be surprisingly normal
• Lymph nodes: Cervical lymphadenopathy (scrofula) — matted, non-tender, may be fluctuant [11]
• Abdomen: Hepatosplenomegaly (miliary/disseminated TB), ascites (peritoneal TB)
• Neurological: Meningismus, cranial nerve palsies (especially CN VI), altered consciousness (TB meningitis) [10]
• Spine: Gibbus deformity (Pott disease), paraspinal tenderness [24]
• Fundoscopy: Choroid tubercles — pathognomonic for miliary TB [12]
• Cardiac: Pericardial friction rub, muffled heart sounds, Beck's triad (TB pericarditis) [14]
• Skin: Erythema nodosum, lupus vulgaris (rare)

11. Lab Studies

Diagnostic labs: [1][9][15]

• AFB smear microscopy: 3 sputum specimens collected 8–24 hours apart (at least one early morning); fluorescence microscopy preferred; sensitivity ~50–80% for smear-positive disease
• Mycobacterial culture (liquid + solid media): Gold standard; takes 2–8 weeks; perform drug susceptibility testing on all positive cultures
• Nucleic acid amplification test (NAAT): Xpert MTB/RIF or Xpert Ultra on initial specimen — results in <2 hours; also detects rifampin resistance [6][9]
• Drug susceptibility testing: First-line (INH, RIF, EMB, PZA) on all positive cultures; second-line if resistance detected

Baseline labs before treatment: [5][15]

• CBC with differential
• Hepatic panel (AST, ALT, bilirubin, alkaline phosphatase)
• BMP (creatinine, electrolytes)
• HIV testing (mandatory for all TB patients)
• Hepatitis B and C serologies
• Uric acid (baseline before PZA)
• Visual acuity and color vision testing (baseline before EMB)
• Pregnancy test in women of childbearing age

Monitoring during treatment: [5][15]

• Monthly sputum AFB smear and culture until 2 consecutive negatives
• LFTs: Monthly if risk factors for hepatotoxicity; otherwise symptom-directed
• DILI criteria: ALT ≥3× ULN with symptoms, or ≥5× ULN without symptoms → stop hepatotoxic drugs [15][19]
• Visual acuity monthly while on EMB

12. Imaging

First-line: Chest radiograph (PA and lateral): [4]

• Classic findings (immunocompetent): Upper lobe infiltrates, cavitation, fibrosis, volume loss
• Atypical findings (HIV/immunosuppressed): Lower lobe infiltrates, hilar/mediastinal lymphadenopathy, interstitial pattern, pleural effusion, or normal CXR [2][4]
• Miliary pattern: Diffuse 1–2 mm nodules throughout both lung fields [12]

CT chest: More sensitive than CXR for detecting cavitation, lymphadenopathy, tree-in-bud pattern, miliary nodules; useful when CXR is equivocal or for extrapulmonary disease evaluation

When imaging is unnecessary: A normal CXR in an immunocompetent patient with no symptoms effectively excludes active pulmonary TB [28]

Extrapulmonary imaging: [24]

• MRI brain/spine: TB meningitis (basal meningeal enhancement, hydrocephalus), spinal TB (vertebral destruction, paraspinal abscess)
• CT abdomen: Necrotic lymph nodes, hepatosplenic microabscesses, peritoneal thickening
• Ultrasound: Pericardial effusion, ascites, lymphadenopathy

13. Special Tests

• Xpert MTB/RIF Ultra: Rapid NAAT with high sensitivity (~88% pooled) and specificity (~99%); simultaneously detects rifampin resistance; results in <2 hours [6]
• TST/IGRA: Supports diagnosis but cannot distinguish LTBI from active disease; a negative result does not exclude active TB (especially in immunosuppressed) [1][5]
• Adenosine deaminase (ADA): Elevated in TB pleural effusion, peritoneal TB, TB meningitis — useful adjunctive test
• Urine lipoarabinomannan (LAM): Point-of-care test useful in HIV-positive patients with low CD4 counts
• Bronchoscopy with BAL: When sputum cannot be obtained or smears are negative; perform under airborne precautions [15]
• Sputum induction: With hypertonic saline when patient cannot spontaneously expectorate
• Biopsy: Lymph node, pleural, peritoneal, or other tissue — caseating granulomas with or without AFB

14. ECG

• Standard first-line regimen (RIPE): The standard 6-month regimen does not carry a sizable risk of QT prolongation [29]
• Fluoroquinolones (moxifloxacin > levofloxacin): QTc prolongation risk; serial ECG monitoring recommended, especially in older patients and those with cardiovascular risk factors [22]
• MDR-TB drugs: Bedaquiline and delamanid both cause modest QTc prolongation; peak effect at 5–8 weeks (delamanid) and 24 weeks (bedaquiline) [21]
• Baseline ECG recommended before starting fluoroquinolones, bedaquiline, or delamanid; repeat at weeks 2, 8, and 16 for bedaquiline-containing regimens [21]
• QTcF >500 ms or increase >60 ms from baseline: Hold offending agent, correct electrolytes (K⁺, Mg²⁺, Ca²⁺), evaluate concomitant QT-prolonging medications [30-31]
• TB pericarditis: Low-voltage QRS, electrical alternans (if large effusion), diffuse ST elevation [14]

15. Assessment

• Active pulmonary TB is a reportable disease — all suspected and confirmed cases must be reported to the local/state health department [1][5]
• Severity stratification:
  • Uncomplicated pulmonary TB: Standard 6-month RIPE regimen
  • Cavitary disease with positive 2-month culture: Extend continuation phase to 7 months (total 9 months) [15]
  • Disseminated/miliary TB: High mortality (16–38%, higher with ARDS); requires ICU-level care if respiratory failure [12-13]
  • TB meningitis: Requires intensified regimen with higher-dose INH and RIF, adjunctive corticosteroids [20]
• Atypical presentations: HIV-positive patients, elderly, children, and immunosuppressed patients frequently present without classic upper lobe cavitary disease [2][4]
• Complications: ARDS, massive hemoptysis, bronchopleural fistula, constrictive pericarditis, Addison disease, amyloidosis, bronchiectasis

16. Treatment Plan

Initial stabilization (ED):

• Airborne isolation immediately upon suspicion (negative-pressure room, N95 respirators for staff) [4]
• Collect 3 sputum specimens for AFB smear, culture, and NAAT before or promptly after starting treatment [9][15]
• Do not delay empiric treatment in seriously ill patients pending results [15]

Standard drug-susceptible regimen: [15-16]

• Intensive phase (8 weeks): INH + RIF + PZA + EMB daily
• Continuation phase (18 weeks): INH + RIF daily or thrice weekly
• Pyridoxine 25–50 mg/day with all INH-containing regimens [16]
• Directly observed therapy (DOT) is strongly recommended [15]

Special situations:

• HIV co-infection: Start ART within 2 weeks if CD4 <50; within 8 weeks for higher CD4 counts; use rifabutin if drug interactions preclude rifampin [19]
• TB meningitis: Extend treatment to 9–12 months; adjunctive dexamethasone [20]
• Drug-resistant TB: Consult infectious disease specialist; bedaquiline-based regimens (BPaL) for MDR-TB [7]
• Pregnancy: INH + RIF + EMB for 9 months (PZA avoided in U.S. guidelines due to limited safety data); pyridoxine essential

Hepatotoxicity management: [15][19][23]

17. Disposition

Admission criteria:

• Hemodynamic instability, respiratory failure, or ARDS
• Suspected miliary/disseminated TB or TB meningitis
• Massive hemoptysis
• Inability to tolerate oral medications
• Social factors precluding safe outpatient isolation (homelessness, congregate living)
• Need for airborne infection isolation when outpatient isolation is not feasible

Discharge criteria: [26]

• On effective multidrug regimen with clinical improvement
• Three consecutive AFB smear-negative sputum specimens collected 8–24 hours apart (at least one early morning)
• Adequate outpatient isolation plan in place
• Coordination with local TB control program for DOT

Observation indications:

• Awaiting sputum results in patients with moderate clinical suspicion
• Rapid molecular testing (Xpert MTB/RIF) can reduce isolation duration from days to hours [32]

Specialist consultation triggers:

• Infectious disease: All confirmed cases; mandatory for drug-resistant TB, HIV co-infection, extrapulmonary TB
• Pulmonology: Massive hemoptysis, need for bronchoscopy
• Neurosurgery: TB meningitis with hydrocephalus requiring shunt
• Cardiothoracic surgery: Constrictive pericarditis, bronchopleural fistula
• Public health department: All suspected and confirmed cases [4]

18. Follow Up / Return Precautions

Follow-up timing:

• Monthly clinical evaluation during treatment (symptoms, weight, medication adherence, adverse effects) [5]
• Monthly sputum cultures until conversion documented [15]
• LFTs monthly if risk factors; otherwise symptom-directed [15]
• Visual acuity testing monthly while on EMB [5]
• End-of-treatment evaluation; some experts recommend CXR at completion

Symptoms requiring immediate reassessment:

• Jaundice, dark urine, severe nausea/vomiting, RUQ pain (hepatotoxicity)
• Visual changes or loss of color discrimination (EMB toxicity)
• Worsening cough, hemoptysis, dyspnea, or fever after initial improvement
• Numbness/tingling in extremities (peripheral neuropathy)
• Rash, persistent fever, or signs of drug hypersensitivity
• Confusion, headache, neck stiffness (CNS involvement)

Patient counseling points:

• TB is curable with complete treatment; adherence to the full course is critical — 16–49% of patients do not complete therapy [18]
• Medications must be taken as prescribed under DOT; missed doses can lead to drug resistance and treatment failure
• Avoid alcohol throughout treatment
• Use reliable contraception (rifampin reduces efficacy of oral contraceptives)
• Respiratory hygiene: Cover cough, wear mask around others until deemed non-infectious
• Expected recovery: Clinical improvement typically within 2–4 weeks; full treatment course is 6–9 months

Expected recovery course: Fever and constitutional symptoms generally improve within 2 weeks of effective therapy. Infectiousness declines rapidly — after 14–21 days of treatment, infectiousness averages <1% of pretreatment levels. [26] Sputum culture conversion typically occurs by 2 months in drug-susceptible TB.