Multisystem Processes & Disorders

Tuberculosis: extrapulmonary manifestations

Clinical Overview and When to Suspect Extrapulmonary TB

— Foreign-born patient from high-prevalence region (India, China, Philippines, Vietnam, Mexico, sub-Saharan Africa)

— HIV/AIDS, especially CD4 <200

— Immunosuppression: TNF-α inhibitors, chronic steroids, post-transplant, ESRD, diabetes

— Homelessness, incarceration, IV drug use, healthcare worker exposure

— Indolent, chronic constitutional symptoms (weeks–months of low-grade fever, night sweats, weight loss, anorexia) without an obvious source

— Site-specific clues: chronic cervical lymphadenopathy, sterile pyuria, chronic monoarthritis, lymphocytic exudative effusion, basilar meningitis

Extrapulmonary TB (EPTB) accounts for ~20–25% of all TB cases in the US and >50% in HIV-coinfected patients

Caused by Mycobacterium tuberculosis via hematogenous, lymphatic, or contiguous spread from a primary (often subclinical) pulmonary focus

Most common sites in descending order: lymphatic > pleural > bone/joint > genitourinary > meningeal > peritoneal > pericardial > cutaneous

When to suspect EPTB:

Key distinction: Pulmonary TB presents with cough and infiltrates; EPTB presents with organ-specific findings often without respiratory symptoms — up to 30–50% have a normal CXR

Pathophysiology pearl: EPTB reflects either reactivation at extrapulmonary seeded sites or disseminated (miliary) disease from impaired cell-mediated immunity

Board pearl: Any chronic granulomatous disease in a foreign-born or immunocompromised patient = test for TB before steroids or biologics. A patient about to start infliximab who has a positive IGRA needs latent TB treatment before biologic initiation — missing this triggers reactivation and is a classic Step 3 vignette

Step 3 management: When EPTB is suspected, always also evaluate for concurrent pulmonary TB (CXR + sputum × 3 for AFB smear/culture/NAAT) because ~10–50% have coexisting pulmonary disease and respiratory isolation decisions hinge on this

Always test for HIV in any newly diagnosed TB patient — non-negotiable

Presentation Patterns and Key History

— Painless, firm, unilateral cervical or supraclavicular nodes, weeks–months

— May progress to matted nodes, fluctuance, sinus tracts with caseous drainage

— Children and young adults from endemic regions; consider NTM (M. avium) in US-born children

— Subacute fever, pleuritic chest pain, nonproductive cough, dyspnea

— Unilateral exudative effusion, often without parenchymal infiltrate on CXR

— Chronic back pain, gibbus deformity, neurologic deficits from cord compression

— Lower thoracic/upper lumbar spine; paraspinal cold abscess is pathognomonic

— Peripheral monoarthritis (hip, knee) — chronic, indolent, "cold" joint

— Sterile pyuria with negative routine cultures is the classic clue

— Dysuria, hematuria, flank pain, infertility, epididymal mass, endometrial involvement causing infertility/menstrual irregularity

— Subacute (1–3 weeks) headache, fever, vomiting, cranial nerve palsies (CN VI > III, IV, VII), confusion

— Basilar meningeal involvement → hydrocephalus, stroke from vasculitis

— Ascites, abdominal pain, weight loss, low-grade fever; "doughy" abdomen on exam

— Dyspnea, chest pain, signs of tamponade or constriction; common in HIV/Africa

— Disseminated; multiorgan, hepatosplenomegaly, choroidal tubercles on funduscopy

— Travel/birth in endemic country, TB contact, prior incomplete TB treatment

— HIV status, immunosuppressants, steroid use, biologics, diabetes, ESRD

— Silicosis (greatly increases TB risk)

Lymphadenitis (scrofula) — most common EPTB in US

Pleural TB

Skeletal TB (Pott disease most classic)

Genitourinary TB

TB meningitis

TB peritonitis

TB pericarditis

Miliary TB

Key history red flags:

Board pearl: Choroidal tubercles on fundoscopy = miliary TB until proven otherwise — and they bypass the need for lung biopsy in many vignettes

Step 3 management: A young immigrant with chronic painless cervical adenopathy + weight loss → excisional biopsy (not FNA alone) with AFB stain, culture, and NAAT

Physical Exam Findings and Site-Specific Signs

— Cachexia, low-grade fever (often evening), tachycardia disproportionate to fever

— Pallor (anemia of chronic disease), clubbing in chronic disease

— Firm, nontender, matted cervical/supraclavicular nodes

— Fluctuance, overlying violaceous skin, sinus tracts with caseous discharge (collar-stud abscess)

— Dullness to percussion, decreased breath sounds, decreased fremitus over effusion

— Pleural rub early in disease

— Pott disease: focal spinal tenderness, gibbus (sharp kyphotic angulation), paraspinal mass

— Neurologic deficits: paraparesis, sensory level, bladder dysfunction → emergency

— Cold abscess: fluctuant mass without overlying erythema or warmth

— Epididymal beading or nontender mass; prostate nodules

— Costovertebral angle tenderness if renal involvement

— Meningismus may be subtle compared to bacterial

— CN VI palsy most common; CN III, IV, VII also; papilledema from hydrocephalus

— Focal deficits from tuberculomas or vasculitic stroke

— Altered mental status correlates with stage (BMRC staging: I = alert; II = lethargic/focal; III = comatose)

— Distended abdomen, shifting dullness, "doughy" feel from fibrinous adhesions

— Friction rub, muffled heart sounds, pulsus paradoxus, elevated JVP, Kussmaul sign (constrictive)

— Hemodynamic compromise → tamponade physiology

— Lupus vulgaris (reddish-brown plaques, face), erythema nodosum, scrofuloderma

— Choroidal tubercles (yellowish retinal nodules) in miliary TB

General

Lymphatic

Pleural

Skeletal

CNS (TB meningitis)

Peritoneal

Pericardial

Cutaneous

Ocular

Key distinction: A "cold abscess" (no erythema, no warmth) over the spine or psoas is TB until proven otherwise — not pyogenic

Board pearl: TB meningitis BMRC stage at treatment initiation is the single strongest predictor of mortality and neurologic outcome — never delay empiric therapy waiting for confirmation

Step 3 management: Suspected Pott disease with new neuro deficit → urgent MRI spine + neurosurgery consult same day

Diagnostic Workup — Initial Labs, Imaging, and Site-Directed Studies

— CBC (anemia, leukopenia, pancytopenia in miliary), CMP, LFTs (baseline before RIPE), HIV test, hepatitis B/C serologies

— HbA1c, pregnancy test in reproductive-age women

— IGRA (QuantiFERON or T-SPOT) preferred over TST; both detect infection, not active disease, and can be falsely negative in severe/disseminated TB or HIV with low CD4

— CXR in every patient — looks for pulmonary co-disease, upper-lobe cavitation, miliary pattern (2–3 mm diffuse nodules)

— Sputum × 3 (AFB smear, culture, NAAT/Xpert MTB/RIF) if any pulmonary findings

— Lymphadenitis: US or CT neck → excisional biopsy (highest yield); send for AFB smear, mycobacterial culture, NAAT, histopathology (caseating granulomas)

— Pleural TB: thoracentesis → lymphocyte-predominant exudate, ADA >40 U/L highly suggestive, low glucose, pH <7.3; pleural fluid AFB smear low yield (~10%), culture ~30%; pleural biopsy culture + histology ~80% yield

— Skeletal: MRI spine/joint (vertebral body destruction with disc sparing early, paraspinal abscess); CT-guided biopsy for AFB/culture/NAAT/histo

— GU TB: UA shows sterile pyuria; 3 morning urines for AFB; CT urogram (calyceal distortion, ureteral strictures, "putty kidney")

— TB meningitis: LP — opening pressure elevated, lymphocytic pleocytosis (100–500), low glucose, high protein (often >100), CSF AFB smear low yield; send CSF NAAT (Xpert Ultra) and large-volume culture; CSF ADA supportive; MRI brain with contrast (basilar meningeal enhancement, hydrocephalus, tuberculomas, infarcts)

— Peritoneal: paracentesis — lymphocytic exudate, SAAG <1.1, ADA >39 U/L, peritoneal biopsy via laparoscopy = gold standard

— Pericardial: echo (effusion ± constriction), pericardial fluid ADA, pericardial biopsy

Universal initial workup for suspected EPTB

Site-specific imaging and sampling

Board pearl: Pleural fluid ADA >40 U/L in a young patient with lymphocytic exudative effusion = treat empirically for TB pleuritis

Step 3 management: Suspected TB meningitis → start empiric RIPE + dexamethasone immediately after LP; do not wait for cultures

Advanced and Confirmatory Studies

— Culture (gold standard): liquid (MGIT, 1–3 weeks) + solid (Löwenstein-Jensen, 4–8 weeks); enables drug susceptibility testing

— NAAT (Xpert MTB/RIF, Xpert Ultra): rapid (<2 hours), detects M. tuberculosis + rifampin resistance; sensitivity highest in smear-positive disease; Ultra has improved sensitivity in paucibacillary EPTB (meningitis, lymphadenitis)

— AFB smear (Ziehl-Neelsen / auramine-rhodamine): requires ~10,000 organisms/mL; low sensitivity in EPTB

— Caseating granulomas with Langhans giant cells, lymphocytes, epithelioid macrophages

— AFB stain on tissue may be negative even when culture positive; absence does not exclude TB

— Useful in pleural, peritoneal, pericardial, and CSF fluids

— Released by activated T-lymphocytes; high sensitivity, modest specificity (lymphoma, empyema, RA can elevate)

— Phenotypic (culture-based, weeks) and genotypic (line probe assays, whole genome sequencing) — essential to detect MDR-TB (resistant to INH + rifampin) and XDR-TB

— Miliary TB: high-resolution CT chest shows diffuse 1–3 mm nodules

— CNS: MRI > CT for tuberculomas, basilar meningitis, hydrocephalus, vasculitic infarcts

— Skeletal: MRI superior to CT for early vertebral marrow edema and cord compression

— Biopsy is the single highest-yield step for most EPTB sites — always send tissue for AFB stain, mycobacterial culture, NAAT, and histopathology (4-way split)

— Bone marrow biopsy and liver biopsy useful in miliary TB with cytopenias or hepatic involvement

— Fundoscopy for choroidal tubercles can be diagnostic shortcut in miliary disease

Microbiologic confirmation hierarchy

Histopathology

Adenosine deaminase (ADA)

Drug susceptibility testing (DST)

Imaging adjuncts

Specialized tests

Key distinction: NAAT positive confirms TB and guides rifampin sensitivity, but a negative NAAT does NOT rule out EPTB due to paucibacillary nature — clinical + histologic + ADA + response to therapy often drive treatment

Board pearl: In TB meningitis, CSF Xpert Ultra is the highest-yield rapid test; sensitivity ~70%, but negative result does not stop empiric therapy

Step 3 management: Always obtain DST on every initial isolate; resistance changes regimen and duration dramatically

Risk Stratification and First-Line Management Logic

— Is there concurrent pulmonary disease? → airborne isolation (negative-pressure room, N95) until 3 negative sputum AFB smears

— Drug-susceptible vs MDR-TB? → DST drives regimen

— Severity/site → adjuvant corticosteroids indicated?

— HIV coinfection → timing of ART

— Pregnancy, hepatic disease, renal disease → drug modifications

— TB meningitis — dexamethasone taper over 6–8 weeks reduces mortality (especially BMRC stage II/III); start with first dose of RIPE

— TB pericarditis — prednisone in HIV-negative patients reduces constriction/effusion recurrence; controversial in HIV+

— Selected severe miliary TB with respiratory failure

— Not routinely for pleural, lymphatic, GU, or skeletal TB

— Most EPTB: 6 months (2 months RIPE intensive + 4 months INH/RIF continuation) — same as pulmonary

— TB meningitis: 9–12 months

— Bone/joint TB (Pott disease): 6–9 months, often extended to 9–12 in severe cases

— Disseminated/miliary: 6–9 months (12 if CNS involvement)

— TB is a mandatory reportable disease in all 50 states — notify local health department immediately on suspicion or confirmation

— Public health initiates contact tracing and may provide directly observed therapy (DOT) — DOT is standard of care to improve adherence

— CD4 <50 → start ART within 2 weeks of TB therapy

— CD4 ≥50 → start ART within 8 weeks

— Exception: TB meningitis with HIV → delay ART ~8 weeks regardless of CD4 (IRIS risk to CNS catastrophic)

Initial decision tree once EPTB suspected/confirmed

Sites requiring adjuvant corticosteroids (high-yield)

Treatment duration by site

Reporting and public health

HIV coinfection timing

CCS pearl: Orders day 1 for suspected EPTB in inpatient setting — airborne isolation, HIV test, CXR, sputum × 3 if any pulmonary findings, site-specific biopsy/aspiration, baseline LFTs/CBC/CMP/visual acuity/color vision, hepatitis B/C, pregnancy test, notify public health, infectious disease consult

Board pearl: Steroids save lives in TB meningitis and pericarditis — memorize these two indications

Pharmacotherapy — First-Line RIPE Regimen

— Rifampin 10 mg/kg (max 600 mg) daily

— Isoniazid (INH) 5 mg/kg (max 300 mg) daily + pyridoxine (B6) 25–50 mg daily to prevent peripheral neuropathy

— Pyrazinamide (PZA) 25 mg/kg daily

— Ethambutol 15–20 mg/kg daily (drop once pan-sensitive confirmed)

— Duration depends on site (see chunk 6)

— Isoniazid: hepatotoxicity (age-related, EtOH risk), peripheral neuropathy (give B6), drug-induced lupus, SIADH; CYP450 inhibitor

— Rifampin: orange discoloration of body fluids (benign, counsel), hepatotoxicity (cholestatic), flu-like syndrome, thrombocytopenia, potent CYP450 inducer — decreases efficacy of OCPs, warfarin, methadone, PIs/NNRTIs, DOACs, tacrolimus

— Pyrazinamide: hyperuricemia (avoid in gout flare), hepatotoxicity, arthralgia

— Ethambutol: optic neuritis — dose-dependent, reversible if caught early; check baseline + monthly visual acuity and red-green color discrimination

— Rifampin + most PIs/NNRTIs = contraindicated or dose-adjusted

— Rifabutin (less potent CYP3A4 inducer) substituted for rifampin when on PIs

— Baseline LFTs, CBC, BUN/Cr, uric acid, visual exam

— Symptomatic LFT monitoring monthly; routine repeat if baseline abnormal, age >40, EtOH, HIV, pregnant, hepatitis

— Hold all hepatotoxic TB drugs if ALT >3× ULN with symptoms OR >5× ULN asymptomatic

— Standard of care; can be in-person or video DOT; provided by health department

Intensive phase (first 2 months): RIPE

Continuation phase (after 2 months): INH + Rifampin

Key adverse effects to monitor

HIV coinfection drug interactions

Monitoring

DOT (directly observed therapy)

Board pearl: Rifampin turns urine/tears/sweat orange — warn about contact lens staining; this is harmless but commonly tested

Step 3 management: New peripheral neuropathy on TB therapy → check if pyridoxine was prescribed; if not, add B6 50 mg daily (especially in diabetics, alcoholics, malnourished, HIV, pregnancy, ESRD)

Procedures and Site-Specific Interventions

— Excisional biopsy is both diagnostic and therapeutic in many cases

— Avoid incision and drainage of fluctuant nodes (creates chronic sinus tracts)

— Paradoxical enlargement during therapy is common (especially HIV/IRIS) — does not mean treatment failure; continue regimen

— Therapeutic thoracentesis for symptomatic effusions

— Most effusions resolve with medical therapy; chest tube rarely needed unless empyema

— Medical therapy alone for most cases without instability or neuro deficit

— Surgical indications:

— Spinal cord compression with neurologic deficit

— Spinal instability or significant kyphosis

— Large paraspinal/psoas abscess not responding to therapy

— Failure of medical therapy

— Drainage of psoas/cold abscesses by IR when symptomatic

— Ureteral stenting or percutaneous nephrostomy for obstructive uropathy

— Reconstructive surgery (ureteral reimplantation, augmentation cystoplasty) after chemotherapy completion

— Nephrectomy for nonfunctioning ("putty") kidney with persistent symptoms

— VP shunt or EVD for obstructive hydrocephalus — often emergent

— Repeat LPs not routinely needed

— Pericardiocentesis for tamponade or diagnostic fluid

— Pericardiectomy for constrictive pericarditis not responding to medical therapy

— Diagnostic laparoscopy with peritoneal biopsy (gold standard)

— Adhesiolysis if bowel obstruction develops

— Supportive care; ICU if respiratory failure or septic physiology

— Consider bone marrow or liver biopsy if diagnosis unclear

Lymphadenitis

Pleural TB

Skeletal TB (Pott disease)

GU TB

TB meningitis

TB pericarditis

Peritoneal TB

Miliary/disseminated

CCS pearl: Pott disease with cord compression → MRI spine STAT → neurosurgery consult → start RIPE + dexamethasone — surgery is often decompressive laminectomy + debridement + instrumentation; do not delay anti-TB therapy waiting for OR

Board pearl: Paradoxical reaction (worsening nodes, new infiltrates, fevers) 1–3 months into therapy with documented adherence and DST confirming susceptibility = continue therapy, add steroids if severe; do not switch regimen

Special Populations — Elderly, Renal, and Hepatic Impairment

— Higher reactivation risk; atypical presentations (failure to thrive, falls, isolated fever)

— Increased INH and PZA hepatotoxicity risk — monthly LFT monitoring

— Polypharmacy: rifampin's CYP450 induction reduces warfarin, statin, calcium channel blocker, DOAC efficacy

— Lower threshold to check baseline visual acuity for ethambutol (cataracts, glaucoma confound monitoring)

— INH and Rifampin — no dose adjustment (hepatic clearance)

— PZA and Ethambutol — renally cleared; reduce dosing frequency to 3× weekly (not daily) in CrCl <30 or HD

— Administer all doses after hemodialysis to avoid removal

— Increased risk of ethambutol-induced optic neuritis in renal failure — vigilant monitoring

— Baseline LFTs essential; INH, RIF, PZA all hepatotoxic; PZA most, followed by INH, then RIF

— Mild–moderate disease (Child A): standard RIPE with close monitoring

— Advanced disease (Child B/C) or acute hepatitis: modify regimen

— Avoid PZA; consider regimen of RIF + INH + ethambutol + fluoroquinolone (e.g., levofloxacin/moxifloxacin)

— If both INH and RIF must be avoided: ethambutol + fluoroquinolone + injectable (amikacin/streptomycin) ± linezolid — ID consult

— Stop all hepatotoxic agents if ALT >3× ULN with symptoms or >5× ULN asymptomatic

— Once LFTs normalize, reintroduce sequentially: RIF first (least hepatotoxic), then INH, then PZA (or omit PZA if severe initial reaction and extend total duration)

— Slower sputum conversion, higher relapse risk — strict glycemic control improves outcomes

— Rifampin lowers serum levels of sulfonylureas and may unmask hyperglycemia

— High hepatotoxicity risk; counsel cessation; monthly LFTs; pyridoxine essential

Elderly (>65)

Renal impairment / ESRD on dialysis

Hepatic impairment

Drug-induced hepatitis management

Diabetics

Alcohol use disorder

Board pearl: Ethambutol dosing must be reduced in renal failure — missing this is a classic Step 3 error leading to irreversible optic neuritis

Step 3 management: Patient on warfarin starts rifampin → INR will drop within 1–2 weeks; preempt with closer INR monitoring and dose escalation

Special Populations — Pregnancy, Pediatrics, HIV

— Untreated active TB is far more dangerous than therapy — treat promptly

— Safe in pregnancy: INH, Rifampin, Ethambutol; pyridoxine required with INH

— Pyrazinamide: not used routinely in US pregnancy (limited teratogenicity data, though WHO endorses); regimen becomes INH + RIF + ETH for 2 months, then INH + RIF for 7 months = 9 months total if PZA omitted

— Streptomycin: contraindicated — fetal ototoxicity (CN VIII damage)

— Latent TB: defer treatment to postpartum unless recent conversion, HIV+, or close contact of active case

— Breastfeeding: all first-line drugs compatible; infant should receive pyridoxine if mother on INH

— Evaluate infant for congenital TB

— If mother smear-positive at delivery: separate temporarily, give INH prophylaxis to infant, check TST at 3 months

— EPTB more common in children (lymphatic, meningeal, miliary)

— Avoid ethambutol in young children who cannot report visual changes (use only when necessary)

— Doses are weight-based; pediatric ID consultation recommended

— BCG vaccine in country of origin: does not cause persistently positive IGRA (use IGRA over TST in BCG-vaccinated)

— Same RIPE regimen; duration usually unchanged unless CNS or bone involvement

— Rifampin–ART interaction: use rifabutin with PIs; efavirenz tolerates rifampin

— ART timing: CD4 <50 → start ART within 2 weeks; CD4 ≥50 → within 8 weeks; TB meningitis → delay ART to ~8 weeks regardless of CD4

— IRIS (immune reconstitution inflammatory syndrome): paradoxical worsening 2–12 weeks after ART start; treat with NSAIDs or steroids; continue both TB therapy and ART

— Screen with IGRA pre-treatment; treat latent TB before TNF-α inhibitor, JAK inhibitor, or transplant

Pregnancy

Neonate of mother with active TB

Pediatrics

HIV coinfection (critical)

Transplant recipients / biologics

Board pearl: Streptomycin = ototoxic to fetus; PZA omitted in US pregnancy → extends regimen to 9 months

Step 3 management: HIV+ patient newly diagnosed with TB meningitis → start RIPE + dexamethasone now, delay ART 8 weeks to avoid catastrophic CNS IRIS

Complications and Adverse Outcomes

— TB meningitis: hydrocephalus, vasculitic stroke, cranial nerve palsies, tuberculomas, SIADH, seizures, permanent cognitive/motor deficits; mortality 20–50%

— Pott disease: paraplegia from cord compression, kyphotic deformity (gibbus), psoas abscess, chronic pain

— Pleural TB: trapped lung, fibrothorax, chronic restrictive lung disease, empyema

— Pericardial TB: tamponade, constrictive pericarditis (up to 30%), chronic heart failure

— GU TB: ureteral strictures, hydronephrosis, autonephrectomy ("putty kidney"), infertility, end-stage renal disease

— Peritoneal TB: adhesions, bowel obstruction, fistulas

— Lymphadenitis: chronic draining sinus tracts, disfigurement, scarring

— Miliary: ARDS, multiorgan failure, DIC, hemophagocytic lymphohistiocytosis

— Hepatitis: INH > PZA > RIF; can be fulminant

— Optic neuritis: ethambutol; check vision monthly

— Peripheral neuropathy: INH (prevent with B6)

— Hyperuricemia/gout: PZA

— Cytopenias: rifampin (thrombocytopenia), linezolid in MDR regimens

— Drug-drug interactions: rifampin loss of contraceptive efficacy → counsel barrier method

— Paradoxical reaction: worsening lesions during effective therapy due to delayed hypersensitivity; treat with steroids if severe; continue same regimen

— IRIS in HIV: similar mechanism after ART initiation

— Transmission to household contacts before isolation

— Drug resistance from incomplete therapy → MDR/XDR-TB

— TB meningitis BMRC stage III, HIV with low CD4, drug resistance, miliary with ARDS, age extremes, delay in therapy

Disease-related complications by site

Drug-related complications

Treatment-related phenomena

Public health complications

Mortality predictors

Board pearl: Constrictive pericarditis developing 6–12 months after TB pericarditis → consider pericardiectomy; medical therapy alone insufficient

Key distinction: Treatment failure (positive cultures at 4 months) vs paradoxical reaction (clinical worsening but cultures sterile) — management is opposite (broaden vs steroids)

When to Escalate — ICU, Consults, and Inpatient Triage

— Miliary TB with ARDS or respiratory failure

— TB meningitis BMRC stage II/III, altered mental status, seizures, signs of elevated ICP, herniation risk

— TB pericarditis with tamponade — emergent pericardiocentesis

— Massive hemoptysis (rare in EPTB, but consider with concurrent pulmonary disease/aspergilloma)

— Septic shock, multiorgan failure

— DIC, HLH

— Initial diagnosis of disseminated/severe EPTB requiring biopsy and parenteral therapy

— Inability to tolerate oral medications

— Need for airborne isolation when home isolation infeasible (homeless, congregate setting, infants in household)

— Drug-induced hepatitis requiring IV regimen modification

— Suspected MDR-TB

— Pott disease with neurologic deficit pending surgery

— Infectious disease — for all confirmed EPTB; mandatory for HIV coinfection, MDR-TB, pregnancy, pediatric

— Public health department — mandatory reporting and DOT setup

— Neurosurgery — TB meningitis with hydrocephalus, Pott disease with cord compression

— Cardiothoracic surgery — constrictive pericarditis

— Urology — GU TB with obstruction

— Ophthalmology — baseline + monthly for ethambutol; choroidal tubercle evaluation

— Pulmonology — pleural TB with trapped lung, concurrent cavitary disease

— Hepatology — drug-induced hepatitis with worsening synthetic function

— Effective therapy for at least 2 weeks, clinical improvement, 3 consecutive negative AFB sputum smears, household contacts evaluated and able to be safely exposed

ICU admission indications

Inpatient admission (non-ICU) indications

Consults to obtain early

Discharge from isolation criteria (if concurrent pulmonary)

CCS pearl: TB meningitis vignette — Order set: airborne isolation, LP (after head CT if focal deficits/papilledema), MRI brain with contrast, RIPE + dexamethasone NOW, ID consult, neurosurgery consult if hydrocephalus, HIV test, public health notification, ophthalmology baseline

Step 3 management: Never delay empiric anti-TB therapy in TB meningitis pending confirmation — every hour of delay worsens neurologic outcome

Key Differentials — Other Mycobacterial and Granulomatous Diseases

— M. avium complex (MAC) — cervical lymphadenitis in US-born children (unilateral, no constitutional sx); disseminated MAC in AIDS (CD4 <50)

— M. kansasii — pulmonary > extrapulmonary; mimics TB but rifampin-based therapy works

— M. marinum — cutaneous nodules from aquarium/fish exposure

— Distinction: NAAT specific for M. tuberculosis differentiates; cultures with speciation; epidemiology critical

— Noncaseating granulomas (vs caseating in TB)

— Bilateral hilar lymphadenopathy + parenchymal disease, hypercalcemia, elevated ACE

— Erythema nodosum, uveitis, lupus pernio

— Lymphocytic pleural effusion with low ADA; biopsy with noncaseating granulomas

— Steroid-responsive; ruling out TB before steroids is mandatory

— Histoplasmosis (Ohio/Mississippi River valleys) — cavitary pulmonary, hepatosplenomegaly, oral ulcers; urine antigen

— Coccidioidomycosis (Southwest US) — pulmonary, meningitis, erythema nodosum

— Blastomycosis — skin, bone, prostate, lung; broad-based budding yeast

— Cryptococcosis in HIV — meningitis with high opening pressure, India ink, CrAg

— Distinction: fungal stains, urinary/serum antigens, geographic exposure

— Spinal involvement mimicking Pott (typically lumbar rather than thoracolumbar); animal exposure, unpasteurized dairy; agglutination titers

— Sulfur granules (actinomyces), branching gram-positive rods; cervicofacial or pulmonary; Nocardia: weakly acid-fast, CNS abscesses

— Regional lymphadenitis with cat exposure; serology

— Lymphadenopathy, especially in immunocompromised; CNS ring-enhancing lesions in AIDS

Nontuberculous mycobacteria (NTM)

Sarcoidosis

Fungal infections

Brucellosis

Actinomycosis / Nocardia

Cat-scratch disease (Bartonella)

Toxoplasmosis

Key distinction: Caseating granulomas + AFB = TB; noncaseating = sarcoid, Crohn, berylliosis, GPA, foreign body

Board pearl: Hypercalcemia + bilateral hilar adenopathy + uveitis = sarcoidosis; before steroids, rule out TB with IGRA + CXR — missing this triggers reactivation

Key Differentials — Non-Granulomatous Mimics by Site

— Lymphoma (Hodgkin, NHL): painless, rubbery nodes, B symptoms overlap with TB; excisional biopsy distinguishes

— Metastatic carcinoma: supraclavicular (Virchow node) = GI/lung primary; hard, fixed nodes

— HIV-related lymphadenopathy, infectious mononucleosis, syphilis

— Parapneumonic effusion/empyema: neutrophilic exudate, positive bacterial cultures

— Malignant effusion: older patient, cytology positive, often hemorrhagic

— Connective tissue (RA, lupus): low complement/glucose; ADA can be elevated in RA

— PE with effusion: typically small, exudative

— Pyogenic vertebral osteomyelitis: S. aureus most common, more acute, involves disc early (vs TB which spares disc until late), no paraspinal cold abscess

— Metastatic spine disease: older patient, known primary, posterior elements often involved (TB spares posterior elements)

— Multiple myeloma: lytic lesions, M-spike, hypercalcemia

— Recurrent bacterial UTI, interstitial cystitis, bladder cancer (especially with hematuria, smoker)

— Schistosomiasis (S. haematobium) — endemic regions, eggs in urine

— Cryptococcal meningitis in HIV; bacterial meningitis (acute, neutrophilic); viral meningitis (lymphocytic, normal glucose); carcinomatous meningitis; neurosarcoidosis; neurosyphilis

— Distinction: TB meningitis has low CSF glucose (unlike viral); subacute course; basilar enhancement on MRI

— Peritoneal carcinomatosis (ovarian, GI primary), cirrhotic ascites (SAAG >1.1), SBP (neutrophilic)

— Peritoneal mesothelioma

— Uremic, viral (Coxsackie), post-MI (Dressler), neoplastic, autoimmune pericarditis

— Metastatic carcinoma (thyroid, breast, RCC, melanoma), fungal (histo, blasto), silicosis, sarcoidosis, hypersensitivity pneumonitis

Lymphadenopathy

Pleural disease

Skeletal / spinal

CNS

Peritoneal

Pericardial

Miliary pattern on CXR/CT

Board pearl: Pyogenic osteomyelitis destroys the disc early; TB Pott spares the disc and crosses multiple vertebral bodies via the anterior longitudinal ligament — classic imaging distinction

Key distinction: CSF glucose low in TB and bacterial meningitis; normal in viral — guides empiric therapy

Secondary Prevention and Long-Term Plan

— Indications: positive IGRA/TST in close contacts, HIV+, recent conversion, immunosuppressed, pre-biologic (TNF-α, JAK inhibitors), pre-transplant, ESRD, silicosis, healthcare workers, immigrants from high-prevalence regions

— Preferred regimens (CDC 2020):

— 3HP: INH 15 mg/kg + rifapentine weekly × 12 weeks (DOT preferred) — short course, high completion

— 4R: rifampin daily × 4 months — short, well-tolerated

— 3HR: INH + rifampin daily × 3 months

— 6–9H: INH daily × 6–9 months — longest, lowest completion

— Clinical assessment + symptom screen at end of therapy; CXR if pulmonary involvement

— Routine follow-up cultures not required if good clinical response and DST-confirmed susceptibility

— Educate patient on relapse symptoms (recurrent fever, night sweats, weight loss, site-specific symptoms)

— Most EPTB not contagious (no pulmonary involvement) — clarify to patient and family

— Lymphadenitis with draining sinus is contact-transmissible — wound precautions

— Alcohol avoidance during therapy (hepatotoxicity)

— Smoking cessation — strongly associated with TB recurrence and worse outcomes

— Public health investigates all close contacts; offer IGRA/TST and CXR

— Treat latent infection in contacts per above

— BCG: not routinely given in US; used in some high-prevalence countries for newborns; protects against severe pediatric TB (meningitis, miliary), less effective for adult pulmonary

— Ensure routine vaccines (influenza, pneumococcal, COVID) up to date during immunosuppression from disease/steroids

— Counseling on residual deficits (kyphosis, infertility, neurologic) and rehab

Latent TB infection (LTBI) treatment — prevents reactivation

Post-treatment surveillance for active TB

Counseling on contagion and lifestyle

Contact tracing and household screening

Vaccination considerations

Long-term outcomes

Board pearl: 3HP (12-dose weekly INH + rifapentine) is now preferred LTBI regimen for most patients ≥2 years old, including HIV (with ART compatibility checked)

Step 3 management: Patient about to start adalimumab with positive IGRA → start 4R or 3HP for LTBI; biologic can usually begin after 1 month of LTBI treatment per most rheumatology guidelines

Follow-Up, Monitoring, and Rehab/Counseling

— Monthly clinical visits during entire treatment course

— Symptom review, weight, adherence, side effects (hepatotoxicity, visual changes, neuropathy, rash, GI)

— Pill count, DOT records review, refills

— Baseline: LFTs, CBC, BUN/Cr, uric acid, HIV, HBV, HCV, pregnancy test

— Routine LFT monitoring monthly if: age >35, alcohol use, HIV, hepatitis, pregnancy/postpartum, abnormal baseline; otherwise symptom-triggered

— Discontinue hepatotoxic drugs per thresholds (chunk 9)

— Baseline + monthly visual acuity and red-green color discrimination

— Stop ethambutol immediately if vision changes; usually reversible

— Pulmonary co-disease: sputum monthly until 2 consecutive negative cultures (typically by 2 months); persistent positive at 3 months → reassess for drug resistance, adherence

— TB meningitis: serial neuro exams; repeat MRI if clinical change; monitor for hydrocephalus

— Pott disease: serial imaging at 3, 6 months; physical therapy; bracing for stability

— Pericarditis: serial echos for constriction

— GU TB: repeat imaging at 3 months and end of therapy for ureteral stricture surveillance; CT urogram

— DOT is standard — in-person or video-observed; coordinated through public health

— Pill organizers, social work for housing/transport, addiction counseling, language-concordant care

— Pott disease: PT, occupational therapy, bracing, gait training

— TB meningitis: cognitive rehab, speech/PT for deficits, seizure precautions

— Pulmonary co-disease: pulmonary rehab if functional limitation

— Stigma reduction (still significant globally), depression screening, family support

— Address food insecurity, housing — strong determinants of completion

— Clinical assessment, site-specific imaging, document cure

— No need for prolonged surveillance if successful completion with susceptible organism

Follow-up cadence during therapy

Laboratory monitoring

Visual monitoring (ethambutol)

Site-specific monitoring

Adherence support

Rehabilitation

Psychosocial counseling

End-of-treatment evaluation

Board pearl: Persistently positive sputum culture at month 3 = treatment failure → reassess adherence, repeat DST, consider MDR-TB and ID re-consultation

Step 3 management: Ethambutol-treated patient develops blurred vision → stop ethambutol immediately, urgent ophthalmology referral, document time course

Ethical, Legal, and Patient Safety Considerations

— TB (active disease, both pulmonary and extrapulmonary) is a legally reportable disease in all 50 states

— Report to local/state public health department typically within 24 hours of suspicion or confirmation — failure to report can result in legal penalties for clinicians

— Public health initiates contact tracing, DOT, and may invoke directly observed therapy

— Considered standard of care for active TB; not punitive but adherence-supportive

— Court-ordered DOT or, in extreme cases, involuntary detention/isolation legal under public health statutes when patients are nonadherent with infectious pulmonary TB — requires due process, least restrictive means, demonstrated risk to public

— Empiric treatment in TB meningitis: start therapy before full confirmation due to mortality risk; document rationale and discuss with surrogate if patient unable to consent

— Pregnancy: discuss teratogenicity risk vs disease risk; document shared decision-making

— HIV testing: required as part of TB workup; in most states, opt-out testing with notification suffices

— TB carries significant stigma; balance public health duties (contact tracing) with patient privacy

— Workplace and immigration implications — counsel patients on rights; coordinate with social work

— Discharge from hospital before public health and DOT coordinated → high risk of nonadherence, resistance, transmission

— Ensure public health notification, DOT plan, ID outpatient follow-up appointment, and medications dispensed before discharge — handoff bundle

— Medication reconciliation: rifampin's CYP induction means many home medications need dose adjustment at discharge (warfarin, OCPs → barrier method, methadone, DOACs, tacrolimus); failure to communicate to outpatient pharmacy/PCP is a known adverse event

— Healthcare workers exposed without proper PPE require IGRA/TST baseline and 8–10 week follow-up testing; offer LTBI treatment if conversion

— Homeless, undocumented, incarcerated: ensure equitable access to treatment regardless of insurance/immigration status; Ryan White and public health TB programs typically fund care

Mandatory reporting

Directly observed therapy (DOT)

Informed consent edge cases

Confidentiality and stigma

Transition-of-care risks (Step 3 favorite)

Occupational health

Vulnerable populations

Board pearl: A patient with infectious pulmonary TB who refuses isolation/treatment → escalate to public health for legal isolation order as last resort; document attempts at education and voluntary adherence first

Step 3 management: Always notify public health at time of suspicion, not just confirmation — early reporting initiates contact tracing and prevents transmission

High-Yield Associations and Rapid-Fire Facts

Scrofula = cervical TB lymphadenitis; classic in young immigrant adults

Pott disease = TB spondylitis, lower thoracic/upper lumbar, disc spared, gibbus deformity, cold paraspinal/psoas abscess

Sterile pyuria + chronic urinary symptoms = GU TB until proven otherwise

Putty kidney = end-stage autonephrectomy from GU TB; calcified, nonfunctional

Pleural fluid ADA >40 U/L + lymphocytic exudate = TB pleuritis

CSF: low glucose + lymphocytic + high protein + basilar enhancement = TB meningitis

CN VI palsy = most common cranial neuropathy in TB meningitis

Choroidal tubercles on fundoscopy = miliary TB

Caseating granulomas with Langhans giant cells = TB; noncaseating = sarcoid

BMRC staging in TB meningitis predicts mortality (I → III worsening)

Rifampin → orange body fluids, CYP450 inducer, decreases OCP efficacy → barrier contraception

INH → hepatotoxicity, peripheral neuropathy (give B6), drug-induced lupus, SIADH

PZA → hyperuricemia (gout flare), hepatotoxicity; omit in US pregnancy

Ethambutol → optic neuritis (red-green color blindness first); reduce dose in renal failure

Streptomycin → ototoxic; contraindicated in pregnancy (fetal CN VIII)

Dexamethasone improves survival in TB meningitis and pericarditis

IGRA preferred over TST in BCG-vaccinated patients

3HP (INH + rifapentine weekly × 12 weeks) preferred LTBI regimen

Rifabutin substituted for rifampin when on HIV protease inhibitors

HIV TB meningitis → delay ART 8 weeks even with low CD4 (IRIS risk)

TB pericarditis → up to 30% develop constrictive pericarditis → pericardiectomy

MDR-TB = resistance to INH + rifampin; XDR-TB = MDR + fluoroquinolone + injectable

Paradoxical reaction during therapy ≠ treatment failure; continue regimen + add steroids

Silicosis dramatically increases TB risk; screen miners and sandblasters

TNF-α inhibitor initiation requires LTBI screening with IGRA

Pott vs pyogenic osteo: TB spares disc, multiple bodies; pyogenic destroys disc early

Board pearl: Memorize the steroid-indicated EPTB sites: meningitis and pericarditis — almost guaranteed Step 3 question

Key distinction: Acid-fast staining detects mycobacteria; Nocardia is weakly acid-fast; M. leprae and M. tuberculosis strongly acid-fast

Board Question Stem Patterns

— Young foreign-born adult with chronic painless cervical adenopathy, weight loss, night sweats

— Best next step: excisional biopsy (not FNA alone) → AFB stain, culture, NAAT, histology; start RIPE if confirmed

— Subacute effusion, lymphocyte-predominant exudate, ADA elevated, glucose low

— Diagnosis: TB pleuritis; pleural biopsy higher yield than fluid culture

— HIV+ or foreign-born patient, 2–3 weeks of headache, fever, CN VI palsy

— CSF: lymphocytic pleocytosis, low glucose, high protein

— Best next step: CSF Xpert + start RIPE + dexamethasone empirically; MRI brain

— Middle-aged immigrant with thoracic kyphosis, paraspinal mass on MRI, disc relatively preserved

— Diagnosis: Pott disease; biopsy + RIPE × 6–9 months; surgery if cord compression

— Recurrent UTI symptoms with negative routine cultures; CT shows calyceal distortion

— Best next test: 3 morning urines for AFB culture

— Patient with RA scheduled for infliximab, positive IGRA, normal CXR

— Diagnosis: latent TB; treat with 3HP or 4R before starting biologic

— Patient on warfarin/OCP/methadone starts TB therapy → unexpected effect (subtherapeutic INR, pregnancy, withdrawal)

— Answer: rifampin = CYP450 inducer; adjust other drug and counsel

— Patient on TB therapy develops blurred vision, red-green color deficit

— Best next step: stop ethambutol immediately, ophthalmology referral

— TB lymphadenitis patient 6 weeks into RIPE with new node enlargement and fever; cultures sterile

— Answer: continue regimen ± steroids; not treatment failure

— Newly diagnosed TB and HIV with CD4 30 → start ART within 2 weeks

— TB meningitis with HIV → delay ART 8 weeks regardless of CD4

— Pregnant patient with active TB → INH + RIF + ETH + B6 × 9 months (omit PZA in US)

— Months after TB pericarditis treatment, patient develops JVD, Kussmaul sign, hepatic congestion → constrictive pericarditis; pericardiectomy

Stem 1: Cervical lymphadenitis in immigrant

Stem 2: Lymphocytic pleural effusion

Stem 3: Subacute meningitis with low CSF glucose

Stem 4: Chronic back pain with gibbus

Stem 5: Sterile pyuria

Stem 6: Pre-biologic screening

Stem 7: Rifampin drug interaction

Stem 8: Ethambutol toxicity

Stem 9: Paradoxical reaction

Stem 10: HIV coinfection ART timing

Stem 11: Pregnancy

Stem 12: Pericardial TB → constriction

Board pearl: Distractor traps: FNA alone for scrofula (insufficient), starting steroids in sarcoid without ruling out TB, missing rifampin–OCP interaction, delaying ART inappropriately in TB meningitis

One-Line Recap

Extrapulmonary TB is reactivation or dissemination of M. tuberculosis into nonpulmonary sites — most commonly lymphatic, pleural, skeletal, GU, meningeal, peritoneal, and pericardial — diagnosed by site-directed biopsy (AFB stain, culture, NAAT, caseating granulomas) and treated with standard RIPE for 6 months (9–12 months for CNS or bone), with dexamethasone added for meningitis and pericarditis, mandatory public health reporting, and HIV co-testing in every patient.

Diagnosis: Biopsy is king — always split tissue 4 ways (AFB stain, mycobacterial culture, NAAT, histopathology); ADA helpful in pleural/peritoneal/pericardial/CSF fluids; IGRA confirms infection but not active disease and can be falsely negative in severe EPTB

Treatment skeleton: RIPE × 2 months → INH/RIF × 4 months (longer for CNS 9–12 mo, bone 6–9 mo); pyridoxine with INH; steroids only for meningitis and pericarditis; modify for pregnancy (no PZA in US, no streptomycin), renal failure (reduce PZA/ETH frequency), and HIV (rifabutin with PIs, ART timing depends on site and CD4)

Monitoring: Monthly clinical visits with DOT, LFTs in high-risk groups, monthly visual acuity/color vision on ethambutol, site-specific imaging follow-up; stop hepatotoxic drugs at ALT >3× ULN with symptoms or >5× ULN asymptomatic

Public health and safety: TB is mandatorily reportable in all 50 states — notify within 24 hours of suspicion; coordinate DOT, contact tracing, and discharge handoff including rifampin drug-interaction reconciliation (warfarin, OCPs → barrier contraception, methadone, DOACs, tacrolimus); screen latent TB before TNF-α inhibitors and transplant with 3HP or 4R as preferred regimens