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Enteric Fever (Typhoid Fever)

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Etiology and Microbiology

• Agent: S. Typhi (major cause); S. Paratyphi A, B, C (less frequent). Unlike non-typhoidal Salmonella, these serovars have no known animal reservoir - humans are the only host.
• S. Typhi possesses three key antigens: O (somatic), H (flagellar), and Vi (virulence/capsular polysaccharide). At least 80 phage types exist, useful for epidemiological tracing.
• Survives intracellularly in tissue macrophages; readily killed by drying, pasteurization, and common disinfectants.

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Epidemiology

• Global burden: An estimated 9.2-21 million typhoid cases and 5 million paratyphoid cases occur annually, with 110,000-280,000 deaths per year.
• Endemic regions: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, and Africa bear the highest burden. Incidence can exceed 1,000 cases per 100,000 children in some urban areas of South Asia.
• In developed countries: Disease is rare; most cases (~78%) are travel-associated, predominantly from travelers to India, Pakistan, and Bangladesh. In the US, ~5,700 cases are estimated annually (far more than the ~350 reported).
• Highest incidence age group: 5-19 years. Males are more often affected; females have a higher chronic carrier rate.
• Transmission: Fecal-oral route via contaminated food or water. Risk factors include contaminated drinking water/ice, raw produce fertilized with sewage, street food, prior H. pylori infection (associated with reduced gastric acidity), and ill household contacts.

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Pathogenesis

1. S. Typhi penetrates the small intestinal mucosa, particularly via M cells overlying Peyer's patches.
2. Organisms are phagocytosed by macrophages and transported to mesenteric lymph nodes.
3. A primary bacteremia follows, with seeding of the liver, spleen, gallbladder, bone marrow, and Peyer's patches.
4. Bacterial replication in macrophages and a secondary bacteremia produce the classic sustained fever.
5. The gallbladder is a key site of colonization - organisms re-enter the intestinal lumen in bile, causing characteristic hyperplasia, ulceration, and necrosis of Peyer's patches in the third/fourth week.

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Clinical Course

• Headache: 80%
• Fever: >75%
• Chills: 35-45%
• Cough: 30%
• Anorexia: 55%
• Abdominal pain: 30-40%
• Nausea: 18-24%, vomiting: 18%
• Diarrhea: 22-28%; constipation: 13-16%

• Rose spots (~30%): Faint, salmon-colored, blanching maculopapular rash on the trunk/chest; 2-3 crops; lasts 2-5 days. S. Typhi can be cultured from biopsy of these lesions.
• Relative bradycardia (<50% at peak fever)
• Hepatosplenomegaly (3-6%)
• Coated tongue (51-56%)

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Complications (~27% of hospitalized patients)

• Intestinal hemorrhage (6%): From ulceration of Peyer's patches in the 3rd-4th week
• Intestinal perforation (1%): Life-threatening; requires immediate surgery + broad-spectrum antibiotics for polymicrobial peritonitis

• Meningitis, Guillain-Barré syndrome, neuritis
• "Muttering delirium" or "coma vigil" (picking at bedclothes - characteristic of typhoid encephalopathy)

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Carriers

• Temporary (convalescent): Excrete bacilli for 6-8 weeks; 4% still positive at 3 months
• Chronic: Excrete for >1 year (sometimes decades); organisms persist in the gallbladder/biliary tract; faecal carriers more common than urinary carriers; Vi antibody present in ~80% of chronic carriers
• Famous historical example: "Typhoid Mary" - caused >1,300 cases over her lifetime

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Diagnosis

• Blood culture: Positive in 40-80% during the first 2 weeks (sensitivity declines after week 2)
• Bone marrow culture: Most sensitive (85-95%), positive even after partial antibiotic treatment - preferred in antibiotic-pre-treated cases
• Stool culture: Positive in weeks 2-3; less sensitive early
• Rose spot biopsy: Can grow the organism

• Leukopenia/neutropenia (15-25%)
• Leukocytosis more common in children and in complications (perforation, secondary infection)
• Mildly elevated liver enzymes and muscle enzymes

• Widal test (anti-O and anti-H antibodies): Widely used but poor specificity and sensitivity; not reliable in endemic areas; cross-reactions common
• Typhidot: Detects IgM/IgG against a 50 kDa outer membrane protein - faster, more sensitive
• Vi antibody: Present in ~80% of chronic carriers - useful for carrier detection

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Treatment

Antibiotic Therapy (based on susceptibility)

• XDR typhoid: Ongoing epidemic in Pakistan since 2016 (Sindh province); susceptible only to azithromycin and carbapenems. Multiple imported cases documented in the US and UK.
• In the US, >66% of S. Typhi isolates are DSC - empiric fluoroquinolones should NOT be used, especially in South Asia travelers.
• Relapse rates are lower with azithromycin than with fluoroquinolones or ceftriaxone.

• Corticosteroids (dexamethasone): For severe/complicated disease with delirium, coma, or shock - IV dexamethasone 3 mg/kg initial dose, then 1 mg/kg every 6 hours x 48 hours total

• 4 weeks of oral ciprofloxacin or norfloxacin (concentrated in bile)
• Cholecystectomy + antibiotics if medical therapy fails

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Vaccination

• TCVs are recommended by WHO for routine immunization in endemic countries. A 2025 Cochrane review (PMID: 40326553) confirmed their superiority over earlier Vi polysaccharide vaccines in providing durable protection.
• Neither vaccine is 100% protective; food/water precautions remain essential.

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Prevention and Control (Three Lines of Defence - Park's)

1. Control of reservoir: Early diagnosis + isolation; treatment of cases; identification and treatment of carriers (ampicillin/amoxicillin 4-6 g/day + probenecid x 6 weeks, or cholecystectomy); follow-up stool/urine cultures
2. Sanitation: Safe water supply, sewage treatment, food hygiene - the "weakest link in the chain"
3. Immunization: Especially for travelers to endemic areas and school-age children in endemic regions

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Key Points to Remember

• Enteric fever is a misnomer - fever is present in >75% but abdominal pain in only 30-40%
• Rose spots are pathognomonic when present but seen in only ~30%
• Bone marrow culture is the gold standard diagnostic test
• XDR typhoid from Pakistan is a growing threat - only azithromycin and carbapenems work
• Chronic carriage (gallbladder) is a risk factor for gallbladder cancer
• Complications peak in the 3rd-4th week - intestinal perforation is the most feared surgical emergency

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Hemorrhagic Stroke

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Classification

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Part 1: Intracerebral Hemorrhage (ICH)

Etiology and Causes

1. Hypertensive vasculopathy - most common; long-standing hypertension causes lipohyalinosis and degenerative changes in small penetrating arteries → rupture → deep/basal ganglia hemorrhage
2. Cerebral amyloid angiopathy (CAA) - amyloid deposition in cerebral vessel walls; typically in older adults; tends to cause lobar hemorrhages; increasingly important as hypertension control improves (now accounts for >50% of cases on some neurology services)

1. Primary (hypertensive) ICH
2. Ruptured saccular aneurysm
3. Ruptured arteriovenous malformation (AVM) / venous malformations
4. Cavernous angioma
5. Trauma (including posttraumatic delayed apoplexy)
6. Hemorrhagic disorders: leukemia, aplastic anemia, thrombocytopenia, liver disease, anticoagulant/thrombolytic therapy, hemophilia
7. Hemorrhage into brain tumors (primary or metastatic)
8. Septic embolism, mycotic aneurysm
9. Hemorrhagic transformation of ischemic stroke
10. Cerebral venous sinus thrombosis (CVST)
11. Sympathomimetic drugs (cocaine, amphetamines)
12. Moyamoya disease, PRES, RCVS

High-risk features suggesting secondary ICH: lobar location, intraventricular blood, and younger age.

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Sites of Hemorrhage (and Clinical Features)

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Pathophysiology

1. Mass effect from the hematoma
2. Activation of the coagulation cascade
3. Release of inflammatory cytokines
4. Blood-brain barrier (BBB) disruption
5. Perihematomal edema (develops over hours to days)
6. Raised intracranial pressure (ICP) → cerebral herniation

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Hematoma Expansion

• Occurs in 20-40% of patients in the first few hours
• Contrast extravasation on CTA ("spot sign") predicts ongoing bleeding and hematoma expansion
• Expansion is a major determinant of poor outcome

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Clinical Presentation

• Sudden onset focal neurologic deficits corresponding to hematoma location
• Headache (more common in ICH than ischemic stroke, but not universal)
• Nausea, vomiting
• Decreased level of consciousness (may progress rapidly to coma)
• Seizures (~10%)
• No single clinical feature reliably distinguishes ICH from ischemic stroke - neuroimaging is mandatory

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Diagnosis

• Hyperdense (bright white) lesion = acute blood
• Highly sensitive for hemorrhages >1 cm
• Performed immediately; results guide all subsequent management

• Identifies underlying aneurysm, AVM, or fistula
• Detects "spot sign" (contrast extravasation = hematoma expansion risk)
• CT venography (CTV) to rule out CVST

• Better sensitivity for underlying lesions (tumors, cavernous malformations)
• Gradient echo (GRE) / susceptibility-weighted imaging (SWI) highly sensitive for microbleeds and subacute/chronic blood

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ICH Score (Prognostic Scale)

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Management of ICH

A. Airway/Breathing/Circulation

• Intubate for GCS ≤ 8 or deteriorating airway
• Maintain oxygen saturation >94%
• Avoid hypotension

B. Blood Pressure Control

• Target SBP <140 mmHg (AHA/ASA guidelines) for patients presenting with SBP 150-220 mmHg - safe and reduces hematoma expansion
• A 2025 meta-analysis (PMID: 40739079) confirms intensive BP lowering reduces hematoma expansion but does not clearly improve functional outcome - the evidence remains nuanced
• IV agents: labetalol, nicardipine, clevidipine
• Avoid excessive lowering (target MAP ≥ 70 mmHg to maintain cerebral perfusion)

C. Reversal of Anticoagulation

• Warfarin (INR elevated): Vitamin K (IV) + 4-factor prothrombin complex concentrate (4F-PCC) - preferred over FFP due to faster, more complete reversal
• Heparin: Protamine sulfate
• Direct oral anticoagulants (DOACs):
  • Dabigatran → Idarucizumab (specific reversal)
  • Factor Xa inhibitors (rivaroxaban, apixaban) → Andexanet alfa or 4F-PCC
• Antiplatelet agents: Platelet transfusion no longer routinely recommended (may worsen outcome)

D. ICP Management

• Head of bed at 30°
• Avoid hypotonic fluids
• Osmotic therapy: mannitol or hypertonic saline
• External ventricular drain (EVD) for hydrocephalus
• Avoid steroids (not beneficial in ICH, may worsen outcomes)

E. Glucose and Temperature Control

• Treat hyperthermia (>38°C) aggressively
• Treat hypo- and hyperglycemia
• Target normoglycemia

F. Seizure Management

• Clinical seizures: treat with levetiracetam or fosphenytoin
• Prophylactic antiepileptics not recommended routinely

G. Surgical Intervention

• Cerebellar hemorrhage >3 cm with neurological deterioration or brainstem compression → urgent surgical evacuation (suboccipital craniotomy)
• Supratentorial ICH: controversial - minimally invasive surgery (MIS) techniques (endoscopic evacuation, stereotactic aspiration) are gaining evidence
• A 2025 Cochrane review (PMID: 40673401) on surgery for supratentorial ICH found benefit for MIS approaches, though definitive evidence is still evolving
• Craniotomy for large superficial hemorrhages in deteriorating patients may be considered

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Part 2: Subarachnoid Hemorrhage (SAH)

Etiology

• ~80%: Ruptured saccular (berry) aneurysms - small, thin-walled outpouchings at vessel bifurcations, particularly within the circle of Willis
• Remainder: AVMs, cavernous angiomas, mycotic aneurysms, CNS vasculitis, perimesencephalic hemorrhage (benign)
• ~25% of people with a berry aneurysm have multiple aneurysms

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Clinical Presentation

• Onset may be associated with exertion, Valsalva, or sexual intercourse
• Headaches peaking >60 minutes after onset are unlikely to be SAH

• Syncope (often the initial manifestation)
• Nausea and vomiting
• Neck stiffness (meningismus)
• Photophobia
• Seizures

• Up to 20% have focal neurologic deficits
• Pupil dilation + third nerve palsy → posterior communicating artery aneurysm compressing CN III
• Altered or fluctuating consciousness (~50%)
• Subhyaloid (pre-retinal) hemorrhages on fundoscopy (Terson syndrome)

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SAH Grading Scales

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Diagnosis

1. Non-contrast CT head (first test): Highly sensitive for SAH in the first 6-12 hours (sensitivity ~98% within 6 h)
   • Hyperdense blood in the basal cisterns, Sylvian fissures, and sulci
2. Lumbar puncture (LP): If CT is negative but SAH is suspected (≥6 hours after headache onset)
   • Look for xanthochromia (yellow discoloration of CSF) - most specific finding
   • Elevated RBC count that does not decrease from tube 1 to tube 4
3. CT angiography (CTA): Non-invasive; good sensitivity (~95%) for aneurysms >3mm
4. Digital subtraction angiography (DSA): Gold standard for aneurysm identification and planning treatment; recommended in all cases of suspected aneurysmal SAH

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Complications of SAH

• Occurs in ~30% of SAH patients
• Prevented and treated with nimodipine (oral calcium channel blocker) - the only drug proven to improve neurological outcome in SAH
• Maintained euvolemia (avoid dehydration)
• Induced hypertension if vasospasm is refractory ("triple H" therapy is now more refined - mainly hypertension + euvolemia)

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Management of SAH

Immediate stabilization

• Airway, breathing, circulation
• Treat hypertension cautiously (do not drop BP precipitously before aneurysm is secured, as perfusion pressure may be needed)
• Analgesia and antiemetics
• Strict bed rest, quiet environment, avoid Valsalva

Securing the aneurysm (prevents rebleeding)

• Endovascular coiling: Preferred for most aneurysms; catheter-based; lower procedural morbidity
• Neurosurgical clipping: Open craniotomy; preferred for large/complex aneurysms or those with associated hematoma requiring surgical evacuation
• The choice between coiling and clipping depends on aneurysm morphology, location, patient age, and institutional expertise

Prevention of vasospasm/DCI

• Nimodipine 60 mg PO every 4 hours x 21 days (standard of care)
• Maintain euvolemia; avoid hypovolemia
• Serial transcranial Doppler (TCD) monitoring
• If vasospasm confirmed: induced hypertension, cerebral angioplasty ± intra-arterial vasodilators

ICP management

• EVD for hydrocephalus or ICP monitoring
• Head of bed at 30°

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Key Distinguishing Features

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Recent Evidence (2025)

• Blood pressure lowering in ICH (PMID: 40739079, 2025 meta-analysis): Intensive BP lowering (target SBP <140) reduces hematoma expansion, though functional outcome benefit remains uncertain at the population level.
• Surgery for supratentorial ICH (PMID: 40673401, Cochrane 2025): Evolving evidence supporting minimally invasive surgical evacuation over craniotomy.
• Cerebral amyloid angiopathy guidelines (PMID: 40721902, 2025): Updated international statement on CAA diagnosis and management, reflecting its growing role as a cause of lobar ICH.

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Recent Neuroimaging Findings in Intracerebral Hemorrhage (ICH) - 2024-2026

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1. Non-Contrast CT (NCCT): Hematoma Texture Signs for Predicting Expansion

• History of hypertension
• NCCT acquired within ≤3 hours of onset
• Combined heterogeneity (black hole + blend sign)
• Combined irregularity (satellite + island sign)

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2. CT Angiography (CTA) and the Spot Sign - Critical Reappraisal

• Single-phase CTA spot sign features that improve predictive accuracy:
  • Number of spots (more = higher risk)
  • Volume of each spot
  • CT density of the spot
  • Co-localization with NCCT hypodensities (blend/black hole signs)
• Multiphase/dynamic CTA (newer approach) adds dynamic information:
  • Timing of contrast appearance
  • Volume increase over phases = active expansion
  • Volume decrease = tissue dispersion (different biology)
  • Density changes across phases

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3. "CTA-for-All" in Acute ICH - Ending Diagnostic Nihilism

1. Etiological diagnosis: CTA identifies secondary causes (aneurysm, AVM, dural arteriovenous fistula, CVST, tumoral bleeding) in a clinically significant proportion - driving specific acute and secondary prevention decisions
2. Prognostication: CTA improves outcome prediction beyond NCCT alone
3. Treatment prediction: Spot sign and related features can predict HE expansion and select patients for targeted interventions
4. Safety: Minimal risk of contrast nephropathy; no meaningful procedural delay when integrated into standard stroke imaging protocol
5. Cost: A "CTA-for-all-ICH" approach is economically justified given diagnostic yield
6. Implementation: Simply continuing the same ischemic stroke imaging protocol through the hemorrhagic phase

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4. Deep Learning and AI-Assisted Imaging in ICH

4a. DL for Hematoma Expansion Prediction from NCCT

• Best model: 2D-ResNet-101 achieved AUC = 0.777 on external validation
• Outperformed the BRAIN score and combined clinical-radiomics models (AUC improvement of 0.087-0.119)
• Gradient-weighted class activation mapping (Grad-CAM) revealed the model focused on hematoma margins and heterogeneous density regions - biologically plausible areas of active bleeding
• Key implication: NCCT-based DL can predict HE without requiring CTA, which is important in resource-limited settings

4b. AI-Driven Hematoma Segmentation and Surgical Planning

• nnU-Net-based automated hematoma and skull segmentation (Dice similarity coefficient 0.90 for hematoma, 0.99 for skull)
• CT reorientation using ocular landmarks
• Safety zone delineation with dual anatomical corridors
• Automated trajectory planning for minimally invasive surgery (MIS)

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5. Perihematomal Edema (PHE) as an Imaging Biomarker

• PHE volume on CT/MRI predicts neurological deterioration independent of hematoma volume
• PHE growth in the acute stage (measured on serial CT) is now being modeled with prediction algorithms (Zhang et al., Clin Neurol Neurosurg, PMID: 39126898)
• A 2026 RCT post-hoc analysis (Polymeris et al., Neurocrit Care, PMID: 40399657) examined the relationship between hemoglobin levels and PHE after ICH, finding that lower hemoglobin correlates with greater PHE - suggesting anemia management as a potential imaging-linked therapeutic target
• APOE ε4 genotype influences PHE severity (Wang et al., 2025, PMID: 40764846): APOE ε4 carriers have significantly greater PHE, offering a radiogenomic link relevant to CAA patients
• A 2025 RCT (Chen et al., BMC Medicine, PMID: 41353144) used PHE on imaging as a primary outcome measure to assess normobaric hyperoxia as a neuroprotective intervention - PHE was meaningfully reduced in the treatment arm

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6. Cerebral Amyloid Angiopathy (CAA) - Advanced MRI Biomarkers

• Lobar microbleeds on susceptibility-weighted imaging (SWI) / gradient echo (GRE)
• Cortical superficial siderosis (CSS) - linear hemosiderin deposits along cortical surface
• Centrum semiovale perivascular spaces (enlarged)
• White matter hyperintensities in CAA-specific patterns

• Amyloid PET (Pittsburgh Compound B, florbetapir): can detect vascular amyloid-β in vivo, potentially enabling pre-symptomatic CAA diagnosis
• The concept of "dynamic natural history" (periods of high CAA activity vs. remission) is now proposed to explain episodic imaging changes
• Iatrogenic CAA (from amyloid-β inoculation, e.g., via contaminated growth hormone) is a newly described entity with distinct neuroimaging characteristics - providing a unique "pure model" of CAA with known exposure time

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7. Population-Based Neuroimaging Risk Assessment (2026 Perspective)

• Neuroimaging markers are now guiding both primary ICH prevention (e.g., white matter hyperintensity burden, microbleed counts guiding anticoagulation decisions) and secondary prevention (e.g., whether to restart anticoagulation after ICH)
• ICH survivors face competing risks: ICH recurrence vs. arterial ischemic events - neuroimaging phenotyping (lobar vs. deep ICH, microbleed distribution, CAA vs. hypertensive pattern) drives these individualized decisions
• Hematoma volume and perihematomal edema are becoming modifiable targets, not just prognostic markers
• Recovery after ICH is significantly slower than after ischemic stroke, with improvement documented through 1 year post-ictus - reinforcing the need for serial imaging follow-up

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Summary Table: Recent Neuroimaging Advances in ICH

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Tuberculosis — Consultant-Level Review

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I. General Principles and Historical Context

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II. Etiologic Agent

• M. tuberculosis (sensu stricto) - most common and clinically important
• M. africanum - isolated from West, Central, and East Africa
• M. bovis - bovine tubercle bacillus; characteristically resistant to pyrazinamide; transmitted by unpasteurized milk; responsible for ~140,000 human cases/year worldwide (half in Africa)
• M. caprae - related to M. bovis
• M. pinnipedii, M. mungi, M. orygis, M. microti - rare zoonotic variants
• M. canetti - rare, produces smooth colonies; considered closest to a putative progenitor type

• Rod-shaped, non-spore-forming, thin aerobic bacterium: 0.5 × 3 μm
• Neutral on Gram staining; once stained, cannot be decolorized by acid alcohol → acid-fast bacilli (AFB)
• Acid-fastness due to: high mycolic acid content + long-chain cross-linked fatty acids + arabinogalactan-peptidoglycan complex
• Doubling time: ~15-20 hours (slow grower - explains prolonged treatment requirements)
• No known environmental reservoir for any member of the complex

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III. Epidemiology

Global Burden

• ~10.6 million new TB cases annually (2022 WHO data)
• Leading endemic regions: South/Southeast Asia, sub-Saharan Africa, Eastern Europe
• Case fatality: >70% untreated; ~1-5% with appropriate treatment
• HIV co-infection found in ~8% of all TB cases globally; in sub-Saharan Africa this may reach 50%+

Transmission

• Primarily airborne via droplet nuclei (1-5 μm particles)
• Generated by coughing, sneezing, singing, talking
• Infectious dose: very low (as few as 1-10 bacilli)
• A single cavitary TB patient may infect 10-15 contacts/year
• NOT transmitted by fomites, surfaces, or casual contact

Risk factors for infection

• Household/close contact with infectious case
• Overcrowding, poverty, institutional settings (prisons, homeless shelters)
• Occupational exposure (health care workers)
• Immigration from high-burden countries

Risk factors for progression from infection → disease

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IV. Pathogenesis and Immunology

The Primary Infection Sequence

• Activated macrophages neutralize bacilli
• Central caseous necrosis develops (cheese-like, inspissated)
• Lesion may calcify (Ghon lesion + calcified hilar nodes = "Ranke complex" on CXR)
• Viable bacilli persist in latent state - Latent TB Infection (LTBI)

• In children, immunosuppressed, or those with high inoculum
• Caseous material liquefies → cavity formation
• Bacilli flood the airways → endobronchial spread
• Hematogenous dissemination → miliary TB, TB meningitis

The Immunology - Consultant Detail

1. Phagocytosis and intracellular killing via reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI, especially nitric oxide)
2. Cytokine secretion: TNF-α (granuloma formation, fever, wasting), IL-1, IL-12 (drives Th1 differentiation)

• CD4+ Th1 cells: Primary effectors - produce IFN-γ → macrophage activation. CD4 depletion (as in HIV) dramatically impairs TB control
• CD8+ T cells: Cytotoxic; kill infected macrophages; also produce IFN-γ; particularly important in early infection and reactivation phase
• γδ T cells and NK cells: Important innate responders in early infection

• Prevents phagosomal acidification and lysosome fusion
• Produces lipoarabinomannan (LAM) - scavenges reactive oxygen intermediates
• Mycolic acid coat resists enzymatic digestion
• Induces anti-apoptotic pathways in host macrophages
• Can enter dormancy (non-replicating persistent state) inside granulomas

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V. Clinical Manifestations

A. Pulmonary TB (most common - ~2/3 of all cases)

• Often asymptomatic or mild, self-limiting illness
• In children: fever, mild respiratory symptoms, erythema nodosum, phlyctenular conjunctivitis
• Primary progressive TB: severe pneumonitis, cavitation (uncommon except in children and immunosuppressed)
• Lower/mid-lobe infiltrate + hilar lymphadenopathy on CXR

• Classic: Upper lobe (apical and posterior segments) or superior segments of lower lobes - due to high O₂ tension favoring mycobacterial growth
• Fibro-nodular infiltrates with or without cavitation
• Cavitation (30-40% of cases): thick-walled, irregular cavity; associated with high bacterial load and high infectivity
• Miliary pattern: 1-3 mm bilateral nodules (millet seeds) in hematogenous dissemination
• Primary TB pattern: Middle or lower zone infiltrate + hilar/mediastinal lymphadenopathy
• Atypical patterns common in HIV (see below)
• Old TB: fibronodular scarring, calcified granulomas (Ghon focus), traction bronchiectasis, destroyed lobe

B. Extrapulmonary TB

1. Lymph Node TB (Scrofula) - Most common extrapulmonary site

• Cervical > axillary > inguinal nodes
• Painless, firm, discrete initially → matted → fluctuant ("cold abscess") → collar-stud abscess with skin thinning → spontaneous sinus tract formation
• Diagnosis: Excision biopsy (caseous granuloma on histology; culture/PCR)
• Key differential: lymphoma, metastatic carcinoma, NTM, cat-scratch disease

2. Pleural TB

• Most common cause of exudative pleural effusion in young adults in endemic areas
• Mechanism: Rupture of subpleural focus → hypersensitivity reaction in pleural space
• Effusion: exudate (protein >3 g/dL); lymphocyte-predominant (>80%)
• Low glucose, elevated ADA (adenosine deaminase >40 U/L - highly sensitive/specific)
• AFB smear of pleural fluid: <10% positive
• Pleural biopsy: 80% diagnostic (granulomas); PCR/culture adds sensitivity
• May be bilateral in HIV

3. Tuberculous Meningitis (TBM)

• Most lethal form of TB; mortality/disability in ~50% even with treatment
• Pathogenesis: Rupture of subependymal focus (Rich focus) into subarachnoid space
• Presentation: Subacute headache (days-weeks), fever, meningismus; CN palsies (III, VI most common); altered consciousness; seizures
• Clinical staging (MRC/British Medical Research Council):
  • Grade I: GCS 15, no focal deficits, no LOC
  • Grade II: GCS 11-14 OR focal neurological signs
  • Grade III: GCS ≤10
• CSF findings:
  • Opening pressure: elevated
  • Cells: 100-500 cells/μL, lymphocyte predominance (early may be neutrophilic)
  • Protein: elevated (>45 mg/dL, often 100-500 mg/dL)
  • Glucose: low (<45 mg/dL), CSF:serum glucose ratio <0.5
  • AFB smear: 10-40% (higher yield with repeat, large volume, centrifuged pellet)
  • Culture: gold standard (2-6 weeks)
  • Xpert MTB/RIF Ultra: sensitivity ~70-80%, specificity >98% - recommended as first test
• Complications: Hydrocephalus (communicating > obstructive), vasculitis → ischemic stroke, CN palsies, SIADH, cerebral herniation
• 2026 Lancet TBM Guidelines (PMID: 40840485): First international evidence-based guideline; recommends Xpert MTB/RIF Ultra as initial diagnostic test; intensified treatment (higher-dose rifampicin IV or rifapentine, + fluoroquinolone); adjunctive dexamethasone for all grades; neurosurgical care for hydrocephalus

4. Pericardial TB

• Exudative pericardial effusion → cardiac tamponade (acute danger)
• Constrictive pericarditis (late fibrotic sequela - months to years later)
• Diagnosis: pericardiocentesis (lymphocytic exudate, elevated ADA), pericardial biopsy
• Adjunctive corticosteroids: Reduce constrictive pericarditis risk (prednisolone 60 mg/day tapered over 11 weeks)
• Pericardiectomy required for established constriction

5. Skeletal TB (Pott's Disease / TB of the Spine)

• Most common site: lower thoracic and upper lumbar vertebrae (Pott's disease)
• Mechanism: hematogenous seeding → anterior vertebral body → disk space involvement → collapse
• Gibbus deformity (angular kyphosis)
• Paravertebral "cold" abscess - tracks along fascial planes; may present as psoas abscess
• Paraplegia (Pott's paraplegia): Cord compression from abscess, granuloma, or instability
• Diagnosis: MRI of spine (imaging modality of choice) + CT-guided biopsy
• Treatment: standard 6-month anti-TB regimen; surgery for instability, cord compression, or failed medical therapy

6. Miliary TB

• Hematogenous dissemination → simultaneous seeding of multiple organs
• CXR: bilateral 1-3 mm uniform "millet seed" nodules
• Presentation: fever, weight loss, night sweats; hepatosplenomegaly; lymphadenopathy; chorioretinal tubercles on fundoscopy (pathognomonic when present)
• Choroidal tubercles on fundoscopy: present in ~30% - diagnostic pearl
• High mortality; requires immediate treatment

7. Genitourinary TB

• Most common presentation: sterile pyuria (WBCs without bacteria on standard culture)
• "Sterile pyuria" in >3 consecutive MSUs → must exclude TB
• Haematuria, frequency, dysuria
• Late: "putty kidney" (dystrophic calcification), ureteric strictures, hydronephrosis, renal failure
• Male: epididymo-orchitis, scrotal sinus
• Female: salpingitis, infertility, Asherman syndrome

8. Abdominal TB

• Peritoneal, intestinal (ileocaecal most common), lymph node involvement
• Ascites: exudative, lymphocyte-rich, elevated ADA
• Ileocaecal TB mimics Crohn's disease, carcinoma - biopsy essential
• Beware: anti-TNF agents for misdiagnosed "Crohn's" can precipitate TB dissemination

9. Adrenal TB

• Bilateral adrenal enlargement → adrenal insufficiency
• Historically, TB was the most common cause of Addison's disease worldwide

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VI. Diagnosis

Microbiological Diagnosis

A. Sputum Smear Microscopy (AFB Smear)

• Ziehl-Neelsen (ZN) stain or auramine-rhodamine fluorescence stain (higher sensitivity)
• Requires ≥5,000-10,000 bacilli/mL for positivity (low sensitivity)
• Sensitivity: 45-80% in pulmonary TB; specificity ~98% but cannot distinguish TB from NTM
• Minimum 3 samples on 3 consecutive days (including one early morning specimen)
• LED fluorescence microscopy has replaced conventional ZN in most settings

B. Mycobacterial Culture

• Gold standard for definitive diagnosis and drug susceptibility testing (DST)
• Liquid media (MGIT - mycobacteria growth indicator tube): results in 9-14 days
• Solid media (Lowenstein-Jensen): results in 3-8 weeks
• Can detect as few as 10-100 bacilli/mL
• Essential for species identification and DST

C. Molecular Diagnostics

• Cartridge-based, fully automated PCR assay
• Results in <2 hours
• Simultaneously detects M. tuberculosis DNA AND rifampicin resistance (rpoB gene mutations - rifampicin resistance is a reliable proxy for MDR-TB)
• Sensitivity: 88% in smear-positive; 67% in smear-negative pulmonary TB; >80% sensitivity in HIV-co-infected patients
• Specificity: >98%
• Xpert MTB/RIF Ultra: Higher sensitivity (5-10% more) due to larger sample volume and multicopy targets; preferred for smear-negative/HIV cases and CSF

• A 2024 Lancet Infectious Diseases meta-analysis (PMID: 38795712) established that tNGS can detect resistance to multiple first- and second-line drugs simultaneously with high sensitivity and specificity - set to transform DST in coming years
• Detects comprehensive resistance profiles from direct clinical specimens without waiting for culture

• GenoType MTBDRplus: detects isoniazid resistance (katG, inhA mutations) and rifampicin resistance (rpoB mutations) - turnaround in hours
• GenoType MTBDRsl: detects resistance to fluoroquinolones and second-line injectables

D. Immunological Tests for TB Infection (LTBI Diagnosis)

• Inject 5 TU PPD (purified protein derivative) intradermally; read induration at 48-72 hours
• Limitations: cross-reactivity with BCG vaccination and NTM; subjective reading; two-visit requirement; "boosting phenomenon" on repeat testing
• Interpretation thresholds:

• QuantiFERON-TB Gold Plus (QFT-Plus): Whole-blood ELISA; measures IFN-γ response to ESAT-6 and CFP-10 antigens (RD1 region, absent in BCG and most NTM)
  • Two tubes: TB1 (CD4+ T cell response) and TB2 (CD4+ and CD8+ T cell responses) - QFT-Plus addition allows enhanced detection
• T-SPOT.TB: ELISPOT assay; counts individual IFN-γ producing cells
• Advantages over TST: Not affected by BCG vaccination; single visit; more specific; preferred by CDC/ECDC for all indications in adults
• Limitations: Cannot distinguish LTBI from active disease; false negatives in severely immunosuppressed; expensive

• Use ESAT-6/CFP-10 antigens (same as IGRAs) but in skin test format
• WHO-assessed accuracy: similar to IGRAs, superior to TST
• Useful in BCG-vaccinated persons, PLWH, and children

E. Additional Diagnostics

• Elevated in TB pleural effusions (>40 U/L), TB ascites, and TB pericardial fluid
• High sensitivity (~93%) and specificity (~90%) for TB pleural effusion in endemic areas
• Low ADA virtually rules out TB pleural effusion

• Detects mycobacterial LAM antigen in urine
• Most useful in PLWH with advanced immunosuppression (CD4 <100/μL)
• Limited sensitivity in HIV-negative and CD4-normal patients
• Point-of-care: Alere Determine TB LAM Ag

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VII. Latent TB Infection (LTBI)

Who to Screen

• All PLWH
• Close contacts of confirmed infectious TB cases
• Immigrants from high-burden countries (within 5 years of entry)
• Residents/employees of high-risk settings (prisons, homeless shelters, nursing homes)
• Health care workers
• Patients initiating immunosuppressive therapy (especially TNF-α inhibitors, JAK inhibitors, transplant)
• History of untreated or inadequately treated TB on CXR

LTBI Treatment Regimens (Harrison's 22e / WHO 2020)

• 3HP (once-weekly isoniazid + rifapentine for 3 months) is now the regimen of choice in most settings - highest completion rates, non-inferior to DOT
• Do not use rifampicin-based regimens in patients on protease inhibitors (HIV) without modification
• Pregnancy: 9H (isoniazid alone) preferred; rifapentine-based regimens not recommended (insufficient safety data)
• Rule out active TB before LTBI treatment (CXR + symptoms review mandatory)

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VIII. Active TB Disease - Treatment

Principles of Treatment

1. Multiple drugs to prevent resistance selection (monotherapy → certain resistance)
2. Adequate duration to eradicate non-replicating persistent bacilli (dormant populations)
3. Adherence support - DOTS (Directly Observed Therapy, Short-course) or enhanced self-administered therapy with support

Standard Drug-Susceptible Pulmonary TB Regimen

Classic 6-Month Regimen (HRZE/HR):

• Intensive phase (2 months): Isoniazid (H) + Rifampicin (R) + Pyrazinamide (Z) + Ethambutol (E) - 2HRZE
• Continuation phase (4 months): Isoniazid + Rifampicin - 4HR
• Total: 6 months

• Cavitary pulmonary disease
• Delayed culture conversion (positive at 2 months)
• Pyrazinamide could not be completed in intensive phase

New 4-Month Regimen (2025 ATS/CDC/ERS/IDSA Guidelines - PMID: 40693952):

"All-oral, shorter treatment regimens for TB are now recommended for use in eligible individuals."

• HRZE/Mfx (TBTC Study 31/ACTG A5349): Rifapentine + Isoniazid + Pyrazinamide + Moxifloxacin for 8 weeks, then Rifapentine + Isoniazid + Moxifloxacin for 9 weeks
• Non-inferior to standard 6-month regimen in a large multinational RCT
• Includes HIV-positive patients with CD4 >100
• Conditionally recommended by WHO and now by ATS/CDC/ERS/IDSA (2025)
• Not for: HIV with CD4 <100, extrapulmonary TB (except lymph node), pregnancy

Pediatric TB:

• Non-severe TB in children: 4-month regimen now recommended (ATS/CDC/ERS/IDSA 2025)
• Severe TB (meningitis, disseminated): still 6-12 months depending on site

First-Line Drug Dosing

• Decreases levels of: antiretrovirals (esp. PIs, NNRTIs), warfarin, oral contraceptives, methadone, antifungals, tacrolimus, cyclosporin, corticosteroids, phenytoin, sulfonylureas
• Rifabutin is preferred over rifampicin in HIV/TB co-treated with PIs (less CYP450 induction)

Monitoring During Treatment

• Baseline: LFTs, FBC, uric acid, creatinine, visual acuity, colour vision
• Repeat LFTs at 2 weeks, 1 month, then monthly (or earlier if symptomatic)
• Stop all drugs if LFTs >5x ULN (asymptomatic) or >3x ULN with symptoms
• Re-challenge protocol once LFTs normalize: rechallenge with rifampicin first (least hepatotoxic in practice), then isoniazid, then pyrazinamide; 1 drug at a time at weekly intervals
• Sputum culture at 2 months (critical milestone): persistent positivity requires reassessment, DST, and extended treatment

Response Assessment

• Clinical improvement: fever resolves, weight gain, symptoms improve within 2-4 weeks
• Sputum smear conversion: 2-4 weeks; culture conversion: 6-8 weeks in drug-susceptible TB
• Radiological improvement: lags behind clinical; fibronodular changes may persist/worsen initially (paradoxical reaction)

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IX. Drug-Resistant TB

Definitions

Epidemiology

• ~410,000 MDR/RR-TB cases diagnosed annually (2022)
• High-burden countries: India, China, Russia, Pakistan, South Africa, Ukraine
• ~15% of MDR-TB cases are now pre-XDR or XDR

Mechanisms of Resistance

MDR-TB Treatment (2025 Guidelines - PMID: 40693952)

• Bedaquiline + Pretomanid + Linezolid (BPaL) - all oral, 6 months
• BPaLM: + Moxifloxacin for fluoroquinolone-susceptible MDR-TB
• TB-PRACTECAL and ZeNix trials demonstrated high culture conversion rates (~90%) with shorter all-oral regimens
• Landmark shift: Entirely replaces injectable-based regimens (streptomycin, amikacin, kanamycin - now deprecated for routine use due to toxicity and inferiority)

• Novel diarylquinoline; inhibits mycobacterial ATP synthase
• Active against drug-susceptible and MDR/XDR strains
• Key safety concern: QTc prolongation (monitor ECG; avoid with moxifloxacin unless benefit outweighs risk)
• Requires informed consent in some jurisdictions due to black box warning

• Nitroimidazole; active against replicating and non-replicating (dormant) M. tuberculosis
• Part of BPaL for XDR-TB

• Oxazolidinone antibiotic
• Dose-dependent toxicities: peripheral neuropathy, optic neuritis, bone marrow suppression
• Dose reduction (600 → 300 mg) after culture conversion improves tolerability without loss of efficacy (ZeNix trial)

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X. TB and HIV Co-Infection

Key Clinical Principles (Harrison's 22e)

• HIV-infected individuals with LTBI: 3-13% annual risk of developing active TB (vs. ~10% lifetime risk in immunocompetent)
• New TB acquired by PLWH can evolve to active disease in weeks rather than months

Treatment Considerations

• Start anti-TB treatment FIRST in all HIV-TB cases
• Timing of ART initiation:
  • CD4 <50/μL: ART within 2 weeks of starting TB treatment
  • CD4 50-200/μL: ART within 2-8 weeks
  • CD4 >200/μL: ART within 8 weeks (or 2 weeks if CD4 is low or patient very unwell)
  • Exception - TB meningitis: ART delayed until 4-8 weeks (early ART increases mortality in TBM due to IRIS)

• Rifampicin drastically reduces levels of: efavirenz (by ~20% - dose unchanged), nevirapine, all PIs
• Replace rifampicin with rifabutin when using boosted PIs
• Preferred ART backbone with rifampicin-based TB treatment: Efavirenz + TDF + FTC (or 3TC)
• Dolutegravir 50 mg twice daily (double dose) when used with rifampicin

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Occurs in ~10% of HIV-TB patients on ART
• Paradoxical IRIS: Worsening of existing TB symptoms after ART initiation (lymphadenopathy, fever, infiltrates worsen)
• Unmasking IRIS: New TB manifestations appear after ART in a patient with previously undiagnosed TB
• Timing: typically 1-3 months after ART initiation
• Higher risk: low baseline CD4, extrapulmonary TB, early ART initiation
• Management:
  • Continue both anti-TB therapy and ART
  • NSAIDs for mild cases
  • Corticosteroids (prednisone 1.5 mg/kg/day, tapered over 6-10 weeks) for moderate-severe IRIS
  • Rule out TB treatment failure before attributing to IRIS
  • Never stop ART for IRIS unless immediately life-threatening

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XI. Special Situations

TB in Pregnancy

• Untreated TB carries greater risk than treatment
• Standard 6-month HRZE regimen is safe
• Pyridoxine (B6) 25-50 mg/day essential throughout
• Avoid: Streptomycin (ototoxicity to fetus), rifapentine-based LTBI regimens (insufficient safety data)
• Breastfeeding: all first-line drugs compatible; continue pyridoxine

TB in Renal Failure

• Renally cleared drugs: Ethambutol, Pyrazinamide (and their metabolites) - reduce dose or increase interval
• Isoniazid and rifampicin are primarily hepatically cleared - standard dosing
• Hemodialysis: dose after dialysis session

TB on Anti-TNF Therapy (Biologic Agents)

• TNF-α is critical for granuloma maintenance → anti-TNF drugs → high risk of TB reactivation
• Screen all candidates with IGRA/TST + CXR before starting anti-TNF
• Treat LTBI before initiating anti-TNF (start anti-TB treatment 1 month prior if possible)
• Risk: infliximab and adalimumab > etanercept (etanercept binds soluble TNF only)
• If active TB develops on anti-TNF: stop anti-TNF, start TB treatment; restart anti-TNF after 2 months

Steroids in TB - Indications

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XII. Prevention and Control

BCG Vaccine

• Live attenuated M. bovis strain
• Highly effective against: childhood miliary TB and TB meningitis (~80% protective)
• Modest efficacy against pulmonary TB in adults (variable: 0-80% in different trials - latitude effect)
• WHO recommendation: universal neonatal vaccination in TB-endemic countries
• Does NOT prevent TB infection - reduces progression to severe disease
• Contraindicated in HIV infection and immunosuppression (live vaccine)

Infection Control

• Airborne precautions (negative pressure rooms, N95 respirators) for all suspected/confirmed pulmonary TB
• Contact tracing with IGRA/TST and CXR for all close contacts
• DOTS/community treatment support for adherence
• Health care worker screening: IGRA preferred over TST (higher PPV)

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XIII. Recent Landmark Evidence (2024-2026)

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XIV. Consultant-Level Diagnostic Pearls

1. TB can mimic anything - consider TB in any patient with unexplained fever/weight loss/night sweats lasting >2-3 weeks, especially from endemic regions or immunosuppressed
2. Negative AFB smear does not exclude TB - smear-negative TB is common (~30-40% of pulmonary; majority of extrapulmonary). Send Xpert MTB/RIF Ultra + culture
3. Culture is mandatory in all cases - for species identification and DST; a positive smear with a negative culture in 8 weeks should prompt review
4. Rifampicin resistance = MDR until proven otherwise - initiate second-line therapy while awaiting full DST
5. ADA in effusions: Any lymphocytic exudative pleural/pericardial/peritoneal effusion with ADA >40 → treat for TB empirically in endemic settings while awaiting culture
6. Steroid effect on TB: Steroids can suppress fever and improve CXR in TB → do not interpret clinical improvement on steroids as ruling out TB
7. "Cold abscess": Any fluctuant, non-tender neck mass with skin changes → high suspicion for TB lymphadenitis; do NOT incise and drain (causes sinus tract); perform excision biopsy
8. Sterile pyuria: Always exclude TB urinary tract disease before attributing to other causes
9. Anti-TNF biologic: Rule out active and latent TB before every prescription; TB can present with unusual extrapulmonary manifestations on anti-TNF therapy
10. IRIS recognition: Worsening despite effective therapy in HIV patients 1-3 months after starting ART - think IRIS; manage with steroids, do NOT stop TB treatment or ART
11. Drug resistance profiling before empiric escalation: Never add a single drug to a failing regimen - always full DST first
12. Pregnancy: Do NOT withhold treatment - untreated TB is far more dangerous to mother and fetus than HRZE therapy

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