Typhoid Fever
Medicine · Infectious Disease · lean revision notes
Typhoid Fever
Typhoid (enteric) fever is a systemic febrile illness caused by Salmonella enterica serotype Typhi, transmitted by the faeco-oral route. It is a perennial NEET PG favourite for its classic "step-ladder fever", relative bradycardia, rose spots, the limitations of the Widal test, and intestinal perforation as the dreaded killer.
Definition & classification
Enteric fever is an umbrella term for a prolonged febrile bacteraemic illness caused by:
- Salmonella Typhi → typhoid fever (classic, more severe).
- Salmonella Paratyphi A, B, C → paratyphoid fever (clinically milder, increasingly common, especially Paratyphi A in India).
Both are Gram-negative, motile, non–lactose-fermenting, facultative anaerobic bacilli of the family Enterobacteriaceae. They are strictly human pathogens (no animal reservoir), which is why typhoid is theoretically eradicable through sanitation and vaccination.
High-yield: Salmonella Typhi has no animal reservoir — humans (acute cases and chronic carriers) are the sole reservoir. Contrast with non-typhoidal Salmonella (NTS, e.g. S. Typhimurium, S. Enteritidis) which are zoonotic and cause gastroenteritis/food poisoning rather than enteric fever.
Antigenic structure (Kauffman–White)
| Antigen | Nature | Notes |
|---|---|---|
| O (somatic) | Lipopolysaccharide | Heat-stable; basis of Widal anti-O titre |
| H (flagellar) | Protein | Heat-labile; basis of Widal anti-H titre |
| Vi (capsular) | Polysaccharide (virulence) | Anti-phagocytic; masks O antigen; basis of Vi polysaccharide vaccine and the carrier-detection Vi antibody |
Etiology & pathophysiology
Transmission is via the 5 Fs — Food, Fingers, Faeces, Flies, Fomites — through ingestion of water/food contaminated by a carrier or patient.
Infective dose: ~10³–10⁶ organisms. A low gastric pH is protective; achlorhydria, antacids, PPIs and H. pylori gastritis lower the infective dose and increase susceptibility.
Stepwise pathogenesis
Ingestion → survive gastric acid → adhere to intestinal M cells over Peyer's patches (terminal ileum) → invade & translocate → engulfed by macrophages (survive intracellularly via Vi antigen) → primary bacteraemia (transient, asymptomatic) → multiply in reticuloendothelial system (liver, spleen, bone marrow, gallbladder) → secondary, sustained bacteraemia → clinical illness.
- The organism's intracellular survival within macrophages explains the prolonged incubation, the need for intracellular-penetrating antibiotics, and the high yield of bone marrow culture.
- Re-invasion of the gut from an infected gallbladder seeds the Peyer's patches a second time → lymphoid hyperplasia → necrosis → ulceration (ulcers oriented longitudinally along the long axis of the ileum, unlike the transverse/circumferential ulcers of intestinal TB) → this is the substrate for haemorrhage and perforation in the 3rd week.
- The gallbladder, especially with gallstones, is the niche for the chronic carrier state.
Incubation period: typically 7–14 days (range 3–21), inversely related to inoculum size.
Clinical features
Classically a stepwise (week-by-week) evolution in the untreated patient:
| Week | Dominant features | Pathological correlate |
|---|---|---|
| 1st | Stepladder rising fever, headache, malaise, dry cough, relative bradycardia; blood culture positive | Bacteraemia |
| 2nd | Sustained high fever, rose spots, abdominal pain, splenomegaly, "coated tongue", toxaemia, stool/urine culture positive | RES seeding, gut re-invasion |
| 3rd | Complications — intestinal haemorrhage & perforation, "typhoid state" (delirium, "coma vigil"), myocarditis | Peyer's patch necrosis/ulceration |
| 4th | Gradual defervescence and recovery (or relapse) | Resolution |
Key clinical signs (all high-yield):
- Stepladder pyrexia — fever rises a little higher each evening with incomplete morning remission.
- Relative bradycardia (Faget sign) — pulse rate inappropriately low for the height of fever. Also seen in brucellosis, leptospirosis, yellow fever, Legionella, drug fever.
- Rose spots — 2–4 mm blanching, pink maculopapules on the lower chest and upper abdomen, appearing in crops in the 2nd week, faint/faded and easily missed (and even harder to see on darker skin). They are embolic (contain organisms on biopsy/culture). Sparse — usually only a dozen or so.
- Coated tongue with red edges, soft splenomegaly, relative leucopenia with eosinopenia.
- Abdomen: mild distension, right iliac fossa gurgling/tenderness, constipation more typical in adults early on; pea-soup diarrhoea more common in children and later weeks.
High-yield: The classic triad examiners love — stepladder fever + relative bradycardia + rose spots — with leucopenia in the haemogram. A high or rising leucocyte count should make you suspect perforation/secondary infection.
High-yield: Rose spots are on the chest/upper abdomen, blanch on pressure, are few and faded, and are an embolic phenomenon — biopsy can grow the organism.
Diagnosis & investigation of choice
Culture — the cornerstone (definitive)
| Specimen | Best timing | Sensitivity / notes |
|---|---|---|
| Blood culture | 1st week (best in first 7–10 days) | ~40–80%; positivity falls with prior antibiotics; investigation of choice in the 1st week |
| Bone marrow culture | Any time, even after antibiotics | ~90–95% — GOLD STANDARD / most sensitive; remains positive up to 5 days after antibiotics |
| Stool culture | 2nd–3rd week | Reflects gut shedding; also screens carriers |
| Urine culture | 2nd–3rd week | Lower yield |
| Duodenal string test (bile) | — | Good yield; uncomfortable, rarely used |
High-yield: Bone marrow culture = most sensitive (gold standard) and stays positive despite prior antibiotic therapy. Blood culture = best/investigation of choice in the first week. Media used: bile broth / selenite F (enrichment), then MacConkey/DCA.
Widal test (serology) — know its LIMITATIONS
Detects agglutinating anti-O and anti-H antibodies. It is non-specific and slow, used only where culture is unavailable.
- A single titre is unreliable; a fourfold rise in paired sera (acute + convalescent, 7–10 days apart) is the meaningful result.
- Commonly quoted significant cut-offs in endemic areas: anti-O ≥ 1:160 (or ≥1:200) and anti-H ≥ 1:160, but these vary by local baseline.
- Anti-O (IgM) rises first and falls → indicates recent/active infection; anti-H (IgG) rises later and persists → less useful for acute diagnosis.
False positives: other Salmonella, prior vaccination, anamnestic response in any febrile illness, malaria, dengue, chronic liver disease, rheumatoid factor, endemic high baseline. False negatives: early presentation (before antibody rise), prior antibiotics, carriers, immunosuppression.
High-yield: Widal becomes positive only by the end of the 1st/start of 2nd week, cannot distinguish current from past infection or vaccination, and is never the investigation of choice — culture is. A single high titre in an endemic zone may just be baseline.
Newer / ancillary tests
- Typhidot (IgM/IgG dot ELISA) against the 50 kDa outer-membrane protein — IgM positivity suggests acute infection; faster than Widal but still not as good as culture.
- Tubex test — detects anti-O9 IgM; rapid.
- Nested PCR (flagellin gene) — research/select settings.
- Haemogram: leucopenia with relative lymphocytosis and eosinopenia, mild anaemia, thrombocytopenia; mildly raised transaminases.
Quick diagnostic flow: Febrile ≥3 days in endemic area → blood culture (week 1) → if negative & still suspicious, bone marrow culture (gold standard) → Widal/Typhidot only as adjuncts.
Management / drug of choice
Treatment is now dictated by the resistance pattern, which has evolved dramatically.
Resistance terminology
- MDR typhoid (multi-drug resistant): resistant to the three first-line drugs — chloramphenicol, ampicillin/amoxicillin, and co-trimoxazole.
- Fluoroquinolone (FQ) resistance / decreased susceptibility: flagged by nalidixic acid resistance (NARST) screening and gyrA mutations; widespread in the Indian subcontinent → ciprofloxacin often fails or relapses.
- XDR typhoid (extensively drug resistant): MDR plus resistance to fluoroquinolones and third-generation cephalosporins (ceftriaxone); first emerged in Pakistan (Sindh, 2016). Treated with azithromycin or carbapenems (meropenem).
Drug of choice by setting
| Scenario | Preferred drug(s) | Notes |
|---|---|---|
| Uncomplicated, FQ-susceptible | Fluoroquinolone (ciprofloxacin/ofloxacin) | Now uncommonly susceptible in India |
| Uncomplicated, FQ-resistant / empirical (endemic) | Azithromycin (oral) | Excellent intracellular penetration; first-line oral agent today |
| Severe / complicated / hospitalised | Ceftriaxone (IV) | First-line parenteral empirical agent |
| XDR typhoid | Carbapenem (meropenem) ± azithromycin | Reserve agents |
| Classic (historical) | Chloramphenicol | High relapse, carrier state, marrow toxicity → abandoned |
High-yield: For empirical therapy of enteric fever in India today, think ceftriaxone (IV, for the sick patient) or azithromycin (oral, for the ambulatory patient) because of widespread fluoroquinolone resistance. Nalidixic-acid resistance predicts fluoroquinolone failure.
Adjuncts
- Dexamethasone (high-dose, Hoffman regimen) in severe typhoid with delirium, obtundation, shock or coma — shown to reduce mortality. Give only with concurrent antibiotics.
- Supportive: antipyretics (paracetamol), fluids, nutrition, monitor for perforation.
- Defervescence is slow even on appropriate therapy — fever may take 5–7 days to settle; don't switch antibiotics prematurely.
Chronic carrier treatment
Defined as excretion of S. Typhi (usually in stool/urine) for >1 year; commoner in women with gallstones/cholelithiasis.
- Prolonged high-dose oral ciprofloxacin (or amoxicillin) for 4–6 weeks, or
- Cholecystectomy if gallstones present and antibiotics fail.
- Classic historical eponym: "Typhoid Mary" (Mary Mallon) — an asymptomatic cook and chronic gallbladder carrier in New York.
Complications
The most-tested area. Most arise in the 3rd week.
| System | Complication | Pearl |
|---|---|---|
| GI | Intestinal perforation | Most common cause of death; terminal ileum; 3rd week |
| GI | Intestinal haemorrhage | From eroded Peyer's patch ulcers; melaena |
| CVS | Myocarditis | Important cause of death; toxic; watch ECG |
| Neuro | Encephalopathy, "typhoid state", coma vigil, delirium | Indication for steroids |
| Hepatobiliary | Hepatitis, acalculous/calculous cholecystitis | |
| Bone/joint | Osteomyelitis (esp. in sickle cell disease) | Salmonella osteomyelitis classically in sickle cell |
| Renal | Glomerulonephritis, immune complex nephritis | |
| Relapse | 5–15% (esp. after chloramphenicol/short courses) | Milder, ~1–2 weeks after recovery |
| Carrier | Chronic gallbladder carriage | Reservoir for spread |
High-yield: Intestinal perforation is the most common cause of death in typhoid; myocarditis is another important fatal complication. Perforation classically presents in the 3rd week with sudden RIF/generalised pain, board-like rigidity, and free gas under the diaphragm — a surgical emergency managed with resuscitation, broad-spectrum antibiotics and laparotomy (perforation closure/resection).
High-yield: Association to remember — typhoid + osteomyelitis = think sickle cell disease.
Key differentials
Enteric fever competes with every cause of prolonged fever in the tropics:
| Differential | Distinguishing clues |
|---|---|
| Malaria | Cyclical fever with rigors/sweats, splenomegaly, peripheral smear/RDT positive, no rose spots |
| Dengue | Retro-orbital pain, myalgia, thrombocytopenia, positive NS1/IgM, haemorrhagic signs |
| Brucellosis | Undulant fever, relative bradycardia, contact with cattle/unpasteurised milk |
| Leptospirosis | Conjunctival suffusion, myalgia (calf), jaundice + AKI (Weil disease), water exposure |
| Intestinal TB | Transverse/circumferential ileal ulcers, chronicity, weight loss, ascites |
| Infective endocarditis | Murmur, peripheral stigmata, positive blood cultures (other organisms) |
| Rickettsial / scrub typhus | Eschar, regional lymphadenopathy, responds to doxycycline |
| Amoebic liver abscess / hepatitis | RUQ pain, tender hepatomegaly, imaging |
Causes of relative bradycardia (mnemonic "Faget"): typhoid, brucellosis, leptospirosis, yellow fever, Legionella, drug fever, beta-blockers, raised ICP.
Prevention & vaccines
- Sanitation, safe water, hand hygiene, food safety — the definitive control.
- Vaccines:
- Ty21a — live attenuated oral, 3–4 doses, not in <6 years/immunocompromised.
- Vi capsular polysaccharide — injectable, single dose, not <2 years, no herd/boosting effect, T-independent.
- Typhoid conjugate vaccine (TCV, Typbar-TCV — Vi conjugated to tetanus toxoid) — immunogenic from 6 months, longer protection, T-dependent, now WHO-prequalified and rolled out in endemic programmes. Preferred vaccine for endemic settings.
High-yield: TCV (Typbar-TCV, an Indian product) is the modern preferred vaccine — usable from 6 months of age, gives longer-lasting protection, and is being introduced in routine immunisation in high-burden areas.
Recently asked / exam angle
- Investigation of choice in the 1st week = blood culture; most sensitive overall (gold standard) = bone marrow culture (positive even after antibiotics). Repeatedly tested single-best-answer.
- Widal limitations — single high titre unreliable, anamnestic/vaccine false positives, becomes positive only after the 1st week → "never the IOC."
- Empirical drug today — image/vignette of FQ-resistant or XDR typhoid → ceftriaxone (severe) / azithromycin (oral); nalidixic acid resistance predicts fluoroquinolone failure.
- Most common cause of death = intestinal perforation (3rd week, terminal ileum); haemorrhage and myocarditis also asked.
- Rose spots — site (chest/upper abdomen), blanching, embolic, sparse/faded.
- Relative bradycardia (Faget sign) — list of causes.
- Ileal ulcers — longitudinal (along long axis) in typhoid vs transverse in intestinal TB — a classic single-line discriminator.
- Chronic carrier — gallbladder/gallstones, women, "Typhoid Mary," Vi antibody for detection, treat with prolonged ciprofloxacin ± cholecystectomy.
- TCV from 6 months — newer vaccine MCQ.
- Vi antigen functions — anti-phagocytic, virulence, vaccine and carrier marker.
Rapid revision
- Cause: Salmonella Typhi — Gram-negative bacillus, human-only reservoir, faeco-oral spread (5 Fs).
- Pathology: infects Peyer's patches of terminal ileum; survives in macrophages; ulcers are longitudinal.
- Classic clinical triad: stepladder fever + relative bradycardia (Faget) + rose spots with leucopenia/eosinopenia.
- Rose spots: 2–4 mm blanching papules on chest/upper abdomen, faint, embolic, in crops, 2nd week.
- Blood culture = best in week 1 (IOC early); stool/urine culture positive in weeks 2–3.
- Bone marrow culture = most sensitive / gold standard, positive even after antibiotics.
- Widal = anti-O (IgM, recent) & anti-H (IgG, late); needs fourfold rise; many false +/−; never the IOC.
- Empirical Rx: ceftriaxone IV (severe) or azithromycin oral; FQ-resistance widespread; nalidixic-acid resistance = predicts FQ failure.
- XDR typhoid (Pakistan): resistant to FQ + 3rd-gen cephalosporins → meropenem/azithromycin.
- Most common cause of death = intestinal perforation (3rd week); myocarditis also lethal; steroids (dexamethasone) for severe encephalopathic typhoid.
- Chronic carrier: gallbladder + gallstones, women, "Typhoid Mary," detect via Vi antibody, treat with prolonged ciprofloxacin ± cholecystectomy.
- Best modern vaccine: TCV (Typbar-TCV) — usable from 6 months, longer protection; Salmonella osteomyelitis → think sickle cell.