Enteric Fever (Typhoid Fever)

Definition & Etiology

Enteric fever is a systemic febrile illness caused by dissemination of Salmonella Typhi or S. Paratyphi (serotypes A, B, and C). The term "typhoid fever" persists from its early confusion with typhus; "enteric fever" was proposed in 1869 to reflect the anatomic site (small intestine) and is now used interchangeably. Unlike nontyphoidal Salmonella, these serovars have no animal reservoir—humans are the sole hosts.

— Harrison's Principles of Internal Medicine 22E, p. 1359

Epidemiology

~9.2–21 million cases of typhoid fever and ~5 million cases of paratyphoid fever occur annually, with 110,000–280,000 deaths/year
Highest incidence: Indian subcontinent (India, Pakistan, Bangladesh, Nepal), Eastern Mediterranean, sub-Saharan Africa — exceeding 1000 cases/100,000 children in some urban areas
Transmission: fecal-oral route via contaminated food/water; chronic carriers are a key reservoir
In the US: ~5700 cases/year; 78% travel-associated, predominantly from the Indian subcontinent; only 3% of affected travelers had been vaccinated

Risk factors: contaminated drinking water/ice, street food, raw produce fertilized with sewage, household contacts with illness, poor hand hygiene, prior H. pylori infection (reduced gastric acidity)

— Harrison's, p. 1359–1360

Pathophysiology

Ingested organisms penetrate the mucosa of the terminal ileum (via M cells overlying Peyer's patches)
Pass to mesenteric lymph nodes → primary bacteremia → dissemination to reticuloendothelial system (liver, spleen, bone marrow)
Secondary bacteremia occurs after intracellular replication → symptomatic disease
Necrosis of Peyer's patches underlies the complications of hemorrhage and perforation

Clinical Course

Incubation period: 5–21 days (mean 10–14 days); depends on inoculum size and host immune status.

Week 1

Stepwise rising fever up to 38.8–40.5°C (101.8–104.9°F)
Headache (80%), chills, malaise, dry cough (30%), myalgias
Relative bradycardia (pulse-temperature dissociation) in up to 50%
Coated tongue (51–56%)

Week 2

Sustained high fever
Rose spots (~30% of patients): faint, salmon-colored, blanching maculopapular lesions on trunk/chest — visible at end of week 1 or during week 2; resolve in 2–5 days; Salmonella can be cultured from punch biopsies

Rose spots of enteric fever — faint salmon-colored maculopapular lesions on the trunk

"Rose spots" of enteric fever due to S. Typhi or S. Paratyphi (Harrison's 22E, Fig. 171-2)

Hepatosplenomegaly (~50%)
Abdominal distension, pain, diarrhea or constipation
CNS: apathy, confusion, delirium, rarely psychosis

Week 3–4

Complications in ~5% of untreated patients: intestinal hemorrhage and perforation (from necrosis of Peyer's patches) — the most feared complications
Rare: pancreatitis, cholecystitis, infective endocarditis, meningitis, pneumonia, hepatic/splenic abscess, orchitis
Untreated illness typically resolves by end of week 4

— Harrison's, p. 1360; Goldman-Cecil Medicine, p. 3146

Diagnosis

Test	Sensitivity	Notes
Blood culture	40–80% (Week 1)	Gold standard; highest yield in week 1
Bone marrow culture	~80–95%	Remains positive even after antibiotics started
Stool culture	~30–40% (Week 2–3)	Higher yield later in illness
Urine culture	~25%	Lower yield
Widal test	Variable	Low specificity in endemic areas; not reliable
PCR	Emerging	Available in research settings

CBC: Leukopenia and neutropenia in ~20%; anemia; thrombocytopenia possible
LFTs: Elevated transaminases are common

Antibiotic Therapy

Overall case-fatality rate is 2.5% (untreated: 10–30%); prompt appropriate treatment reduces mortality to <1%.

Drug Resistance — Critical Context

MDR strains (resistant to chloramphenicol, ampicillin, TMP-SMX): emerged 1980s, widespread
Decreased susceptibility to ciprofloxacin (DSC) / fluoroquinolone resistance: dominant on the Indian subcontinent (clone H58); 66% of US isolates were DSC in 2015
XDR S. Typhi (since 2016, Pakistan): resistant to ceftriaxone + all of the above; susceptible only to azithromycin and carbapenems

Treatment Table (Adults)

Indication	Agent	Dose	Duration
Empirical	Ceftriaxone	2 g/d IV	10–14 days
	Ciprofloxacin*	500 mg bid PO or 400 mg q12h IV	5–7 days
	Azithromycin	1 g/d PO	10 days
Fully susceptible	Ciprofloxacin or Ceftriaxone	As above	As above
Alt.	Amoxicillin / Chloramphenicol / TMP-SMX	Standard doses	14–21 days
MDR	Ceftriaxone or Azithromycin	As above	As above
XDR (Pakistan)	Azithromycin	1 g/d PO	7 days
	Meropenem	1 g q8h IV	10–14 days

⚠ Fluoroquinolones should NOT be used empirically for travelers from South Asia due to high DSC/resistance rates.

— Harrison's 22E, p. 1361; Red Book 2021, p. 1023–1024

Special Situations

Severe disease (delirium, shock, coma): add dexamethasone IV (3 mg/kg loading, then 1 mg/kg q6h × 8 doses = 48 hours)
Relapse (up to 17% within 4 weeks): re-treat; azithromycin has lower relapse rates than fluoroquinolones or ceftriaxone
Chronic carrier state (bile/gallbladder): 4 weeks oral ciprofloxacin or norfloxacin; cholecystectomy + antibiotics if medical therapy fails

Prevention

Vaccines

Two licensed vaccines are available:

Vaccine	Type	Route	Efficacy	Duration
Ty21a (Vivotif)	Live attenuated	Oral, 4 capsules	~50–80%	5 years
Vi capsular polysaccharide (Typhim Vi)	Subunit	IM, single dose	~50–70%	2 years
Typhoid conjugate vaccine (TCV)	Vi-TT conjugate	IM, single dose	~80–85%	Longer (preferred in children)

Neither vaccine protects against S. Paratyphi
TCV (e.g., Typbar-TCV) is WHO-preferred for children; introduced widely in South Asia 2019–2022
Vaccination recommended for travelers to endemic regions, household contacts of carriers, and lab personnel

Infection Control

Standard + contact precautions; in children, continue until 3 negative stool cultures (≥48h after antibiotics)
Exclusion from food handling until culture-negative

Key Points Summary

Feature	Detail
Causative organism	S. Typhi, S. Paratyphi A/B/C
Incubation	5–21 days (mean 10–14 days)
Classic triad	Prolonged fever + relative bradycardia + rose spots
Pathognomonic rash	Rose spots (salmon-colored, trunk/chest, 30%)
Feared complication	Intestinal perforation/hemorrhage (Week 3)
Best diagnostic test	Blood culture (week 1) / bone marrow culture
Drug of choice	Azithromycin or ceftriaxone (region-dependent)
XDR first-line	Azithromycin ± meropenem
Mortality (untreated)	10–30%; treated <1%

Recent evidence (2024–2025): A systematic review (PMID 39623850) found no significant difference in outcomes between ceftriaxone, fluoroquinolones, and azithromycin in RCTs — but most trials predate current resistance patterns. A 2024 systematic review (PMID 38579699) documented hemophagocytic lymphohistiocytosis as a rare but serious complication of enteric fever. Given XDR typhoid expansion from Pakistan, always check local resistance data before prescribing.

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