Enteric (Typhoid) Fever

Basics

S. Typhi (typhoid) + S. Paratyphi A/B/C (paratyphoid). Gram-negative, Enterobacteriaceae. Discovered: Salmon & Smith (1885). S. Typhi: Eberth (1880), Gaffky (1884) — “Eberth-Gaffky bacillus.”

Classification

Clinical: Typhoidal (S. Typhi, S. Paratyphi — human-restricted, enteric fever) vs NTS (broad animal host, gastroenteritis+septicemia).

Antigenic (Kauffmann-White): Serogroup (O antigen, numbered: 2=old A, 4=old B, 9=old D) → Serotype (H antigen). >2500 serotypes.

Molecular: S. enterica + S. bongori. S. enterica → 6 subspecies (enterica, salamae, arizonae, diarizonae, houtenae, indica). Most pathogens = subspecies enterica.

Full name: Salmonella enterica subsp. enterica serotype Typhi → shortened “S. Typhi.”

Antigenic Structure

O (somatic): LPS-based, less immunogenic, EARLY appear/disappear (recent infection marker), compact chalky clumps (55°C), defines SEROGROUP. H (flagellar): flagellin protein, motility, more immunogenic, LATE appear/disappear (convalescence marker), loose fluffy clumps (37°C), defines SEROTYPE. Vi: capsular polysaccharide over O antigen, only in S. Typhi/Paratyphi C/Dublin/some Citrobacter. Poorly immunogenic → NOT in Widal test. Absence in proven case = poor prognosis. Persistence = carrier state. Used: phage typing, vaccine.

Pathogenesis

Oral transmission. Infective dose 10³-10⁶ (higher than Shigella). Risk factors: ↓stomach acid (age<1, antacids, achlorhydria, prior H. pylori), ↓intestinal integrity (IBD, GI surgery, antibiotic flora disruption).

Sequence: M cells → BME (bacteria-mediated endocytosis, type III secretion, membrane ruffling) → vacuole crosses epithelium → submucosa → macrophage phagocytosis → S. Typhi alters LPS, resists lysosomal killing → survives → lymphatics → PRIMARY bacteremia (transient) → disseminate to RE tissues (liver, spleen, LN, marrow) + other organs (gallbladder, kidney, lung) → multiply → SECONDARY bacteremia → clinical disease.

Clinical Manifestations

Incubation: 10-14 days. Manifestations = EXTRAINTESTINAL despite “enteric” name.

Fever: step-ladder remittent pattern. Other: headache, chills, cough, sweating, myalgia, arthralgia. Rose spots: salmon-colored blanching maculopapular rash, trunk/chest, 30% by end wk1. Early GI: abdominal pain, nausea, vomiting, anorexia. Signs: hepatosplenomegaly, epistaxis, relative bradycardia. Complications: GI bleeding, intestinal perforation (wk 3-4). Rare neuro: meningitis, cerebellar ataxia, “muttering delirium”/“coma vigil” (paranoid psychosis, hysteria, delirium, aggression).

Carriage

Fecal carrier (gallbladder multiplication) = MORE common. Urinary carrier (kidney) = rare. Temporary: shed <3mo (10% untreated). Chronic: shed >1yr (2-5%). More in women, infants, elderly. Linked: biliary abnormality+gallstone biofilm (→gallbladder cancer risk), urinary abnormality+S. haematobium. Food handler carriers = dangerous. Classic: Mary Mallon “Typhoid Mary” (1300+ cases).

Epidemiology

Human = only host. Fecal-oral (water/food). WHO: 11-21M cases, 1.2-1.6L deaths/yr (typhoid) vs 6M cases/54,000 deaths (paratyphoid). India >6M cases/yr. Highest incidence: South-Central/SE Asia (>100/100,000/yr). Urban>rural. Children/adolescents>adults. S. Typhi:Paratyphi A ≈ 4:1, but Paratyphi A rising in India (possibly vaccination-driven selection).

Laboratory Diagnosis

Specimen by week: Wk1 = blood/bone marrow/duodenal aspirate. Wk2-3 = serology (Widal). Wk3-4 = urine+stool culture.

Blood Culture

Best in wk1 (90% positive) → declines: 75%(wk2), 60%(wk3), 25%(fever resolution). 8-10mL, BHI monophasic/biphasic or BacT/ALERT, 37°C, nonfastidious (grows <24hr). Blood agar: nonhemolytic moist colonies. MacConkey: round translucent pale NLF colonies.

Stool/Urine Culture

Useful wk3-4 + carrier detection (positive even post-antibiotic). Urine: centrifuge, deposit on MacConkey (rarely positive). Stool: Enrichment (Selenite F, tetrathionate, GN broth) + Selective media.

• MacConkey (low selective)
• DCA — pale colonies, BLACK CENTER
• XLD — RED colonies, BLACK CENTER
• Wilson-Blair bismuth sulfite — JET BLACK metallic sheen (H2S), best for heavily contaminated specimens. S. Paratyphi A (no H2S) = GREEN colonies.

Bone marrow: 55-90% sensitive, even on antibiotics — used if blood culture negative wk1. Duodenal aspirate: if blood+marrow both negative. Blood+marrow+intestinal secretion combo: >90% sensitivity wk1. Other specimens: rose spots, pus, CSF, sputum, autopsy (gallbladder/liver/spleen).

Identification

Gram stain: motile, Gram-neg, non-sporing, non-capsulated, peritrichous flagella. Biochem: catalase+, oxidase-, indole-, citrate-, urease-. TSI: K/A, gas+ (except S. Typhi = anaerogenic). H2S abundant EXCEPT Paratyphi A(none), S. Typhi(small speck at junction). MALDI-TOF: genus level only (shared ribosomal proteins, poor serotype discrimination). Slide agglutination: polyvalent O (confirm genus) → type-specific O (serotype). S. Typhi=O9, Paratyphi A=O2, Paratyphi B=O4.

Widal Test (Fernand Widal, 1896)

Agglutination test: O+H Ab vs S. Typhi + S. Paratyphi A/B. 4 antigens: TO, TH, AH, BH. (Paratyphoid O cross-reacts with typhoid O via shared factor 12 — not used separately.)

Procedure: serial dilution 1:10-1:640, mixed with each antigen. O agglutination = compact chalky clumps. H agglutination = loose fluffy clumps. Titer = highest dilution still agglutinating.

Interpretation:

• TO+TH↑ = S. Typhi
• TO+AH↑ = S. Paratyphi A
• TO+BH↑ = S. Paratyphi B
• TO alone↑ = recent infection (nonspecific)
• TH alone↑ = ? convalescent/anamnestic
• TH+AH+BH all↑ = post-TAB vaccination

Significance: NO single titer universal. India baseline exists (prior exposure) — cutoff varies by locality. Common: H>200, O>100. 4-FOLD RISE (paired sera, 1wk apart) > single high titer. True infection: titer keeps rising. Anamnestic: falls after 1wk.

False positive: anamnestic response (malaria/dengue in prior enteric fever pt), fimbriae-contaminated antigen, inapparent infection, prior TAB vaccine. False negative: wk1, after wk4, carriers, on antibiotics, prozone (fix: serial dilution).

Newer tests:

• Typhidot: 50kDa OMP, dot ELISA, IgM+IgG separately, day 2-3
• IDL Tubex: O9 antigen, semiquantitative colorimetric, IgM ONLY
• IgM dipstick/ELISA: anti-LPS IgM
• Dot blot: flagellar antigen, IgG ONLY

Other Methods

Antigen detection (serum/urine, ELISA). Molecular (nested PCR — flagellin, iroB, fliC genes). Nonspecific: neutropenia 15-25%, leukocytosis in children/early/complicated. AST: disk diffusion (MHA) or MIC (VITEK).

Carrier detection: stool/bile culture (fecal), urine culture (urinary), Vi Ab tube agglutination (Bhatnagar strain, even 1:10 significant, confirm by culture), sewage culture (sewer-swab technique, membrane filtration).

Treatment

Prompt Rx → mortality <1%. Ceftriaxone (1-2g/day IV, 10-14d) = empirical DOC. Azithromycin (1g/day oral, 5d) = oral alternative. Ciprofloxacin (500mg BD, 5d) = NOT empirical (resistance), only if susceptible confirmed. Old drugs (no longer routine): chloramphenicol, amoxicillin, cotrimoxazole.

Drug Resistance

MDR S. Typhi = resistant to chloramphenicol+ampicillin+cotrimoxazole. Emerged 1989 China/SE Asia/India. FQ resistance: after MDR emergence, cipro became DOC 1990s → 3 decades use → >70% resistance in India (2019). Mechanism: gyrA/parC mutations. Ceftriaxone resistance: RARE (<1%), ESBL/AmpC producers reported. “Old is gold”: many strains reverted susceptible to old drugs (disuse).

Carrier Rx: ampicillin/amoxicillin + probenecid, 6 weeks.

Prophylaxis

Control of reservoir: early Dx+Rx, disinfect soiled clothes (5% cresol/2% chlorine/steam), follow-up stool/urine culture (3-4mo + 12mo), carrier detection+Rx (ampicillin/amoxicillin 4-6g/day+probenecid 6wk, ~70% cure), cholecystectomy+ampicillin (80% cure, MOST effective).

Sanitation: water protection/purification, hand hygiene, food hygiene, health education.

Vaccine — short-term protection. Indications: travelers, mela/yatra attendees, household contacts, high-risk (school children), endemic residents (optional).

Vi-CPS: single 25µg dose IM/SC, 2yr protection+booster, ONLY >2yr age (T-independent, poor immunogenicity <2yr). Vi-rEPA: Vi + recombinant P. aeruginosa Exotoxin A conjugate — usable <2yr (↑immunogenicity). Typhoral (oral live Ty21a, Gal-E mutant, self-destructs after 4-5 divisions): >6yr age, enteric-coated capsules, alternate days (1,3,5,7), no antibiotics during. Revaccinate q5yr. Protection starts 7 days post-last-dose, lasts 4yr. Parenteral TAB (heat-killed whole cell): OBSOLETE, side effects.

NTS Bacteremia

Up to 8% NTS gastroenteritis → bacteremia → endovascular infection/metastatic seeding. Risk: invasive serotypes (S. Choleraesuis-pig, S. Dublin-cattle), extremes of age, HIV/immunocompromise, pre-existing valvular heart disease (→NTS endocarditis/arteritis).

What Enteric Fever Is

Enteric fever is a potentially fatal multisystem illness caused by Salmonella Typhi (typhoid fever) and S. Paratyphi A, B, and C (paratyphoid fever). Salmonella is a Gram-negative member of the Enterobacteriaceae, discovered by Salmon and Smith (1885); the type serotype, S. Typhi, was independently observed by Eberth (1880) and Gaffky (1884), hence its older name, the Eberth-Gaffky bacillus.

Classification

Salmonella’s classification has been revised repeatedly. The clinically useful clinical classification splits it into typhoidal serotypes (S. Typhi and S. Paratyphi, restricted to human hosts, causing enteric fever) and non-typhoidal salmonellae (NTS) — the remaining serotypes, colonizing a broad range of animals and causing food-borne gastroenteritis and septicemia in humans (covered separately).

The antigenic (Kauffmann-White) classification groups salmonellae by O (somatic) and H (flagellar) antigens: serogroups (based on O antigen, now numbered rather than lettered — serogroup 2 = old A, serogroup 4 = old B, serogroup 9 = old D) are further split into serotypes (based on H antigen) — over 2,500 serotypes exist in total. The molecular classification recognizes two species — S. enterica and S. bongori — with S. enterica further split into six subspecies (enterica, salamae, arizonae, diarizonae, houtenae, indica); nearly all pathogenic human serotypes fall under subspecies enterica.

The full taxonomic name (Salmonella species enterica subspecies enterica serotype Typhi) is simplified in routine use to Salmonella serotype Typhi, or simply S. Typhi.

Antigenic Structure

Three antigens matter:

• O (somatic) antigen — part of the LPS cell wall; less immunogenic; O antibody appears and disappears early, marking recent infection; forms compact, granular, chalky clumps on agglutination (optimum 55°C); used to define serogroups.
• H (flagellar) antigen — made of flagellin protein, confers motility; more immunogenic; H antibody appears and disappears late, marking convalescence; forms large, loose, fluffy clumps (optimum 37°C); used to define serotypes within a serogroup.
• Vi antigen — a surface polysaccharide capsule covering the O antigen, present only in a few serotypes (S. Typhi, S. Paratyphi C, S. Dublin, some Citrobacter freundii). Named for its presumed link to virulence. It is poorly immunogenic (low antibody titres), so it is not used in the Widal test; but its complete absence in a proven typhoid case suggests poor prognosis, while its persistence after convalescence suggests carrier-state development. Vi-specific bacteriophages allow phage typing, and Vi antigen itself is used in one of the two typhoid vaccines.

Pathogenesis

Transmission is oral, via contaminated food or water. The infective dose (10³–10⁶ bacilli) is higher than Shigella’s. Risk rises with reduced stomach acidity (age <1 year, antacids, achlorhydria, prior H. pylori infection) or reduced intestinal integrity (IBD, prior GI surgery, antibiotic-disrupted flora).

The infection sequence: organisms enter through M cells of the intestinal mucosa via bacteria-mediated endocytosis (BME) — a type III secretion system triggers membrane ruffling that engulfs adherent bacteria into vacuoles. The bacteria-containing vacuoles cross the epithelium into the submucosa, where macrophages phagocytose them; S. Typhi survives inside by altering its LPS surface to resist lysosomal killing. Surviving organisms spread via lymphatics into blood (primary bacteremia, transient), then disseminate throughout the reticuloendothelial tissues (liver, spleen, lymph nodes, bone marrow) and other organs (gallbladder, kidneys, lungs), multiplying further before a secondary bacteremia seeds back into blood and triggers clinical disease.

Clinical Manifestations

Incubation period is 10–14 days. Despite the “enteric” name, manifestations are largely extraintestinal:

• Fever — a step-ladder pattern of remittent fever, rising gradually higher with each spike, never quite returning to normal between spikes.
• Headache, chills, cough, sweating, myalgia, arthralgia.
• Rose spots — faint, salmon-coloured, blanching maculopapular rash on trunk/chest, seen in ~30% of patients by end of the first week.
• Early intestinal symptoms: abdominal pain, nausea, vomiting, anorexia.
• Important signs: hepatosplenomegaly, epistaxis, relative bradycardia.
• Complications: GI bleeding and intestinal perforation, mostly in weeks 3–4.
• Rare neurologic manifestations: meningitis, cerebellar ataxia, and the classic “muttering delirium”/“coma vigil” neuropsychiatric picture — paranoid psychosis, hysteria, delirium, aggression.

Carriage

Untreated patients can become carriers, shedding S. Typhi in faeces (fecal carriers, more common — bacilli multiply in the gallbladder) or urine (urinary carriers, rare — multiplication in kidneys). Temporary carriers shed for up to 3 months (up to 10% of untreated patients); chronic carriers shed for >1 year (2–5% of patients), more common in women, infants, and the elderly, and associated with biliary tract abnormalities (salmonellae biofilm on gallstones, itself linked to increased gallbladder cancer risk) or urinary tract abnormalities with concurrent Schistosoma haematobium infection.

Chronic carriers who work as food handlers are especially dangerous — the textbook example is Mary Mallon (“Typhoid Mary”), whose career as a cook caused more than 1,300 documented cases.

Epidemiology

Humans are the only natural host. Transmission is via contaminated water/food. WHO estimates 11–21 million typhoid cases and 1.2–1.6 lakh deaths annually worldwide (versus 6 million paratyphoid cases, 54,000 deaths), with India bearing the largest single share (>6 million cases/year). Incidence is highest (>100/100,000/year) in South-Central and Southeast Asia. The disease is more common in urban than rural areas, and in children/adolescents than adults. Risk factors: poor sanitation, contaminated water/food/drink, poor hand hygiene, and prior H. pylori infection. S. Typhi outnumbers S. Paratyphi A roughly 4:1, though paratyphoid A is rising in India — plausibly linked to increasing typhoid-specific vaccination.

Laboratory Diagnosis

Specimen choice tracks illness duration: week 1 — blood, bone marrow, or duodenal aspirate culture; weeks 2–3 — serum for serology (Widal); weeks 3–4 — urine and stool culture.

Blood Culture

The ideal method in week 1, positive in ~90% of cases, declining to 75% (week 2), 60% (week 3), and 25% by fever resolution. 8–10 mL of blood is collected into conventional (BHI monophasic/biphasic) or automated (BacT/ALERT) bottles, incubated at 37°C — salmonellae are non-fastidious and grow within 24 hours. Subcultures onto blood agar (nonhemolytic moist colonies) and MacConkey agar (round, translucent, pale, non-lactose-fermenting colonies).

Stool and Urine Culture

Useful in weeks 3–4 and for detecting carriers (remain positive even after treatment). Urine is centrifuged and the deposit plated on MacConkey agar (rarely positive, since urinary shedding is infrequent). Stool culture uses enrichment broths (Selenite F, tetrathionate, Gram-negative broth) plus selective media: low-selective MacConkey agar, and highly selective DCA (pale colonies with black centre), XLD (red colonies with black centre), and Wilson-Blair’s bismuth sulfite medium (jet-black, metallic-sheen colonies from H₂S production — the best medium for heavily contaminated specimens; S. Paratyphi A and other non-H₂S formers produce green colonies instead).

Bone marrow culture (55–90% sensitive, even on antibiotics) is used when blood culture is negative in week 1; duodenal aspirate culture if both blood and bone marrow are negative. The combination of blood + bone marrow + intestinal secretions gives >90% sensitivity in week 1. Other viable specimens: rose spots, pus from suppurative lesions, CSF, sputum, and autopsy specimens (gallbladder, liver, spleen).

Identification

Gram stain: motile, Gram-negative, non-sporing, non-capsulated bacilli with peritrichous flagella. Biochemically: catalase-positive, oxidase-negative, indole-negative, citrate-negative, urease-negative; TSI shows alkaline slant/acid butt, gas present (except S. Typhi, anaerogenic), and H₂S abundant except S. Paratyphi A (none) and S. Typhi (a small speck at the slant-butt junction). MALDI-TOF identifies to genus level but poorly distinguishes serotypes (shared ribosomal proteins). Slide agglutination with polyvalent O antisera confirms genus, then type-specific O antisera confirm serotype: S. Typhi agglutinates O9, S. Paratyphi A agglutinates O2, S. Paratyphi B agglutinates O4.

Widal Test

The oldest and most widely used serological test (Fernand Widal, 1896) — an agglutination test detecting O and H antibodies against S. Typhi and S. Paratyphi A/B, using four antigens: TO (S. Typhi O), TH (S. Typhi H), AH (S. Paratyphi A H), BH (S. Paratyphi B H). Paratyphoid O antigens cross-react with typhoid O (shared factor 12) and so are not used separately.

Patient serum is serially diluted (1:10 to 1:640) and mixed with each antigen; O agglutination shows compact chalky clumps, H agglutination shows loose fluffy clumps; the titre is the highest dilution still showing agglutination.

Interpretation (rise of): TO+TH → S. Typhi infection; TO+AH → S. Paratyphi A; TO+BH → S. Paratyphi B; TO alone → recent infection (nonspecific for which organism); TH alone → possible convalescent/anamnestic response; all of TH+AH+BH → post-TAB vaccination.

No single titre is universally significant — in endemic settings like India, baseline antibody from prior exposure is expected, so only titres above a locally validated cutoff matter (commonly, H titre >200 and O titre >100 in most of India). A fourfold rise between paired sera taken a week apart is far more meaningful than any single high titre, since a true infection’s titre keeps climbing over that week while an anamnestic response typically falls.

False positives arise from anamnestic responses (unrelated infections like malaria/dengue transiently boosting titre in someone with prior enteric fever), antigen suspensions contaminated with fimbriae, inapparent infection, or prior TAB vaccination. False negatives occur in the first week, after the fourth week, in carriers, in patients already on antibiotics, or from the prozone phenomenon (overcome by serial dilution).

Newer antibody tests include Typhidot (50 kDa OMP antigen, dot ELISA, detects IgM and IgG separately from day 2–3), IDL Tubex (O9 antigen, semiquantitative colorimetric IgM detection), IgM dipstick/ELISA (anti-LPS IgM), and dot blot assay (flagellar antigen, IgG only).

Other Methods

Antigen detection (serum/urine, by ELISA); molecular methods (nested PCR targeting flagellin, iroB, fliC genes); nonspecific findings (neutropenia in 15–25%, leukocytosis more common in children/early phase/complicated cases); AST by disk diffusion (Mueller-Hinton) or MIC methods (VITEK).

Carrier detection: stool/bile culture (fecal carriers) and urine culture (urinary carriers); Vi antibody tube agglutination (using Bhatnagar strains — even a titre of 1:10 is significant, but culture confirmation is still required); and community-level tracing via sewage culture (sewer-swab technique on gauze pads, or membrane filtration).

Treatment and Resistance

Prompt appropriate antibiotics reduce mortality to <1%. Current recommendations: ceftriaxone (1–2 g/day IV, 10–14 days) is the empirical drug of choice; azithromycin (1 g/day oral, 5 days) is the oral empirical alternative; fluoroquinolones (ciprofloxacin 500 mg BD, 5 days) should not be used empirically given rising resistance, only once susceptibility is confirmed. Older drugs — chloramphenicol, amoxicillin, cotrimoxazole — have fallen from routine use.

Multidrug-resistant (MDR) S. Typhi (resistant to chloramphenicol, ampicillin, and cotrimoxazole together) first emerged in China/Southeast Asia/India in 1989 and spread widely, driving the shift to ciprofloxacin. Three decades of ciprofloxacin use then drove fluoroquinolone resistance (>70% in India by 2019), mainly via gyrA/parC mutations. Ceftriaxone resistance remains rare (<1%) but has been reported, via ESBL and AmpC β-lactamase-producing strains. Interestingly, many strains have reverted to susceptibility against the “old” drugs (amoxicillin, chloramphenicol, cotrimoxazole) simply because they fell out of use for long enough.

Carriers are treated with ampicillin or amoxicillin plus probenecid for 6 weeks.

Prophylaxis

Three lines of prevention: control of reservoir (early diagnosis and treatment of cases; disinfection of soiled clothes with 5% cresol/2% chlorine/steam; follow-up stool/urine culture at 3–4 and 12 months; carrier detection and treatment — ampicillin/amoxicillin plus probenecid, 4–6 g/day for 6 weeks, eliminating ~70% of carriage; cholecystectomy plus ampicillin is the most effective carrier-elimination approach at 80% cure); sanitation measures (protected/purified drinking water, hand hygiene, food hygiene, health education); and vaccination.

Vaccination gives short-term protection and is indicated for travellers to endemic areas, mela/yatra attendees, household contacts, high-risk groups (school children), and optionally for residents of endemic areas. Two vaccines are current: Vi capsular polysaccharide (Vi-CPS) — a single 25 μg dose IM/SC, protecting for 2 years with booster, only from age 2 (Vi is a T-independent antigen, poorly immunogenic below that age); Vi-rEPA conjugates Vi antigen to recombinant Pseudomonas aeruginosa exotoxin A, boosting immunogenicity enough to be usable below age 2. Typhoral (oral live-attenuated S. Typhi Ty21a, a Gal-E mutant that self-destructs after 4–5 divisions without causing disease) is given from age 6, as enteric-coated capsules on alternate days (days 1, 3, 5, 7, no antibiotics during this period), with revaccination every 5 years; protection starts 7 days after the last dose and lasts 4 years. The older parenteral heat-killed whole-cell TAB vaccine is no longer used due to significant side effects.

Non-Typhoidal Salmonellae (Bloodstream Aspect)

NTS mainly causes gastroenteritis (covered separately), but up to 8% of NTS gastroenteritis progresses to bacteremia, risking endovascular infection or metastatic seeding. Risk factors: specific invasive serotypes (S. Choleraesuis from pigs, S. Dublin from cattle), extremes of age, HIV/immunocompromise, and pre-existing valvular heart disease (which predisposes to NTS endocarditis/arteritis).

Long Essays (3)

Essays (7)

Short Essays (8)

Short Answers (1)

Short Notes (8)

Multiple Choice Questions (2)