Describe the pathogenesis, clinical features, laboratory diagnosis and prevention of enteric fever.

The Organism

• Gram-negative bacilli, motile by peritrichous flagella, non-capsulated (except the Vi antigen), non-lactose fermenting
• Nomenclature — almost all human isolates belong to Salmonella enterica subspecies enterica, named by serotype: S. Typhi, S. Paratyphi A, B and C, S. Typhimurium, S. Enteritidis
• Antigenic structure and the kauffmann-white scheme — classifies over 2,500 serotypes by their O (somatic) and H (flagellar) antigens; S. Typhi additionally carries the Vi (capsular) antigen, which is antiphagocytic, masks the O antigen, and is the basis of both a vaccine and carrier detection
• Biochemical features — S. Typhi produces acid but NO gas from glucose (other salmonellae produce both), and produces only a trace of H2S, whereas other salmonellae produce it abundantly

Pathogenesis of Enteric Fever

Ingestion of a large inoculum in contaminated water or food; gastric acid is a barrier, so achlorhydria and antacids lower the infecting dose → The organism invades the ileal mucosa and PEYER patches → It multiplies within macrophages — an intracellular pathogen, which is why cell-mediated immunity matters and why intracellular antibiotics are needed → Spread to mesenteric lymph nodes and by the thoracic duct to blood — primary bacteraemia, which is asymptomatic → Seeding of liver, spleen, bone marrow and gallbladder, where further multiplication occurs during the incubation period of 7 to 14 days → secondary bacteraemia — and it is now that the illness begins → Organisms excreted in bile re-infect the Peyer patches, which undergo hyperplasia, necrosis and ulceration along the long axis of the ileum → Hence perforation and haemorrhage in the third week

Clinical Features and Complications

• Week 1 — step-ladder fever rising over days, headache, malaise, dry cough, constipation more often than diarrhoea in adults; relative bradycardia (Faget sign)
• Week 2 — sustained high fever, toxaemia, rose spots (sparse blanching pink macules on the trunk, difficult to see on pigmented skin), splenomegaly, abdominal distension, and apathy; leucopenia with an absent eosinophil count is characteristic
• Week 3 — the dangerous week: intestinal perforation and haemorrhage from the ulcerated terminal ileum; also myocarditis, encephalopathy ("typhoid state"), and shock
• Other complications — cholecystitis, osteomyelitis, arthritis, meningitis, nephritis, abortion; and relapse in up to 10%, usually milder
• Carriers — convalescent (up to 3 months) and chronic (over 1 year), in whom the organism persists in the gallbladder, particularly with gallstones; commoner in older women. "Typhoid Mary" is the historical example, and food handlers are the public health concern

Laboratory Diagnosis

• Interpreting the Widal test — O antibody is IgM and indicates recent or active infection; H antibody is IgG, persists for years and rises after vaccination, so a raised H titre alone means little. False positives occur in other infections and in autoimmune disease; false negatives occur early, after antibiotics, and in the immunosuppressed

Differential Diagnosis of Prolonged Fever in India

• Take blood cultures before antibiotics in any prolonged fever; a single prior dose is the commonest reason enteric fever is never confirmed, and it then becomes an untreatable diagnostic problem for weeks

Treatment, Prevention and Applied Aspects

• Ceftriaxone or azithromycin are now first-line in India; fluoroquinolone resistance is widespread, and nalidixic acid resistance predicts it. Chloramphenicol, ampicillin and co-trimoxazole retain activity against some strains, and multidrug-resistant and XDR strains are an increasing problem
• Fever settles slowly, over 3 to 5 days, and persistent fever is not by itself evidence of treatment failure — changing antibiotics prematurely is a common error
• Dexamethasone reduces mortality in severe typhoid with shock or altered consciousness
• Chronic carriers — prolonged ciprofloxacin or amoxicillin, and cholecystectomy where there are gallstones and treatment fails
• Prevention — safe water, sanitation, food hygiene, exclusion and treatment of carriers among food handlers; and vaccination with Vi polysaccharide, oral live Ty21a, or the newer Vi conjugate vaccine (TCV), which unlike plain polysaccharide works in infants and gives longer protection
• Enteric fever remains common in India and must be considered in any prolonged fever; blood cultures should be taken before antibiotics, which in practice is the commonest reason the diagnosis is never confirmed
• Watch for perforation in the third week — sudden abdominal pain with a falling temperature and rising pulse in a patient who was improving; it is a surgical emergency and easily attributed to the illness itself
• Do not treat non-typhoidal Salmonella gastroenteritis with antibiotics in an otherwise healthy patient; they prolong carriage without shortening the illness
• Screen and treat carriers among food handlers; a single chronic carrier can sustain an outbreak for years, and gallstones make eradication difficult
• The typhoid conjugate vaccine works in infants, unlike the plain Vi polysaccharide, and its introduction is a significant addition to control in endemic areas
• Bone marrow culture remains positive after antibiotics and is the most sensitive test; it is worth doing where the diagnosis matters and blood cultures were taken too late
• Interpret a single Widal titre against local baseline values, which differ between regions; many laboratories in India report against a fixed cut-off that has never been validated locally
• Relapse occurs in up to 10%, typically 1 to 3 weeks after treatment ends and usually milder; it is not necessarily evidence of resistance
• Vaccination does not remove the need for safe water; typhoid is a disease of sanitation, and the durable solution is environmental rather than immunological
• Extensively drug-resistant typhoid has emerged in the subcontinent, resistant to fluoroquinolones and third-generation cephalosporins, leaving azithromycin and carbapenems — a serious narrowing of options for a common disease
• Do not stop treatment when the fever settles; the full course is required to prevent relapse and to clear the organism from the gallbladder