Enteric (Typhoid) Fever

How to Cite This Chapter: Zaborowski P. Enteric (Typhoid) Fever. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.18.96.1. Accessed December 04, 2023.
Last Updated: December 18, 2021
Last Reviewed: December 18, 2021
Chapter Information

Definition, Etiology, PathogenesisTop

Systemic febrile and diarrheal disease caused by Salmonella Typhi.

1. Etiologic agent: S enterica subspecies enterica, serotype Typhi (S Typhi)—a cosmopolitan gram-negative bacillus of the family Enterobacteriaceae. Together with S enterica subspecies enterica, serotypes Paratyphi A, B, and C (S Paratyphi A, S Paratyphi B, S Paratyphi C), which cause paratyphoid fever, are called typhoidal Salmonella bacilli.

S Typhi is well adapted to low temperatures and resistant to drying out, and it can survive at the low pH of gastric acid. Factors reducing acidity in the stomach increase the probability of the bacteria penetrating distal segments of the gastrointestinal (GI) tract. S Typhi survives and replicates in mononuclear phagocytes. It can be destroyed by heat and standard disinfectants.

2. Pathogenesis: Having reached the GI tract, the S Typhi bacilli that survived in the gastric acid invade the mucosa, mainly in the ileum, through endocytosis and penetrate the epithelial cells of the intestine. The bacilli replicate in the submucosa and cause overgrowth of gut-associated lymphoid tissue (Peyer patches). Macrophages transfer S Typhi to regional lymph nodes (mesenteric and retroperitoneal), where it replicates. From regional lymph nodes the bacteria disseminate via the vascular and lymphatic systems to the reticuloendothelial system, and the infection spreads. Clinical manifestations develop when bacteria enter the bloodstream and spread to new replication sites. The bacilli reside in macrophages in the liver, spleen, and bone marrow, and grow there in the presence of iron. Bacteremia is most pronounced in the first week of the disease.

Typhoid toxin plays a key role in the pathogenesis of enteric fever. It is not a necessary factor to cause infection, but it modulates the host’s immune response. The toxin is made up of subunits A and B and resembles pertussis toxin. Systemic endotoxemia results in damage to the parenchymal organs, heart, bone marrow, central and peripheral (also vegetative) nervous system; small intestine endotoxemia causes hyperergic reactions in Peyer patches with subsequent necrosis and ulcerations, and bleeding or perforation of the intestinal wall at a later stage, after the necrotic tissue falls off. In week 4 of infection onset, the patient’s condition slowly normalizes and gut healing is observed.

3. Reservoir and transmission: The reservoir is humans: symptomatic individuals and carriers. The size of inoculum that bears infective potential depends on an individual’s defense mechanisms and is smaller in those with risk factors (immunosuppression, increased pH of gastric acid). Chronic carriage (>12 months) occurs in 1% to 5% of those with a history of enteric fever. Carriers may include individuals without a history of enteric fever and/or with biliary tract disease (eg, cholecystitis). Carriage in the urinary tract by persons with urinary tract diseases or schistosomiasis is also possible. The infective material is feces, rarely urine. The infection spreads through the oral route by:

1) Intake of contaminated water or food (water contaminated with sewage, food contaminated by a carrier preparing the meal).

2) Dirty hands, eg, following use of a contaminated toilet.

4. Risk factors for infection: Drinking unboiled water, poor hand and food hygiene, contact with a symptomatic individual or carrier, stay in overpopulated areas with poor sanitation. Risk factors for disease development and progression: Age, immune status, inoculum size, and genetic factors; for instance, TLR4 mutations increase the risk of developing enteric fever, whereas certain variants of HLA-DRB1 and CFTR protect against the disease, and the C282Y mutation associated with hemochromatosis prevents a severe course (because of low iron concentration in macrophages of homozygotes despite iron overload in the body). Use of agents neutralizing or inhibiting the secretion of hydrochloric acid (HCl) in the stomach and diseases causing gastric hypoacidity facilitate transmission of a larger number of pathogens to distal segments of the GI tract, which is one of the risk factors for severe infection.

5. Incubation and contagious period: ~2 weeks (1-4 weeks). The larger the inoculum size, the shorter the incubation period. Maximum duration of the contagious period in asymptomatic carriers has not been established.

Clinical Features and Natural HistoryTop

Clinical features vary depending on the infection stage. The first week after disease onset is dominated by fever, malaise, sleepiness, weakness, chills, abdominal pain; constipation occurs frequently. The bacteremia period (week 2) is characterized by progressive fever, nonproductive cough, relative bradycardia with decreased arterial pressure (intensified bradycardia accompanied by a decrease in blood pressure despite progressive fever is a prominent manifestation—visible as intersections of the temperature and pulse curves), worsening abdominal pain with borborygmi, worsening headache, confusion, and often faint, pink maculopapular rash on the trunk (abdomen and lower chest), hepatosplenomegaly (nonpainful), and jaundice. Diarrhea appears at the end of week 2 or at the beginning of week 3. Worsening of manifestations culminates in week 3 and is accompanied by altered mental status, agitation, transition from insomnia to hypersomnia, dehydration, and oliguria. Increased heart rate with low arterial pressure suggests complications (intestinal hemorrhage and/or perforation; cholangitis; phlebitis of lower extremities; pneumonia).

From week 4 the signs and symptoms slowly subside (including fever, with significant daily temperature fluctuations) and initial recovery is observed: improved wellbeing, increased appetite resulting in weight gain, decrease in spleen size, resolution of diarrhea.

Predictors of severe disease are GI bleeding, features of liver damage, encephalopathy, and cardiac involvement associated with advanced age and prolonged clinical manifestations.


Diagnostic Tests

1. Identification of the etiologic agent:

1) Culture: Blood culture (particularly in patients with fever) in the early days of clinical manifestations (collect 2-3 20-mL samples [can be obtained at the same time]) and stool and urine cultures in weeks 2 and 3 confirm the diagnosis. Blood should be drawn before the patient receives antibiotic treatment. Bone marrow is the best specimen for analysis (positive culture results are obtained in >90% of infected individuals, even after initiation of antibiotic therapy), but biopsy is an invasive procedure and is not routinely performed. Blood culture yields positive results in 50% to 70% of infected individuals, and stool culture, in 30% to 40%. Drug resistance (to fluoroquinolones, third-generation cephalosporins, ampicillin, azithromycin, cotrimoxazole) should also be evaluated on microbiologic examination.

2) Serologic studies can be useful from week 2, after specific antibodies have been produced. These studies are of limited value in endemic regions. The Widal agglutination test (low sensitivity, specificity, and positive predictive value [PPV]); high negative predictive value [NPV]) result is considered positive if the antibody titer against the O antigen is ≥1:200, and against the H antigen, ≥1:400. An increasing antibody titer is crucial for diagnosis. Chronic carriers often have high antibody titers against the Vi antigen, but clinical significance of this has not been clearly established.

2. Other tests:

1) Complete blood count (CBC): Anemia, leukocytosis, or leukopenia are often seen.

2) Increased hepatic enzyme activity and serum C-reactive protein (CRP) concentration.

Differential Diagnosis

At an early disease stage consider paratyphoid fevers, rickettsioses (epidemic typhus), miliary tuberculosis, brucellosis, tularemia, leptospirosis, herpesvirus infections (Epstein-Barr virus [EBV] infection, cytomegalovirus [CMV] infection), malaria, Q fever, leishmaniasis, melioidosis, dengue fever, sepsis, lymphomas, viral hepatitis.


Antibiotic Treatment

1. Infection contracted outside Asia:

1) First-line agents: Fluoroquinolones (ciprofloxacin: 400 mg IV or 500-750 mg orally every 12 h; IV levofloxacin 750 mg every 24 h; oral or IV ofloxacin 400 mg every 12 h) for 7 to 10 days.

2) Second-line agents: IV ceftriaxone 2 g every 24 hours for 7 to 14 days or oral azithromycin in a single dose of 1 g, then 500 mg every 24 hours for 5 to 7 days, or IV chloramphenicol (high risk of resistance) 500 mg every 6 hours for 14 days. In hospitalized patients consider combination therapy with ceftriaxone and azithromycin, aimed at decreasing the risk of developing resistance against azithromycin.

2. Infection contracted in Asia (particularly in India, Pakistan, and Iraq): Do not use fluoroquinolones (due to highly possible drug resistance). Treatment depends on disease severity:

1) Patients without complications: Oral azithromycin in a single dose of 1 g, then 500 mg every 24 hours for 5 to 7 days, or IV ceftriaxone 2 g every 12 to 24 hours for 10 to 14 days, or IV cefotaxime 1 to 2 g every 6 to 8 hours, or oral cefixime 200 mg every 12 hours for 10 to 14 days.

2) Patients with severe disease and complications: IV meropenem 1 to 2 g every 24 hours for 10 to 14 days (imipenem or ertapenem can be used instead—no optimal doses have been established); in the case of lack of improvement, consider adding a second antibiotic, eg, azithromycin.

Since 2016, cases of infection with multidrug-resistant S Typhi bacilli nonsusceptible to fluoroquinolones, ampicillin, third-generation cephalosporins, cotrimoxazole, and chloramphenicol have been observed in Pakistan.

3. Chronic carriers: After susceptibility evaluation: oral ciprofloxacin 500 to 750 mg every 12 hours (90%-93% efficacy) or oral ofloxacin or norfloxacin 400 mg every 12 hours for 4 weeks (lower efficacy in those with cholecystitis); in the case of nonsusceptibility to fluoroquinolones: amoxicillin 75 to 100 mg/kg/d for 4 to 6 weeks or sulfamethoxazole/trimethoprim with or without rifampicin (limited data on efficacy; 10%-80% of strains are resistant).

Symptomatic Treatment

As in infectious diarrhea (see Acute Infectious Diarrhea: General Considerations). In patients with severe disease and complications (altered mental status, shock), limited evidence suggests using additionally IV dexamethasone 3 mg/kg right before antibiotic administration followed by 1 mg/kg every 6 hours for 48 hours.


Ileal perforation, bacteremia caused by bacteria from the GI tract (translocated through microscopic and macroscopic pores of the intestinal mucosa), gallbladder cancer in carriers.


Specific Prevention

Immunoprophylaxis: see Vaccines: Enteric (Typhoid) Fever. Consider vaccination before visiting regions with a high incidence of enteric fever.

Nonspecific Prevention

1. Institutional control over the main sources of infection: Water source protection, sewage and waste management, identification of carriers (they should not be allowed to prepare food), regulations regarding work in food and drink industry and gastronomy.

2. Personal protective measures: Maintaining personal and surrounding hygiene, consuming water and food (including milk) from safe sources, eradicating flies. Medical personnel taking care of infected individuals should take contact isolation precautions.

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