Typhoid fever (enteric fever) is a systemic disease caused by the gram-negative bacterium Salmonella enterica serotype Typhi (S. Typhi). Symptoms are high fever, prostration, abdominal pain, and a rose-colored rash. Diagnosis is clinical and confirmed by culture. Treatment is with ceftriaxone, a fluoroquinolone, or azithromycin.
(See also Overview of Salmonella Infections.)
In the United States, typhoid is uncommon and occurs mainly among travelers returning from endemic regions. Worldwide, in 2019, an estimated 9.2 million typhoid fever cases and 110,000 deaths occurred, with the highest estimated incidence in regions in Southeast Asia, the Eastern Mediterranean, and Africa (1).
Transmission
Humans are the only natural host and reservoir. Typhoid bacilli are shed in stool of asymptomatic carriers or in stool or urine of people with active disease. The infection is transmitted by ingestion of food or water contaminated with feces. Inadequate hygiene after defecation may spread S. Typhi to community food or water supplies. In endemic areas where sanitary measures are generally inadequate, S. Typhi is transmitted more frequently by water than by food. In areas where sanitary measures are generally adequate, transmission is chiefly by food that has been contaminated during preparation by healthy carriers. Flies may spread the organism from feces to food.
Occasional transmission by direct contact (fecal-oral route) may occur in children during play and in adults during sexual practices. Rarely, hospital personnel who have not taken adequate enteric precautions have acquired the disease when changing soiled sheets and blankets.
The organism enters the body via the gastrointestinal tract and gains access to the bloodstream via the lymphatic channels. Ingestion of large numbers of S. Typhi is necessary to overcome gastric acidity. Loss of gastric acidity, which is common among older adults and among people who use acid-suppressing medications, can markedly decrease the infective dose. Antibiotics disrupt the normal protective effect of gut microbial flora and increase the risk of infection. Intestinal ulceration, hemorrhage, and perforation may occur in severe cases.
SalmonellaSalmonella carrier state
About 3% of untreated patients, referred to as chronic enteric carriers, harbor organisms in their gallbladder and shed them in stool for > 1 year. Some carriers have no history of clinical illness. Most of the estimated 2000 carriers in the United States are older women with chronic biliary disease. Obstructive uropathy related to schistosomiasis or nephrolithiasis may predispose certain patients with typhoid to urinary carriage.
Epidemiologic data indicate that typhoid carriers are more likely than the general population to develop hepatobiliary cancer (2).
General references
1. Hancuh M, Walldorf J, Minta AA, et al. Typhoid Fever Surveillance, Incidence Estimates, and Progress Toward Typhoid Conjugate Vaccine Introduction—Worldwide, 2018–2022. MMWR Morb Mortal Wkly Rep. 2023;72:171–176. Published 2023 Feb 17. doi:10.15585/mmwr.mm7207a2
2. Nagaraja V, Eslick GD. Systematic review with meta-analysis: the relationship between chronic Salmonella typhi carrier status and gall-bladder cancer. Aliment Pharmacol Ther. 2014;39(8):745-750. doi:10.1111/apt.12655
Symptoms and Signs of Typhoid Fever
For typhoid fever, the incubation period (usually 8 to 14 days) is inversely related to the number of organisms ingested. Onset is usually gradual, with fever, headache, arthralgia, pharyngitis, constipation, anorexia, and abdominal pain and tenderness. Less common symptoms include dysuria, nonproductive cough, and epistaxis.
Without treatment, the temperature rises in steps over 2 to 3 days, remains elevated (usually 39.4 to 40° C) for another 10 to 14 days, begins to fall gradually at the end of the third week, and reaches normal levels during the fourth week. Prolonged fever is often accompanied by relative bradycardia and prostration. Central nervous system symptoms such as delirium, stupor, or coma occur in severe cases. In uncomplicated cases, 5 to 30% of patients may have discrete, pink, blanching lesions (rose spots) in crops on the chest and abdomen during the second week and resolve in 2 to 5 days.
Splenomegaly, leukopenia, anemia, liver function abnormalities, proteinuria, and a mild consumption coagulopathy are common. Acute cholecystitis and hepatitis may occur.
Late in the disease, when intestinal lesions are most prominent, florid diarrhea may occur, and the stool may contain blood (occult in 20% of patients, gross in 10%). In about 2% of patients, severe bleeding occurs during the third week, with a high case fatality rate (1). An acute abdomen and leukocytosis during the third week may suggest intestinal perforation, which usually involves the distal ileum and occurs in 1 to 2% of patients.
Pneumonia may develop during the second or third week and may be due to secondary pneumococcal infection, although S. Typhi itself can also cause pneumonia. Bacteremia occasionally leads to focal infections such as osteomyelitis, endocarditis, meningitis, soft-tissue abscesses, glomerulitis, or genitourinary tract involvement.
Atypical presentations of typhoid fever, such as pneumonitis, fever only, or, very rarely, symptoms consistent with urinary tract infection, may delay diagnosis.
Convalescence may last several months.
In up to 10% of untreated patients with typhoid fever, symptoms and signs similar to the initial clinical syndrome recur about 2 weeks after defervescence (1). For unclear reasons, antibiotic therapy during the initial illness often increases the incidence of febrile relapse. If antibiotics are restarted at the time of relapse, the fever abates rapidly, unlike the slow defervescence that occurs during the primary illness. Occasionally, a second relapse occurs.
Symptoms and signs reference
1. Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Engl J Med. 2002;347(22):1770-1782. doi:10.1056/NEJMra020201
Diagnosis of Typhoid Fever
Cultures
Typhoid fever should be considered in patients with fever in or those returning from endemic areas, particularly if fever has lasted more than 3 days or there is diarrhea, abdominal pain, or constipation.
Cultures of blood, stool, and urine should be obtained. Because drug resistance is common, standard susceptibility testing is essential. The nalidixic acid susceptibility screening test is not recommended because it does not reliably predict susceptibility to ciprofloxacin. Blood cultures are usually positive only during the first 2 weeks of illness and are not highly sensitive, but stool cultures are usually positive during the third to fifth weeks. If these cultures are negative and typhoid fever is strongly suspected, culture from a bone marrow biopsy specimen (which is highly sensitive) may reveal the organism.
Typhoid bacilli contain antigens O and H that stimulate the host to form corresponding antibodies. A 4-fold rise in O and H antibody titers in paired specimens obtained 2 weeks apart suggests S. Typhi infection (Widal test). However, this test is only moderately (70%) sensitive and lacks specificity (1); many nontyphoidal Salmonella strains cross-react, and liver cirrhosis causes false-positives.
Other infections causing a similar presentation to that of typhoid fever include other Salmonella infections, the major rickettsioses, leptospirosis, disseminated tuberculosis, malaria, brucellosis, tularemia, infectious hepatitis, psittacosis, Yersinia enterocolitica infection, and lymphoma.
Diagnosis reference
1. Mengist HM, Tilahun K. Diagnostic value of widal test in the diagnosis of typhoid fever: a systematic review. J Med Microbiol Diagn. 2017;6:248. doi: 10.4172/2161-0703.1000248
Treatment of Typhoid Fever
Ceftriaxone
Sometimes a fluoroquinolone or azithromycin
Antibiotic resistance is common and increasing, particularly in endemic areas, so susceptibility testing should guide antibiotic selection.
In general, preferred antibiotics include
Ceftriaxone for 14 days
Fluoroquinolones for 7 to 10 days
Fluoroquinolones may be used in children, but caution is required. For fluoroquinolone-resistant strains, azithromycin 1 g orally on day 1, then 500 mg once a day for 6 days can be tried. Resistance rates to alternative therapies (eg, amoxicillin, trimethoprim/sulfamethoxazole [TMP/SMX], chloramphenicol) are high, so use of these antibiotics depends on in vitro sensitivity.
Corticosteroids may be added to antibiotics to treat severe toxicity. Defervescence and clinical improvement usually follow. Prednisone 20 to 40 mg orally once a day (or equivalent) for the first 3 days of treatment usually suffices. Higher doses of corticosteroids (eg, dexamethasone 3 mg/kg IV initially, followed by 1 mg/kg IV every 6 hours for 48 hours total) are used in patients with marked delirium, coma, or shock.
Nutrition should be maintained with frequent feedings. While febrile, patients are usually kept on bed rest. Salicylates (which may cause hypothermia and hypotension), as well as laxatives and enemas, should be avoided. Diarrhea may be minimized with a clear liquid diet; parenteral nutrition may be needed temporarily. Fluid and electrolyte therapy and blood replacement may be needed.
Intestinal perforation and associated peritonitis call for surgical intervention and broad gram-negative and anti–Bacteroides fragilis coverage.
Relapses are treated the same as the initial illness, although duration of antibiotic therapy seldom needs to be > 5 days.
Patients must be reported to the local health department and prohibited from handling food until proven free of the organism. Typhoid bacilli may be isolated for as long as 3 to 12 months after the acute illness in people who do not become carriers. Thereafter, 3 stool cultures at monthly intervals must be negative to exclude a carrier state.
Carriers
Carriers with normal biliary tracts should be given antibiotics based on susceptibility testing. The cure rate is high (eg, 80 to 90%) with ciprofloxacin given for 4 to 6 weeks. Alternative antibiotics include amoxicillin and TMP/SMX; however, eradication rates with these antibiotics may be lower (1).
In some carriers with gallbladder disease, eradication has been achieved with TMP/SMX and rifampin. In other cases, cholecystectomy with 1 to 2 days of preoperative antibiotics and 2 to 3 days of postoperative antibiotics is effective. However, cholecystectomy does not ensure elimination of the carrier state, probably because of residual foci of infection elsewhere in the hepatobiliary tree.
Treatment reference
1. McCann N, Scott P, Parry CM, Brown M. Antimicrobial agents for the treatment of enteric fever chronic carriage: A systematic review. PLoS One. 2022;17(7):e0272043. Published 2022 Jul 29. doi:10.1371/journal.pone.0272043
Prognosis for Typhoid Fever
Without antibiotics, the case fatality rate is about 10 to 15%. With prompt therapy, the case fatality rate is 1% (1). Most deaths occur in people who are undernourished, infants, and older adults.
Stupor, coma, or shock reflects severe disease and a poor prognosis.
Complications occur mainly in patients who are untreated or in whom treatment is delayed.
Prognosis reference
1. Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ. 2004;82(5):346-353.
Prevention of Typhoid Fever
Drinking water should be purified, and sewage should be disposed of effectively.
Chronic carriers should avoid handling food and should not provide care for patients or young children until they are proved free of the organism; adequate patient isolation precautions should be implemented. Special attention to enteric precautions is important.
Travelers in endemic areas should avoid ingesting raw leafy vegetables, other foods stored or served at room temperature, and untreated water (including ice cubes). Unless water is known to be safe, it should be boiled or chlorinated before drinking.
Vaccination
A live-attenuated oral typhoid vaccine is available (Ty21a strain); it is used for travelers to endemic regions and is about 40 to 80% effective (1). It may also be considered for household or other close contacts of carriers.
The Ty21a typhoid vaccine is given orally every other day for a total of 4 doses, which should be completed ≥ 1 week before travel. A booster is required after 5 years for people who remain at risk. The vaccine should be delayed for > 72 hours after patients have taken any antibiotic and should not be used with the antimalarial mefloquine. Because the vaccine contains living S. Typhi organisms, it is contraindicated in patients who are immunosuppressed. In the United States, the Ty21a vaccine is not used in children < 6 years.
An alternative is the single-dose, IM Vi capsular polysaccharide typhoid vaccine (ViCPS), given ≥ 2 weeks before travel. This vaccine is 50 to 80% effective and is well-tolerated (1), but it is not used in children < 2 years. For people who remain at risk, a booster is required after 2 years.
Prevention reference
1. Jackson BR, Iqbal S, Mahon B; Centers for Disease Control and Prevention (CDC). Updated recommendations for the use of typhoid vaccine--Advisory Committee on Immunization Practices, United States, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(11):305-308.
Key Points
Typhoid fever is spread enterically and causes fever and other constitutional symptoms (eg, headache, arthralgia, anorexia, abdominal pain and tenderness); later in the disease, some patients develop severe, sometimes bloody diarrhea and/or a characteristic rash (rose spots).
Bacteremia occasionally causes focal infections (eg, pneumonia, osteomyelitis, endocarditis, meningitis, soft-tissue abscesses, glomerulitis).
A chronic carrier state develops in about 3% of untreated patients; they harbor organisms in their gallbladder and shed them in stool for > 1 year.
Diagnose using blood and stool cultures; because drug resistance is common, susceptibility testing is essential.
Treat with ceftriaxone, a fluoroquinolone, or azithromycin, guided by susceptibility testing; corticosteroids may be given to decrease severe symptoms.
Give carriers a prolonged course of antibiotics; sometimes cholecystectomy is necessary.
Patients must be reported to the local health department and prohibited from handling food until they are proved free of the organism.
Vaccination may be appropriate for certain travelers to endemic regions.
