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Typhoid Fever

By

Larry M. Bush

, MD, FACP, Charles E. Schmidt College of Medicine, Florida Atlantic University;


Maria T. Vazquez-Pertejo

, MD, FCAP, Wellington Regional Medical Center

Last full review/revision Feb 2020| Content last modified Feb 2020
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Typhoid 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, ciprofloxacin, or azithromycin.

In the US, typhoid is uncommon and occurs mainly among US travelers returning from endemic regions. Worldwide, about 21 million cases occur each year.

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 developed countries, 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 bedclothes.

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. Low gastric acidity, which is common among older people and among people who use acid-suppressing drugs, can markedly decrease the infective dose. Intestinal ulceration, hemorrhage, and perforation may occur in severe cases.

Salmonella 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 US are older women with chronic biliary disease. Obstructive uropathy related to schistosomiasis or nephrolithiasis may predispose certain typhoid patients to urinary carriage.

Epidemiologic data indicate that typhoid carriers are more likely than the general population to develop hepatobiliary cancer.

Symptoms and Signs

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 3rd week, and reaches normal levels during the 4th 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 about 10 to 20% of patients, discrete pink, blanching lesions (rose spots) appear in crops on the chest and abdomen during the 2nd 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 3rd week, with a mortality rate of about 25%. An acute abdomen and leukocytosis during the 3rd week may suggest intestinal perforation, which usually involves the distal ileum and occurs in 1 to 2% of patients.

Pneumonia may develop during the 2nd or 3rd 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 8 to 10% of untreated patients with typhoid fever, symptoms and signs similar to the initial clinical syndrome recur about 2 weeks after defervescence. For unclear reasons, antibiotic therapy during the initial illness increases the incidence of febrile relapse to 15 to 20%. 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 2nd relapse occurs.

Diagnosis

  • Cultures

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.

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 no longer recommended because it no longer reliably predicts susceptibility to ciprofloxacin. Blood cultures are usually positive only during the first 2 weeks of illness, but stool cultures are usually positive during the 3rd to 5th weeks. If these cultures are negative and typhoid fever is strongly suspected, culture from a bone marrow biopsy specimen 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; many nontyphoidal Salmonella strains cross-react, and liver cirrhosis causes false-positives.

Prognosis

Without antibiotics, the mortality rate is about 12%. With prompt therapy, the mortality rate is 1%. Most deaths occur in malnourished people, infants, and older people.

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.

Treatment

  • Ceftriaxone

  • Sometimes a fluoroquinolone or azithromycin

Antibiotic resistance is common and increasing, particularly in endemic areas, so susceptibility testing should guide drug selection.

In general, preferred antibiotics include

  • Ceftriaxone 1 g IM or IV every 12 hours (25 to 37.5 mg/kg in children) for 14 days

  • Various fluoroquinolones (eg, ciprofloxacin 500 mg orally 2 times a day for 10 to 14 days, levofloxacin 500 mg orally or IV once a day for 14 days, moxifloxacin 400 mg orally or IV once a day for 14 days)

Chloramphenicol 500 mg orally or IV every 6 hours is still widely used, but resistance is increasing.

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]) are high, so use of these drugs 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 (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 broader 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. The cure rate is about 80% with amoxicillin, TMP/SMX, or ciprofloxacin given for 4 to 6 weeks.

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.

Prevention

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 70% effective. It may also be considered for household or other close contacts of carriers.

The Ty21a 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 drug mefloquine. Because the vaccine contains living S. Typhi organisms, it is contraindicated in patients who are immunosuppressed. In the US, the Ty21a vaccine is not used in children < 6 years.

An alternative is the single-dose, IM Vi capsular polysaccharide vaccine, given ≥ 2 weeks before travel. This vaccine is 64 to 72% effective and is well-tolerated, but it is not used in children < 2 years. For people who remain at risk, a booster is required after 2 years.

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.

Drugs Mentioned In This Article

Drug Name Select Trade
No US brand name
CILOXAN, CIPRO
OZURDEX
IQUIX, LEVAQUIN, QUIXIN
ZITHROMAX
AVELOX
AMOXIL
ROCEPHIN
RAYOS
RIFADIN, RIMACTANE
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