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Typhoid Fever

by Larry M. Bush, MD, Maria T. Perez, MD

Typhoid fever is a systemic disease caused by Salmonella serotype Typhi (see Overview of Salmonella Infections). Symptoms are high fever, prostration, abdominal pain, and a rose-colored rash. Diagnosis is clinical and confirmed by culture. Treatment is with ceftriaxone or ciprofloxacin.

Epidemiology

About 400 to 500 cases of typhoid fever are reported annually in the US, mainly among US travelers returning from endemic regions. Typhoid bacilli are shed in stool of asymptomatic carriers or in stool or urine of people with active disease. 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 GI tract and gains access to the bloodstream via the lymphatic channels. Intestinal ulceration, hemorrhage, and perforation may occur in severe cases.

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 yr. Some carriers have no history of clinical illness. Most of the estimated 2000 carriers in the US are elderly 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

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 wk, and reaches normal levels during the 4th wk. Prolonged fever is often accompanied by relative bradycardia and prostration. CNS 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 wk 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 wk, with a mortality rate of about 25%. An acute abdomen and leukocytosis during the 3rd wk 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 wk and may be due to secondary pneumococcal infection, although S. Typhi can also cause pulmonary infiltrates. Bacteremia occasionally leads to focal infections such as osteomyelitis, endocarditis, meningitis, soft-tissue abscesses, glomerulitis, or GU tract involvement. Atypical presentations, such as pneumonitis, fever only, or, very rarely, symptoms consistent with UTI, may delay diagnosis. Convalescence may last several months.

In 8 to 10% of untreated patients, symptoms and signs similar to the initial clinical syndrome recur about 2 wk 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 include other Salmonella infections, the major rickettsioses, leptospirosis, disseminated TB, 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. Blood cultures are usually positive only during the first 2 wk of illness, but stool cultures are usually positive during the 3rd to 5th wk. 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 wk apart suggests S. Typhi infection. 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 the elderly. 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 q 12 h (25 to 37.5 mg/kg in children) for 14 days and various fluoroquinolones (eg, ciprofloxacin 500 mg po bid for 10 to 14 days, levofloxacin 500 mg po or IV once/day for 14 days, moxifloxacin 400 mg po or IV once/day for 14 days). Chloramphenicol 500 mg po or IV q 6 h is still widely used, but resistance is increasing. Fluoroquinolones may be used in children, but caution is required. Alternative therapies, depending on in vitro sensitivity, include amoxicillin 25 mg/kg po qid, trimethoprim/sulfamethoxazole (TMP/SMX) 320/1600 bid or 10 mg/kg (of the TMP component) bid, and azithromycin 1 g po on day 1, then 500 mg once/day for 6 days.

Corticosteroids may be added to antibiotics to treat severe toxicity. Defervescence and clinical improvement usually follow. Prednisone 20 to 40 mg once/day po (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 q 6 h for 48 h 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 to12 mo 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 wk.

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, sewage should be disposed of effectively, and milk should be pasteurized. Chronic carriers should avoid handling food and should not provide care for patients or young children; 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. Unless water is known to be safe, it should be boiled or chlorinated before drinking.

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. It is given every other day for a total of 4 doses, which should be completed ≥ 1 wk before travel. The vaccine should be delayed for > 72 h 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 yr. An alternative is the single-dose, IM VI polysaccharide vaccine, which is 64 to 72% effective and is well-tolerated, but it is not used in children < 2 yr.

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, 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 yr.

  • 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.

  • Vaccination may be appropriate for certain travelers to endemic regions.

Resources In This Article

Drugs Mentioned In This Article

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

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