Typhoid & Paratyphoid Fever

Infectious Agent

Salmonella enterica serotypes Typhi and Paratyphi A, Paratyphi B (tartrate negative), and Paratyphi C cause a potentially severe and occasionally life-threatening bacteremic illness referred to respectively as typhoid and paratyphoid fever, and collectively as enteric fever.

Transmission

Humans are the only source of these bacteria; no animal or environmental reservoirs have been identified. Typhoid and paratyphoid fever are most often acquired through consumption of water or food that has been contaminated by feces of an acutely infected or convalescent person or a chronic, asymptomatic carrier. Transmission through sexual contact, especially among men who have sex with men, has been documented rarely.

Epidemiology

An estimated 26 million cases of typhoid fever and 5 million cases of paratyphoid fever occur worldwide each year, causing 215,000 deaths. In the United States, approximately 300 culture-confirmed cases of typhoid fever and 80 cases of paratyphoid fever caused by S. enterica serotype Paratyphi A are reported each year. Cases of paratyphoid fever caused by serotypes Paratyphi B (tartrate negative) and Paratyphi C are rarely reported. Approximately 85% of typhoid fever and 90% of paratyphoid fever cases in the United States are among international travelers; of those, 75% of typhoid and 90% of paratyphoid fever cases are caused by serotype Paratyphi A acquired by travelers to southern Asia (such as India, Pakistan, or Bangladesh). Other high-risk regions for typhoid and paratyphoid fever include Africa and Southeast Asia; lower-risk regions include East Asia, South America, and the Caribbean.

Travelers who are visiting friends and relatives are at increased risk (see Chapter 8, Immigrants Returning Home to Visit Friends and Relatives [VFRs]). Although the risk of acquiring typhoid or paratyphoid fever increases with the duration of stay, travelers have acquired typhoid fever even during visits of <1 week to countries where the disease is highly endemic (such as India, Pakistan, or Bangladesh).

Clinical Presentation

The incubation period of typhoid and paratyphoid infections is 6–30 days. The onset of illness is insidious, with gradually increasing fatigue and a fever that increases daily from low-grade to as high as 102°F–104°F (38°C–40°C) by the third to fourth day of illness. Headache, malaise, and anorexia are nearly universal, and abdominal pain, diarrhea, or constipation are common. Hepatosplenomegaly can often be detected. A transient, macular rash of rose-colored spots can occasionally be seen on the trunk. Fever is commonly lowest in the morning, reaching a peak in late afternoon or evening. This clinical presentation is often confused with malaria, and typhoid fever should be suspected in a person with a history of travel to an endemic area who is not responding to antimalarial medication. Untreated, the disease can last for a month. The serious complications of typhoid fever generally occur after 2–3 weeks of illness and may include life-threatening intestinal hemorrhage or perforation.

Diagnosis

Infection with typhoid or paratyphoid fever results in a low-grade septicemia. Although blood culture is the mainstay of diagnosis in typhoid and paratyphoid fever, a single culture is positive in only approximately 50% of cases. Multiple cultures increase the sensitivity and may be required to make the diagnosis. Bone marrow culture increases the diagnostic yield to approximately 80% of cases and is relatively unaffected by prior or concurrent antibiotic use. Stool culture is not usually positive during the first week of illness, so blood culture is preferred. Urine culture has no higher diagnostic yield than stool culture for acute cases.

The Widal test is unreliable but is widely used in developing countries because of its low cost. It is a serologic assay that may react in patients with typhoid or paratyphoid fever, but is not specific and false positives may occur. Serologic assays are not an adequate substitute for blood, stool, or bone marrow culture.

Because there is no definitive serologic test for typhoid or paratyphoid fever, the initial diagnosis often has to be made clinically. The combination of a history of risk for infection and a gradual onset of fever that increases in severity over several days should raise suspicion of typhoid or paratyphoid fever. Typhoid fever is a nationally notifiable disease.

Treatment

Specific antimicrobial therapy shortens the clinical course of enteric fever and reduces the risk for death. Fluoroquinolones are recommended for empiric treatment of enteric fever in adults, but quinolone resistance is >80% for Typhi and Paratyphi A infections in travelers to South and Southeast Asia, which suggests that treatment failures will occur. Injectable third-generation cephalosporins are often the empiric drug of choice when the possibility of fluoroquinolone resistance is high. Azithromycin and ceftriaxone are increasingly used to treat typhoid fever or paratyphoid fever because of the emergence of multidrug-resistant strains, although increasing resistance to azithromycin in Typhi strains has been documented outside the United States. In contrast, no cases of ceftriaxone resistance have been reported among Typhi and Paratyphi A isolates tested by the CDC National Antimicrobial Monitoring System through 2013. Additional data on antimicrobial resistance among enteric fever cases in the United States can be found at www.cdc.gov/narmsnow.

Patients treated with an antibiotic may continue to have fever for 3–5 days, although the height of the fever generally decreases each day. Patients may actually feel worse during the several days it takes for the fever to end. If fever in a person with culture-confirmed typhoid or paratyphoid fever does not subside within 5 days, alternative antimicrobial agents or other foci of infection such as abscesses, bone or joint infections, and other extraintestinal sites should be considered.

Prevention

Food and Water

Safe food and water precautions and frequent handwashing (especially before meals) are important in preventing typhoid and paratyphoid fever (see Chapter 2, Food & Water Precautions). Although vaccines are recommended to prevent typhoid fever, they are not 100% effective; therefore, even vaccinated travelers should follow recommended food and water precautions. For paratyphoid fever, food and water precautions are the only prevention method, as no vaccines are available.

Vaccine

Indications for Use

CDC recommends typhoid vaccine for travelers to areas where there is an increased risk of exposure to S. enterica serotype Typhi. Destination-specific vaccine recommendations are available at the CDC Travelers’ Health website (www.cdc.gov/travel).

Two typhoid vaccines are available in the United States:

  • Vi capsular polysaccharide vaccine (ViCPS) (Typhim Vi, manufactured by Sanofi Pasteur) for intramuscular use
  • Oral live attenuated vaccine (Vivotif, manufactured from the Ty21a strain of serotypeTyphi by PaxVax)

Both typhoid vaccines protect 50%–80% of recipients; travelers should be reminded that typhoid immunization is not 100% effective, and typhoid fever could still occur. Available typhoid vaccines offer no protection against paratyphoid fever.

Vaccine Administration

Table 3-21 provides information on vaccine dosage, administration, and revaccination. The time required for primary vaccination differs for the 2 vaccines, as do the lower age limits.

Table 3-21. Vaccines to prevent typhoid fever
VaccinationAge (y)Dose, Mode of AdministrationNumber of DosesDosing IntervalBoosting Interval
Oral, Live Attenuated Ty21a Vaccine (Vivotif) 1
Primary series≥61 capsule, 2 oral448 hoursNot applicable
Booster≥61 capsule, 2 oral448 hoursEvery 5 years
Vi Capsular Polysaccharide Vaccine (Typhim Vi)
Primary series≥20.5 mL, intramuscular1Not applicableNot applicable
Booster≥20.5 mL, intramuscular1Not applicableEvery 2 years
1 The vaccine must be kept refrigerated (35.6°F–46.4°F, 2°C–8°C).
2 Administer with cool liquid no warmer than 98.6°F (37°C).

Primary vaccination with ViCPS consists of one 0.5 mL (25 mg) dose administered intramuscularly. One dose should be given ≥2 weeks before travel. The manufacturer does not recommend the vaccine for infants and for children <2 years old. A booster dose is recommended every 2 years for people who remain at risk.

Primary vaccination with oral Ty21a vaccine consists of 4 capsules, 1 taken every other day. The capsules should be kept refrigerated (not frozen), and all 4 doses must be taken to achieve maximum efficacy. Each capsule should be taken with cool liquid no warmer than 98.6°F (37°C), approximately 1 hour before a meal and ≥2 hours after a previous meal. This regimen should be completed ≥1 week before potential exposure. What to do when a dose of the oral vaccine is missed or taken late is unclear. Some suggest that minor deviations in the dosing schedule, such as taking a dose one day late, may not have a large effect on how well the vaccine works. However, we are unaware of any studies showing the effect of such deviations; thus, if 4 doses are not completed as directed, optimal immune response may not be achieved. The vaccine manufacturer recommends that Ty21a not be administered to infants or to children aged <6 years. A booster dose is recommended every 5 years for people who remain at risk.

Vaccine Safety and Adverse Reactions

Adverse reactions to Ty21a vaccine are rare and mainly consist of abdominal discomfort, nausea, vomiting, and rash. ViCPS vaccine is most often associated with headache (16%–20%) and injection-site reactions (7%). Adverse reactions should be reported to the Vaccine Adverse Event Reporting System by visiting https://vaers.hhs.gov/index or calling 1-800-822-7967.

Precautions and Contraindications

No information is available on the safety of these vaccines in pregnancy; it is prudent on theoretical grounds to avoid vaccinating pregnant women. However, the benefits of vaccinating pregnant women may outweigh potential risks when the likelihood of typhoid exposure is high; the inactivated vaccine (ViCPS) may be considered in these situations. Live attenuated Ty21a vaccine should not be given to pregnant women or immunocompromised travelers, including those infected with HIV. The intramuscular vaccine presents a theoretically safer alternative for immunocompromised travelers. (The Advisory Committee on Immunization Practices does not recommend against vaccinating household contacts of immunocompromised people with Ty21a; although vaccine organisms can be shed transiently in the stool of vaccine recipients, secondary transmission of vaccine organisms has not been documented.) The only contraindication to vaccination with ViCPS vaccine is a history of severe local or systemic reactions after a previous dose. Neither vaccine should be given to people with an acute febrile illness.

Theoretical concerns have been raised about the immunogenicity of live, attenuated Ty21a vaccine in people concurrently receiving antimicrobial agents (including antimalarial chemoprophylaxis), viral vaccines, or immune globulin. The growth of the live Ty21a strain is inhibited in vitro by various antibacterial agents, and vaccination with Ty21a should be delayed for >72 hours after the administration of any antibacterial agent. Available data do not suggest that simultaneous administration of oral polio or yellow fever vaccine decreases the immunogenicity of Ty21a. If typhoid vaccination is warranted, it should not be delayed because of administration of viral vaccines. Simultaneous administration of Ty21a and immune globulin does not appear to pose a problem.

CDC website: www.cdc.gov/typhoid-fever

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Authors

Michael C. Judd, Eric D. Mintz