Chapter 4 Travel-Related Infectious Diseases
Typhoid & Paratyphoid Fever
Grace D. Appiah, Michael J. Hughes, Kevin Chatham-Stephens
Please note: As of December 2020, the maker of the oral (pill) typhoid vaccine will temporarily stop making and selling this vaccine. The vaccine may be in limited supply or unavailable. If typhoid vaccine is recommended for your destination, talk to your doctor about getting the injectable (shot) vaccine instead.
Salmonella enterica serotypes Typhi and Paratyphi A, Paratyphi B, and Paratyphi C cause potentially severe and occasionally life-threatening bacteremic illnesses referred to respectively as typhoid and paratyphoid fever, and collectively as enteric fever. Paratyphi B is differentiated into 2 distinct pathotypes on the basis of their ability to ferment tartrate—one is unable to ferment tartrate and is associated with paratyphoid fever (referred to as Paratyphi B), and the other ferments tartrate and is associated with uncomplicated gastroenteritis (referred to as Paratyphi B var. L(+) tartrate+).
Humans are the only source of these bacteria; no animal or environmental reservoirs have been identified. Typhoid and paratyphoid fever are acquired through consumption of water or food contaminated by feces of an acutely infected or convalescent person or a chronic, asymptomatic carrier. Risk for infection is high in low- and middle-income countries with endemic disease and poor access to safe food, water, and sanitation. Transmission through sexual contact, especially among men who have sex with men, has been documented rarely.
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 during 2008–2015, approximately 350 culture-confirmed cases of typhoid fever and 90 cases of paratyphoid fever caused by Paratyphi A were reported each year. Cases of paratyphoid fever caused by Paratyphi B and Paratyphi C are rarely reported. Approximately 85% of typhoid fever and 92% of paratyphoid fever cases in the United States occur among international travelers; of those, 80% of typhoid and 91% of paratyphoid fever cases caused by Paratyphi A are acquired by travelers to southern Asia (primarily 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 visiting friends and relatives are at increased risk, as they may be less careful with food and water while abroad and may not seek pretravel health consultation or typhoid vaccination (see Chapter 9, Visiting Friends and Relatives: VFR Travel). Although the risk of illness with 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).
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. Fever is commonly lowest in the morning, peaking in the late afternoon or evening. Headache, malaise, and anorexia are nearly universal, and abdominal pain, diarrhea, or constipation are common. Vomiting and diarrhea are more common in children compared with adults. People can also have fatigue, myalgias, dry cough, and sore throat. Hepatosplenomegaly can often be detected. A transient, maculopapular rash of rose-colored spots can occasionally be seen on the trunk.
The 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, and reported case-fatality ratios are 10%–30%. In comparison, the case-fatality ratio in disease treated early is usually <1%. The serious complications of typhoid fever occur in 10%–15% of hospitalized patients, generally after 2–3 weeks of illness, and may include life-threatening gastrointestinal hemorrhage, intestinal perforation, and encephalopathy. Paratyphoid fever is usually described as less severe than typhoid fever; however, severe cases of Paratyphi A infection have been reported from Asia.
Patients with typhoid or paratyphoid fever have bacteremia. Blood culture is the mainstay of diagnosis in typhoid and paratyphoid fever; however, 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 previous or concurrent antibiotic use. Stool culture is not usually positive during the first week of illness, so blood culture is preferred. Urine culture has a lower 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 measures elevated antibody titers in patients with recent typhoid or paratyphoid fever but may not accurately distinguish acute from past infection and lacks specificity, resulting in false-positive results. Serologic assays are not an adequate substitute for blood, stool, or bone marrow culture.
Because there are no definitive rapid diagnostic tests for typhoid or paratyphoid fever, the initial diagnosis often has to be made clinically. Typhoid and paratyphoid fever are clinically indistinguishable. The combination of a risk factor for infection and gradual onset of fever that increases in severity over several days should raise suspicion of typhoid or paratyphoid fever. Typhoid and paratyphoid fever are nationally notifiable diseases.
Antibiotic therapy shortens the clinical course of enteric fever and reduces the risk for death. Fluoroquinolones (such as ciprofloxacin) are often used for empiric treatment of enteric fever in adults and are considered the treatment of choice for fluoroquinolone-susceptible infections. However, most infections in the United States are acquired during travel abroad, particularly to regions where enteric fever is endemic and fluoroquinolone nonsusceptibility among Typhi and Paratyphi A isolates is common. Fluoroquinolone-nonsusceptible infections are also usually resistant to the synthetic quinolone, nalidixic acid, and have been associated with treatment failure or delayed clinical response.
In the United States, ≥90% of Typhi and Paratyphi A infections in travelers to South Asia were found to be fluoroquinolone-nonsusceptible or nalidixic acid–resistant, which suggests that treatment failures may occur among patients treated empirically with fluoroquinolones. Increasingly, azithromycin and ceftriaxone are being used to treat enteric fever. Through 2015, there was only 1 azithromycin-resistant Typhi isolate and no ceftriaxone-resistant Typhi or Paratyphi A isolates among isolates tested by CDC’s National Antimicrobial Resistance Monitoring System. Additional data on antibiotic resistance among enteric fever cases in the United States can be found at www.cdc.gov/narmsnow. Emerging resistance to azithromycin and ceftriaxone among Typhi strains has been reported outside the United States.
Patients treated with an antibiotic may continue to have fever for 3–5 days, although the maximum temperature generally decreases each day. Patients may actually feel worse during the several days it takes for the fever to resolve. If fever in a person with a culture-confirmed typhoid or paratyphoid infection does not subside within 5 days, alternative antibiotics or persistent foci of infection such as an abscess, bone or joint infection, and other extraintestinal site of infection should be considered.
Relapse, reinfection, and chronic carriage can also occur. In up to 10% of patients, relapse occurs 1–3 weeks after clinical recovery, requiring additional antibiotic treatment. An estimated 1%–4% of treated patients become asymptomatic chronic carriers, excreting bacteria in stool for ≥12 months after acute infection and requiring a prolonged antibiotic course for eradication.
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, and vaccine-induced immunity can be overwhelmed by a large bacterial inoculum; 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.
INDICATIONS FOR USE
The Advisory Committee on Immunization Practices (ACIP) recommends typhoid vaccine for travelers to areas where there is a recognized risk for exposure to Typhi. Destination-specific vaccine recommendations are available at the CDC Travelers’ Health website (www.cdc.gov/travel).
Two unconjugated typhoid vaccines are licensed and 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 serotype Typhi by Emergent BioSolutions)
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. Neither licensed typhoid vaccine is indicated to prevent paratyphoid fever, although limited data from efficacy trials suggest that the live, oral typhoid Ty21a vaccine may provide some cross-protection against infection with Paratyphi B.
Newer, protein-conjugate Vi vaccines have been shown to have greater efficacy in children <2 years old and longer duration of protection than provided by Vi unconjugated polysaccharide vaccines. Two typhoid Vi conjugate vaccines (TCV) have been licensed in India (Typbar-TCV, manufactured by Bharat Biotech, and Peda Typh, manufactured by Biomed) for administration as a single 0.5-mL injection in children aged ≥6 months. Although neither vaccine is licensed or available in the United States currently, Tybar-TCV received WHO prequalification in 2018 and may be available in the future.
Table 4-22 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. 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 or 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 1 day late, may not have a large effect on how well the vaccine works. However, no studies have shown 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 the Ty21a vaccine 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
ViCPS vaccine is most often associated with headache (16%–20%) and injection-site reactions (7%). Adverse reactions to Ty21a vaccine are rare and mainly consist of abdominal discomfort, nausea, headache, fever, diarrhea, vomiting, and rash. Adverse reactions should be reported to the Vaccine Adverse Event Reporting System by visiting https://vaers.hhs.gov/index.html or calling 1-800-822-7967.
PRECAUTIONS AND CONTRAINDICATIONS
Neither the ViCPS nor the Ty21a vaccine should be given to those with an acute febrile illness; in addition, Ty21a is not recommended for use in people with acute gastroenteritis. No information is available on the safety of either vaccine 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. ACIP does not recommend against vaccinating household contacts of immunocompromised people with the Ty21a vaccine; 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.
Theoretical concerns have been raised about the immunogenicity of live, attenuated Ty21a vaccine in people concurrently receiving antimicrobial agents, live vaccines, or immune globulin. The growth of the live Ty21a strain is inhibited in vitro by various antibacterial agents. The manufacturer advises that vaccination with the Ty21a vaccine should be delayed for >72 hours after the administration of any antibacterial agent, and antibiotics should not be given to a patient within 72 hours of the last dose of the Ty21a vaccine.
Available data do not suggest that simultaneous administration of yellow fever vaccine decreases the immunogenicity of the Ty21a vaccine. If typhoid vaccination is warranted, it should not be delayed because of administration of viral vaccines. No data are available on coadministration of the Ty21a vaccine and the oral cholera vaccine (lyophilized CVD 103-HgR [Vaxchora]); taking the first Ty21a vaccine dose ≥8 hours after oral cholera vaccine may decrease potential interference between the vaccines. Simultaneous administration of the Ty21a vaccine and immune globulin does not appear to pose a problem.
CDC website: www.cdc.gov/typhoid-fever
Table 4-22. Vaccines to prevent typhoid fever
|AGE (y)||DOSE, MODE OF ADMINISTRA-
|NUMBER OF DOSES||DOSING INTERVAL||BOOSTING INTERVAL|
|Oral, Live, Attenuated Ty21a Vaccine (Vivotif)1|
|Primary series||≥6||1 capsule,2 oral||4||48 hours||Not applicable|
|Booster||≥6||1 capsule,2 oral||4||48 hours||Every 5 years|
|Vi Capsular Polysaccharide Vaccine (Typhim Vi)|
|Primary series||≥2||0.50 mL, intramuscular||1||Not applicable||Not applicable|
|Booster||≥2||0.50 mL, intramuscular||1||Not applicable||Every 2 years|
1The vaccine must be kept refrigerated (35.6°F–46.4°F, 2° C–8°C).
2Administer with cool liquid no warmer than 98.6°F (37°C).
- Buckle GC, Walker CL, Black RE. Typhoid fever and paratyphoid fever: systematic review to estimate global morbidity and mortality for 2010. J Glob Health. 2012 Jun;2(1):010401.
- Crump JA, Mintz ED. Global trends in typhoid and paratyphoid fever. Clin Infect Dis. 2010 Jan 15;50(2):241–6.
- Crump JA, Sjölund-Karlsson M, Gordon MA, Parry CM. Epidemiology, clinical presentation, laboratory diagnosis, antimicrobial resistance, and antimicrobial management of invasive Salmonella infections. Clin Microbiol Rev. 2015 Oct 1;28(4):90137.
- Date KA, Bentsi-Enchill A, Marks F, Fox K. Typhoid fever vaccination strategies. Vaccine. 2015 Jun 19;33:C55–61.
- Date KA, Newton AE, Medalla F, Blackstock A, Richardson L, McCullough A, et al. Changing patterns in enteric fever incidence and increasing antibiotic resistance of enteric fever isolates in the United States, 2008–2012. Clin Infect Dis. 2016 Aug 1;63(3):322–9.
- Effa EE, Bukirwa H. Azithromycin for treating uncomplicated typhoid and paratyphoid fever (enteric fever). Cochrane Database Syst Rev. 2008(4):CD006083.
- Gupta SK, Medalla F, Omondi MW, Whichard JM, Fields PI, Gerner-Smidt P, et al. Laboratory-based surveillance of paratyphoid fever in the United States: travel and antimicrobial resistance. Clin Infect Dis. 2008 Jun 1;46(11):1656–63.
- Jackson BR, Iqbal S, Mahon B. Updated recommendations for the use of typhoid vaccine—Advisory Committee on Immunization Practices, United States, 2015. MMWR Morb Mortal Wkly Rep. 2015 Mar;64(11):305–8.
- Klemm EJ, Shakoor S, Page AJ, Qamar FN, Judge K, Saeed DK, et al. Emergence of an extensively drug-resistant Salmonella enterica serovar Typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins. mBio. 2018 Mar 7;9(1):e00105–18.
- Lynch MF, Blanton EM, Bulens S, Polyak C, Vojdani J, Stevenson J, et al. Typhoid fever in the United States, 1999–2006. JAMA. 2009 Aug 26;302(8):859–65.