Author(s): Michael Hughes, Grace Appiah, Louise Francois Watkins

Typhoid Fever

Paratyphoid Fever

Infectious Agent

Salmonella enterica serotypes Typhi, Paratyphi A, Paratyphi B, and Paratyphi C cause potentially severe and occasionally life-threatening bacteremic illnesses referred to as typhoid fever (for Typhi serotype) and paratyphoid fever (for Paratyphi serotypes), and collectively as enteric fever. Paratyphi B strains are differentiated into 2 distinct pathotypes on the basis of their ability to ferment tartrate: the first pathotype, Paratyphi B, is unable to ferment tartrate and is associated with paratyphoid fever; the second pathotype, Paratyphi B var. L(+) tartrate(+), ferments tartrate and is associated with gastroenteritis typical of nontyphoidal salmonellosis. For more details on nontyphoidal salmonellosis, see the Sec. 5, Part 1, Ch. 19, Nontyphoidal Salmonellosis.

Transmission

Humans are the only source of the bacteria that cause enteric fever; 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 person with chronic, asymptomatic carriage. Risk for infection is high in low- and middle-income countries with endemic disease and poor access to safe food and water, and poor sanitation. Sexual contact, particularly among men who have sex with men, has been documented as a rare route of transmission.

Epidemiology

An estimated 11–21 million cases of typhoid fever and 5 million cases of paratyphoid fever occur worldwide each year, causing an estimated 135,000–230,000 deaths. In the United States during 2016–2018, ≈400 culture-confirmed cases of typhoid fever and 50–100 cases of paratyphoid fever caused by Paratyphi A were reported each year; paratyphoid fever caused by Paratyphi B and Paratyphi C is rarely reported. Approximately 85% of typhoid fever and 92% of paratyphoid fever cases in the United States occur among international travelers; most are in travelers returning from South Asia, primarily Bangladesh, India, and Pakistan. Other high-risk regions for infection include Africa, Latin America, and Southeast Asia; lower-risk regions include East Asia and the Caribbean.

Travelers visiting friends and relatives are at increased risk because they might be less careful with food and water while abroad than other travelers and might not seek pretravel health consultation or typhoid vaccination (see Sec. 9, Ch. 9, Visiting Friends & Relatives: VFR Travel). Although the risk of acquiring illness 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 (e.g., Bangladesh, India, Pakistan).

Clinical Presentation

The incubation period of both 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 102°F–104°F (38°C–40°C) by the third or fourth day of illness. Fever is commonly lowest in the morning, peaking in the late afternoon or evening. Anorexia, headache, and malaise are nearly universal, and abdominal pain, constipation, or diarrhea are common. Diarrhea and vomiting are more common in children than in adults. People also can have dry cough, fatigue, myalgias, and sore throat. Hepatosplenomegaly often can 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. Suspect enteric fever 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%. By comparison, the case-fatality ratio in patients treated early is usually <1%. Serious complications of typhoid fever occur in 10%–15% of hospitalized patients, generally after 2–3 weeks of illness, and include life-threatening gastrointestinal hemorrhage, intestinal perforation, and encephalopathy. Paratyphoid fever appears to have a lower case-fatality ratio than typhoid fever; however, severe cases do occur.

Diagnosis

Typhoid and paratyphoid fever are nationally notifiable diseases in the United States. Clinicians should report cases to their state or local health department. Identification of a domestically acquired case should prompt a public health investigation to prevent other cases.

Blood Culture

Patients with typhoid or paratyphoid fever typically have bacteremia; blood culture is therefore the preferred method of diagnosis. A single culture is positive in only ≈50% of cases, however. Multiple blood cultures increase the sensitivity and might be required to make the diagnosis. Depending on the blood culture system used, cultures might need to be held and observed for up to 7 days before reporting a negative result. Although bone marrow culture is more invasive (and therefore less commonly performed), it increases the sensitivity to ≈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 and has less diagnostic sensitivity than blood culture. Urine culture has a lower diagnostic yield than stool culture.

Rapid Diagnostic Tests

Globally, several commercial rapid diagnostic tests for typhoid fever are available, but their sensitivity and specificity are not optimal. The Widal test measures elevated antibody titers; it is unreliable but widely used in developing countries because of its low cost. Serologic tests do not distinguish acute from past infection or vaccination and lack specificity; thus, blood culture remains the preferred method to diagnose acute infections.

Clinical Diagnosis

Poor sensitivity and specificity of rapid antibody tests and the time it takes to obtain a positive culture mean that the initial diagnosis must often be made clinically. Typhoid and paratyphoid fever are clinically indistinguishable. The combination of risk factors for infection and gradual onset of fever that increases in severity over several days should raise suspicion of enteric fever.

Treatment

Antibiotic therapy shortens the clinical course of enteric fever and reduces the risk for death. Treatment decisions are complicated by high rates of resistance to many antimicrobial agents, and antimicrobial treatment should be guided by susceptibility testing. A careful travel history can inform empiric treatment choices while awaiting culture results.

Multidrug-Resistant Infection

Established resistance to older antibiotics (e.g., ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole) has led to these agents being recommended only as alternative antibiotics for infections with known susceptibility. Multidrug-resistant (MDR) Typhi with resistance to all 3 of these antibiotics has been present for decades. Regional estimates for MDR Typhi range from 9% in South Asia (2015–2018) to 35%–59% in parts of Africa (2010–2014).

Fluoroquinolones (e.g., ciprofloxacin) are still considered the treatment of choice for fluoroquinolone-susceptible infections in adults. Most Typhi and Paratyphi A infections in the United States are fluoroquinolone-nonsusceptible, however, and most (>90%) have occurred among travelers returning from South Asia. Fluoroquinolone-nonsusceptible infections have been associated with treatment failure or delayed clinical response. Therefore, azithromycin and ceftriaxone, antibiotics with historically low rates of resistance globally, are increasingly being used as empiric treatment for enteric fever.

Extensively Drug-Resistant Infection

In 2017, among all Typhi and Paratyphi A isolates tested by CDC’s National Antimicrobial Resistance Monitoring System (NARMS), <1% were resistant to azithromycin or to ceftriaxone, based on resistance criteria for Typhi. Resistance to both agents is emerging, however. In 2016, an outbreak of extensively drug-resistant (XDR) typhoid fever began in Sindh Province, Pakistan. These XDR Salmonella Typhi isolates are typically resistant to ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole, but susceptible to azithromycin and carbapenem antibiotics.

The first US cases of XDR typhoid fever associated with travel to Pakistan were diagnosed in 2018, and by early 2021 >70 XDR infections had been documented among residents of the United States, including 9 cases among patients who did not travel internationally in the 30 days before illness began. Ceftriaxone resistance also has been identified in Typhi isolates from US travelers returning from Iraq. Additionally, resistance to azithromycin has been identified among Typhi and Paratyphi strains isolated from patients in Bangladesh, Cambodia, India, Nepal, Pakistan, Saudi Arabia, and the United States.

Empiric treatment should be guided by the patient’s travel history. For patients with suspected typhoid fever who traveled to Iraq or Pakistan, or who did not travel internationally before their illness began, empirically treat uncomplicated illness with azithromycin, and treat complicated illness with a carbapenem. Ceftriaxone remains an appropriate empiric treatment option for travelers returning from most other countries. Once culture results are available, use susceptibility information to guide treatment. Case reports have suggested that patients with XDR Typhi infection who do not improve on a carbapenem alone might benefit from the addition of a second antibiotic (e.g., azithromycin). Updated information about antimicrobial resistance among isolates from US patients with enteric fever in the United States can be found at the NARMS website.

Cases Unresponsive to Treatment

Patients treated with antimicrobial agents can continue to have fever for 3–5 days, but the maximum temperature generally decreases each day. Patients sometimes feel worse during the first few days after commencing antibiotic treatment. If fever in a person with typhoid or paratyphoid infection does not subside within 5 days of initiating antibiotic therapy, however, consider treatment with alternative antibiotics or begin looking for a persistent focus of infection (e.g., an abscess, or an infection in a bone, joint, or other extraintestinal site).

Relapse, Reinfection & Chronic Carriage

Relapse, reinfection, and chronic carriage also can occur. Relapse occurs in ≤10% of patients 1–3 weeks after clinical recovery, requiring further antibiotic treatment. An estimated 1%–4% of treated patients become asymptomatic chronic carriers (defined as people who excrete the organism in stool for ≥12 months); a prolonged antibiotic course is usually required to eradicate the organism.

Prevention

Food & Water Precautions

Safe food and water precautions and frequent handwashing, especially before meals, are important in preventing both typhoid and paratyphoid fever (see Sec. 2, Ch. 8, Food & Water Precautions). Although recommended by the Advisory Committee on Immunization Practices (ACIP), typhoid vaccines are not 100% effective, and a large bacterial inoculum can overwhelm vaccine-induced immunity. Therefore, vaccinated travelers should follow recommended food and water precautions to prevent enteric fever and other infections. No vaccines are available for paratyphoid fever; thus, food and water precautions are the only prevention methods.

Vaccines

Indications

The ACIP recommends typhoid vaccine for travelers going to areas where risk for exposure to Typhi is recognized. Destination-specific vaccine recommendations are available at the CDC Travelers’ Health website. Two typhoid vaccines are licensed for use in the United States: Vi capsular polysaccharide vaccine (ViCPS) (Typhim Vi, manufactured by Sanofi Pasteur) for intramuscular use; and live attenuated vaccine (Vivotif, manufactured from the Ty21a strain of serotype Typhi by PaxVax) for oral use. Both vaccines are unconjugated, which means the polysaccharide antigens are not paired with a protein to elicit a strong response from the immune system. Because these vaccines protect 50%–80% of recipients, remind travelers that typhoid immunization is not 100% effective, and take the opportunity to reinforce safe food and water precautions. Neither vaccine is licensed to prevent paratyphoid fever, although limited data from efficacy trials suggest that the Ty21a vaccine might provide some cross-protection against Paratyphi B.

Newer, protein conjugated Vi vaccines have greater efficacy in children <2 years old and protect people for longer than Vi unconjugated polysaccharide vaccines. Three typhoid Vi conjugate vaccines (TCV) have been licensed in India: Peda Typh (manufactured by Biomed); Typbar-TCV (manufactured by Bharat Biotech); and Zyvac TCV (manufactured by Zydus Cadila). Typbar-TCV also is licensed in Cambodia, Nepal, and Nigeria. Although none of these vaccines are licensed or available in the United States, Tybar-TCV received prequalification from the World Health Organization in 2018. The vaccine is approved for use in people ≥6 months old. In a human challenge study, Typbar-TCV had ≈87% protective efficacy. Interim analysis from a large field study in Nepal has shown Typbar-TCV effectiveness of 81.6% in children after 15 months of follow-up.

Administration

For information on dosage, administration, and revaccination for the 2 typhoid vaccines licensed in the United States, see Table 5-07. The time required for primary vaccination differs, as do the lower age limits for each.

VI Capsular Polysaccharide Vaccine

Primary vaccination with ViCPS consists of one 0.5-mL (25-μg) dose administered intramuscularly ≥2 weeks before travel. The vaccine is approved for use in people ≥2 years old. A dose is recommended every 2 years for those who remain at risk.

Live Attenuated Ty21A Vaccine

Primary vaccination with 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 swallowed whole (not chewed) and 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. The manufacturer recommends avoiding alcohol consumption 1 hour before and 2 hours after administration, because alcohol can disintegrate the enteric coating.

Travelers should complete the Ty21a vaccine regimen ≥1 week before potential exposure. The approach for addressing a missed oral vaccine dose or taking a dose late is undefined. Some suggest that minor deviations in the dosing schedule (e.g., taking a dose 1 day late) might not alter vaccine efficacy; no studies have shown the effect of such deviations, however. If travelers do not complete 4 doses as directed, they might not achieve an optimal immune response. The vaccine is approved for use in people ≥6 years old. A booster dose is recommended every 5 years for those who remain at risk.

Adverse Reactions

Adverse reactions most often associated with ViCPS vaccine include headache, injection-site reactions, fever, and general discomfort. Adverse reactions to Ty21a vaccine are rare and mainly consist of abdominal discomfort, diarrhea, fever, headache, nausea, vomiting, and rash. Report adverse reactions to the Vaccine Adverse Event Reporting System at the website or by calling 800-822-7967.

Precautions & Contraindications

Neither the ViCPS nor the Ty21a vaccine should be given to people with an acute febrile illness; in addition, Ty21a is not recommended for use in people with acute gastroenteritis. Live vaccines, including Ty21a vaccine, should not be given to pregnant or immunocompromised people, including those with HIV. No information is available on the safety of the inactivated vaccine (ViCPS) in pregnancy; consider ViCPS for pregnant people when the benefits of vaccination outweigh potential risks (e.g., when the likelihood of exposure to Typhi is high).

The intramuscular vaccine (ViCPS) presents a theoretically safer alternative than the live, oral vaccine (Ty21a) for immunocompromised travelers. The Ty21a vaccine can be administered to household contacts of immunocompromised people; 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 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 antimicrobial agents. The manufacturer advises that vaccination with the Ty21a vaccine should be delayed for >72 hours after the administration of any antimicrobial agent, and antibiotics should not be given to a patient ≤72 hours after the last dose of the Ty21a vaccine.

Ty21a vaccine can be administered simultaneously or at any interval before or after live virus vaccines (e.g., measles-mumps-rubella, oral polio, or yellow fever vaccines). Available data do not suggest that simultaneous administration of live virus vaccines 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 might decrease potential interference between the vaccines. Simultaneous administration of the Ty21a vaccine and immune globulin does not appear to pose a problem.

CDC website: Typhoid fever and paratyphoid fever