Typhoid Fever: Which Travelers Have High Risk?

Abstract & Commentary

Synopsis: The great majority of typhoid fever cases diagnosed in the United States occur in patients who have visited friends and relatives overseas, especially travelers returning from South-central and Southeast Asia, including short-term travelers. Among other precautions, typhoid fever vaccine should be recommended to these high-risk travelers.

Source: Steinberg EB, et al. Typhoid Fever in Travelers: Who Should Be Targeted For Prevention? Clin Infect Dis. 2004;39:186-191.

Steinberg and colleagues reviewed laboratory-confirmed cases of typhoid fever occurring in the United States from January 1994 through December 1999. A total of 1393 patients with acute Salmonella enterica infection, serotype Typhi, were reported to the Centers for Disease Control and Prevention from 44 states and 2 United States territories. California and New York reported the most cases.

A total of 1027 (74%) cases were associated with travel, and the destinations included 64 countries. The median age was 22 years; 64 (7%) were younger than 2 years old, and 310 (34%) were 2-17 years old. The 6 leading countries made up 76% of all travel-related cases. These were: India (30%), Pakistan (13%), Mexico (12%), Bangladesh (8%), The Philippines (8%), and Haiti (5%).

Patients were surveyed about their reasons for travel and duration of stay. Among the patients who specified 1 reason for travel (147), 80% reported visiting relatives or friends overseas, 16% reported emigrating to the United States, 3% traveled as tourists, and 1% traveled for business. Only 36 (4%) cases reported typhoid vaccination. Among the travelers who reported their duration of stay (626), 5% stayed for under 1 week, 16% stayed for under 2 weeks, 27% stayed for under 3 weeks, 37% stayed for under 4 weeks, 54% stayed for under 5 weeks, and 60% stayed for under 6 weeks.

Laboratory results revealed only positive blood cultures for S. typhi in 718 cases (70%), positive stool cultures alone in 156 cases (15%), organisms from both sources in 126 cases (13%), and from blood/stool/other sites in 17 (2%). 10 cases (1%) were diagnosed from an unidentified source.

Steinberg et al also reviewed adverse events associated with typhoid vaccine during the same period, and found 688 events, 297 of which occurred after vaccination against typhoid alone. The majority of adverse events (68%) were attributed to the parenteral heat-inactivated vaccine. Based on Steinberg et al’s estimate that 5.5 million doses of typhoid vaccines (oral live-attenuated, parenteral heat-inactivated, and parenteral capsular polysaccharide) were administered, estimated rates for hospitalization, disability, and death were 0.47, 0.03, and 0 per 100,000 vaccine recipients, respectively.

Comment by Lin H. Chen, MD

Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serotype Typhi. After ingestion, the bacteria reach the small intestine, penetrate the mucosa, spread via the lymphatic system to the liver and spleen, and then to the circulation. Following an asymptomatic period of 7-14 days (range, 3-60), an infected person may develop symptoms that include fever, chills, malaise, headache, anorexia, abdominal discomfort, dry cough, and myalgia.1 The diagnosis is confirmed by isolation of the organism from blood culture, stool culture, or other sites such as urine, although diagnosis is frequently made on clinical grounds in resource-poor settings. Steinberg et al demonstrated that, while positive blood cultures frequently established the diagnosis, 15% of cases were diagnosed via positive stool cultures alone. Thus, stool cultures should be obtained when clinical suspicion of typhoid fever is high.

The Widal serological test has been used, but it is insensitive. Molecular techniques have led to development of some inexpensive tests for the rapid detection of S. typhi infection. A study of Multi-Test Dip-S-Ticks, TyphiDot, and TUBEX to detect immunoglobulin G (IgG), IgG and IgM, and IgM, respectively was performed to compare them to the Widal test.2 Sensitivity was highest during the second week of illness for all tests. TyphiDot and TUBEX, with sensitivity and specificity of 79 and 89%, and 78 and 89%, respectively, performed better than the Widal test.2 These new tests may play a greater role in the future for the diagnosis of typhoid fever.

A recent analysis of the global burden of typhoid fever estimated the annual total for the year 2000 to be at least 21 million illnesses and at least 210,000 deaths.3 Areas are rated by incidence: high (> 100/100,000 cases/year), medium (10-100/100,000 cases/year), and low (< 10/100,000 cases/year). South-central Asia and Southeast Asia have high incidence; eastern Asia, western Asia, Africa, Latin America, the Caribbean, and Oceania (excluding Australia and New Zealand) have medium incidence; developed countries including North America, Europe, Japan, Australia, and New Zealand have low incidence.3 Although the data reported by Steinberg et al support a global typhoid fever epidemiology, calculations of risk based on the number of visitors to each country would have been very useful.

Laboratory surveillance of typhoid fever cases in the United States from 1996 to 1997 showed that 81% were imported.4 The majority of the cases were acquired from travel to the Indian subcontinent, and travelers who were visiting friends and relatives were at highest risk; the rate of typhoid fever was estimated to be 0.93 cases per 100,000 travelers arriving to the United States by air from typhoid-endemic countries.4 Additionally, 24% of S. typhi isolates were resistant to at least 1 antibiotic, 16% were resistant to multiple antibiotics, and 7% were resistant to nalidixic acid, the parent drug of the fluoroquinolones.4 Travel to the Indian subcontinent (India, Bangladesh, Pakistan, and Viet Nam) was most frequently associated with drug resistance in the S. typhi isolates from the United States.4 A number of recent reports have illustrated increasing multidrug-resistance, nalidixic acid-resistance, and decreased fluoroquinolone sensitivity.5-8 Although minimum inhibitory concentrations of the fluoroquinolones are usually within the susceptible range, the decreased clinical response to fluoroquinolone in nalidixic acid-resistant strains has led to reconsideration of the current fluoroquinolone breakpoints for Salmonellae.6 Because therapy may be problematic when treating resistant strains of S. typhi, travelers planning to visit countries with high rates of resistant S. typhi such as India, Pakistan, Bangladesh, and Viet Nam should have a low threshold for immunization.

Two typhoid vaccines are currently available in the United States, the Vi capsular polysaccharide vaccine and the Ty21a attenuated live oral vaccine. The Ty21A live oral vaccine requires refrigeration, and the capsules need to be taken 48 hours apart, 1 hour before or 2 hours after meals, which result in a compliance rate of 53-68%.9 It is only approved for use in persons at least 6 years old, while the Vi capsular polysaccharide vaccine is approved for use in persons at least 2 years old. Both vaccines have demonstrated protective efficacies of approximately 70%.10-11 Therefore, vaccine failures can occur in previously vaccinated travelers. Post-marketing surveillance from July 1990 through June 2002, via VAERS, identified adverse event rates of 7.5% and 5.5%, respectively, for the parenteral Vi capsular polysaccharide vaccine and the Ty21a vaccine.12

In summary, the study by Steinberg et al on typhoid fever highlight the following: 1) Typhoid fever associated with international travel represents the majority (74%) of all typhoid fever cases diagnosed in the United States; 2) the Indian subcontinent continues to be the region with highest risk for typhoid fever; 3) children younger than 18 years of age comprise a large proportion (41%) of all travel-related cases; 4) persons traveling for the purpose of visiting friends and relatives (80%) represented the leading risk group; 5) short-term travelers are also at risk for typhoid; and 6) typhoid fever vaccines are well tolerated, and should be utilized to prevent infections.

Travel medicine providers should immunize high-risk travelers with the typhoid fever vaccine, particularly travelers who plan to visit South-central Asia and Southeast Asia, those who travel to visit friends and relatives, as well as pediatric travelers. A typhoid vaccine that can be safely administered to young children, and with improved protective efficacy, would be desirable. Finally, because the current vaccines do not achieve full protection, typhoid fever should remain within the differential diagnosis of febrile travelers returning from developing countries, even if the traveler had prior immunization with the typhoid vaccine.

References

1. Parry CM, et al. Typhoid Fever. N Eng J Med. 2002; 347(22):1770-1782.

2. Olsen SJ, et al. Evaluation of Rapid Diagnostic Tests for Typhoid Fever. J Clin Microbiol. 2004;42(5):1885-1889.

3. Crump JA, et al. The Global Burden of Typhoid Fever. Bull World Health Organ. 2004;82(5):346-353.

4. Ackers ML, et al. Laboratory-Based Surveillance of Salmonella Serotype Typhi Infections in the United States: Antimicrobial Resistance on the Rise. JAMA. 2000;283:2668-2673.

5. Rodrigues C, et al. Salmonella typhi in the Past Decade: Learning to Live With Resistance. Clin Infect Dis. 2002;34:126.

6. Crump JA, et al. Reevaluating Fluoroquinolone Breakpoints for Salmonella enterica Serotype Typhi and for Non-Typhi Salmonellae. Clin Infect Dis. 2003; 37(1):75-81.

7. Parry CM. The Treatment of Multidrug-Resistant and Nalidixic Acid-Resistant Typhoid Fever in Vietnam. Trans R Soc Trop Med Hyg. 2004;98(7):413-422.

8. Rupali P, et al. Treatment Failure in Typhoid Fever With Ciprofloxacin Susceptible Salmonella enterica Serotype Typhi. Diagn Microbiol Infect Dis. 2004; 49(1):1-3.

9. Stubi CL, et al. Compliance to Live Oral Ty21a Typhoid Vaccine, and its Effect on Viability. J Travel Med. 2000; 7:133-137.

10. Panchanathan V, et al. Comparison of Safety and Immunogenicity of a Vi Polysaccharide Typhoid Vaccine With a Whole-Cell Killed Vaccine in Malaysian Air Force Recruits. Bull World Health Organ. 2001;79:811-817.

11. Levine MM, et al. Duration of Efficacy of Ty21a, Attenuated Salmonella typhi Live Oral Vaccine. Vaccine. 1999;17 suppl 2:S22-27.

12. Begier EM, et al. Postmarketing Safety Surveillance for Typhoid Fever Vaccines From the Vaccine Adverse Event Reporting System, July 1990 through June 2002. Clin Infect Dis. 2004;38(6):771-779.

Lin H. Chen, MD, Clinical Instructor, Harvard Medical School Director, Travel Resource Center, Mt. Auburn Hospital, Cambridge, Mass. is Associate Editor of Treavel Medicine Advisor.