Focus on Vaccines

Typhoid and Malaria: Now in Your Waiting Room

July 1, 2007

We frequently see children who have just returned from India with fever, diarrhea, and constitutional symptoms. It is our job to determine whether they have a benign viral illness or something more serious. Some of the children have received malaria prophylaxis (usually mefloquine( [Lariam] and occasionally atovaquone( and proguanil( [Malarone]). The number of children who have been vaccinated against hepatitis A infection is certainly on the rise, but few have been vaccinated against typhoid fever.

What clinical cues would make you suspect malaria or typhoid? What laboratory tests are helpful (anemia? thrombocytopenia? elevated liver enzyme levels?)? When would you perform blood smears for malaria? When would you start treatment (pending test results)? When are stool cultures for Salmonella typhi indicated?

— David M. Schwartz, MD
  Samuel C. Schwartz, MD
  Schwartz Pediatrics Bartlett, Ill

I certainly agree that medical issues relating to international travel and adoption are reasons why families increasingly seek help from their pediatricians. It is also clear that children who travel with their parents to the parents' country of origin are less likely to receive recommended travel vaccines and prophylaxis than are those who travel for business, recreation, or religious activities. The reason is that the parents did not receive these vaccines or prophylactic antimicrobial agents when they were growing up in countries such as India, so they are not as likely to see the need for their children.

Preparing for Travel

Most travel clinics recommend routine hepatitis A and typhoid vaccines for those traveling to any developing country. Actually, the Committee on Infectious Diseases of the American Academy of Pediatrics and the Advisory Committee on Immunization Practices at the CDC recommend universal immunization for hepatitis A. Although patients with hepatitis A are usually anicteric and the infection is quite mild in young children, these younger family members are often the contact source for their parents and adult relatives, in whom disease can be more severe. Reported mortality among the older age groups is 3 per 1000 cases.

Hepatitis A vaccine is licensed for children 1 year and older. However, limited data indicate good antibody responses in infants as young as 6 months. For this reason, it seems prudent to immunize children this young if they are traveling to countries with a high prevalence of disease.

Typhoid fever is common in developing countries. This disease accounts for significant morbidity and mortality in residents of all ages. Although 2 killed vaccines are available, the live oral vaccine is as efficacious as the killed vaccines and is preferred for all ages. However, at this time, the live oral vaccine is not approved in the United States for children younger than 6 years. The primary reason for this limitation is that young children are usually unwilling to swallow capsules. Vaccine trials using a suspension formulation demonstrated higher efficacy and safety in children than that observed for the capsule when employed in adult studies.

A parenteral vaccine, Typhoid( Vi (Typhim), the capsular polysaccharide (ViCPS) of Salmonella typhi, is approved for administration to children 2 years and older. It requires only a single injection for immunization, but local reactions occur in 7% of recipients. Protective efficacy for the oral vaccine lasts for 5 to 6 years, compared with the ViCPS vaccine, which requires a booster every 2 years. Of the 3 typhoid vaccines currently licensed in the United States, only the older parenteral heat-phenol-inactivated product is licensed for children as young as 6 months.

A reasonable approach for young children is to open the capsule and give the contents with a gelatin dessert, banana, or other preferred food of infants using the same schedule recommended for older children. Keep in mind that this is a live bacterial vaccine; it is quite safe but is not recommended for patients who are immunosuppressed or for young children who live in a household with an immunosuppressed adult. For reasons not completely understood, mefloquine may reduce the immunogenicity of typhoid vaccine. Therefore, this drug should be given more than 24 hours before or after a vaccine dose.

Returning Patients With Fever, Diarrhea, and/or Constitutional Symptoms

The adage among travel medicine specialists is that any traveler with fever returning from a country in which malaria is endemic has malaria until proved otherwise. However, given a combination of fever, diarrhea, and other symptoms, travelers diarrhea is perhaps a more likely diagnosis if the timing is appropriate. Disease usually occurs after the first week of travel and is generally mild and self-limited. The incidence is highest among persons visiting Latin America, Africa, Asia, and the Middle East. Numerous organisms are responsible, but the vast majority are enterotoxigenic Escherichia coli.

A single dose of azithromycin( (10 mg/kg) or a 5-day course of ciprofloxacin( or trimethoprim(/sulfamethoxazole might be considered in older children once other causes are ruled out. For infants and children younger than 2 years, fluids with a high electrolyte content—such as those contained in oral rehydration solutions—are recommended.

Malaria is best identified with thick and thin blood smears obtained when the patient is febrile. Parasites may be present in 5% or more of red blood cells with Plasmodium falciparum but may be far fewer with other species. Therefore, multiple blood smears may be necessary for most cases of malaria acquired in regions where P falciparum is not endemic. Both P falciparum and Plasmodium vivax are found in India.

The diagnosis of typhoid fever is usually made on clinical grounds, serological measurement (of S typhi O and H antibodies), and cultures. Characteristic of typhoid fever is the temperature-pulse dissociation (ie, the pulse rate does not increase 8 to 10 beats per degree of fever as is seen with almost all other infections). However, this finding is only present in 30% to 40% of cases. During the initial phases of typhoid, stool cultures may be positive; however, there is an increased yield from the stool culture between 3 and 4 weeks of disease. Initially, blood cultures are positive in 80% to 90% of patients. Other sites that can be cultured are bone marrow and biopsies of rose spots. Antibody titers become positive after the first week of illness.

— Russell Steele, MD
  Division Head, Pediatric Infectious Diseases
  Ochsner Children's Health Center
  Clinical Professor of Pediatrics
  Tulane University School of Medicine