The 2006 summer film Snakes on a Plane pandered to every flyer's fear of being exposed to a deadly threat while en route to a vacation destination. Unfortunately, real world global travel is potentially far more risky to a child's health than anything Hollywood could ever imagine.
Perinatal conditions, lower respiratory infections, HIV/AIDS, diarrhea, malaria, and tuberculosis were all among the leading causes of global disease burden in 2001 . None of these are in the top 10 causes of disease burden in the United States and other high-income countries.1 According to the Centers for Disease Control and Prevention (CDC), only 52 pediatric HIV cases and 1,257 malaria cases were reported to the CDC in 2006. Just over 14,000 cases of active tuberculosis infection were reported in 2005, with a provisional estimate of 1,500 to 2,000 deaths.2
In sharp contrast, the morbidity and mortality associated with these infections is staggering in the rest of the world. Almost one fifth of all deaths in 2001 (10.5 million of 56 million) were in children younger than 5 years, and more than half of these deaths were caused by five preventable and treatable infections - acute respiratory infections, measles, diarrhea, malaria, and HIV/AIDS.' Essentially all of these children lived in low- and middle-income countries.
Pediatricians are often apprehensive and uncertain when asked to make recommendations for a child planning to travel outside the United States, particularly to developing countries. Visions of exotic and rare diseases immediately come to mind, which have not been thought of since medical school. In this article, several of the most likely infectious concerns for the international pediatric traveler are reviewed.
In 2006, an American Express Travel survey reported that family travel was increasing, with 57% of travel agents polled reported booking international family vacations, and 62% booking outdoor adventure vacations, as opposed to the usual vacation tourist spots.3 Indeed, more than 1.6 billion people fly each year and more than 2 million children travel overseas annually.4
The good news is that a child who lives in United States who travels to less developed areas of the world is not as likely to contract a serious infectious disease during their stay as the local populace. First of all, most American children are well-nourished and in better health than the local population, which allows them to handle on infection more effectively. Second, the majority of American children have been vaccinated for the routine childhood illnesses. Lastly, the length of time children are exposed to pathogens is relatively short and limited by the length of the trip. However, the widespread prevalence and infectivity of these infections, as well as exposure to a novel pathogen to a naïve immune system, can easily lead to a sick child.
The CDC publishes its "Yellow Book," more formally known as Health Information for International Travel, which provides useful guidelines for travelers, every two years. The CDC also has an excellent Web site (http:// www.cdc.gov/travel) that can be more up-to-date and easier to access. Both are region- and country-specific, but can be daunting for the casual user because of their comprehensiveness.
Although there are many diseases that international travelers can contract, the majority can be grouped into three general categories: food and waterborne diseases, vectorborne diseases, and airborne diseases.
FOOD ANDWATERBORNE DISEASES
Traveler's diarrhea (aka, "turista") is the most common illness that afflicts international travelers, affecting 30% to 70%, or 10 million to 15 million travelers annually, depending on the destination and its associated risks. This calculates to about 40,000 to 50,000 cases daily.5 High-risk areas include developing countries in Central and tropical South America, Africa, the Middle East, and Asia. In contrast to the more serious food and waterborne diseases, traveler's diarrhea, rarely becomes life-threatening and usually can be treated supportively rather than requiring hospitalization. Traveler's diarrhea is caused by a broad spectrum of pathogens, primarily enterotoxigenic Escherichia coli, Salmonella sp., and Shigella sp.
Only been two studies have examined pediatric traveler's diarrhea. Pitzinger et al studied 363 children from Switzerland and found the overall incidence was 30%, with a slightly higher incidence of 39% during the first 2 weeks of travel. In children younger than 3 years, the attack rate jumped to 60%. Diarrhea rates were highest in North Africa and India (greater than 60%) and less than 40% for the rest of Africa, Southeast Asia, and Central America.6 One limitation of this study is that more than two-thirds of the children were 14 years and older. A more recent study by Hill surveyed 784 American travelers who received appropriate travel recommendations before visiting developing countries for 90 days or less. About 34% developed traveler's diarrhea. Diarrhea was more severe in children younger than 1 2 years, requiring over 4 times more use of medical care (39% versus 9%) and almost twice as much alteration of plans and activity (46% versus 26%).7
Pediatric traveler's diarrhea is best defined as an acute change from a normal stool pattern, with increased frequency (three or more episodes per day) and change to an unformed consistency. The child may also experience nausea, vomiting, abdominal cramping and pain, bloating, urgency, fever, and malaise; boys and girls are equally at risk. Most cases resolve within 48 hours, and 90% resolve within one week.8 However, long-lasting immunity does not seem to develop after traveler's diarrhea, and more than one episode can occur during a single trip.
Treatment of traveler's diarrhea is largely supportive and is based on the 2003 CDC guidelines (also adopted by the American Academy of Pediatrics in 2004) for management of acute gastroenteritis. Oral rehydration solutions are the mainstay. Notably, the guidelines point out that use of the commonly recommended BRAT diet (bananas, rice, applesauce, and toast) is not advised. The diet is well tolerated by the bowel and may make the symptoms seem better but it actually impedes recovery because it is low in the protein and fat the body needs as nutrients to heal.9
A study by Figueroa-Quintanilla et al using bismuth subsalicylate (PeptoBismol) given to infants every 4 hours reported a decrease in the duration and frequency of diarrhea, without any significant toxicity and suggests that it may be a safe and effective adjunct to oral rehydration therapy.10 Antimotility agents and antibiotic prophylaxis are still not recommended by most experts or by the CDC. Prophylactic antibiotics are ineffective against viruses, parasites, and the increasing number of bacteria which have developed resistance to commonly used antibiotics. More seriously, they lull users into a false sense of security, causing them to forget or to ignore food and water precautions, the cornerstone of preventing traveler's diarrhea. An acute, significant infection can be treated with a 3-day course of azithromycin at 10 mg/ kg/d. Ciprofloxacin at 20 to 30 mg/kg/d divided twice per day can be considered for older children. Although ciprofloxacin is not approved by the U.S. Food and Drug Administration (FDA) for this indication for patients younger than 18 years, it has been given limited approval by the FDA for resistant urinary tract infections and pyelonephritis in 1- to 17 year olds, so some experts recommend using a short course at 20 to 30 mg/kg/d divided twice per day in children.11
Prevention of traveler's diarrhea and other food and waterborne diseases is best achieved by adhering closely to dietary precautions. The phrase "Boil it, cook it, peel it, or forget it," summarizes this approach. Foods should be wellcooked, and liquids should be bottled, carbonated, or boiled. Raw fruits, vegetables, and meat, as well as undercooked meat, foods washed in water, and food from street vendors are high risk and should be avoided. If a fresh fruit or vegetable is chosen, it should be fully peelable by the traveler, because most of the pathogens cannot penetrate the peel. Infants and children are at higher risk of becoming dehydrated from the fluid losses of traveler's diarrhea because of their higher proportion of water per body mass and higher daily turnover of total body water. Their hydration status and fluid intake should be monitored closely. Probiotics like Lactobacillus and Saccharomyces boulardii have been studied as prophylaxis for traveler's diarrhea, but recent studies have shown no clear benefit.12 Paton et al recently tried a new approach, using a recombinant E coli, which expresses a lipopolysaccharide that binds the heat labile toxin produced by enteroxigenic E coli.13 Where possible, infants should continue being breastfed to benefit from maternal antibodies and to avoid exposure to potentially contaminated fluids. Formula-fed infants should be given full-strength bottled or canned formula, which does not require any reconstitution. Patients who are receiving antacids, H2 blockers, or proton pump inhibitors are at increased risk of developing traveler's diarrhea, because of decreased gastric acidity, which may allow pathogens to pass into the small and large bowel.
Malaria Prophylactic Agents for Infants and Children21
Other infections that can be transmitted via water or food contaminated with fecal pathogens include viruses such as hepatitis A and B, and rotavirus. In contrast to the 70% to 80% of traveler's diarrhea caused by bacteria, only about 15% to 20% is caused by viruses.5 Fortunately, virtually all Americans younger than 20 years have been immunized against hepatitis B, and with the new 2007 vaccine recommendations, all children will now be immunized for rotavirus and hepatitis A.
The remaining 10% or so of traveler's diarrhea is caused by parasites. Giardia intestinalis and Cryptosporidia species are the most common parasites acquired by travelers, but they are not limited to developing countries. Giardia has a 20% to 30% prevalence rate in children in the developing world and a rate of 2% to 5% in industrialized countries. Studies in the United States have found that 4% to 7% of stools from patients with diarrheal illness test positive for Giardia, and more than 25,000 cases of giardiasis are reported annually.14 Because many cases may not be confirmed or come to medical attention, the true number of cases could be more than 10 to 100 times higher. Although Giardia cysts can be found on stool ova and parasite tests, Giardia antigen detection tests of the stool have become the gold standard for confirming giardiasis because of their excellent sensitivity and specificity. Metronidazole divided three times daily for one week or nitazoxanide twice daily for three days 4 result in a 80% to 95% cure rate.
Cryptosporidia species (ie, C. hominis and C. parvum) is also common and H may be responsible for up to 20% of childhood diarrhea in developing countries.15 About 20,000 Cryptosporidia infections were reported to the CDC in 2006, and these likely represent only a fraction of the actual cases.2 An enzyme-linked immunoassay is the diagnostic test of choice, because routine « stool ova and parasite tests will not detect this parasite, and these EIAs must be specifically ordered. Cryptosporid- * ial diarrhea is usually self-limited and resolves within 5 to 10 days; however, more severe infections can be treated with nitazoxanide at 100, 200, or 500 mg by mouth twice per day for 3 days, depending on the patient's age.15
Malaria is usually the first vector-borne infection most people think of when traveling internationally, and rightly so. It is a common infection in more than 100 countries in the world, primarily in tropical and subtropical areas. More than 125 million people visit these countries annually, with more than 10,000 diagnosed with a malarial illness after their return home. Most experts be- f lieve this number underestimates the true number of cases because of incomplete reporting, and the actual figure could be 30,000 or more.16
Approximately 40% of the world's children live in malaria endemic countries. Nearly 300 million to 500 million people contract malaria every year. One million die, and more than 75% of these are African children younger than 5 years. Malaria is responsible for 1 in 5 * childhood deaths in Africa.17
Malaria is caused by infection by one of four Plasmodium protozoa: P. malariae, P. vivax, P. ovale, and P. falciparum. P. falciparum is the most fatal type and also, unfortunately, is the most common species worldwide. The Plasmodium parasites are carried by female Anopheles mosquitoes which are primarily seeking victims from dusk to dawn.
The malaria incubation period is at least 1 week or longer. Most malaria illness occurs within 3 months of infection, although rarely illness from P. vivax or P. ovale has occurred years after the original infection. The classic presentation starts with high fever, chills, rigors, sweats, and headaches, which can be paroxysmal and later the cyclic tertian or (every 48 to 72 hours) quartan fever. Nausea, vomiting, diarrhea, cough, arthalgias, myalgias, and hepatosplenomegaly can also be seen, with pallor and jaundice developing reflecting hemolysis.
The most severe symptoms occur with P falciparum infection and begin with a non-specific influenza-like illness without localizing signs or symptoms. If the disease becomes more severe, the patient can develop hypoglycemia, respiratory failure with metabolic acidosis, severe anemia, and may progress to vascular collapse and shock. Cerebral malaria is another severe, usually early childhood complication, which is often fatal and can leave survivors with permanent neurological sequelae.18
Currently, only chemoprophylaxis exists for malaria. Several vaccines are in development but are still years away from release.19 One of the more promising is a GlaxoSmithKline candidate designated RTS.S/AS02A, which was tested in Mozambique on children 1 to 4 years in 2004. Within 6 months of vaccination, a child's risk of developing malaria was reduced 30%, while the risk for developing severe malaria was reduced by more than 55%. This increased to a 70% reduction if the child was younger than 2 years. Time to first infection was prolonged by almost 50%. 20
Malaria prevention is summarized by ABCD- Awareness of the level of risk and timing and symptoms of malaria, Bite precautions for mosquitoes, Compliance with prophylactic medications, and Doctor evaluation if fever develops 1 week or more after exposure.
The usual prophylactic medications include chloroquine, mefloquine, and atovaquone-proguanil in pediatrics. Chemoprophylaxis is becoming more difficult because of the widespread multidrug resistant P. falciparum. Currently, chloroquine prophylaxis can be recommended only for areas of risk in the Caribbean and Middle East. For the rest of the malarious areas of the world, either mefloquine or atovaquone-proguanil is used in children. Doxycycline, which is sometimes used in adults, is avoided because of the adverse effects in children, including dental enamel hypoplasia and permanent discoloration, gastrointestinal upset, photosensitivity rashes, and normal pressure hydrocephalus. The Table (see page 348) summarizes dosing and side effects of the pediatric chemoprophylactic agents.21 Again, it is important to emphasize to travelers that prophylaxis is not 100% effective and that formal medical evaluation should be obtained if any suspicious symptoms develop.
Evaluation for the need for malaria prophylaxis needs to consider where the traveler is going, for how long, and the accommodations. This can be further complicated by travel to different locales and various accommodations. Within many countries, the risk of malaria varies, depending on whether the traveler stays only in urban areas or visits remote undeveloped regions and/or stays with relatives in rural areas. In the last case, the decision for prophylaxis should be based on the highest reported risk for the different locations being visited.
Special attention should be paid to the children in families who have moved to a non-endemic area and are now bringing the children back visit with relatives and friends. Malaria immunity can wane after 6 months of living in a non-endemic area. Travel with infants and children to areas with chloroquine-resistant P. falciparum should be discouraged because of the rapid life-threatening sequelae that can occur with infection. However, if the family is not dissuaded, they should receive counseling, emphasizing protection against mosquito bites and the importance of chemoprophyIaxis. Insect repellant should be applied daily, especially from the late afternoon to early morning, carefully following the manufacturer's instructions and not exceeding the recommended dose. Appropriate repellante include products containing diethyltoluamide (DEET), picaridin (KBR 3023), permethrin, and oil of lemon eucalyptus. DEET's advantage is that in higher concentrations, it lasts longer than any of the other compounds. High concentrations of the others seem to be equivalent to low concentrations of DEET and need to be reapplied more frequently to maintain protection.16 Insecticide-treated bed netting is also an important adjunct when sleeping quarters do not have windows, doors, or walls that can keep out mosquitoes.
Fortunately, tuberculosis (TB), one of the most common global infections that is readily spread through the air, is not common in travelers. TB infection typically requires close, repeated exposure to an infectious individual for prolonged periods, which the very nature of a typical vacation precludes. However, TB should be considered in the child who has spent a long period in a country considered to have a high incidence in the population. The World Health Organization (WHO) cites a number of such countries, listed in the Sidebar (see page 349). 16
Additional good news is that studies have shown there is very little risk of infections being transmitted onboard the airplanes used to travel. Most modern aircraft have ventilation systems that completely change the cabin air every 2 to 3 minutes. Any recirculated air goes through HEPA (high-efficiency particulate air) filters, which can trap bacteria, viruses, and fungi. If transmission occurs, it typically happens the same way most respiratory infections spread - through direct contact with respiratory droplets expelled by the infectious person. Most of this contact is inadvertent, by being sneezed or coughed on, or by touching a surface where droplets have landed directly, or indirectly via the touch of an intermediary person.
Measles and chicken pox (varicella-zoster virus) are also extremely contagious and spread readily through the air. Again, the majority of children from the United States should have been vaccinated against both of the viruses. This continues to underscore the importance of insuring that all immunizations are up-to-date for the potential pediatric traveler. This is also why international travel is not recommended for infants, since they are relatively immunocompromised and have only partially completed the primary series of vaccinations. It is also important to remember that vaccines may not produce adequate protective antibody titers, even in those who have completed the appropriate series. In 2004, the CDC reported the case of a college student returning from India on a commercial airliner who was infected with measles and, in turn, infected the passenger sitting next to him, despite the latter having documentation of two MMR (measles/ mumps/rubella) vaccinations.22
First and foremost, pediatric travelers should be up-to-date on all recommended vaccinations - DTaP, hepatitis B, Haemophilus influenzae type b, polio, MMR, as well as pneumococcal, varicella, and annual influenza vaccinations. Vaccination against rotavirus and hepatitis A is now routine for younger children, as is vaccination against meningococcus and human papilloma virus in adolescents.
There is only one mandatory vaccination for travel to certain countries in South America and Africa - yellow fever. Other recommendations for travel vaccines can be based on the overall risk assessment, which includes factors such as risk of exposure to the disease, age, overall state of health, vaccination history, allergies and reactions to previous vaccines, infectious risk to others, and cost of vaccination versus its benefits. Vaccines in this category include cholera, Japanese encephalitis, rabies, and tick-bome encephalitis and are infrequently required or recommended.
However, many travelers should consider vaccination for typhoid fever, a bacterial infection caused by Salmonella typhi, ingested from contaminated food or drink. Although only 264 cases were reported in the United States in 2006 (the majority acquired from travel to endemic countries),2 typhoid fever is a potentially severe systemic disease that infects more than 16 million patients annually and causes more than half a million deaths. Approximately 2% to 5% of resolved typhoid patients become chronic carriers, spreading the disease to others. Two vaccines are recommended by the CDC for protection, even for short trips to endemic areas, especially South Asia. The first is Typhim- Vi, a Vi capsular polysaccharide vaccine (ViCPS) given as an intramuscular injection. The second is Vivotif, a series of four oral gel capsules taken every other day that contain a live attenuated strain of S typhi, Ty21a. The drawback with oral Ty21a is a potential interaction with medications used for malaria prophylaxis. Recent studies have found that simultaneous administration of either chloroquine or mefloquine does not affect the immunogenicity of the oral Ty21a vaccine. However, both atovaquone and, to a greater extent, proguanil (which together comprise the antimalarial drug Malarone) can interfere with and diminish the immune response of oral Ty21a. Proguanil and antibiotics should not be given less than 24 hours before the first dose of oral Ty21a and 10 days after the fourth dose. ViCPS vaccine requires boosting at least every 2 years, Ty21a every 5 years. Adverse reactions to both are similar and include fever and headache. ViCPS is also associated with local reactions at the injection site, Ty21a with occasional gastrointestinal symptoms, including abdominal discomfort, nausea, vomiting, rash, and urticaria. ViCPS recipients must be at least 2 years old, and the vaccine should be given at least 2 weeks prior to travel to an endemic area. Ty21a recipients must be at least 6 years old and able to swallow the gel caps, and the gel caps should be completed as least 1 week prior to travel.23
As more and more families travel to exotic, off-the-beaten-path locations internationally, pediatricians should expect more and more questions from parents concerned about potential infectious risks for their children. It is important for pediatricians to become aware of and be comfortable discussing the basics of the more likely infections, such as traveler's diarrhea and malaria, as well as what precautions are recommended to minimize the risk of disease. General pediatric care has always emphasized anticipatory guidance, and it is our duty and responsibility to be able to provide appropriate medical service to children to ensure they grow to become healthy, non-compromised adults.
The popular Final Destination movies imply that no matter what measures you take, you cannot escape your fate. Too many parents and pediatricians seem to have this philosophy when it comes to international travel with children and illnesses. The reality is far more comforting - with the proper knowledge and preventative measures, global travel with children cannot only be fun and a memorable adventure, but a safe and non-stressful experience as well.
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20. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS.S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet. 2004;364(9443):141 1-1420.
21. Moon TD, Oberhelman RA. Antiparasitic therapy in children. Pediatr Clin North Am 2005;52(3):9 17-948.
22. Postexposure prophylaxis, isolation, and quarantine to control an import-associated measles outbreak-Iowa, 2004.Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal WkIy Rep. 2004 Oct 22;53(41 ):969-7 1 . Guzman CA, Borsutzky S, Griot- Wenk M, et al. Vaccines against typhoid fever. Vaccine 2006;24(18):3804-3811.
Malaria Prophylactic Agents for Infants and Children21