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ESSENTIALS OF DIAGNOSIS
Twofold increase in the frequency of unformed bowel movements, usually more than four or five stools per day.
Abrupt onset while traveling or soon after returning home.
Usually associated with abdominal cramps, rectal urgency, bloating, and malaise.
Generally is self-limiting after 3–4 days.
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General Considerations
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Travelers’ diarrhea occurs in a significant number of people who travel to foreign countries, and approximately 30–50% of travelers to high-risk areas (Mexico, Latin America, Africa, Asia, and the Middle East) will develop diarrhea during a 1–2 week stay. It is caused by fecal-oral contamination of food or water by bacteria, parasites, and viruses. The condition is more common in young adults, and the best chance for prevention involves strict attention to hygiene, sanitation, and food preparation, as outlined earlier. Food from restaurants and street vendors are common sites for exposure, and thus eating in a private home may be safer. It is extremely difficult to avoid all dangers in food and drink, and multiple studies have shown no correlation between personal hygiene measures and travelers’ diarrhea. Nevertheless, it is prudent to follow basic hygiene measures while abroad.
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In contrast to the developed world, where viruses are the most common cause of diarrhea, enterotoxigenic E. coli and other bacteria such as Shigella, Salmonella, Vibrio, and Campylobacter species, are the most common causes of diarrhea in most parts of the developing world. There are significant regional differences.
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Travelers’ diarrhea is characterized by the abrupt onset of at least a twofold increase in loose stools, usually four to five stools per day. Most episodes begin 4–14 days after arrival but can occur sooner if the concentration of bacteria ingested is sufficiently high. Common signs and symptoms include loose or watery stool, abdominal cramping, bloating, urgency, malaise, and nausea. Vomiting occurs in ≤15% of those affected. Symptoms usually resolve in 3–4 days if not treated but can last longer. Depending on the cause, fever, bloody stool, and painful defecation may occur, but these symptoms are not common. Physical findings include a benign abdomen with diffuse tenderness but no rigidity and increased bowel sounds. Patients may appear dehydrated depending on the severity of the diarrhea. Although travelers’ diarrhea rarely is life-threatening, it can result in significant morbidity; one in five travelers with diarrhea is bedridden for a day, and >33.3% have to alter their activities. Stool examination and culture may yield a causative agent, but in 40–70% of cases no pathogen is identified. It is very difficult to differentiate enterotoxic and nonpathogenic E. coli. Examination for C. parvum,C. microsporidium, or other less common organisms should be initiated only when diarrhea has persisted for >10–14 days.
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Treatment for travelers’ diarrhea includes fluid replacement and usually includes fluoroquinolone antibiotics (or in children, azithromycin) (Table 52-4). Trimethoprim-sulfamethoxazole and doxycycline are no longer generally recommended because of the development of widespread resistance. Rifaximin can also be used to treat noninvasive E. coli–induced travelers’ diarrhea. It is very useful in Latin America and Mexico, but is less useful when Campylobacter is the causative pathogen. In some countries, particularly Thailand and Nepal, Campylobacter infections may be resistant to fluoroquinolones; thus azithromycin or other antibiotics may be needed. Although a 3–5-day course on antibiotics is usually recommended, there is evidence that 1–2 days of treatment may be sufficient.
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Bismuth subsalicylate can be used by chewing two tablets (or taking 1 oz of liquid) every 30 minutes in up to eight doses. The potential for salicylate toxicity should be considered in patients taking aspirin, pregnant women, or children. Loperamide or diphenoxylate may be used for adults but never in the presence of high fever or bloody stool. Generally, it is best to combine these agents with antibiotics, especially if diarrhea is moderate or severe.
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Fluid replacement using World Health Organization ORS salts are available in most countries. In the United States the salts can be obtained through Cera Products (www.ceraproductsinc.com). A simple rehydration solution can be prepared at home using ½ teaspoon of table salt, ½ teaspoon of baking soda, and 4 tablespoons of sugar in 1 L of water; orange juice can be added to provide potassium. Adults should drink 8 oz after every diarrheal stool. Children aged <2 years should be given 2–4 oz and those aged 2–10 years, 4–7 oz. Acetorphan (Racecadotril), available in Europe but not in the United States, may be an effective adjunct to oral rehydration solutions. Women who are breastfeeding an infant with diarrhea should continue to do so. Patients can also be instructed to eat boiled rice, which often leads to faster resolution of the diarrhea.
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Although, as mentioned earlier, the effectiveness of dietary precautions have not been conclusively proven to prevent travelers’ diarrhea, it is important for travelers to observe good hygiene and sanitation and pay strict attention to food preparation and avoid high-risk food and adventuresome eating behavior.
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The CDC does not recommend antibiotic prophylaxis for most travelers; however, it may be indicated in patients with active inflammatory bowel disease, brittle diabetes mellitus type 1, AIDS and other immunosuppressive disorders, unstable heart disease, and those on proton pump inhibitors. Travelers planning an exceptionally critical short trip, where even 1 day of illness could impact the purpose of the trip, may wish to use a prophylactic medication.
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Fluoroquinolones have been found to provide ~90% protection. Ciprofloxacin 500 mg daily, levofloxacin 500 mg daily, norfloxacin 400 mg daily, or ofloxacin 300 mg daily, have all been used. Rifaximin has also been found to be safe and effective and provides 72% protection against travelers’ diarrhea. Bismuth subsalicylate (Pepto-Bismol two tablets 4 times a day) provides ~ 60% protection against travelers’ diarrhea. Probiotics have also been studied, but results are not conclusive. They seem to reduce the risk of travelers’ diarrhea by ~8%. There is no antibiotic with proven efficacy for prophylaxis against Campylobacter species, which are a more common cause of travelers’ diarrhea in South and Southeast Asia
+
Brunette
GW, ed. CDC Health Information for International Travel 2008. US Dept of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention. New York: Oxford University Press, 2012.
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Drugs for travelers’ diarrhea. Med Lett. 2008; 28:50(1291):58–59.
+
Dupont
HL
et al.. A randomized, double-blind, placebo-controlled trial of
rifaximin to prevent travelers’ diarrhea.
Ann Intern Med. 2005; 142:805.
[PubMed: 15897530]
+
Hill
DR, Ericsson
CD, Pearson
RD, Keystone
JS, Freedman
DO, Kozarsky
PE
et al.. The practice of travel medicine: guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006; 43(12):1499–1539.
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Shah
N
et al.. Global etiology of travelers’ diarrhea: systematic review from 1973 to the present.
Am J Trop Med Hyg. 2009; 80(4):609–614.
[PubMed: 19346386]
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ESSENTIALS OF DIAGNOSIS
Abrupt onset of fever, headache, chills, myalgias, and malaise during or after returning from an area in which malaria is endemic.
Recurrence of symptoms every 1–2 days (highly variable).
Thick and thin Giemsa-stained blood smears showing Plasmodium (diagnostic gold standard), or confirmation by rapid diagnostic testing for malaria.
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General Considerations
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Malaria is a major international public health problem, responsible for considerable morbidity and mortality around the world each year. At least 40% of the world’s population live in areas in which malaria is endemic, and ~5% are infected at any one time. It causes an estimated 1 million deaths per year. Although 90% of cases occur in sub-Saharan Africa, the disease is found throughout the tropics. In most countries the distribution is spotty. Few Americans know much about the disease because it was eradicated in the United States in the 1940s. In the United States about 1500 cases of malaria acquired abroad are reported annually to the CDC.
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Malaria is caused by infection with Plasmodium falciparum, P. vivax, P. malariae, P. ovale (two subspecies: P. ovale curtisi and P. ovale wallikeri) or P. knowlesi. The first two species account for the majority of infections, and most cases of severe infection and death are due to P. falciparum. The vector for transmission to humans is the female Anopheles mosquito. With the exception of Central America and parts of the Middle East, most P. falciparum infections are resistant to chloroquine, and some strains of P. vivax are also resistant. Travelers to the tropics should receive prophylaxis based on the latest CDC recommendations.
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Incubation periods differ among the Plasmodium species (Table 52-5), and at times they may be much longer than those usually reported. P. falciparum, P. malariae and P. knowlesi do not form hypnozoites and do not produce chronic liver infection. Thus, infected patients should not relapse if treatment is adequate. This is not the case with P. vivax and P. ovale. Reactivation of dormant hypnozoites in the liver can occur with these species leading to relapse—sometimes decades after the original infection.
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Clinical Findings and Diagnosis
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A. Symptoms and Signs
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Classical symptoms of malaria in a nonimmune person are fever, chills and sweats, headache, and muscle and joint pains. Nausea, vomiting, abdominal pain, and diarrhea can also occur. Symptoms usually begin 10 days to 4 weeks after infection; however, malaria symptoms might start as early as 7 days or as late as 1 year, depending on the species, after the traveler returns from a malarial area. Physical findings include fever, tachycardia, and flushed skin; mental confusion and jaundice may be present. The spleen and liver are often palpable, especially in persons who have had repeated infections. Symptoms may be much milder in a semi-immune person and may be only a headache or general body aches.
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Severe malarial infection, usually due to P. falciparum, causes a multitude of complications, including cerebral malaria (with seizures, coma, or death), renal failure, hemoglobinuria (also called “black water fever”), hemolytic anemia, acute respiratory failure, shock, and hypoglycemia. Long-term complications include hypersplenism, nephrotic syndrome, and a seizure disorder.
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B. Laboratory Findings
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The gold standard for diagnosis remains detection of parasites by Giemsa-stained thick and thin blood smears. Thick films are more sensitive for picking up infections and for measuring parasite density, and thin films are more accurate for identification of species. The films must be fixed and stained properly, and experience is required to interpret the findings. Reputable laboratories can be difficult to identify by a traveler abroad. Also, where malaria is no longer endemic (ie, the United States), healthcare providers may not be familiar with the disease. Clinicians seeing a febrile patient may not consider malaria among the potential diagnoses and thus would not order the needed diagnostic tests. Laboratory workers may lack experience with malaria and fail to detect parasites when examining blood smears.
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Data have now emerged to support routine use of rapid diagnostic tests (RDT) for diagnosis of malaria in endemic areas as the standard of care. Thus far only one RDT has been approved by the US FDA: the BinaxNOW malaria test kit. It tests for the histidine-rich protein II (HRP2) antigen specific for P. falciparum plus a panmalarial antigen specific for all human plasmodia. Sensitivity and specificity to P. falciparum is 95% and 94%, respectively. P. vivax sensitivity and specificity are 69% and 100%, respectively.
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Limitations of the BinaxNOW® malaria test kit include: samples containing P. falciparum are needed as a positive control, negative results require confirmation by thick and thin smears, and both viable and nonviable organisms are detected, including gametocytes are sequestered P. falciparum parasites. Therefore, this test may not be used for monitoring response to therapy since antigen persists after elimination of the parasite. HRP2-based techniques may also be limited by mutations of the HRP2 gene or antibody interference at high levels of HRP2.
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Some representative websites with information on rapid diagnostic tests for malaria include http://www.alere.com/us/en.html, http://www.rapidtest.com, and http://www.premiermedcorp.com. Complete information about these diagnostic tests is also available from the WHO web site at http://www.wpro.who.int/malaria/sites/rdt/.
+
Hendriksen
IC, Mtove
G, Pedro
AJ, Gomes
E, Silamut
K, Lee
SJ
et al.. Evaluation of a PfHRP2 and a pLDH-based rapid diagnostic test for the diagnosis of severe malaria in 2 populations of African children. Clin Infect Dis. 2011; 52(9): 1100.
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Masanja
MI, McMorrow
M, Kahigwa
E
et al.. Health workers’ use of malaria rapid diagnostic tests (RDTs) to guide clinical decision making in rural dispensaries, Tanzania. Am J Trop Med Hyg. 2010; 83(6):1238.
+
McCutchan
TF, Piper
RC, Makler
MT. Use of malaria rapid diagnostic test to identify Plasmodium knowlesi infection. Emerg Infect Dis. 2008; 14(11):1750.
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C. Differential Diagnosis
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The differential diagnosis of malaria includes most febrile tropical illnesses prevalent in the area that the traveler has visited (see the section on fever in a returning traveler, later in this chapter). The illnesses most often confused with malaria include influenza and viral infections, dengue fever, babesiosis, relapsing fever, yellow fever, hepatitis, typhoid fever, kala-azar, urinary tract infections, tuberculosis, endocarditis, and meningitis (especially in patients with cerebral symptoms).
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The medications used for the treatment of malaria vary and are frequently used in combinations. Ideally, determination of the correct treatment involves identification of the species of malaria, knowledge of where the traveler has been, and the medical history of the patient. No one drug acts on all stages of the disease, and different species of parasites show different responses. Full discussion of the treatment of malaria is beyond the scope of this chapter and may be found at www.cdc.gov/malaria/diagnosis_treatment/treatment.html.
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A traveler who plans to visit a remote area without adequate medical facilities may wish to take along a reliable supply of medication for a full course of presumptive treatment if symptoms of malaria develop. Presumptive self-treatment should never take the place of being evaluated at a medical facility; however, it could be lifesaving if there is no nearby help. Table 52-6 includes two suggestions for presumptive self treatment: atovaquone-proguanil (Malarone) or artemether-lumefantrine (Coartem). Malarone should not be used if the patient is taking this as prophylaxis, and Coartem should not be used in patients taking mefloquine prophylaxis.
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Artemisinin derivatives such as artemether and artesunate are well tolerated and are given in combination with another drug such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, or lumefantrine. Artemether-lumefantrine is the only artemisinin-based combination therapy (ACT) currently available in the United States, but others are available abroad. There have been a few reports of resistance to artemisinin. Combination therapy has the advantages of slowing the development of resistance, reducing the length of the required treatment course, and more effectiveness.
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For more information about malaria in general, visit the Roll Back Malaria website at http://www.rbm.who.int. CDC clinicians are also on-call 24 hours to provide advice to clinicians on the diagnosis and treatment of malaria and can be reached through the Malaria Hotline 770-488-7788 (or toll-free at 855-856-4713).
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A common approach to malaria prevention is to follow the “A, B, C, D” rule. (awareness of risk, bite avoidance, compliance with chemoprohylaxis, and prompt diagnosis in case of fever).
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Travelers to endemic areas should be advised about basic measures to prevent mosquito bites, including wearing long sleeves, long pants, and light-colored clothing at dusk; avoiding perfumes that might attract mosquitoes; and treating bed nets with permethrin. A mosquito repellent containing 30–50% DEET (N,N-diethyl-meta-toluamide) is recommended. In Europe, 20% of picaridin and 35% of DEET have shown comparable efficacy for protection against malaria vectors for ≤8 hours after application.
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Advice for Travelers. Treatment guidelines, Med Lett. 2006; 4: 25.
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B. Malaria Prophylaxis
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Chemoprophylaxis is a strategy that uses medications before, during, and after the exposure period to prevent the disease caused by malaria parasites. The aim of prophylaxis is to prevent or suppress symptoms caused by blood-stage parasites. In addition, presumptive antirelapse therapy (also known as terminal prophylaxis) uses a medication (primaquine) toward the end of the exposure period (or immediately thereafter) to prevent relapses or delayed-onset clinical presentations of malaria caused by dormant liver stages of P. vivax or P. ovale.
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In choosing an appropriate chemoprophylactic regimen, the traveler and the healthcare provider should consider several factors. The travel itinerary should be reviewed in detail to determine whether the traveler is actually at risk for acquiring malaria. The next step is to determine whether significant antimalarial drug resistance has been reported in that location. Resistance to antimalarial drugs has developed in many regions of the world. Healthcare providers should consult the latest information on resistance patterns before prescribing prophylaxis for their patients.
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Five medications are currently available and approved in the United States for malaria prophylaxis: chloroquine (or hydroxychloroquine), mefloquine, doxycycline, atovaquone/proguanil and primaquine. See Table 52-6 for prophylactic dosages in adults and children.
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This drug is still effective for prophylaxis in Central America above the Panama Canal and in some areas of the Middle East. It should not be used for prophylaxis in other areas. Most strains of P/ falciparum and some strains of P. vivax have developed resistance to chloroquine. Some of its side effects are pruritus, headache, blurred vision, myalgia, alopecia, and spotty depigmentation. It can cause exacerbations of psoriasis, eczema, and dermatitis, and caution should be used if it is prescribed to people with these disorders. Retinal injury may occur with lifetime doses of >100 g. Chloroquine is safe in pregnancy and breastfeeding. Prophylaxis should begin 1–2 weeks before the traveler’s planned arrival in a malaria-endemic area and should continue for 4 weeks after return.
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This agent is effective for prophylaxis in most of the world except the border areas between Thailand, Myanmar, Cambodia, and Vietnam. P. falciparum shows a patchy, but increasing, resistance to the drug in some areas. It is considered safe to use in pregnancy and breastfeeding, although small amounts of drug are passed in breast milk. The most serious side effects are neuropsychiatric, such as bad dreams, paresthesias, hallucinations, and even psychotic reactions. Other side effects include vertigo, seizures, hepatotoxicity, headache, confusion, gastrointestinal upset, pruritus, and depression. It is contraindicated with serious psychiatric disorders or seizures. Caution is advised in patients with cardiac conduction abnormalities. Prophylaxis should begin at least 2 weeks before arrival in a malaria-endemic area and continue for 4 weeks after return.
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This drug is effective and safe for children, but there is insufficient evidence to recommend it for use in pregnant women, children weighing <5 kg, or women breastfeeding infants weighing <5 kg. It is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min). Side effects are generally mild and include abdominal pain, vomiting, and headache. Prophylaxis should begin 1–2 days before arrival in a malaria-endemic area and continue for 7 days after return.
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This agent is efficacious, safe, and the least expensive choice for prophylaxis. Its use is contraindicated in pregnancy, breastfeeding, and in children aged <8 years. Side effects include gastrointestinal upset, esophagitis, vaginal yeast infection, phototoxicity, hepatic toxicity, pseudomembranous colitis, and increased intracranial pressure. Prophylaxis should begin 1 day before arrival in a malaria-endemic area and continue for 4 weeks after return.
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Primaquine may be used as primary prophylaxis in areas with primarily P. vivax. It is taken 1–2 days before travel to a malarial area and daily for 7 days after return. Terminal prophylaxis is not needed if primaquine is used as primary prophylaxis. When used as terminal prophylaxis, it is taken daily for 14 days after leaving the malarial area. Adverse effects include gastrointestinal upset. In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, it can cause hemolysis, which can be severe and even fatal. It should be used only in those with documented evidence of a normal (G6PD) level.
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Alto
WA. The Little Black Book of International Medicine. Sudbury, MA: Jones and Bartlett; 2009.
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Brunette
GW, ed. CDC Health Information for International Travel 2008. US Deparmentt of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention. New York: Oxford University Press; 2012.
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Freedman
DO. Malaria prevention in short-term travelers.
N Engl J Med, 2008;359(6): 603–612.
[PubMed: 18687641]