Clinical Syndrome in Returning Travelers
Undifferentiated fever (no localizing signs)
Acute diarrheal disease
Non-diarrheal gastrointestinal disease
SOME INFECTIONS TO CONSIDER
Animals or their products
Blood and body fluids
Dogs, cats, bats, monkeys
Raw or undercooked shellfish
Unpasteurized milk/milk products
Relapsing fever (Borrelia spp.)
African tick bite fever (R. africae)
Boutonneuse fever (R. conorii)
Rocky Mountain spotted fever (R. rickettsii, parts of Central and South America)
Hiking in the bush
African tick-bite fever (Southern Africa)
Scrub typhus (O. tsutsugamushi, mite vectors, eastern Asia, western Pacific)
Artemether/Lumefantrine (CoartemTM) Pediatric Dosing
5 kg to < 15 kg
1 tablet at hour 0 and at hour 8 on the first day, then 1 tablet twice daily (in the morning and evening) on days 2 and 3 (total of 6 tablets per treatment course)
15 kg to < 25 kg
2 tablets at hour 0 and at hour 8 on the first day, then 2 tablets twice daily (in the morning and evening) on days 2 and 3 (total of 12 tablets per treatment course)
25 kg to < 35 kg
3 tablets at hour 0 and at hour 8 on the first day, then 3 tablets twice daily (in the morning and evening) on days 2 and 3 (total of 18 tablets per treatment course)
≥35 kg (adult dosing)
4 tablets at hour 0 and at hour 8 on the first day, then 4 tablets twice daily (in the morning and evening) on days 2 and 3 (total of 24 tablets per treatment course
Atovaquone/proquanil Pediatric Dosing
125 mg/50 mg PO daily x 3d
187.5 mg/75 mg PO daily x3d
250 mg/100 mg PO daily x3d
500 mg/200 mg PO daily x 3d
750 mg/300 mg PO daily x3d
1000 mg/400 mg PO daily x3d
Each dose should be taken with fatty food to be effective because lumefantrine is highly lipophilic.
Use with caution for treatment in persons with low GFR (10-50 ml/min). It is unlikely to be removed by hemodialysis or peritoneal dialysis. Atovaquone has a 2-3 day half-life whereas the proguanil has a half-life of 12-21 hours.
Off label use for the treatment of mild S. typhi infection acquired in Southeast Asia when other agents not well tolerated
Cross allergy with penicillin is lower than with first-generation cephalosporins; it has been used effectively in the treatment of enteric fever.
Remains effective prophylaxis and treatment for malaria in some areas. Pruritis is not uncommon in persons with darker skin pigmentation. Lower side effect profile than mefloquine.
Studies were done in the 1950s comparing chloroquine and hydroxychloroquine for treatment in rheumatoid arthritis demonstrating a lower side effect profile for hydroxychloroquine. Similar trials have not been done comparing malaria prophylactic and treatment regimens for these 2 drugs in terms of side effects although efficacy is equivalent.
Do not use for prophylaxis or treatment of P. falciparum acquired in Thailand, Laos, or Cambodia. Best administered with food; coadministration with fluoroquinolones, antiarrhythmics, and macrolides may prolong QTc.
A higher dose (30 mg vs previously used 15 mg) may be associated with neutropenia and leukopenia in some persons. Hepatic metabolism. Assess G6PD status before administration.
Cinchonism (tinnitus, headache, nausea, abdominal pain, visual disturbances) can be seen during treatment; occasionally see hemolytic anemia in persons with G6PD deficiency
Treatment for severe malaria is essentially its only current use; manufacturing may cease following approval of parenteral artemisinin due to ease of administration of the new drug and better safety profile.
Comment: ABSTRACT: Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, the limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for the treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.
Comment: This is an outstanding review. It provides a useful algorithm to guide the workup of the febrile returning traveler, diagnoses for consideration. Additionally, there are 3 concise tables that would be of great use to the clinician. The first addresses life-threatening conditions (viral, bacterial and protozoal) which should not be missed. The second concisely outlines the critical areas in the travel and medical history to be considered in assessing the febrile returned traveler and the diseases to consider when risks are identified. The third table has both clinical and public health implications as it concisely summarizes the serious transmissible infections.
Comment: This is an excellent editorial that summarizes the pros and cons of the use of the qSOFA vs the standard SOFA. The ability to rapidly apply the qSOFA to guide intervention at the time of presentation to an emergency department without relying on formulae or websites should be considered in assessing this tool’s usefulness. The qSOFA score ranges from 0 to 3. One point is given for each of the following: SBP < /=100 mm Hg; respiratory rate >/= 22/min, and evidence of altered mental status on Glasgow Coma Score (normal = 15, range 3-15).
Comment: The malaria treatment guidelines are provided online for clinicians and updated as needed by CDC. IMPORTANT: All persons treated for severe malaria with IV artesunate should be monitored weekly for up to four weeks after treatment initiation for evidence of hemolytic anemia.
Comment: This alphavirus carried by Aedes spp mosquitos has re-emerged in recent years in Africa, southern and SE Asia and the Indian Ocean islands (and now has appeared for the first time in the Caribbean islands). The disease associated with infection is usually associated with fever, headache, myalgia, rash and arthralgia which can be acute as well as chronic. It traditionally was thought to be associated with varying morbidity but only since 2005 has mortality been noted. Because Aedes spp, particularly Ae. albopictus is common in both Europe and the U.S. and infected larvae can overwinter, this virus poses a threat in the Americas.
Comment: This is an analysis of data collected in the GeoSentinel Surveillance system examining the risk of illnesses amongst 4779 ill travelers to common destinations in Mexico and Central America in the period 1996 to 2010. Although malaria was not commonly diagnosed at participating surveillance sites when compared with travelers to subSaharan Africa or parts of Asia, malaria was seen increasingly with more southern travel. The most frequent presenting syndromes included acute and chronic diarrhea, dermatologic diseases, febrile systemic illness, and respiratory disease. The overall risk of malaria was low; only 4 cases of malaria were acquired in Mexico (Proportionate Morbidity [PM} of 2.0 per1000 ill returned travelers) in 13 years, compared with 18 from Honduras (PM, 79.6 cases per 1000 ill returned travelers) and 14 from Guatemala (PM, 34.4 cases per 1000 ill returned travelers) during the same period. Plasmodium vivax malaria was the most frequent malaria diagnosis.
Comment: This is an analysis of 2004-2008 Salmonella spp isolates submitted to the CDC’s FoodNet foodborne disease active surveillance network in which travel-acquired infections were compared with non-travel associated infections. Among 23,712 reported cases with known travel status, 11% had traveled internationally in the 7 days before illness. Travelers with Salmonella infection tended to be older (median age, 30 years) than non-travelers (median age, 24 years; p< 0.0001), but were similar with respect to gender. The most common destinations reported were Mexico (38% of travel-associated infections), India (9%), Jamaica (7%), the Dominican Republic (4%), China (3%), and the Bahamas (2%). The 2 most commonly reported serotypes, regardless of travel status, were Enteritidis (19% of cases), and Typhimurium (14%). However, serotypes associated with enteric fever (S. typhi and S. paratyphi) were found in 10% of samples from travelers but only 0.5% of samples submitted from non-travelers.
Comment: Examines the increase in dengue worldwide as well as the reintroduction of endemic foci in the U.S. in southern Texas and in Key West and mainland Florida.
Comment: This prospective study of 1,091 adult patients with proven severe malaria (per WHO criteria) admitted to multiple hospital medical services affiliated with a single Indian medical school from September 2003 through December 2005. Severe monoinfection P. vivax was defined as severe malaria by WHO criteria, peripheral blood smear (PBS), rapid diagnostic test (RDT) and polymerase chain reaction (PCR) positive for P. vivax and negative for P. falciparum. Of 1,091 patients with malaria, 635 had P. falciparum malaria and 456 had P. vivax malaria; 40 had evidence of monoinfection of P. vivax; age 18-62 years with a mean of 30 years; most were male. Complications observed among this group were hepatic dysfunction and jaundice in 23 (57.5%) patients, renal failure in 18 (45%) patients, severe anemia in 13 (32.5%) patients, cerebral malaria in 5 patients (12.5%), acute respiratory distress syndrome in 4 patients (10%), shock in 3 patients (7.5%), and hypoglycemia in 1 (2.5%) patient, 2 (5%) died.
Comment: This case series describes 62 (60% males) consecutive adult patients presenting for care after returning to France from overseas with fever (>38oC) and exanthema (widespread rash) between January 2006 and September 2007. The most common diagnoses included chikungunya (35%), dengue (26%), and African tick-bite fever (10%). The cause of the rash was not identified in 8%. Other causes accounting for 1-5% of illnesses were: infectious mononucleosis, primary HIV infection, DMV, measles, rubella, varicella, primary toxoplasmosis, and acute schistosomiasis. When comparing chikungunya with dengue virus infection those with dengue infection had significantly greater leukopenia, neutropenia, lymphopenia, thrombocytopenia, and headache. Notably, those with chikungunya had characteristic arthralgia (100%) whereas arthralgia was absent in those with dengue infection.
Comment: This was a retrospective laboratory-based study of 960 filter paper blood spots collected from slide-positive malaria diagnosed amongst hospitalized persons by the Malaysian Ministry of Health between 2001 and 2006. Diagnostic microscopy recorded 44.6% P. vivax; 32.5% P. malariae, 22.5% P. falciparum, 0.2% P. ovale, and 0.2% mixed infections. P. knowlesi was detected in 260 of 960 (27.7%) of these samples by nested PCR; only 4 (0.4%) were confirmed as P. malariae. Additionally, 54 archived slides from 2003-2005 from outlying district hospitals and clinics with microscopically diagnosed P. malariae were further evaluated after whole blood slide extraction and nested PCR. 46 (85%) were found to be P. knowlesi; 5(15%) were confirmed as P. malariae. Four of the 46 archival cases were fatal; all had high parasitemia and significant hepato-renal dysfunction. These data suggest that P. knowlesi is not as rare as previously thought and suggest that aggressive management similar to that given for P. falciparum is warranted given the observed case fatality.
Comment: This prospective study of 118 febrile (T ≥37.5 oC by axilla) travelers >14 years of age, 10 days before or 10 days after their return without a specific diagnosis made on their first clinic visit upon return to Spain. All had nasopharyngeal swabs, blood, stool cultures collected. Malaria was sought in all patients. Amongst the group 73 had only respiratory symptoms, 12 had gastrointestinal (GI) symptoms, 5 had both respiratory and GI symptoms, and 28 had an undifferentiated febrile illness. In the respiratory and respiratory/GI illness group 44 were found to have a viral or bacterial respiratory pathogen with 46% of travelers to Latin America infected, and 37% of travelers to both Asia and Africa. The influenza virus was isolated from 18 persons (12 influenza A and 6 influenza B). Influenza A virus was isolated from travelers returning from Asia > Africa and Latin America. Rhinovirus was isolated from 11 persons returning from all continents. Parainfluenza viruses were isolated from 6 travelers and RSV and adenovirus from 4 each.
Comment: This is a report from the GeoSentinel Surveillance Network of 24,920 returning ill travelers evaluated in 31 international sites over a 10-year period ending in 2006. Febrile illness was the chief complaint in 6,957 persons (28%) seeking care post-travel; 26% of this group were hospitalized versus 3% of afebrile travelers. Amongst febrile persons, 35% had an undifferentiated fever, 15% had febrile diarrhea, and 14% had a febrile respiratory illness. The etiology of fever was dependent upon the region of the world that was visited and the reason for visit. Malaria was the most common specific diagnosis identified (21%) and accounted for 4 of 12 deaths among febrile travelers. The next most common cause of fever was dengue followed by enteric fever and rickettsial diseases. Vaccine-preventable infections were seen in 3% of travelers with fever (S. typhi infection [n=100], acute hepatitis A [n=41], and influenza A [n=29]. Those traveling to visit friends and relatives, so-called VFR travelers were more likely to have a vaccine-preventable febrile illness when compared to other febrile travelers (Odds Ratio 1.8, confidence interval 1.4-2.4, p< 0.001).
Comment: This is an analysis of data collected from 30 sites participating in the CDC-sponsored GeoSentinel Surveillance Network of specialized travel or tropical medicine clinics on 6 continents regarding 17,353 ill returned travelers (persons who had crossed an international border in the 10 years prior to presenting with their illness). Significant differences were noted in proportionate traveler morbidity and mortality among the developing regions of the world. The systemic febrile illness (SFI) rate was 594 per 1000 persons with SFI and was the highest in sub-Saharan Africa (718/1000). Malaria accounted for the greatest proportionate morbidity (352/1000 with sub-Saharan Africa accounting for 2-4 times the burden as other regions (622/1000). Dengue was the second leading cause of SFI (352/1000) with the greatest burden seen in travelers returning from Asia and the Caribbean. Acute diarrheal illness was most prevalent among travelers returning from south-central Asia whereas dermatological problems were most frequent in those who had visited the Caribbean, Central or South America.
Comment: This is a literature-based review and additional case synthesis by one world expert. There are 15 recognized tick-borne rickettsioses; 8 of the 15 have been reported in international travelers (African tick-bite fever, Mediterranean spotted fever, Indian tick typhus, Astrakhan fever, Rocky Mountain spotted fever, Queensland tick typhus, R. aeschlimannii infection and North Asian tick typhus. Off the ~400 cases of tick-borne rickettsioses reported among international travelers, most are due to either Rickettsia africae (Subsaharan Africa-African tick-bite fever) or R.conorii (North Africa/Mid-East/India--Mediterranean spotted fever). The incidence among travelers appears to be increasing for several possible reasons: increased ecotourism increased travel to previously restricted areas (such as to post-apartheid game parks in the Republic of South Africa), and increased diagnostic awareness. Provides recommendations for treatment.
Comment: Mefloquine/artesunate is more effective in the treatment of multi-drug resistant malaria in Thailand than quinine and was found to be safe in pregnancy.
Comment: CDC no longer recommends exchange transfusion for severe malaria due to limited evidence of any efficacy and potential adverse reactions.
Comment: This is the report of a retrospective case review of 708 febrile returning travelers all of whom were tested for Q fever (Coxiella burnetti infection). Five (0.7%) persons were found to be infected. All patients had a fever, 4/5 had a headache, 3/5 had arthralgia and myalgia, one had a dry cough, one was jaundiced, and one complained of malaise. Chest radiographs were normal in all 5, all 5 had an enlarged liver, spleen or both. All initially had normal white blood cell counts in the setting of thrombocytopenia (13,000-98,000 cells/mL) and abnormal transaminases. Treatment was with either doxycycline or ciprofloxacin. All recovered with no complications.
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