PATHOGENS

  • Approximately 30% of persons seeking medical care following travel have fever. Subsets listed in Table Table 1.
Table 1

Clinical Syndrome in Returning Traveler

Percentage

Undifferentiated Fever (no localizing signs)

35%

Acute diarrheal disease

15%

Respiratory infection

14%

Genitourinary illness

4%

Dermatological conditions

4%

Non-diarrheal gastrointestinal disease

4%

Other

24%

  • Pathogens causing fever: in declining order
    • Plasmodium spp (malaria): the leading cause of fever (21% of all fevers and 59% of undifferentiated fevers) and the leading cause of travel-related hospitalization and death.
      • Species include: P. falciparum (high case fatality rate if untreated), P. vivax, P. ovale, P. malariae, P. knowlesi (simian malaria found in Southeast Asia, rarely transmissible to humans and potential fatal).
    • Diarrhea/dysentery + fever: non-typhoidal Salmonella spp, Shigella spp. and Campylobacter spp. are the most commonly isolated organisms; fever is only seen in 10% of patients with E. histolytica (amebic dysentery).
    • Dengue virus: 6% of all fever and 18% of undifferentiated fever from endemic regions.
    • Salmonella enterica serovar typhi or paratyphi (enteric fever): 2% of all fever and 6% of undifferentiated fever.
    • Rickettsia spp: 2% of all fever and 5% of undifferentiated fever; 75% of these infections are tick-borne.
      • R. africae (cause of tick-bite fever) especially common after safaris or treks in Southern Africa.
    • Urinary tract infection/pyelonephritis: 3% of all fevers.
    • Tuberculosis: < 1% of all fevers.
    • Chikungunya virus: mosquito-borne disease, originally seen in South Asia, is now increasingly found in South East Asia, East and Central sub-Saharan Africa.
      • In 2013, cases reported in the Caribbean region (Saint Martin, Saint Barthelemy, Martinique, Guadeloupe, and Guyana). It may be associated with a fever/undifferentiated fever but is usually associated with arthralgia, which can be severe and may become chronic.
      • Dengue often part of ddx.
  • Uncommon systemic illnesses: also consider leptospirosis , amoebic liver abscess, Q fever, viral meningitis, relapsing fever.

CLINICAL

  • History is KEY in the returned traveler. 23% of returned travelers present with fever; patterns of fever and clinical findings similar for many infections.
    • Obtain detailed geographic travel and exposure history (including modes of possible exposure), vaccination history and treatment history is essential.
  • Always consider:
    • Malaria for every febrile patient who has been in a malarious area.
    • Enteric fever also needs to be considered as both Salmonella typhi and S. paratyphi, types A and B can cause a potentially life-threatening undifferentiated fever without other signs or symptoms.
    • Exposure history provides clues to certain pathogens. See Table Table 2..
  • Physical examination: seek to identify focal signs and symptoms that may assist you. Undifferentiated fever in the returned traveler poses the greatest challenge. Specific localizing findings should be used to help guide the clinician’s evaluation of each patient whenever possible. For example, look carefully for rash, lymphadenopathy, and/or hepatosplenomegaly.
  • Undifferentiated fever, incubation period < 2 wks: list by no means comprehensive.
  • Fever with hemorrhage, incubation period < 2 wks:
    • Meningococcemia
    • Leptospirosis
    • Dengue
    • Yellow fever
    • Congo-Crimean hemorrhagic fever
    • Hemorrhagic fevers of South America (Manchupo, Junin, Sabia, and Guanarito viruses)
    • Hemorrhagic fevers of Africa (Ebola, Rift Valley Fever, Marburg viruses, Lassa fever)
      • Note: regarding Viral hemorrhagic fevers (VHF, all): caused 4 distinct families of RNA, enveloped viruses (arenaviruses, filoviruses, bunyaviruses, and flaviviruses).
        • Most are biosafety level 4 agents, if suspicious immediately notify local/state health authorities.
        • Survival of VHF viruses in nature is dependent on an animal or insect host; geographically restricted distribution of diseases is based upon the host.
        • Humans are not the natural reservoir for any of these viruses. Human cases or outbreaks of VHFs occur sporadically and usually are not easy to predict.
  • Fever with CNS findings, incubation period < 2 wks:
  • Fever with pulmonary findings, incubation period < 2 wks:
  • Undifferentiated fever, incubation 2 wks-2mo:
  • Fever, incubation >2 mo after return:
  • Location of travel (undifferentiated fevers):
    • Sub-Saharan Africa: malaria >>> other causes of undifferentiated fever.
    • Southeast Asia: dengue > malaria >>> other causes of undifferentiated fever.
    • South Central Asia, especially India: malaria = typhoid/paratyphoid fever (especially if visiting family) = dengue.
    • Latin America/Caribbean: dengue > malaria >>> other causes of undifferentiated fever



Table 2.

EXPOSURE

SOME INFECTIONS TO CONSIDER

Animals or their products

Anthrax

Brucellosis

Q fever

Plague

Blood and body fluids

CMV

Hepatitis A, B, C, or D

HIV

Syphilis

Dogs, cats, bats, monkeys
(bites and saliva exposure)

Rabies

Herpes B virus (monkeys)

Fresh water

Leptospirosis

Schistosomiasis

Ingestion:
-- Raw vegetables and water plants
-- Raw or undercooked animal meat


Fascioliasis
Campylobacter,
E. coli O157-H7 (and other STECs)
Toxoplasmosis
Trichinosis

Raw or undercooked shellfish

Clonorchiasis

Hepatitis A

Hepatitis E

Paragonimiasis

Vibrios

Unpasteurized milk/milk products

Brucellosis

Salmonellosis

Tuberculosis

Rodents

Hantavirus

Hemorrhagic fevers including Lassa fever

Plague

Rat-bite fever

Ticks

Relapsing fever (Borrelia spp.)

Hiking in the bush

African tick-bite fever (Southern Africa)

Scrub typhus (eastern Asia, western Pacific)

DIAGNOSIS

  • Initial evaluation: routinely obtain the following,
    • Malaria thick and thin smear if travel to a malarious area regardless of having taking chemoprophylaxis. Obtain serial smears if initial smear is negative in at-risk traveler.
      • Rapid tests (e.g., histidine-rich protein [HRP]-2 antigen detection): highly specific but not as sensitive as thick and thin smears.
      • Five species infect humans: P. falciparum (may be fatal, treatment is urgent), P. vivax, P.ovale, P. malariae, P. knowlesi (may be fatal; treatment is urgent).
        • P. knowlesi usually infects monkeys and rarely humans in SE Asia; can be mistaken for P. malariae on smear; suspect if high-level parasitemia (≥2.5% of RBCs infected) and lab reports P. malariae. PCR identification needed to confirm dx.
      • Usual presentation within 2 wks of return in 65% with falciparum malaria present compared with 27% vivax malaria. Vivax malaria typically presents >2 months after return (60%).
    • CBC with differential and platelets, blood cultures
    • Urinalysis (with culture if abnormal sediment)
    • Liver enzymes
  • Dengue: suspect patient with fever, frontal headache, myalgia with or w/o skin petechial or maculopapular eruption up to 14 day after return.
    • Most (66%) present within 7 d of return.
    • Leukopenia +/- thrombocytopenia.
    • Severe infection may cause hemorrhage, seizures, shock.
    • Diagnosis: serology (IgM, collected >5 days after symptom onset), virus isolation from blood (research labs only), PCR.
  • Rickettsial infection: evaluate for eschar/tache noire [ Figure] may be present from tick bite.
    • Culture is the most sensitive and specific method but is restricted to reference laboratories [bio-hazard].
    • PCR detection possible at specialized laboratories performed on blood, serum or tissue biopsies. Inoculation eschar is the best biopsy sample to assay.
    • Pathogen-specific serology is the most commonly used in dx but often tests available (e.g., Weil-Felix or immunofluorescence assay) cannot distinguish species due to cross reactivity. Western blot and cross-absorption available only in reference laboratories.
    • Hints of rickettsial species based upon geographic location of acquisition.
  • Enteric fever (typhoid or paratyphoid):
    • Blood and stool cultures with best yields.
    • Seismologic tests lack sensitivity and specificity.
    • Bone marrow culture 90% sensitive and not affected by up to 5 days of antibiotics, but rarely performed in US.
    • Current attenuated and killed typhoid vaccines are only 60-70% effective in preventing S. typhi (only).
  • Hemorrhagic fever: pathogens may be transmitted nosocomially, many are Biosafety Level (BSL)-4 agents.
    • Institute barrier isolation in a private room until communicable agents are ruled out.
    • Any returned traveler with hemorrhagic manifestations requires URGENT intervention.
    • Obtain an infectious disease consult, inform infection control and contact the Special Pathogens Branch at CDC Division of Viral Diseases in Atlanta Ga (404.639.1511) for assistance.
  • Fever with pulmonary findings: viral and bacterial cultures of respiratory secretions, CXR or Chest CT.
  • Persistent or relapsing fever: thick and thin blood smears to examine for malaria and Borrelia spp. Obtain blood cultures.
  • Leptospirosis:
    • Serology (MAT preferred, available at CDC)
    • Culture urine, blood, CSF (alert lab, need special media [Fletcher’s media]).
  • Amebic liver abscess: hepatic ultrasound and E. histolytica serology.
    • Liver aspirate (usually not done if serology available).
    • Serology has >95% sensitivity.
  • Viral meningitis: lumbar puncture, culture and PCR for arboviruses, enteroviruses.
  • Chikungunya: three possible diagnostic modalities. All 3 may be positive if collected within the first week after onset of symptoms.
    • Virus isolation: possible isolation from acute serum specimens (< 8 days) of illness.
    • RT-PCR: usually positive in the first week after symptom onset
    • Serology: IgM virus-specific antibody by capture ELISA or a 4-fold rise IgG antibody between acute (during 1st 8 days of illness) and convalescent (10-14 days after the first) antibody.

TREATMENT

Uncomplicated Plasmodium falciparum , Plasmodium knowlesi, or Species Unspecified

  • Treatment for malaria should NOT be initiated until the diagnosis has been confirmed by laboratory investigations unless signs of severe malaria (i.e., complicated malaria) are present.
    • "Presumptive treatment" without the benefit of laboratory confirmation should be reserved for extreme circumstances (strong clinical suspicion, severe disease, impossibility of obtaining prompt laboratory confirmation).
    • If the patient used malaria chemoprophylaxis, choose a different agent for treatment.
  • Chloroquine-sensitive areas: Central America west of Panama Canal; Haiti; the Dominican Republic; and most of the Middle East.
    • Note chloroquine-resistant P. falciparum areas in the Middle East include Iran, Oman, Saudi Arabia and Yemen.
    • Infections acquired in the Newly Independent States of the former Soviet Union and Korea to date have been uniformly caused by P. vivax and should therefore be treated as chloroquine-sensitive infections.
      • Chloroquine phosphate (Aralen and generics) 600 mg base (1,000 mg salt) orally immediately, followed by 300 mg base (500 mg salt) PO at 6h, 24h and 48h. Total dose: 1,500 mg base (2,500 mg salt).
      • Hydroxychloroquine 620 mg base (800 mg salt) PO initially then 310 mg base (400 mg salt) at 6h, 24h and 48h after the initial doses (total 1550 mg = 2000 mg salt).
      • Any treatment for chloroquine-resistant malaria (noted below).
  • Chloroquine-resistant or unknown resistance in persons without severe malaria and who can tolerate oral treatment: fixed drug combinations are preferred as they can be used in adults, pregnant women and pediatric populations.
    • Fixed combination treatments:
      • Artemether/lumefantrine 20 mg/120 mg (CoartemTM) 4 tablets orally at hour 0 and hour 8 during the first 24 hours. Then 4 tablets twice daily on days 2 and 3 (total treatment is 24 tablets. Pediatric dosing for 2 months to 16 years is by weight (see Table Table 3).
      • Atovaquone/proguanil (Malarone, adult tab = 250 mg/100 mg): 4 adult tabs PO daily x 3 days (taken with milk or a fatty meal).
        • Pediatric dosing: per weight basis and should not exceed the adult dose (see Table Table 4).

          Table 3

          Body Weight

          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 day 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


          Table 4

          Body Weight

          Atovaquone/proquanil Pediatric Dosing

          5-8 kg

          125 mg/50 mg PO daily x 3d

          9-10 kg

          187.5 mg/75 mg PO daily x3d

          11-20 kg

          250 mg/100 mg PO daily x3d

          21-30 kg

          500 mg/200 mg PO daily x 3d

          31-40 kg

          750 mg/300 mg PO daily x3d

          >40kg

          1000 mg/400 mg PO daily x3d


    • Alternative regimens:
    • Least preferred treatment: mefloquine (generics only) 684 mg base (750 mg salt) PO as initial dose, followed by 456 mg base (500 mg salt) PO given 6-12 hours after initial dose. Total dose = 1,250 mg salt.

Uncomplicated Plasmodium malariae (All regions of the world)

  • Preferred: chloroquine phosphate (Aralen and generics) 600 mg base (1,000 mg salt) oral immediately followed by 300 mg base (500 mg salt) PO at 6h, 24h and 48h. Total dose: 1,500 mg base (2,500 mg salt).
  • Alternative: hydroxychloroquine (PlaquenilTM and generics) 620 mg base (800 mg salt) PO immediately, followed by 310 mg base (400 mg salt) PO at 6h, 24h and 48h. Total dose: 1,550 mg base (2,000 mg salt).

Uncomplicated Plasmodium vivax and P. ovale

  • All P. ovale is sensitive to chloroquine.
  • All P. vivax is sensitive to chloroquine except that acquired in Papua New Guinea or Indonesia. Although isolated cases of P. vivax have been reported from other areas of the world, initial treatment should be with chloroquine.
  • Chloroquine sensitive P. vivax regions:
    • Chloroquine phosphate 1g salt (600 mg base) orally once, then 500 mg salt (300 mg base) 6 h later, then 500 mg at 24 h and 48 h followed by primaquine phosphate PO x 14 days (see below)
    • Hydroxychloroquine as above.
    • Patients with P. vivax (or P. ovale) must be tested for GGPD deficiency since patients should undergo treatment of liver stage infection with primaquine phosphate following standard blood-stage malaria treatment of infection:
      • Primaquine phosphate, adult dosing 30 mg base PO daily x 14 days
      • Pediatric dosing: 0.5 mg/kg once daily for 14 days not to exceed a maximum dose: 30 mg/day.
      • Consult an infectious or tropical diseases specialist for treatment of patients with G6PD deficiency or with decreased G6PD activity.
  • Chloroquine-resistant P. vivax regions: (Papua New Guinea and Indonesia):
    • Atovaquone/proguanil (MalaroneTM): 250 mg atovaquone/ 100 mg proguanil (adult tab), 4 adult tabs PO daily x 3 days (taken with milk or a fatty meal).
      • Pediatric dosing: single per weight dose per day x 4 days as in Table Table 4 above.
    • Quinine sulfate plus either doxycycline or tetracycline (contraindicated in children < 8 years) followed by primaquine phosphate as above
    • Children < 8 years option: mefloquine 15 mg/kg followed 12 hours later by 10 mg/kg/dose followed by primaquine phosphate as outlined above.
    • If clinical improvement is not seen within 48-72 hours, an alternative therapy should be used for retreatment.
  • Alternative treatments options for chloroquine-resistant P. vivax regions: If other treatments not available, if treatment not being tolerated or if treatment benefits outweigh the risks:
    • Artemether/lumefantrine 20 mg/120 mg (CoartemTM) 4 tablets orally at hour 0 and hour 8 during the first 24 hours. Then 4 tablets twice daily on days 2 and 3 (total treatment is 24 tablets. Pediatric dosing for 2 months to 16 years is by weight (See Table Table 3). Persons with P.vivax or P. ovale should receive primaquine to prevent relapse ( 0.5 mg/kg orally once daily for 14 days (maximum dose = 30 mg base).
  • Areas where chloroquine-resistant P. falciparum co-circulates with P. vivax: consider treatment with one of the oral treatments outline for uncomplicated P. falciparum provided in previous sections.

Uncomplicated Malaria Treatment Options for Pregnant Women

  • Plasmodium (all species) chloroquine-sensitive areas: chloroquine and hydroxychloroquine are considered safe in pregnancy but can only be used to treat sensitive malaria species. The treatment regimen is the same as for non-pregnant patients.
    • Primaquine phosphate is contraindicated in pregnancy and breast feeding women and should not be used at the end of treatment for the liver stage of P. vivax or P. ovale.
    • Following treatment for P. vivax or P. ovale, the pregnant patient should be maintained on chloroquine or hydroxycloroquine at chemoprophylactic doses for the remainder of pregnancy and then women without G6PD deficiency should be receive treated with primaquine phosphate following delivery.
    • If breastfeeding is planned, the chemoprophylactic regimen should be maintained throughout breastfeeding and final primaquine treatment provided at the end of breast feeding.
  • Chloroquine-resistant P. falciparum: use quinine sulfate plus clindamycin.
    • Quinine sulfate: 542 mg base (650 mg salt) PO three times daily x 3 to 7 days AND clindamycin: 20 mg base/kg/day PO divided three times daily x 7 days.
    • The quinine duration varies due to where the individual acquired the infection:
      • Southeast Asia = 7 days
      • Infections acquired elsewhere = 3 days
  • Chloroquine-resistant P. vivax (Papua New Guinea and Indonesia):
    • Quinine sulfate 650 mg salt PO three times daily three times daily x 7 days.
    • Thereafter, the woman should be maintained on weekly mefloquine at chemprophylactic dosing for the remainder of pregnancy as mefloquine is FDA approved for chemoprophylaxis in pregnancy.
    • Women without G6PD deficiency should receive primaquine phosphate following delivery. If breastfeeding is planned, the chemoprophylactic regimen should be maintained throughout breastfeeding and final primaquine treatment provided at the end of breast feeding.
  • General comments regarding drugs in pregnancy:
    • Primaquine is contraindicated in pregnant and lactating women.
    • Mefloquine is generally not recommended for treatment in pregnant women due to a possible increase in stillbirths; however, it may be used if it is the only treatment option available and if the potential benefit is judged to outweigh the potential risks. Mefloquine is approved for use in pregnancy for chemoprophylaxis.
    • Doxycycline and tetracycline are not generally used in pregnant women. However one or the other may be used in combination with quinine if other treatment options are not available or not tolerated.
    • Atovaquone/proguanil (MalaroneTM) and artemether/lumafantrine (CoartemTM) are classified as pregnancy Category C agents, not usually recommended. However, if other treatment options are not available or not tolerated, agents can be considered. After delivery, women without G6PD deficiency should be treated with primaquine phosphate as previously outlined.

Complicated/Severe Plasmodium falciparum or Intolerance of Oral Treatment (All regions)

  • Oral treatment is NOT recommended for the treatment of severe/complicated malaria.
    • Preferred: quinidine gluconate 10 mg salt/kg IV loading dose (max 600 mg) in saline over 1-2h, then constant drip of 0.02 mg quinidine salt/kg/min until parasitemia < 1% PLUS
      • Doxycycline 100 mg IV or orally twice daily OR
      • Clindamycin (5 mg base/kg every 8 hours)
      • Continue parenteral therapy until the parasite density is < 1%. Then change to an oral regimen outlined for uncomplicated malaria for a combined course of treatment of 7 days.
      • Oral doxycycline or clindamycin can be used if the patient has no problem with oral intake.
    • IMPORTANT: use of IV quinidine requires admission to a telemetry unit to monitor closely for EKG changes (QT prolongation and ventricular arrhythmia), hypoglycemia and hypotension.
    • To determine availability of this drug, call call Eli Lilly Customer Services at (800) 821-0538 or (317) 276-2000.
  • Indication for use of investigational artesunate (IV):
  1. Quinidine is unavailable.
  2. Patient has adverse effects from quinidine or contraindications to quinidine.
  3. >10% parasitemia present
  • IV artesunate available through the CDC Malaria Hotline: 770-488-7788 (M-F, 8 a.m.- 4:30 p.m., Eastern Time), or after hours, call: 770-488-7100, and request to speak with a HHS/CDC Malaria Branch clinician.
  1. Exchange transfusion: no longer considered routine recommendation, some still consider in presence of parasitemia >10%, cerebral malaria, ARDS, or renal complications. Exchange transfusion has not been proven to be beneficial in an adequately powered randomized clinical trial.
  2. Monitor parasite density every 12 hours until it falls to < 1%.

Febrile Diarrhea/Dysentery

  • Non-typhoidal Salmonella spp:
    • Ill but immunocompetent persons with severe diarrhea (9-10 stools/d), high fever, or who require hospitalization for management should receive antibiotics (note: diarrhea alone is NOT an indication for treatment of those with non-typhoidal gastroenteritis):
      • Antibiotic resistance patterns should guide treatment or modification of empiric therapy. Fluoroquinolone resistance is increasing worldwide.
      • Empiric treatment:
        • Ceftriaxone 1-2 g IV once daily
        • Cefotaxime 2 g IV every 8 h
        • Change to other agent based on resistance pattern.
      • All immunocompromised persons (organ transplant, HIV-infected, persons received corticosteroids or immunosuppressive therapies), those with sickle cell disease, hemoglobinopathies, cirrhosis, cancer or lymphoproliferative disease): treat regardless of severity of symptoms.
  • Shigella spp: healthy adults, most shigella infections are self-limiting but for public health reasons, all persons with a positive stool culture should be treated to decrease shedding and person-to-person spread.
    • Antibiotic resistance is widespread.
    • Empiric rx should be provided to the following groups before culture results are reported:
      • Age >64 years, malnourished persons, all HIV-infected persons regardless of CD4 count or viral load, bacteremic persons, food handlers.
      • Ciprofloxacin 500 mg orally twice daily x 5 d (consider 7-10 days for immunocompromised pts).
      • Other fluoroquinolones may also be used.
      • Base final treatment on culture and sensitivity results.
  • Campylobacter spp: treat if fever/dysentery or severe illness. Other indications include >64 years, pregnant, immunocompromised should also be treated.
    • Drug resistance is widespread.
    • Preferred: erythromycin stearate 500 mg orally twice daily for 5 days
    • Alternative: azithromycin
  • Amebic dysentery/colitis:
    • Metronidazole 500-750 mg orally three times daily for 10 d
    • Tinidazole 600 mg orally twice daily for 5 d
    • Above therapies should be followed by a luminal amebicidal agent active against E. histolytica cysts:
      • Iodoquinol 650 mg orally three times daily for 20 d
      • Paromomycin 25-35 mg/kg/d orally divided three times daily for 7 d
      • Diloxanide (not available in the U.S.) 500 mg orally three times daily for 10 d

Enteric Fever (Salmonella enterica serovar Typhi or Paratyphi)

  • Locale of acquisition will impact treatment choices due to local resistance patterns. Empiric recommendations given below. Adjust based on culture results.
    • Acquired in South-central Asia or East Asia:
      • Uncomplicated infection:
      • Complicated infection:
    • Acquired in Eastern Europe, Middle East, South America or Sub-Saharan Africa:
      • Uncomplicated infection:
      • Complicated infection:
    • Acquisition location unknown or in Southeast Asia:
      • Uncomplicated infection:
      • Complicated infection:
  • Dexamethasone use controversial, may decrease mortality in severe typhoid fever cases where delirium, coma, obtundation or stupor are present.
  • An infectious disease specialist should be consulted in all cases of typhoid fever given its low prevalence in the developed world.
  • Consult a surgeon if GI perforation, GI hemorrhage is suspect.
  • Ileal perforation usually occurs in the third week of febrile illness.
  • Relapse (typhoid fever): occurs in 1-6% of immunocompetent persons, typically 2-3 weeks following resolution of symptoms.

Chikungunya

  • No chikungunya-specific antiviral drug treatment available
  • Symptomatic treatment is recommended (after excluding more serious conditions including malaria, enteric fever and dengue)
    • Avoid aspirin because of bleeding in a small number of patients and the risk of Reye’s syndrome in children younger than 12 years of age
    • Acetaminophen or NSAIDs may help to relieve the arthritic component of the disease
    • Fluid repletion important

Dengue

  • No dengue-specific treatments available.
    • Usually a self-limited disease; requires only supportive treatment.
    • Avoid NSAIDs, aspirin, and steroids.
  • Closely monitor all patients with evidence of hemorrhagic associated symptoms: tachycardia, prolonged capillary refill time, cool or mottled skin, evidence of volume depletion, narrowed pulse pressure, hypotension, rising packed cell volume or falling platelet count. Such patients should be hospitalized for correction of volume deficits and for monitoring.
  • If dengue hemorrhagic fever is suspected, consider consult with a specialist.

Rickettsial Infections

  • If suspected, begin treatment empirically since diagnostic test results often delayed.
  • Preferred:
    • Outpatient: doxycycline 100 mg orally twice daily x 5 d or until 48h after defervescence.
    • Severely ill/hospitalized: doxycycline 100 mg IV twice daily for up to 24 h after defervescence, then change to oral doxycycline 100 mg twice daily to complete 5 days post defervescence. Consider doxycycline 200mg loading dose.
  • Pregnant women: if life-threatening infection, doxycycline should be used despite being a Category D agent. Consider consultation with an infectious disease expert.

TREATMENT REGIMEN DETAILS

Severe Malaria:

  • Persons with a positive blood smear OR history of recent possible exposure and no other recognized pathology who have one or more of the clinical criteria listed below are considered to have severe malaria:
    • Impaired consciousness/coma
    • Severe normocytic anemia
    • Renal failure
    • Pulmonary edema
    • Acute respiratory distress syndrome
    • Circulatory shock
    • Disseminated intravascular coagulation
    • Spontaneous bleeding
    • Acidosis
    • Hemoglobinuria
    • Jaundice
    • Repeated generalized convulsions
    • Parasitemia of >5%
  • Severe malaria is practically always due to P. falciparum.
    • Aggressive treatment required with parenteral antimalarial therapy, if available.
      • Treatment with IV quinidine should be initiated as soon as possible after diagnosis secured. Use IV loading dose of quinidine unless they have received more than 40 mg/kg of quinine in the preceding 48 hours or if they have received mefloquine within the preceding 12 hours.
      • Consultation with a cardiologist and a physician with experience treating malaria (if available) is advised when treating malaria with quinidine.  
      • Quinidine IV use requires:
        • Blood pressure monitoring (hypotension)
        • Cardiac monitoring (widened QRS complex and/or lengthened QTc interval)
        • Blood glucose checks (hypoglycemia)
      • Cardiac complications: if severe may warrant temporary discontinuation of the drug or slowing of the intravenous infusion. Do NOT delay treatment with quinidine while waiting for parenteral artesunate (to arrive from CDC, for example).
    • See Treatment of complicated/severe P. falciparum section for use of investigational artemesin for patients with severe malaria.
  • Exchange transfusion if the parasite density (i.e. parasitemia) is >10% remains a consideration though less favored now than historically [4] OR if the patient has altered mental status, non-volume overload pulmonary edema, or renal complications.
  • Parasite density: estimate by examining a monolayer of red blood cells (RBCs) on the thin smear under oil immersion magnification. Slide should be examined where the RBCs are more or less touching (approximately 400 RBCs per field). Parasite density estimated by percentage of infected RBCs; monitor q 12h.
    • If exchange transfusion employed, continue until the parasite density is < 1% (usually requires 8-10 units).
    • IV quinidine administration should not be delayed for exchange transfusion and can be given concurrently throughout the exchange transfusion.
  • Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy.

Selected Drug Comments

Drug

Recommendation

Artemether/lumefantrine (CoArtem)

Each dose should be taken with fatty food to be effective because lumefantrine is highly lipophilic .

Atovaquone/proquanil (MalaroneTM)

Use with caution for treatment in persons with low GFR (10-50 ml/min). It is unlikely to removed by hemodialysis or peritoneal dialysis. Atovoquone has a 2-3 day half-life whereas the proguanil has a half life of 12-21 hours.

Azithromycin

Off label use for the treatment of mild S. typhi infection acquired in Southeast Asia when other agents not well tolerated

Ceftriaxone

Cross allergy with penicillin lower than with first generation cephalosporins; it has been used effectively in the treatment of enteric fever.

Chloroquine

Remains an effective prophylaxis and treatment for malaria in some areas. Pruritis not uncommon in persons with darker skin pigmentation. Lower side effect profile than mefloquine.

Hydroxychloroquine

Studies done in the 1950s comparing chloroquine and hydroxychloroquine for treatment in rhematoid 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.

Mefloquine

Do not use for prophylaxis or treatment of P. falciparum acquired in Thailand, Laos, or Cambodia. Best administered with food; coadminstration with fluroquinolones, antiarrhythmics, macrolides may prolong QTc.

Primaquine

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.

Quinine

Cinchonism (tinnitis, headache, nausea, abdominal pain, visual disturbances) can be seen during treatment; occasionally see hemolytic anemia in persons with G6PD deficiency

Quinidine

Treatment for severe malaria is essentially its only current use; manufacturing may cease following approval of parenteral artemesinin due to ease of administration of the newe drug and better safety profile.

OTHER INFORMATION

  • Consider consultation with an infectious disease or tropical medicine expert for any returned traveler with undifferentiated fever.--especially if suspects include malaria, enteric fever, viral hemorrhagic fever, or patient has neurological findings.
  • Malaria in pregnancy is associated with high rates of both maternal and perinatal morbidity and mortality. Pregnant women are three times more likely to develop severe disease than non pregnant women acquiring infection in the same area. Infection in pregnancy can lead to spontaneous abortion, premature delivery, low birth weight, congenital infection, and perinatal death.

Basis for recommendation

  1. Centers for Disease Control and Prevention; Treatment of Malaria (Guidelines For Clinicians); http://www.cdc.gov/malaria/resources/pdf/clinicalguidance.pdf. April 2011.

    Comment: The malaria treatment guidelines are provided on-line for clinicians and updated as needed by CDC.

  2. Jensenius M, Fournier PE, Raoult D: Rickettsioses and the international traveler. Clin Infect Dis 39:1493, 2004  [PMID:15546086]

    Comment: This is a literature-based review and additional case synthesis by one world experts. There are 15 recognized tick-borne rickettsioses; 8 of the 15 have ben 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 ecotoursim, 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.

References

  1. Burt FJ et al: Chikungunya: a re-emerging virus. Lancet 379:662, 2012  [PMID:22100854]

    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, particulary Ae. albopictus is common in both Europe and the U.S. and infected larvae can overwinter, this virus poses a threat in the Americas.
    Rating: Important

  2. CDC. Exchange tranfusion no longer recommended. http://www.cdc.gov/malaria/new_info/2013/exchange_transfusion.html (July 2013)

    Comment: CDC no longer recommends exchange transfusion for severe malaria due to limited evidence of any efficacy and potential adverse reactions.

  3. Flores-Figueroa J et al: Patterns of illness in travelers visiting Mexico and Central America: the GeoSentinel experience. Clin Infect Dis 53:523, 2011  [PMID:21832261]

    Comment: This is an analysis of data collected in the GeoSentinel Surveillance system examining 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 (Proprotionate 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.

  4. Franco C et al: The dengue threat to the United States. Biosecur Bioterror 8:273, 2010  [PMID:20718665]

    Comment: Examines the increase in dengue worldwide as well as reintroduction of endemic foci in U.S. in southern Texas and in Key West and mainland Florida.

  5. Griffith KS et al: Treatment of malaria in the United States: a systematic review. JAMA 297:2264, 2007  [PMID:17519416]

    Comment: This review provides the underlying rationale for the CDC’s treatment guidelines utilizing an in-depth Medline review of the literature from 1966-2006. The safety and efficacy of each of the regimens is provided.
    Rating: Important

  6. Johnson LR et al: Salmonella infections associated with international travel: a Foodborne Diseases Active Surveillance Network (FoodNet) study. Foodborne Pathog Dis 8:1031, 2011  [PMID:21563923]

    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-aquired 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 nontravelers (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), 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.

  7. McGready R et al: Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 94:689, 2000 Nov-Dec  [PMID:11198658]

    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.

  8. Pan American Health Organization. Preparedness and Response for Chikungunya Virus: Introduction in the Americas. Washington D.C: PAHO. 2011. ISBN: 978-92-75-11632-6

    Comment: Document reflects on growing frequency of CHKV outbreaks and how they could be limited.

  9. Hochedez P et al: Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg 78:710, 2008  [PMID:18458301]

    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, 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.

  10. Wilson ME et al: Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis 44:1560, 2007  [PMID:17516399]

    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 undifferentiated fever, 15% had febrile diarrhea, and 14% had a febrile respiratory illness. The etiology of fever was dependent upon region of the world that was visited and 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 travellers 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).
    Rating: Important

  11. Freedman DO et al: Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 354:119, 2006  [PMID:16407507]

    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 travellers (persons who had crossed an international border in the 10 years prior to presenting with their illness). Significant differences were noted in proportionate traveller morbidity and mortality among the developing regions of the world. Systemic febrile illness (SFI) rate was 594 per 1000 persons with SFI and was 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.
    Rating: Important

  12. Ta TH et al: Q Fever in returned febrile travelers. J Travel Med 15:126, 2008 Mar-Apr  [PMID:18346248]

    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 fever, 4/5 had 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.

  13. Kochar DK et al: Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg 80:194, 2009  [PMID:19190212]

    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.
    Rating: Important

  14. Camps M et al: Incidence of respiratory viruses among travelers with a febrile syndrome returning from tropical and subtropical areas. J Med Virol 80:711, 2008  [PMID:18297697]

    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 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 travellers to both Asia and Africa. Influenza virus 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.

  15. Cox-Singh J et al: Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis 46:165, 2008  [PMID:18171245]

    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 suggests that aggressive management similar to that given fro P. falciparum is warranted given the observed case fatality.
    Rating: Important

Media

Figure

Fever in the returned traveler from tropical areas is a sample topic from the Johns Hopkins Antibiotic (ABX) Guide.

To view other topics, please or purchase a subscription.

Johns Hopkins Guides provide diagnosis, management, and treatment guidance for infectious diseases, diabetes, and psychiatric conditions. Learn more.

Last updated: February 26, 2014