Fever in the returned traveler from tropical areas

Noreen A. Hynes, M.D., M.P.H., D.T.M.&H.

PATHOGENS

CLINICAL

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

Syphilis

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

Rabies

Herpes B virus (monkeys)

Freshwater

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

Vibrio spp.

Unpasteurized milk/milk products

Brucellosis

Salmonellosis

Tuberculosis

Rodents

Hantavirus

Hemorrhagic fevers including Lassa fever

Plague

Rat-bite fever

Ticks

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)

DIAGNOSIS

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 including 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).
      • Alternatives: 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). DO NOT USE if this drug was used for chemoprophylaxis.
        • 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 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


          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:
      • Quinine sulfate plus one of the following: doxycycline, tetracycline or clindamycin.
      • Quinine sulfate: 542 mg base (650 mg salt) PO three times daily x 3 (if malaria acquired outside of Southeast Asia) to 7 days (for malaria acquired in Southeast Asia).
      • Doxycycline: 100 mg PO twice daily x 7 days. DO NOT use for treatment if this agent was used for chemoprophylaxis
      • Tetracycline 250 mg PO four times daily x 7 days. DO NOT use for treatment if this doxycycline was used for chemoprophylaxis
      • Clindamycin 20 mg base/kg/day PO divided in three times daily x 7 days (clindamycin may be less efficacious than doxycycline or tetracycline when combined with quinine).
    • 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. DO NOT use for treatment if this agent was used for chemoprophylaxis

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 for liver stage infection (antirelapse treatment):
      • 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.
      • Tafenoquine
        • Adult dosing: 300 mg orally once
        • Pediatric dosing (for patients 16 years and older): 300 mg orally once
      • Consult an infectious or tropical diseases specialist for the 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, alternative therapy should be used for retreatment.
  • Alternative treatments options for chloroquine-resistant P. vivax regions: If other treatments are not available, if treatment is 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, 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 breastfeeding 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 hydroxychloroquine at chemoprophylactic doses for the remainder of the 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 breastfeeding.
  • 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 x 7 days.
    • Thereafter, the woman should be maintained on weekly mefloquine at chemoprophylactic 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 breastfeeding.
  • 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/lumefantrine (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 drugs (all regions)

  • Oral treatment is NOT recommended for the treatment of severe/complicated malaria.
  • See additional detailed information in the Treatment Regimen Details section below.
    • Recommended
      • Adult and Pediatric Regimen: Artesunate (now commercially available or if not in stock or unable to administer within 24 hours, call CDC’s Malaria Hotline: 9 am to 5 pm Mon-Fri --- 770-488-7100 or Toll-free 855-856-4713; After hours, weekends, and holidays: 770-488-7100)
        • Artesunate
          • 1 dose = 2.4 mg/kg
          • IV doses (3 in total) at 0, 12, and 24 hours
          • NOTA BENE: If IV artesunate is not readily available: INITIALLY give ORAL antimalarials (see the above) while obtaining IV Artesunate. When IV artesunate arrives, discontinue oral antimalaria and initiate IV treatment. IF ORAL TREATMENT is NOT tolerated, consider administration by nasogastric tube or give after and antiemetic.
        • PLUS reassessment and follow-on treatment below
      • Reassessment and Follow-On Treatment (See Uncomplicated falciparum malaria above for oral dosing)
        • Reassess parasite density at least 4 hours after the 3rd IV dose of artesunate
        • Parasite density less than or equal to 1 percent AND the patient is tolerating oral medications: Give a COMPLETE follow-on ORAL regimen with one of the following:
          • Artemether-lumefantrine (CoArtemTM): PREFERRED; or
          • Atovoquone-proguanil (MalaroneTM); or
          • Quinine sulfate PLUS doxycycline OR in children less than 8 years or pregnant women substitute doxycycline with clindamycin; or
          • Mefloquine (only if NO OTHER TREATMENT OPTIONS ARE AVAILABLE)
        • Parasite density greater than 1 percent: continue IV artesunate at the same dose, each day for up to 6 more days until the parasite density is 1 percent or less.
          • Able to take oral medications: Give the complete follow-on regimen (See Uncomplicated falciparum malaria above for oral dosing)
          • If unable to take oral medications, continue IV artesunate every day for up to 6 more days until the patient can take oral medication and then give the complete follow-on regimen
  • IMPORTANT: All persons treated for severe malaria with IV artesunate should be monitored WEEKLY for up to 4 WEEKS after treatment initiation for evidence of hemolytic anemia.
    • IV artesunate is well tolerated.
    • While rare, delayed post-artemisinin hemolytic anemia has been noted in published case reports following treatment of severe malaria with IV artesunate.
    • Persons with higher parasite density seem to have a higher likelihood of delayed hemolytic anemia after treatment.
    • Weekly laboratory evaluation should include:
      • Hemoglobin,
      • Reticulocyte count,
      • Haptoglobin,
      • Lactate dehydrogenase (LDH), and
      • Total bilirubin.
    • Depending on the intensity of hemolysis and the presence of anemia signs and symptoms, a blood transfusion may be needed.
    • Reporting cases of delayed post-artemisinin hemolytic anemia:
      • Those receiving IV artesunate from CDC should be reported to CDC no longer than 24 hours after diagnosis.
      • Those receiving commercially available Artesunate for InjectionTM should be reported to MedWatch, FDA’s Safety Information and Adverse Event Reporting Program.
  • Exchange transfusion: no longer considered routine recommendation as this procedure has not been proven to be beneficial in an adequately powered randomized clinical trial.

Febrile Diarrhea/Dysentery

  • Non-typhoidal Salmonella spp:
    • Ill but immunocompetent persons with severe diarrhea (9-10 or more 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 (see above) should guide treatment or modification of empiric therapy.
      • Empiric treatment:
        • Ceftriaxone 1-2 g IV once daily
        • Cefotaxime 2 g IV every 8 h
        • Change to other agents based on resistance pattern.
      • All immunocompromised persons (organ transplant, HIV-infected, persons who received corticosteroids or immunosuppressive therapies), those with sickle cell disease, hemoglobinopathies, cirrhosis, cancer or lymphoproliferative disease: treat regardless of the severity of symptoms.
  • Shigella spp: In 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 and increasing. High levels of multidrug resistance (ciprofloxacin, trimethoprim-sulfamethoxazole, and azithromycin) in the Asian Subcontinent and Sub-Sahran Africa)
    • 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.
      • Levofloxacin: 500 mg orally once daily x 3 d
      • Ciprofloxacin 500 mg orally twice daily x 5 d
      • Azithromycin: 500 mg orally once daily x 3 days
      • Cefixime: 200 mg orally twice daily for 5 days
      • Trimethoprim-sulfamethoxazole 160/800 mg (one double-strength tablet) orally twice daily x 5 days
      • Ampicillin: 500 mg orally every 6 hours x 5 days
      • Base final treatment on culture and sensitivity results (consider adding 2-4 days of treatment for immunocompromised patients)
  • Campylobacter spp: treat if fever/dysentery or severe illness. Other indications include >64 years, pregnant, immunocompromised should also be treated.
    • Drug resistance is widespread and increasing and is higher for fluoroquinolones compared with macrolides.
    • Preferred: azithromycin 500 mg orally every day x 3 days or until signs and symptoms of de
    • Alternative erythromycin stearate 500 mg orally twice daily for 5 days
  • Amebic dysentery/colitis:
    • Metronidazole
      • Adults: 500-750 mg orally three times daily x 10 d
      • Children: 35 - 50 mg/kg/day in 3 divided doses x 7-10 d
    • Tinidazole
      • Adults:2 grams orally x 3 d
    • Ornidazole
      • Adults: 500 mg orally daily x 3 d
      • Children: 40 mg/kg/d orally x 3 d
    • Secnidazole
      • Adults: 2 grams orally daily x 1-3 d
      • Children: 30 mg/kg/d orally x 1-3 d
    • Pregnancy
    • 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
    • Fulminant cases should include treatment of gram-negative organisms. In the uncommon setting of toxic megacolon, surgical intervention may be needed.

Enteric Fever (Salmonella enterica serovar typhi or paratyphi)

  • Locale of acquisition will impact treatment choices due to local resistance patterns. Empiric recommendations are given below. Adjust based on culture results.
    • Severe or complicated disease
      • Infections acquired outside of Pakistan or Iraq
      • Infection acquired in Pakistan or Iraq due to the presence of extensively drug-resistant S Typhi
        • Meropenem: 1 -2 g IV every 8 h x 7-14 d
        • May substitute other carbapenems if meropenem is not available.
    • Uncomplicated Disease Acquired in Eastern Europe, Middle East, South America or sub-Saharan Africa:
      • Uncomplicated infection:
        • Adults:
          • Ciprofloxacin 250-500 mg orally twice daily for 7-14d
          • Cefixime: 200 mg orally twice daily x 10-14 d
          • Azithromycin: 1 g orally then 500 mg orally daily OR 1 g orally once daily x 5-7 d
        • Children
          • Cefixime: 20 mg/kg orally in 2 divided doses (maximum 400 mg per day) x 10-14 d
          • Azithromycin: 10 - 20 mg/kg orally conce per day (maximum 1000 mg/d) x 5-7 d
      • Complicated infection or for those who cannot tolerate oral medications:
        • Ciprofloxacin 500 mg IV every 12 h daily for 10-14d
        • Ceftriaxone: 2 g IV once or twice daily x 10-14 d
        • Cefotaxime: 150-200 mg/kg IV/d in 3-4 divided doses (maximum 8 g/d) x 10-14 d
    • Acquisition location unknown or in Southeast Asia (not Pakistan or Iraq):
      • Uncomplicated infection:
        • Adults:
          • Ciprofloxacin 250-500 mg orally twice daily for 7-14d
          • Cefixime: 200 mg orally twice daily x 10-14 d
          • Azithromycin: 1 g orally then 500 mg orally daily OR 1 g orally once daily x 5-7 d
        • Children
          • Cefixime: 20 mg/kg orally in 2 divided doses (maximum 400 mg per day) x 10-14 d
          • Azithromycin: 10 - 20 mg/kg orally once per day (maximum 1000 mg/d) x 5-7 d
      • Complicated infection or for those who cannot tolerate oral medications:
        • Adults:
          • Ciprofloxacin 500 mg IV every 12 h daily for 10-14d
          • Ceftriaxone: 2 g IV once or twice daily x 10-14 d
          • Cefotaxime: 150-200 mg/kg IV/d in 3-4 divided doses (maximum 8 g/d) x 10-14 d
        • Children:
          • Ciprofloxacin (justified use in severe infection): 20 mg/kg/d in 2 divided doses (maximum 800 mg/d) x 7-10 d
          • Ceftriaxone: 50-100 mg/kg IV in 1 or 2 divided doses (maximum 4 g/d) x 10-14 d
          • Cefotaxime: 150-200 mg/kg IV in 3-4 divided doses (maximum 8 g/d) x 10-14
  • 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 is 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

Rickettsial infections

  • If suspected, begin treatment empirically since diagnostic test results are often delayed or not performed.
  • 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.
  • Pregnant women: if a life-threatening infection, doxycycline should be used despite being a Category D agent. Consider consultation with an infectious disease expert.

Urinary Tract Infections/pyelonephritis

Dengue

  • No Dengue-specific treatments are 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 consulting with a specialist.

Zika virus

  • No Zika-specific treatment or vaccine is available.
    • Usually is a self-limited disease requiring only supportive measures.
    • Avoid NSAIDs, aspirin, and steroids
  • Pregnant women need to be assessed and monitored by a maternal-fetal expert.
  • Sexual transmission to all partners is possible, and therefore either abstaining from sex or using latex condoms/dental dams for every mucosally lined orifice contact for at least 2 months with partners of infected women and at least 6 months with partners of infected men is recommended.
  • A risk of Guillain Barre syndrome is present for weeks following infection although the proportionate risk is small.

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 is required with parenteral antimalarial therapy, if available.
      • Treatment with IV quinidine should be initiated as soon as possible after diagnosis is 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 artemisinin for patients with severe malaria.
  • Exchange transfusion if the parasite density (i.e. parasitemia) is >10% remains less favored now than historically[17] OR if the patient has altered mental status, non-volume overload pulmonary edema, or renal complications. Since 2013, CDC does not recommend red blood cell exchange transfusion.
  • Parasite density: estimated by examining a monolayer of red blood cells (RBCs) on the thin smear under oil immersion magnification. The slide should be examined where the RBCs are more or less touching (approximately 400 RBCs per field). Parasite density estimated by the percentage of infected RBCs; monitor q 12h.
    • If exchange transfusion is 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 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.

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 is lower than with first-generation cephalosporins; it has been used effectively in the treatment of enteric fever.

Chloroquine

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.

Hydroxychloroquine

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.

Mefloquine

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.

Primaquine

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.

Quinine

Cinchonism (tinnitus, 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 artemisinin due to ease of administration of the new drug and better safety profile.

OTHER INFORMATION

Basis for recommendation

  1. Ballard SB, Salinger A, MPHc, et al. Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States. MMWR Morb Mortal Wkly Rep. 2018;67(14):424-431.  [PMID:29649190]

    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.

  2. Thwaites GE, Day NP. Approach to Fever in the Returning Traveler. N Engl J Med. 2017;376(6):548-560.  [PMID:28177860]

    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.

  3. Lamontagne F, Harrison DA, Rowan KM. QSOFA for Identifying Sepsis Among Patients With Infection. JAMA. 2017;317(3):267-268.  [PMID:28114531]

    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).

  4. Centers for Disease Control and Prevention. Treatment of Malaria: Guidelines for Clinicians (United States). Accessed 29 April 2022; last reviewed by CDC 2 Nov 2020. Found at: https://www.cdc.gov/malaria/diagnosis_treatment/clinicians1.html

    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.

References

  1. Burt FJ, Rolph MS, Rulli NE, et al. Chikungunya: a re-emerging virus. Lancet. 2012;379(9816):662-71.  [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, 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.
    Rating: Important

  2. Flores-Figueroa J, Okhuysen PC, von Sonnenburg F, et al. Patterns of illness in travelers visiting Mexico and Central America: the GeoSentinel experience. Clin Infect Dis. 2011;53(6):523-31.  [PMID:21832261]

    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.

  3. Johnson LR, Gould LH, Dunn JR, et al. Salmonella infections associated with international travel: a Foodborne Diseases Active Surveillance Network (FoodNet) study. Foodborne Pathog Dis. 2011;8(9):1031-7.  [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-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.

  4. Franco C, Hynes NA, Bouri N, et al. The dengue threat to the United States. Biosecur Bioterror. 2010;8(3):273-6.  [PMID:20718665]

    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.

  5. Kochar DK, Das A, Kochar SK, et al. Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg. 2009;80(2):194-8.  [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

  6. Hochedez P, Canestri A, Guihot A, et al. Management of travelers with fever and exanthema, notably dengue and chikungunya infections. Am J Trop Med Hyg. 2008;78(5):710-3.  [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, 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.

  7. Cox-Singh J, Davis TM, Lee KS, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008;46(2):165-71.  [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 suggest that aggressive management similar to that given for P. falciparum is warranted given the observed case fatality.
    Rating: Important

  8. Camps M, Vilella A, Marcos MA, et al. Incidence of respiratory viruses among travelers with a febrile syndrome returning from tropical and subtropical areas. J Med Virol. 2008;80(4):711-5.  [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 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.

  9. Wilson ME, Weld LH, Boggild A, et al. Fever in returned travelers: results from the GeoSentinel Surveillance Network. Clin Infect Dis. 2007;44(12):1560-8.  [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 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).
    Rating: Important

  10. Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med. 2006;354(2):119-30.  [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 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.
    Rating: Important

  11. Jensenius M, Fournier PE, Raoult D. Rickettsioses and the international traveler. Clin Infect Dis. 2004;39(10):1493-9.  [PMID:15546086]

    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.

  12. McGready R, Brockman A, Cho T, 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. 2000;94(6):689-93.  [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.

  13. CDC. Exchange transfusion is 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.

  14. Ta TH, Jiménez B, Navarro M, et al. Q Fever in returned febrile travelers. J Travel Med. 2008;15(2):126-9.  [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 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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