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malaria

From the Italian mal' aria meaning bad air. Etiology: 1) disease transmitted by Anopheles mosquito infected with a) Plasmodium vivax b) Plasmodium ovale c) Plasmodium falciparum d) Plasmodium malariae e) Plasmodium knowlesi 2) transfusion-induced malaria Epidemiology: 1) generally occurs between 45 degrees north & 40 degrees south 2) Central America (chloroquine-sensitive) 3) South America (chloroquine-resistant Plasmodium falciparum) - northern Argentina (chloroquine-sensitive) 4) sub-Saharan Africa a) chloroquine-resistant Plasmodium falciparum b) if malaria is acquired in Africa, likelihood that pathogen is Plasmodium falciparum is 3:1 [4,17] 5) Egypt, Turkey, northern Saudi Arabia (chloroquine-sensitive) 6) middle east (chloroquine-resistant Plasmodium falciparum) 7) India (chloroquine-resistant Plasmodium falciparum) 8) south-east Asia: chloroquine- & mefloquine-resistant Plasmodium falciparum) a) Cambodia: artemisinin- & mefloquine-resistant Plasmodium falciparum b) Thailand: mefloquine-resistant Plasmodium falciparum [4,11] c) Laos: mefloquine-resistant Plasmodium falciparum c) Plasmodium knowlesi (chloroquine sensitive) [4] d) dihydroartemisinin + piperaquine resistance in > 80% of Plasmodium falciparum isolates in parts of Southeast (2018) [23] 9) Polynesia (chloroquine-resistant Plasmodium falciparum) 10) chloroquine-resistance - Plasmodium vivax & Plasmodium falciparum - not Plasmodium ovale or Plasmodium knowlesi - rare in Plasmodium malariae [4] 11) malaria without travel to endemic area 12) most common cause of fever in returning travelers [4] 13) transmitted by Anopheles mosquitoes Pathology: 1) adherence of parasitized erythrocytes to vascular endothelium is a key factor in pathogenesis 2) TNF-alpha upregulates expression of adherence receptors ICAM-1 & E-selectin 3) platelets kill intraerythrocytic malarial parasites, provide host immunity to malaria [8] 4) intravascular hemolysis & splenic sequestration of infected erythrocytes 5) Plasmodium falciparum & Plasmodium knowlesi cause most severe disease 6) no risk of relapse with Plasmodium falciparum or Plasmodium knowlesi [4] 7) mosquitoes attracted to certain odors in infected patients [20] Genetics: - polymorphisms in CD35 may predispose cerebral malaria - polymorphism in NCR3 is associated with mild suceptibility to malaria - polymorphisms in TNF-alpha are involved in susceptibility to malaria - individuals with sickle cell trait have reduced susceptibility to cerebral malaria Clinical manifestations: 1) incubation period of a) 8-25 days (Plasmodium falciparum) b) 10-20 days (Plasmodium ovale) c) 10-30 days (Plasmodium vivax) d) 15-35 days (Plasmodium malariae) 2) prodrome of headache, myalgia & malaise [17] 3) fever/chills, rigors & diaphoresis (abrupt onset) a) fever lasts 1-8 hours b) recurrence of fever 1] 48 hours (Plasmodium vivax & Plasmodium ovale) 2] 48 hours or irregular (Plasmodium falciparum) 3] 72 hours (Plasmodium malariae) c) in early phases of malaria, fever is frequently NOT periodic d) drenching sweats e) Plasmodium vivax & Plasmodium ovale hypnozoites may lay dormant in the liver & present several years later with fevers/chills [14] 4) nausea/vomiting, abdominal pain, diarrhea [4] 5) drowsiness & lethargy 6) enlarged & tender spleen during paroxysms 7) jaundice 8) dark urine results from hemoglobinuria with Plasmodium falciparum (Blackwater fever) [4,11] 9) retinal abnormalities a) retinal edema b) obstructed vessels & retinal hemorrhage c) predicitive of poor outcome 10) cerebral malaria* - seizures, coma (bad prognosis) 11) respiratory distress, pulmonary edema (bad prognosis) 12) septic shock * individuals with sickle cell trait have reduced susceptibility to cerebral malaria Laboratory: 1) complete blood count (CBC) a) anemia b) thrombocytopenia > 50% [4,11] 2) serum chemistries - bilirubin in serum may be elevated [11] - mildly elevated serum transaminases - metabolic acidosis - kidney injury - hypoglycemia [4] - elevated serum lactate dehydrogenase (hemolysis) 3) peripheral blood smears - Giemsa stain a) obtained during or just prior to paroxysms - obtain at least 3 smears to rule-out malaria [25] b) Plasmodium falciparum parasitemia 1] level of parasitemia of RBC is > 2% 2] only ring forms are present 3] banana-shaped gametocytes are seen 4] RBC of all sizes are affected 5] numerous multiply infected RBC are seen 6] RBC contain no Schuffner granules c) Plasmodium knowlesi parasitemia - level of parasitemia of RBC is also may be > 2% d) Plasmodium identified in blood by light microscopy 4) urine chemistries a) hemoglobin in urine: hemoglobinuria b) 24-hour urine urobilinogen: increased urobilinogen 5) Plasmodium serology: IFA 6) Plasmodium antigen in blood - dipstick antigen testing for P. falciparum - > 100% sensitivity for > 60 parasites/mL - 88% specificity 7) Plasmodium lactate dehydrogenase in blood 8) Plasmodium DNA 9) breathprint may be useful for rapid diagnosis of malaria in low resource settings [20] 9) see ARUP consult [10] Differential diagnosis: - Trypanosoma brucei - Trypanosoma brucei-rhodesiense is lethal if not treated Complications: 1) death due to cerebral malaria (P. falciparum) - most deaths in African children < 4 years of age 2) both Plasmodium falciparum & Plasmodium knowlesi may cause severe malaria & death [4] 3) multidrug resistance of P. falciparum Management: 1) do NOT withhold empiric therapy until peripheral smear is positive 2) chloroquine or hydroxychloroquine a) non-falciparum malaria acquired outside of Papua New-Guinea or Indonesia [14] b) malaria acquired in areas where chloroquine-resistant P falciparum has not been reported: Central America, Haiti, Dominican Republic [4] c) eradicates dormant hypnozoites in liver [14] d) oral therapy for uncomplicated malaria 1] 10 mg/kg, followed by 2] 10 mg/kg at 24 h & 5 mg/kg at 48 h, or 3] 5 mg/kg at 12, 14 % 36 hours 4] for P. vivax or P. ovale, add primaquine 0.24 mg/kg for 14 days e) parenteral therapy for severe disease 1] 10 mg/kg IV over 8 h, followed by 2] 15 mg/kg over 24 h, or 3] 3.5 mg/kg IM or SC every 6 hours for a total dose of 25 mg/kg 2) mefloquine a) 15 mg/kg single dose b) add 2nd dose of 10 mg/kg in areas of mefloquine resistance 3) atavoquone + proguanil [4] (P. falciparum) 4) artemether + lumefantrine [4] a) oral therapy for uncomplicated malaria (P. falciparum) - same as for artesunate b) parenteral therapy for severe disease - 3.2 mg/kg IM followed by 1.6 mg/kg/day 5) artesunate - drug of choice for severe P. falciparum [6,22] a) oral therapy for uncomplicated malaria 1] in combination with mefloquine 25 mg/kg - 10-12 mg/kg given in divided doses over 3-5 days a] 4 mg/kg for 3 days b] 4 mg/kg, followed by 1.5 mg/kg for 5 days 2] used alone - 10 to 12 mg/kg given in divided doses over 7 days a] 4 mg/kg, followed by b] 2 mg/kg on days 2 & 3 & 1 mg/kf on days 4-7 b) parenteral therapy for severe disease [6] 1] 2.4 mg/kg IV or IM, followed by 2] 1.2 mg/kg & 12 & 24 h, then 3] 1.2 mg/kg QD 4] useful for severe mefloquine-resistant malaria [4] 6) 3-day treatment with artemisinin for Plasmodium falciparum - not for use as monotherapy [13] - dihydroartemisinin + piperaquine had been 1st line southeast Asia [23] - artemisinin-resistance now found in Africa as well as southeast Asia [24] 7) halofantrine 500 mg every 6 hours 8) sulfadoxine/pyrimethamine a) adults: 1500 mg sulfadoxine/75 mg pyrimethamine single oral dose (3 tablets) b) 20/1 mg/kg children c) self treatment in areas of chloroquine-resistant malaria for travelers taking mefloquine or doxycycline prophylaxis 9) quinine a) oral therapy for uncomplicated malaria - 10 mg/kg every 8 hours for 7 days, plus tetracycline 4 mg/kg QID, or doxycycline 3 mg/kg QD for 7 days b) parenteral therapy for severe disease 1] 20 mg/kg IV infusion over 4 hours, followed by 10 mg/kg over 2-8 h every 8 hours 2] addition of clindamycin may shorten parasite clearance time 10) quinidine (discontinued in U.S.) [22] a) parenteral therapy for severe disease, including cerebral malaria - 10 mg/kg IV infusion over 1-2 hours, followed by 0.02 mg/kg/min with ECG monitoring b) only available parenteral agent in USA c) may add clindamycin 11) primaquine a) non-falciparum malaria acquired outside of Papua New-Guinea or Indonesia [14] b) eradicates dormant hypnozoites in liver [14] 12) tafenoquine eradicates dormant hypnozoites in liver [4] 13) pentoxifylline may be of benefit, especially for cerebral malaria 14) avoid antiplatelet agents [8] 15) prophylaxis (see prophylaxis for malaria)

Related

malaria without travel to endemic area Plasmodium prophylaxis for malaria

Useful

antimalarial

Specific

blackwater fever (malarial hemoglobinuria) cerebral malaria HIV1/malaria coinfection

General

coccidiosis mosquito borne infection

Database Correlations

OMIM correlations

References

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  5. Prescriber's Letter 8(9):54 2001
  6. Dondorp A, Nosten F, Stepniewska K, Day N, White N; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005 Aug 27-Sep 2;366(9487):717-25. PMID: 16125588 - Magill A, Panosian C. Making antimalarial agents available in the United States. N Engl J Med. 2005 Jul 28;353(4):335-7. Epub 2005 Jul 6. No abstract available. PMID: 16000347
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  8. McMorran BJ et al. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 2009 Feb 6; 323:797. PMID: 19197068
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  10. ARUP Consult: Plasmodium Species - Malaria The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/plasmodium-species
  11. The NNT: Malaria in Returning Travelers Diagnostics and Likelihood Ratios, Explained http://www.thennt.com/lr/malaria-in-returning-travelers/ - Taylor SM, Molyneux ME, Simel DL et al Does this patient have malaria? JAMA. 2010 Nov 10;304(18):2048-56 PMID: 21057136
  12. Cullen KA and Arguin PM Centers for Disease Control and Prevention (CDC) Malaria Surveillance - United States, 2011 MMWR. November 1, 2013 / 62(ss05);1-17 http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6205a1.htm
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  14. Redig AJ et al Interactive medical case. A Chilly Fever. N Engl J Med 2014; 371:e24O. ctober 16, 2014 PMID: 25317891 http://www.nejm.org/doi/full/10.1056/NEJMimc1315897
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  17. Biddinger PD et al Case 28-2015 - A 32-Year-Old Man with Fever, Headache, and Myalgias after Traveling from Liberia. N Engl J Med 2015; 373:1060-1067. September 10, 2015 PMID: 26352818 http://www.nejm.org/doi/full/10.1056/NEJMcpc1503828
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  20. Walker M The Sweet Smell of Malaria: 'Breath Test' Promising for Dx - Mosquitoes attracted to certain odors in infected patients. MedPage Today. November 07, 2017 https://www.medpagetoday.com/meetingcoverage/astmh/69106 - Schaber C, et al Breathprinting reveals malaria-associated biomarkers and mosquito attractants American Society of Tropical Medicine & Hygiene (ASTMH) 2017; Abstract 609.
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  22. CDC News Release. March 28, 2018 CDC: Artesunate Now First-Line Treatment for Severe Malaria in the United States. https://www.cdc.gov/media/releases/2019/s0328-artesunate-first-line-treatment.html
  23. Hamilton WL, Amato R, van der Pluijm RW et al Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study. Lancet Infectious Diseases. July 22, 2019 PMID: 31345709 Free Article https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30392-5/fulltext - van der Pluijm RW, Imwong M, Chau NH et al Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infectious Diseases. July 22, 2019 PMID: 31345710 Free Article https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30391-3/fulltext - Menard D, Fidock DA Accelerated evolution and spread of multidrug-resistant Plasmodium falciparum takes down the latest first-line antimalarial drug in southeast Asia. Lancet Infectious Diseases. July 22, 2019 PMID: 31345711 Free Article https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30394-9/fulltext
  24. Balikagala B, Fukuda N, Ikeda M et al Evidence of Artemisinin-Resistant Malaria in Africa. N Engl J Med 2021; 385:1163-1171 PMID: 34551228 https://www.nejm.org/doi/10.1056/NEJMoa2101746
  25. NEJM Knowledge+
  26. National Institute of Allergy and Infectious Diseases (NIAID) Malaria https://www.niaid.nih.gov/diseases-conditions/malaria - Guidelines for Treatment of Malaria in the United States Centers for Disease Control and Prevention (CDC) http://www.cdc.gov/malaria/pdf/treatmenttable.pdf - Malaria Diagnosis & Treatment in the United States Centers for Disease Control and Prevention (CDC) http://www.cdc.gov/malaria/diagnosis_treatment/ - CDC Malaria Hotline: (770) 488-7788 Mon-Fri 8 AM-4:30 PM EST (770) 488-7100 after hours, weekends and holidays