malaria
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Introduction
From the Italian mal' aria meaning bad air.
Etiology
- disease transmitted by Anopheles mosquito infected with
- transfusion-induced malaria
Epidemiology
- generally occurs between 45 degrees north & 40 degrees south
- Central America (chloroquine-sensitive)
- South America (chloroquine-resistant Plasmodium falciparum)
- northern Argentina (chloroquine-sensitive)
- sub-Saharan Africa
- chloroquine-resistant Plasmodium falciparum
- if malaria is acquired in Africa, likelihood that pathogen is Plasmodium falciparum is 3:1[4][17]
- Egypt, Turkey, northern Saudi Arabia (chloroquine-sensitive)
- middle east (chloroquine-resistant Plasmodium falciparum)
- India (chloroquine-resistant Plasmodium falciparum)
- south-east Asia: chloroquine- & mefloquine-resistant Plasmodium falciparum)
- Cambodia: artemisinin- & mefloquine-resistant Plasmodium falciparum
- Thailand: mefloquine-resistant Plasmodium falciparum[4][11]
- Laos: mefloquine-resistant Plasmodium falciparum
- Plasmodium knowlesi (chloroquine sensitive)[4]
- dihydroartemisinin + piperaquine resistance in > 80% of Plasmodium falciparum isolates in parts of Southeast (2018)[23]
- Polynesia (chloroquine-resistant Plasmodium falciparum)
- chloroquine-resistance
- malaria without travel to endemic area
- most common cause of fever in returning travelers[4]
- transmitted by Anopheles mosquitoes
Pathology
- adherence of parasitized erythrocytes to vascular endothelium is a key factor in pathogenesis
- TNF-alpha upregulates expression of adherence receptors ICAM-1 & E-selectin
- platelets kill intraerythrocytic malarial parasites, provide host immunity to malaria[8]
- intravascular hemolysis & splenic sequestration of infected erythrocytes
- Plasmodium falciparum & Plasmodium knowlesi cause most severe disease
- no risk of relapse with Plasmodium falciparum or Plasmodium knowlesi[4]
- 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
- incubation period of
- 8-25 days (Plasmodium falciparum)
- 10-20 days (Plasmodium ovale)
- 10-30 days (Plasmodium vivax)
- 15-35 days (Plasmodium malariae)
- prodrome of headache, myalgia & malaise[17]
- fever/chills, rigors & diaphoresis (abrupt onset)
- fever lasts 1-8 hours
- recurrence of fever
- 48 hours (Plasmodium vivax & Plasmodium ovale)
- 48 hours or irregular (Plasmodium falciparum)
- 72 hours (Plasmodium malariae)
- in early phases of malaria, fever is frequently NOT periodic
- drenching sweats
- Plasmodium vivax & Plasmodium ovale hypnozoites may lay dormant in the liver & present several years later with fevers/chills[14]
- nausea/vomiting, abdominal pain, diarrhea[4]
- drowsiness & lethargy
- enlarged & tender spleen during paroxysms
- jaundice
- dark urine results from hemoglobinuria with Plasmodium falciparum (Blackwater fever)[4][11]
- retinal abnormalities
- retinal edema
- obstructed vessels & retinal hemorrhage
- predicitive of poor outcome
- cerebral malaria* - seizures, coma (bad prognosis)
- respiratory distress, pulmonary edema (bad prognosis)
- septic shock
* individuals with sickle cell trait have reduced susceptibility to cerebral malaria
Laboratory
- complete blood count (CBC)
- serum chemistries
- bilirubin in serum may be elevated[11]
- mildly elevated serum transaminases
- metabolic acidosis
- kidney injury
- hypoglycemia[4]
- elevated serum lactate dehydrogenase (hemolysis)
- peripheral blood smears - Giemsa stain
- obtained during or just prior to paroxysms
- Plasmodium falciparum parasitemia
- level of parasitemia of RBC is > 2%
- only ring forms are present
- banana-shaped gametocytes are seen
- RBC of all sizes are affected
- numerous multiply infected RBC are seen
- RBC contain no Schuffner granules
- Plasmodium knowlesi parasitemia
- level of parasitemia of RBC is also may be > 2%
- Plasmodium identified in blood by light microscopy
- urine chemistries
- Plasmodium serology: IFA
- Plasmodium antigen in blood
- dipstick antigen testing for P. falciparum
- 88% specificity
- Plasmodium lactate dehydrogenase in blood
- Plasmodium DNA
- breathprint may be useful for rapid diagnosis of malaria in low resource settings[20]
- see ARUP consult[10]
Complications
- death due to cerebral malaria (P. falciparum)
- most deaths in African children < 4 years of age
- both Plasmodium falciparum & Plasmodium knowlesi may cause severe malaria & death[4]
- multidrug resistance of P. falciparum
Differential diagnosis
- Trypanosoma brucei
- Trypanosoma brucei-rhodesiense is lethal if not treated
Management
- do NOT withhold empiric therapy until peripheral smear is positive
- chloroquine or hydroxychloroquine
- non-falciparum malaria acquired outside of Papua New-Guinea or Indonesia[14]
- malaria acquired in areas where chloroquine-resistant P falciparum has not been reported: Central America, Haiti, Dominican Republic[4]
- eradicates dormant hypnozoites in liver[14]
- oral therapy for uncomplicated malaria
- 10 mg/kg, followed by
- 10 mg/kg at 24 h & 5 mg/kg at 48 h, or
- 5 mg/kg at 12, 14 % 36 hours
- for P. vivax or P. ovale, add primaquine 0.24 mg/kg for 14 days
- parenteral therapy for severe disease
- mefloquine
- 15 mg/kg single dose
- add 2nd dose of 10 mg/kg in areas of mefloquine resistance
- atavoquone + proguanil[4] (P. falciparum)
- artemether + lumefantrine[4]
- oral therapy for uncomplicated malaria (P. falciparum)
- same as for artesunate
- parenteral therapy for severe disease
- 3.2 mg/kg IM followed by 1.6 mg/kg/day
- oral therapy for uncomplicated malaria (P. falciparum)
- artesunate - drug of choice for severe P. falciparum[6][22]
- oral therapy for uncomplicated malaria
- in combination with mefloquine 25 mg/kg
- 10-12 mg/kg given in divided doses over 3-5 days
- 4 mg/kg for 3 days
- 4 mg/kg, followed by 1.5 mg/kg for 5 days
- used alone
- 10 to 12 mg/kg given in divided doses over 7 days
- 4 mg/kg, followed by
- 2 mg/kg on days 2 & 3 & 1 mg/kf on days 4-7
- in combination with mefloquine 25 mg/kg
- parenteral therapy for severe disease[6]
- 2.4 mg/kg IV or IM, followed by
- 1.2 mg/kg & 12 & 24 h, then
- 1.2 mg/kg QD
- useful for severe mefloquine-resistant malaria[4]
- oral therapy for uncomplicated malaria
- 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]
- halofantrine 500 mg every 6 hours
- sulfadoxine/pyrimethamine
- adults: 1500 mg sulfadoxine/75 mg pyrimethamine single oral dose (3 tablets)
- 20/1 mg/kg children
- self treatment in areas of chloroquine-resistant malaria for travelers taking mefloquine or doxycycline prophylaxis
- quinine
- 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
- parenteral therapy for severe disease
- 20 mg/kg IV infusion over 4 hours, followed by 10 mg/kg over 2-8 h every 8 hours
- addition of clindamycin may shorten parasite clearance time
- oral therapy for uncomplicated malaria
- quinidine (discontinued in U.S.)[22]
- 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
- only available parenteral agent in USA
- may add clindamycin
- parenteral therapy for severe disease, including cerebral malaria
- primaquine
- non-falciparum malaria acquired outside of Papua New-Guinea or Indonesia[14]
- eradicates dormant hypnozoites in liver[14]
- tafenoquine eradicates dormant hypnozoites in liver[4]
- pentoxifylline may be of benefit, especially for cerebral malaria
- avoid antiplatelet agents[8]
- prophylaxis (see prophylaxis for malaria)
More general terms
More specific terms
Additional terms
References
- ↑ DeGowin & DeGowin's Diagnostic Examination, 6th edition, RL DeGowin (ed), McGraw Hill, NY 1994, pg 892
- ↑ Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996, pg 1260-64
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 1180-89
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ Prescriber's Letter 8(9):54 2001
- ↑ 6.0 6.1 6.2 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/16000347 - ↑ Centers for Disease Control and Prevention; Filler SJ, MacArthur JR, Parise M, Wirtz R, Eliades MJ, Dasilva A, Steketee R. Locally acquired mosquito-transmitted malaria: a guide for investigations in the United States. MMWR Recomm Rep. 2006 Sep 8;55(RR-13):1-9. Corresponding NGC guideline withdrawn Dec 2011 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16960552
- ↑ 8.0 8.1 8.2 McMorran BJ et al. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 2009 Feb 6; 323:797. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19197068
- ↑ Dondorp AM et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009 Jul 30; 361:455. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/19641202 <Internet> http://content.nejm.org/cgi/content/full/361/5/455
- ↑ 10.0 10.1 ARUP Consult: Plasmodium Species - Malaria The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/plasmodium-species
- ↑ 11.0 11.1 11.2 11.3 11.4 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: https://www.ncbi.nlm.nih.gov/pubmed/21057136 - ↑ 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
- ↑ 13.0 13.1 Ashley EA et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2014 Jul 31; 371:411 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25075834 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1314981
White NJ et al. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med 2014 Jul 31; 371:403 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25075833 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1315860
Greenwood B. Treatment of malaria - A continuing challenge. N Engl J Med 2014 Jul 31; 371:474. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25075840 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMe1407026 - ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Redig AJ et al Interactive medical case. A Chilly Fever. N Engl J Med 2014; 371:e24O. ctober 16, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25317891 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMimc1315897
- ↑ Baird JK Effectiveness of Antimalarial Drugs N Engl J Med 2005; 352:1565-1577. April 14, 2005. http://www.nejm.org/doi/full/10.1056/NEJMra043207
- ↑ Blevins SM, Greenfield RA, Bronze MS Blood smear analysis in babesiosis, ehrlichiosis, relapsing fever, malaria, and Chagas disease. Cleve Clin J Med. 2008 Jul;75(7):521-30 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18646588
- ↑ 17.0 17.1 17.2 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26352818 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcpc1503828
- ↑ Genton B, D'Acremont V. Malaria prevention in travelers. Infect Dis Clin North Am. 2012 Sep;26(3):637-54. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22963775
- ↑ White NJ, Pukrittayakamee S, Hien TT et al Malaria. Lancet. 2014 Feb 22;383(9918):723-35. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/239W53767
- ↑ 20.0 20.1 20.2 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. - ↑ Hahn WO, Pottinger PS. Malaria in the Traveler: How to Manage Before Departure and Evaluate Upon Return. Med Clin North Am. 2016 Mar;100(2):289-302. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26900114 Free PMC Article
- ↑ 22.0 22.1 22.2 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
- ↑ 23.0 23.1 23.2 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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/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: https://www.ncbi.nlm.nih.gov/pubmed/31345711 Free Article https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30394-9/fulltext - ↑ 24.0 24.1 Balikagala B, Fukuda N, Ikeda M et al Evidence of Artemisinin-Resistant Malaria in Africa. N Engl J Med 2021; 385:1163-1171 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34551228 https://www.nejm.org/doi/10.1056/NEJMoa2101746
- ↑ 25.0 25.1 NEJM Knowledge+
- ↑ 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