### Microbiology Plasmodia are in phylum *Apicomplexa*, a group of parasitic eukaryotes. *P*. *falciparum*, *P*. *malariae*, *P*. *ovale* (two species), *P*. *ovale*, *P*. *knowlesi*, *P*. simium, *P*. *cynomolgi*. 200 species all told. The cause of malaria. ### Epidemiologic Risks Usually getting bit by a mosquito, occasionally from transfusions. [^1] There is this weird case in Italy where one roommate in the hospital spread malaria to the other with no reason found. [^2] Everyone knows about sickle cells protection against malaria, but there are a large number of polymorphisms that give resistance to malaria. [^3] I bet no organism has left more footprints on the human genome. Iron deficiency may be protective. [^4] *P*. *falciparum* is mostly sub-Saharan Africa and SE Asia. For excellent maps of endemicity, go to *A new world malaria map: Plasmodium falciparum endemicity in 2010*. [^5] Malaria distribution will have change a bit due to climate change and human interventions. Kind of the same thing, I guess. *P*. *malariae*: the tropics of all continents. In SE Asia there can be a severe, sometimes fatal malaria that looks like *P*. *malariae* but is actually a simian malaria, *P*. *knowlesi*. [^6] [^7] *P*. *knowlesi*: SE Asia, especially Malaysia where it is the most common form. [^8] It comes from monkeys and is indistinguishable from on smear from *P*. *malariae*, but will have a higher number of parasitized red cells. > "Severe *knowlesi* malaria occurs only in adults; Intravenous artesunate is warranted initially for those with parasitemia >15 000/μL ." [^9] At least three different populations of *P*. *knowlesi."* [^10] Or perhaps I should say there are no less... *P*. *ovale*: Africa and Asia. Turns out there are 2 types of *P*. *ovale* that are 2 distinct species that look the same, *P*. *ovale* *curtisi* and *P*. *ovale* *wallikeri* . [^11] *P*. *ovale* *wallikeri* may be a bit worse clinically. [^12] For relapse after therapy, *P*. *ovale* *curtisi* strains will relapse after initial blood clearance but no relapse of *P*. *ovale* *wallikeri* is seen. [^13] *P*. *vivax*: Asia and South America.  Parasitemia can be below the level of microscopic detection and needs a PCR to diagnose. [^14] *P*. *simium*: Brazilian Atlantic forest; looks like *P*. vivax, found in monkeys but can infect humans. [^15] *P*. *cynomolgi* and *P*. *knowlesi* (monkey *Plasmodia*) can both cause asymptomatic human infections. [^16] For risk of a given county go to CDC travel information site. [^17] Don't let the lack of a travel history dissuade you from considering malaria in a patient with cyclic fevers: there were over 50 local outbreaks of malaria in the US in the last half of the last century in people who have not traveled. [^18] Texas and Florida have had local transmission as well. [^19] The mosquito and/or an infected human is a plane flight away. Cool. Your skin bacteria flora makes products that attract malaria. [^20] Thanks a lot, microbiome. > "Splenectomy is associated with a high risk of malaria, greater for *P*. *vivax* than *P*. *falciparum*." [^21] Many people don't take prophylaxis when traveling, especially expatriates, and in one study none completed it: > "Visiting family in the country of origin (27.8%) was the commonest reason for travel. However, this was exceeded by the combined numbers traveling for business and holidays (22.5% and 20.1%, respectively). Sixty percent of patients took no prophylaxis. Of those who did, none of the patients finished their chemoprophylaxis regimen." [^22] ### Syndromes Better know as malaria. Fevers mostly; q 48 hours with *P*. *vivax* or *P*. *ovale*, q 72 with *P*. *malariae*, *P*. *falciparum* is usually q 48, but is more variable and the patient is sicker. Severe *P*. *falciparum* can cause sludging and organ infarction, especially worrisome in the brain. [^23] Risks are being non-black, having had prior malaria and having > 2% parasitemia. [^24] Obesity and diabetes increase the risk for severe malaria. [^25] And travelers from the West to malarious countries and can occur with > "*P*. *falciparum* (9.4%), *P*. vivax (7.7%), *P*. *ovale* (5.3%), *P*. *malariae* (3.3%), and mixed *P*. *falciparum* episodes (21.1%)." [^26] If you see schizonts on the smear, expect up to a 16 fold increase in parasitemia and a bad prognostic sign. *P*. *knowlesi* patients are a lot sicker than those infected with *P*. *malariae*. Anyone who has a fever in a malarious region is treated for malaria, but do they have malaria when febrile? It depends on the prevalence of malaria, but in > "16,903 children surveyed, 3% were febrile and infected, 9% were febrile without infection, 12% were infected but were not febrile and 76% were uninfected and not febrile...in areas where community-based infection prevalence in childhood is above 34-37%, 50% or more of fevers are likely to be associated with malaria." [^27] Take home: just because they have a fever and got therapy for malaria, doesn't mean they had malaria. *P*. *simium* is in Brazil, comes from monkeys and looks like *P*. vivax on the smear. [^28] Time for Hickam not Occam: In SE Asia, 15% of falciparum malaria patients will also have often unsuspected bacteremia; they are also more likely to die. [^29] ### Treatment Given the changing resistance in malaria, **always** check the CDC site for up to date information. [^30] Call the CDC malaria hot line for help: 770-488-7788. And believe me, you will need help. This is a disease that can go south with remarkable rapidity. The specific therapy depends on the type of malaria and the risk of resistance. Any specific recommendations/regimens are likely out of date before I finish typing this sentence/ *P*. *falciparum*: No chloroquine resistance: chloroquine still works. Chloroquine resistance: Mefloquine OR Quinine and doxycycline OR Atovaquone plus proguanil aka Malarone® OR Azithromycin plus artesunate [^31] OR Azithromycin plus quinine ) are safe and efficacious combination treatments for uncomplicated *falciparum* malaria OR Artemether plus lumefantrine OR Dihydroartemisinin and piperaquine, is more effective and better tolerated against multidrug-resistant *P*. *falciparum* and *P*. *vivax* infections. [^32] OR Pyronaridine--Artesunate. [^33] In severe disease, iv artesunate is the first line therapy but you have to call the CDC to get it. IV quinidine, yes, the anti-arrhythmic, was the old school treatment. When last i checked, iv quinidine was not longer available in the US. When I was an intern, we (erroneously) suppressed all ectopy and gave tons of quinidine. Acetaminophen is renoprotective bin severe malaria. [^34] Protects the kidneys, not Nevada cities. Exchange transfusions doesn't help for severe disease. [^35] *P*. *malariae*/*P*. *knowlesi*: Chloroquine, an old school drug that still works. *P*. *knowlesi*: Atovaquone-proguanil and primaquine has been used with success. Early artesunate therapy has lower mortality. [^36] *P*. *ovale*: chloroquine AND primaquine 15 mg base qd for 14 days. Check for G-6-PD deficiency before starting primaquine. *P*. *vivax*: chloroquine one gram, then 500 mg 6 hours later, then 500 mg at 24 and 48 hours or dihydroartemisinin-piperaquine AND primaquine for the liver phase. 7-day of 1 mg/kg/d is as good as 14-day primaquine 0.5 gm/kg/d. [^38] Check for G-6-PD deficiency before starting primaquine. For *P*. vivax there is also 300 mg single dose tafenoquine. Maybe not as good as primaquine: > "In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group, 27.7% in the placebo group, and 69.6% in the primaquine group for the liver phase." [^37] [^39] Check for G-6-PD deficiency before starting primaquine. Chloroquine resistance is increasing in SE Asia. **Prevention**: Start 1-2 weeks before travel and continuing weekly for 4 weeks after leaving. Applies to non-pregnant adults only. *P*. *vivax*, *P*. *ovale*, *P*. *malariae*, and *chloroquine* susceptible *P*. *falciparum*: chloroquine phosphate 500 mg (300 mg base) once weekly. Chloroquine-resistant *P*. *falciparum*: mefloquine. But prevention is a moving target, so look it up depending on where the patient is traveling. And do not forget the importance of nets and DEET. ### Notes Resistance is increasing, especially in SE Asia where mefloquine resistance occurs. It killed King Tut. Really. [^45] And citronella with vanillin not only leads to a better smelling French car but does prevent mosquito bites, just not as well as DEET. [^40] In Uganda blackwater fever, and acute intravascular hemolysis, fever, and dark or red urine is a complication of recent or concurrent Plasmodium *falciparum* malaria infection in non-immune adults Africa. Associated with chloroquine it is making a comeback perhaps due to the use of artemisinin-based combination therapies. [^41] No good deed ever goes unpunished. I have heard it estimated half of everyone who has ever died, died of malaria. It's not true, but malaria is still an impressive killer. [^42] Malaria changes your breath to attract mosquitoes: > "...infection correlates with significantly higher breath levels of 2 mosquito-attractant terpenes, α-pinene and 3-carene." [^43] and could be used to diagnose the disease using dogs or rats. Poor animals, sniffing humans to diagnose cancer or Tb or *C*. *difficile*. Blech. *P*. *vivax* came out of Africa where it infected humans and apes and is still found in African apes and could jump into humans in Africa again. [^44] ### Puswhisperers [Bad Singing](http://www.pusware.com/PW1/BadSinging.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop35.mp3) [Bad Air](http://www.pusware.com/PW1/BadAir.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop179.mp3) [Bad Air Redux](http://www.pusware.com/PW1/BadAirRedux.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop180.mp3) [A True Story](http://www.pusware.com/PW1/ATrueStory.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop.mp3 [Bad Air Re Re Duex Duex](http://www.pusware.com/PW1/BadAirReduxRedux.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop184.mp3) [Simple Disease, Complicated Infection](http://www.pusware.com/PW3/SimpleDisease.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop445.mp3) [First World / Third World](http://www.pusware.com/PW4/FirstWorldThirdWorld.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop578.mp3) [African Roulette](http://www.pusware.com/PW6/AfricanRoulette.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop791.mp3) [Does he or doesn't he? No hairdresser to ask.](http://www.pusware.com/PW7/DoesHe.html) [Audio. The Gobbet 'o Pus Podcast](http://www.pusware.com/gobbet/gop933.mp3) ### Rationalizations [^1]: Ehsan Ahmadpour, Masoud Foroutan-Rad, Hamidreza Majidiani, Sirous Mehrani Moghaddam, Kareem Hatam-Nahavandi, Seyed-Abdollah Hosseini, Mohammad Taghi Rahimi, Aleksandra Barac, Salvatore Rubino, Mehdi Zarean, Alexander G Mathioudakis, Muge Cevik, Transfusion-Transmitted Malaria: A Systematic Review and Meta-analysis, _Open Forum Infectious Diseases_, Volume 6, Issue 7, July 2019, ofz283, [https://doi.org/10.1093/ofid/ofz283](https://doi.org/10.1093/ofid/ofz283) [^2]: Gruell H, Hamacher L, Jennissen V, Tuchscherer A, Ostendorf N, Löffler T, Hallek M, Kochanek M, Tannich E, Böll B, Fätkenheuer G. On Taking a Different Route: An Unlikely Case of Malaria by Nosocomial Transmission. Clin Infect Dis. 2017 Oct 15;65(8):1404-1406. doi: 10.1093/cid/cix520. PMID: 28575383. [^3]: Lwanira CN, Kironde F, Kaddumukasa M, Swedberg G. Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda. Malar J. 2017 Aug 9;16(1):322. doi: 10.1186/s12936-017-1970-1. PMID: 28793894; PMCID: PMC5551019. [^4]: Muriuki JM, Mentzer AJ, Kimita W, Ndungu FM, Macharia AW, Webb EL, Lule SA, Morovat A, Hill AVS, Bejon P, Elliott AM, Williams TN, Atkinson SH. Iron Status and Associated Malaria Risk Among African Children. Clin Infect Dis. 2019 May 17;68(11):1807-1814. doi: 10.1093/cid/ciy791. PMID: 30219845; PMCID: PMC6522755. [^5]: Gething, P.W., Patil, A.P., Smith, D.L. _et al._ A new world malaria map: _Plasmodium falciparum_ endemicity in 2010. _Malar J_ **10**, 378 (2011). https://doi.org/10.1186/1475-2875-10-378 [^6]: Cox-Singh J, Davis TM, Lee KS, Shamsul SS, Matusop A, Ratnam S, Rahman HA, Conway DJ, Singh B. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008 Jan 15;46(2):165-71. doi: 10.1086/524888. PMID: 18171245; PMCID: PMC2533694. [^7]: Centers for Disease Control and Prevention (CDC). Simian malaria in a U.S. traveler--New York, 2008. MMWR Morb Mortal Wkly Rep. 2009 Mar 13;58(9):229-32. PMID: 19282815. [^8]: Yusof, R., Lau, Y.L., Mahmud, R. _et al._ High proportion of knowlesi malaria in recent malaria cases in Malaysia. _Malar J_ **13**, 168 (2014). https://doi.org/10.1186/1475-2875-13-168 [^9]: Matthew J Grigg, Timothy William, Bridget E Barber, Giri S Rajahram, Jayaram Menon, Emma Schimann, Kim Piera, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Christopher J Drakeley, Tsin W Yeo, Nicholas M Anstey, Age-Related Clinical Spectrum of _Plasmodium knowlesi_ Malaria and Predictors of Severity, _Clinical Infectious Diseases_, Volume 67, Issue 3, 1 August 2018, Pages 350–359, [https://doi.org/10.1093/cid/ciy065](https://doi.org/10.1093/cid/ciy065) [^10]: Divis P, Lin LC, Rovie-Ryan JJ, et al. Three Divergent Subpopulations of the Malaria Parasite Plasmodium knowlesi. _Emerging Infectious Diseases_. 2017;23(4):616-624. doi:10.3201/eid2304.161738. [^11]: Sutherland CJ, Tanomsing N, Nolder D, Oguike M, Jennison C, Pukrittayakamee S, Dolecek C, Hien TT, do Rosário VE, Arez AP, Pinto J, Michon P, Escalante AA, Nosten F, Burke M, Lee R, Blaze M, Otto TD, Barnwell JW, Pain A, Williams J, White NJ, Day NP, Snounou G, Lockhart PJ, Chiodini PL, Imwong M, Polley SD. Two nonrecombining sympatric forms of the human malaria parasite Plasmodium ovale occur globally. J Infect Dis. 2010 May 15;201(10):1544-50. doi: 10.1086/652240. PMID: 20380562. [^12]: Rojo-Marcos G, Rubio-Muñoz J, Ramírez-Olivencia G, et al. Comparison of Imported Plasmodium ovale curtisi and P. ovale wallikeri Infections among Patients in Spain, 2005–2011. _Emerging Infectious Diseases_. 2014;20(3):417-424. doi:10.3201/eid2003.130745. [^13]: Groger M, Veletzky L, Lalremruata A, Cattaneo C, Mischlinger J, Manego Zoleko R, Kim J, Klicpera A, Meyer EL, Blessborn D, Winterberg M, Adegnika AA, Agnandji ST, Kremsner PG, Mordmüller B, Mombo-Ngoma G, Fuehrer HP, Ramharter M. Prospective Clinical and Molecular Evaluation of Potential Plasmodium ovale curtisi and wallikeri Relapses in a High-transmission Setting. Clin Infect Dis. 2019 Nov 27;69(12):2119-2126. doi: 10.1093/cid/ciz131. PMID: 31066448; PMCID: PMC6880329. [^14]: Moreira CM, Abo-Shehada M, Price RN, Drakeley CJ. A systematic review of sub-microscopic Plasmodium vivax infection. Malar J. 2015 Sep 22;14:360. doi: 10.1186/s12936-015-0884-z. PMID: 26390924; PMCID: PMC4578340. [^15]: Brasil P, Zalis MG, de Pina-Costa A, Siqueira AM, Júnior CB, Silva S, Areas ALL, Pelajo-Machado M, de Alvarenga DAM, da Silva Santelli ACF, Albuquerque HG, Cravo P, Santos de Abreu FV, Peterka CL, Zanini GM, Suárez Mutis MC, Pissinatti A, Lourenço-de-Oliveira R, de Brito CFA, de Fátima Ferreira-da-Cruz M, Culleton R, Daniel-Ribeiro CT. Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation. Lancet Glob Health. 2017 Oct;5(10):e1038-e1046. doi: 10.1016/S2214-109X(17)30333-9. Epub 2017 Aug 31. PMID: 28867401. [^16]: Mallika Imwong, Wanassanan Madmanee, Kanokon Suwannasin, Chanon Kunasol, Thomas J Peto, Rupam Tripura, Lorenz von Seidlein, Chea Nguon, Chan Davoeung, Nicholas P J Day, Arjen M Dondorp, Nicholas J White, Asymptomatic Natural Human Infections With the Simian Malaria Parasites _Plasmodium cynomolgi_ and _Plasmodium knowlesi_, _The Journal of Infectious Diseases_, Volume 219, Issue 5, 1 March 2019, Pages 695–702, [https://doi.org/10.1093/infdis/jiy519](https://doi.org/10.1093/infdis/jiy519) [^17]: https://wwwnc.cdc.gov/travel/destinations/list [^18]: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5513a1.htm [^19]: Blackburn D, Drennon M, Broussard K, Morrison AM, Stanek D, Sarney E, Ferracci C, Huard S, Brennan W, Eaton J, Nealeigh S, Barber N, Zimler RA, Adams JN, Blackmore C, Gordillo M, Mercado R, Vore H, Scanlan K, Motie I, Stanfield L, Farooq A, Widel K, Tomson K, Kerr N, Nasir J, Cone M, Rice C, Larkin T, Hernandez E, Bencie J, Lesser CR, Dersch M, Ramirez-Lachmann S, Clark M, Rollo S, Bashadi A, Tyler R, Bolling B, Moore B, Sullivan B, Fonken E, Castillo R, Gonzalez Y, Olivares G, Mace KE, Sayre D, Lenhart A, Sutcliffe A, Dotson E, Corredor C, Rogers E, Raphael BH, Sapp SGH, Qvarnstrom Y, Ridpath AD, McElroy PD. Outbreak of Locally Acquired Mosquito-Transmitted (Autochthonous) Malaria - Florida and Texas, May-July 2023. MMWR Morb Mortal Wkly Rep. 2023 Sep 8;72(36):973-978. doi: 10.15585/mmwr.mm7236a1. PMID: 37676839; PMCID: PMC10495185. [^20]: Verhulst NO, Beijleveld H, Knols BG, Takken W, Schraa G, Bouwmeester HJ, Smallegange RC. Cultured skin microbiota attracts malaria mosquitoes. Malar J. 2009 Dec 17;8:302. doi: 10.1186/1475-2875-8-302. PMID: 20017925; PMCID: PMC2804688. [^21]: Kho S, Andries B, Poespoprodjo JR, Commons RJ, Shanti PAI, Kenangalem E, Douglas NM, Simpson JA, Sugiarto P, Anstey NM, Price RN. High Risk of Plasmodium vivax Malaria Following Splenectomy in Papua, Indonesia. Clin Infect Dis. 2019 Jan 1;68(1):51-60. doi: 10.1093/cid/ciy403. PMID: 29771281; PMCID: PMC6128403. [^22]: Qubekani M Moyo, Martin Besser, Roderick Lynn, Andrew M L Lever, Persistence of Imported Malaria Into the United Kingdom: An Epidemiological Review of Risk Factors and At-risk Groups, _Clinical Infectious Diseases_, Volume 69, Issue 7, 1 October 2019, Pages 1156–1162, [https://doi.org/10.1093/cid/ciy1037](https://doi.org/10.1093/cid/ciy1037) [^23]: Trampuz A, Jereb M, Muzlovic I, Prabhu RM. Clinical review: Severe malaria. Crit Care. 2003 Aug;7(4):315-23. doi: 10.1186/cc2183. Epub 2003 Apr 14. PMID: 12930555; PMCID: PMC270697. [^24]: Phillips A, Bassett P, Zeki S, Newman S, Pasvol G. Risk factors for severe disease in adults with falciparum malaria. Clin Infect Dis. 2009 Apr 1;48(7):871-8. doi: 10.1086/597258. PMID: 19243243. [^25]: Wyss K, Wångdahl A, Vesterlund M, Hammar U, Dashti S, Naucler P, Färnert A. Obesity and Diabetes as Risk Factors for Severe Plasmodium falciparum Malaria: Results From a Swedish Nationwide Study. 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[^34]: Katherine Plewes, Hugh W F Kingston, Aniruddha Ghose, Thanaporn Wattanakul, Md Mahtab Uddin Hassan, Md Shafiul Haider, Prodip K Dutta, Md Akhterul Islam, Shamsul Alam, Selim Md Jahangir, A S M Zahed, Md Abdus Sattar, M A Hassan Chowdhury, M Trent Herdman, Stije J Leopold, Haruhiko Ishioka, Kim A Piera, Prakaykaew Charunwatthana, Kamolrat Silamut, Tsin W Yeo, Sue J Lee, Mavuto Mukaka, Richard J Maude, Gareth D H Turner, Md Abul Faiz, Joel Tarning, John A Oates, Nicholas M Anstey, Nicholas J White, Nicholas P J Day, Md Amir Hossain, L Jackson Roberts II, Arjen M Dondorp, Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial, _Clinical Infectious Diseases_, Volume 67, Issue 7, 1 October 2018, Pages 991–999, [https://doi.org/10.1093/cid/ciy213](https://doi.org/10.1093/cid/ciy213) [^35]: Tan KR, Wiegand RE, Arguin PM. 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