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==Overview==
==Overview==
'''''Plasmodium knowlesi''''' is a simian parasite that cause malaria; the natural hosts are macaques.<ref name="pmid29011028">{{cite journal |vauthors=Napier LE, Campbell HGM |title=Observations on a Plasmodium Infection Which Causes Hæmoglobinuria in Certain Species of Monkey |journal=Ind Med Gaz |volume=67 |issue=5 |pages=246–249 |date=May 1932 |pmid=29011028 |pmc=5231784 |doi= |url=}}</ref> Human cases of Plasmodium knowlesi malaria have been reported throughout the Southeast Asia; most cases have been reported from Malaysia, particularly the eastern Malaysian states of Sabah and Sarawak.<ref name="pmid27494405">{{cite journal |vauthors=Shearer FM, Huang Z, Weiss DJ, Wiebe A, Gibson HS, Battle KE, Pigott DM, Brady OJ, Putaporntip C, Jongwutiwes S, Lau YL, Manske M, Amato R, Elyazar IR, Vythilingam I, Bhatt S, Gething PW, Singh B, Golding N, Hay SI, Moyes CL |title=Estimating Geographical Variation in the Risk of Zoonotic Plasmodium knowlesi Infection in Countries Eliminating Malaria |journal=PLoS Negl Trop Dis |volume=10 |issue=8 |pages=e0004915 |date=August 2016 |pmid=27494405 |pmc=4975412 |doi=10.1371/journal.pntd.0004915 |url=}}</ref> this malaria is generally acquired in forest or forest-fringe areas; those at risk include farmers, plantation workers, and individuals undertaking other activities in forested areas. Adult population is commonly affected more than children and the mortality increases as the age increases. <ref name="pmid29873683">{{cite journal |vauthors=Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, Piera K, Wilkes CS, Patel K, Chandna A, Drakeley CJ, Yeo TW, Anstey NM |title=Age-Related Clinical Spectrum of Plasmodium knowlesi Malaria and Predictors of Severity |journal=Clin. Infect. Dis. |volume=67 |issue=3 |pages=350–359 |date=July 2018 |pmid=29873683 |pmc=6051457 |doi=10.1093/cid/ciy065 |url=}}</ref>
'''''Plasmodium knowlesi''''' is a simian parasite that cause malaria; the natural hosts are macaques.  Human cases of Plasmodium knowlesi malaria have been reported throughout the Southeast Asia; most cases have been reported from Malaysia, particularly the eastern Malaysian states of Sabah and Sarawak. this malaria is generally acquired in forest or forest-fringe areas; those at risk include farmers, plantation workers, and individuals undertaking other activities in forested areas. Adult population is commonly affected more than children and the mortality increases as the age increases.  


==Epidemiology==
==Epidemiology==
*Reports of human ''P. knowlesi'' infections are confined to Southeast Asia,<ref>{{cite journal | author=Chin W, Contacos PG, Coatney RG, Kimbal HR. | journal=Science | year=1965 | title=A naturally acquired quotidian-type malaria in man transferable to monkeys | volume=149 | pages=865 | id=PMID 14332847 }}</ref><ref>{{cite journal | journal=Trans R Soc Trop Med Hyg | year=1971 | volume=65 | issue=6 | pages=839&ndash;40 | title=A presumptive case of naturally occurring ''Plasmodium knowlesi'' malaria in man in Malaysia | author=Yap FL, Cadigan FC, Coatney GR. | id=PMID 5003320 }}</ref> particularly Malaysia,<ref name="Singh2004">{{cite journal | journal=Lancet | year=2004 | volume=363 | pages=1017&ndash;24 | title=A large focus of naturally acquired ''Plasmodium knowlesi'' infections in human beings | author=Singh B, Lee KS, Matusop A, Radhakrishnan A, Shamsul SSG, Cox-Singh J, Thomas A, Conway DJ | doi=10.1016/S0140-6736(04)15836-4 }}</ref> but there are also reports on the Thai-Burmese border.<ref>{{cite journal | journal=Emerg Infect Dis | year=2004 | volume=10 | issue=12 | pages=2211&ndash;3 | title=Naturally acquired ''Plasmodium knowlesi'' malaria in human, Thailand | author=Jongwutiwes S, Putaporntip C, Iwasaki T, Sata T, Kanbara H. | id=PMID 15663864 }}</ref>  A fifth of the cases of malaria diagnosed in [[Sarawak]], [[Malaysian Borneo]] are due to ''P. knowlesi''.<ref name="Singh2004"/>
*Reports of human ''P. knowlesi'' infections are confined to Southeast Asia, particularly Malaysia, but there are also reports on the Thai-Burmese border. A fifth of the cases of malaria diagnosed in [[Sarawak]], [[Malaysian Borneo]] are due to ''P. knowlesi''<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>


*''P. knowlesi'' infection is normally considered an infection of long-tailed (''Macaca fascicularis'') and pig-tailed (''M. nemestrina'') macaques, but humans who work at the forest fringe or enter the rainforest to work are at risk of being infected with ''P. knowlesi''.
*''P. knowlesi'' infection is normally considered an infection of long-tailed (''Macaca fascicularis'') and pig-tailed (''M. nemestrina'') macaques, but humans who work at the forest fringe or enter the rainforest to work are at risk of being infected with ''P. knowlesi''. <ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*The first case of naturally acquired human infection with P. knowlesi was reported in 1965 in a United States national working in Malaysia.<ref name="pmid14332847">{{cite journal |vauthors=CHIN W, CONTACOS PG, COATNEY GR, KIMBALL HR |title=A NATURALLY ACQUITED QUOTIDIAN-TYPE MALARIA IN MAN TRANSFERABLE TO MONKEYS |journal=Science |volume=149 |issue=3686 |pages=865 |date=August 1965 |pmid=14332847 |doi= |url=}}</ref>
*The first case of naturally acquired human infection with P. knowlesi was reported in 1965 in a United States national working in Malaysia.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*The mosquito ''[[Anopheles latens]]'' is attracted to both macaques and humans and has been shown to be the main vector transmitting ''P. knowlesi'' to humans in the Kapit Division of Sarawak, Malaysian Borneo''<ref name="Vythilingam2006">{{cite journal | author=Vythilingam I, Tan CH, Asmad M, Chan ST, Lee KS, Singh B. | title=Natural transmission of ''Plasmodium knowlesi'' to humans by ''Anopheles latens'' in Sarawak, Malaysia | journal=Trans R Soc Trop Med Hyg | year=2006 | volume=100 | pages=1087&ndash;88 | doi=10.1016/j.trstmh.2006.02.006 }}</ref>.  ''Within the monkey population in Peninsular Malaysia,'' ''[[Anopheles hackeri|''A. hackeri'']]'', ''is believed to be the main vector of'' ''''P. knowlesi'''' : ''although'' ''''A. hackeri'''' ''is capable of transmitting malaria to humans'',<ref>{{cite journal | author=Wharton RH, Eyles DE. | title=''Anopheles hackeri,'' a vector of '''''Plasmodium knowlesi''''' in Malaya | year=1961 | journal=Lancet | journal=Science | volume=134 | pages=279&ndash;80 }}</ref> ''it is not normally attracted to humans and therefore cannot be an important vector for transmission.''<ref>{{cite journal | author=Reid JA, Weitz B. | year=1961 | title=Anopheline mosquitoes as vectors of animal malaria in Malaya | journal=Ann Trop Med Parasitol | volume=55 | pages=180&ndash;6 }}</ref>
*The mosquito ''[[Anopheles latens]]'' is attracted to both macaques and humans and has been shown to be the main vector transmitting ''P. knowlesi'' to humans in the Kapit Division of Sarawak, Malaysian Borneo''.  ''Within the monkey population in Peninsular Malaysia,[[Anopheles hackeri|''A. hackeri'']]'', ''is believed to be the main [[vector]] of'' '<nowiki/>P. knowlesi'<nowiki/>'''<nowiki/>''' : ''although'<nowiki/>''<nowiki/>''A. hackeri'<nowiki/>'''''<nowiki/>''' ''is capable of transmitting malaria to humans'','' it is not normally attracted to humans and therefore cannot be an important vector for transmission.
===Transmission and risk factors for infection===
===Transmission and risk factors for infection===
*Human-mosquito-human transmission has been demonstrated in the laboratory setting but has not yet been proven to occur in the natural environment.<ref name="pmid4385130">{{cite journal |vauthors=Chin W, Contacos PG, Collins WE, Jeter MH, Alpert E |title=Experimental mosquito-transmission of Plasmodium knowlesi to man and monkey |journal=Am. J. Trop. Med. Hyg. |volume=17 |issue=3 |pages=355–8 |date=May 1968 |pmid=4385130 |doi= |url=}}</ref>
*Human-mosquito-human transmission has been demonstrated in the laboratory setting but has not yet been proven to occur in the natural environment.<ref name="pmid25149186">{{cite journal |vauthors=Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, Fornace KM, Anstey NM, Yeo TW, Cox J |title=Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol |journal=BMJ Open |volume=4 |issue=8 |pages=e006004 |date=August 2014 |pmid=25149186 |pmc=4156811 |doi=10.1136/bmjopen-2014-006004 |url=}}</ref>
*Cases of P. knowlesi in humans have been reported to occur in clusters, affecting individuals of all ages.
*Cases of P. knowlesi in humans have been reported to occur in clusters, affecting individuals of all ages.<ref name="pmid25149186">{{cite journal |vauthors=Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, Fornace KM, Anstey NM, Yeo TW, Cox J |title=Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol |journal=BMJ Open |volume=4 |issue=8 |pages=e006004 |date=August 2014 |pmid=25149186 |pmc=4156811 |doi=10.1136/bmjopen-2014-006004 |url=}}</ref>
*Transmission is predominantly zoonotic but it appears possible that human-mosquito-human transmission may occur (at least to some degree) in endemic areas.<ref name="pmid23216947">{{cite journal |vauthors=Barber BE, William T, Dhararaj P, Anderios F, Grigg MJ, Yeo TW, Anstey NM |title=Epidemiology of Plasmodium knowlesi malaria in north-east Sabah, Malaysia: family clusters and wide age distribution |journal=Malar. J. |volume=11 |issue= |pages=401 |date=December 2012 |pmid=23216947 |pmc=3528466 |doi=10.1186/1475-2875-11-401 |url=}}</ref>
*Transmission is predominantly [[zoonotic]] but it appears possible that human-mosquito-human transmission may occur (at least to some degree) in endemic areas.
*Risk factors for acquiring P. knowlesi infection include:<ref name="pmid28758162">{{cite journal |vauthors=Grigg MJ, Cox J, William T, Jelip J, Fornace KM, Brock PM, von Seidlein L, Barber BE, Anstey NM, Yeo TW, Drakeley CJ |title=Individual-level factors associated with the risk of acquiring human Plasmodium knowlesi malaria in Malaysia: a case-control study |journal=Lancet Planet Health |volume=1 |issue=3 |pages=e97–e104 |date=June 2017 |pmid=28758162 |pmc=5531251 |doi=10.1016/S2542-5196(17)30031-1 |url=}}</ref>
*Risk factors for acquiring P. knowlesi infection include:<ref name="pmid25149186">{{cite journal |vauthors=Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, Fornace KM, Anstey NM, Yeo TW, Cox J |title=Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol |journal=BMJ Open |volume=4 |issue=8 |pages=e006004 |date=August 2014 |pmid=25149186 |pmc=4156811 |doi=10.1136/bmjopen-2014-006004 |url=}}</ref>
#Male gender
**Male gender
#Age greater than 15 years
**Age greater than 15 years
#Sleeping outside
**Sleeping outside
#Proximity to monkeys in the preceding four weeks
**Proximity to monkeys in the preceding four weeks
#Presence of open eaves or gaps in walls
**Presence of open eaves or gaps in walls
#Presence of long grass around dwelling
**Presence of long grass around dwelling
*Protective factors against P. knowlesi infection in one study included:<ref name="pmid28758162">{{cite journal |vauthors=Grigg MJ, Cox J, William T, Jelip J, Fornace KM, Brock PM, von Seidlein L, Barber BE, Anstey NM, Yeo TW, Drakeley CJ |title=Individual-level factors associated with the risk of acquiring human Plasmodium knowlesi malaria in Malaysia: a case-control study |journal=Lancet Planet Health |volume=1 |issue=3 |pages=e97–e104 |date=June 2017 |pmid=28758162 |pmc=5531251 |doi=10.1016/S2542-5196(17)30031-1 |url=}}</ref>
*Protective factors against P. knowlesi infection in one study included:
#G6PD deficiency
**[[Glucose 6 phosphate dehydrogenase deficiency|G6PD deficiency]]
#Residual insecticide spraying of household walls
**Residual insecticide spraying of household walls
#Presence of sparse forest or rice paddies around the house
**Presence of sparse forest or rice paddies around the house
#Use of bed nets was not protective
**Use of bed nets was not protective
*children Less than 15 years accounted for only 10 % of all P. knowlesi cases in Sabah, Malaysia, between 2010 and 2014.<ref name="pmid26690736">{{cite journal |vauthors=Rajahram GS, Barber BE, William T, Grigg MJ, Menon J, Yeo TW, Anstey NM |title=Falling Plasmodium knowlesi Malaria Death Rate among Adults despite Rising Incidence, Sabah, Malaysia, 2010-2014 |journal=Emerging Infect. Dis. |volume=22 |issue=1 |pages=41–8 |date=January 2016 |pmid=26690736 |pmc=4696710 |doi=10.3201/eid2201.151305 |url=}}</ref>
*Children Less than 15 years accounted for only 10 % of all P. knowlesi cases in Sabah, Malaysia, between 2010 and 2014.<ref name="pmid25149186">{{cite journal |vauthors=Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, Fornace KM, Anstey NM, Yeo TW, Cox J |title=Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol |journal=BMJ Open |volume=4 |issue=8 |pages=e006004 |date=August 2014 |pmid=25149186 |pmc=4156811 |doi=10.1136/bmjopen-2014-006004 |url=}}</ref>
*Transfusion-transmitted P. knowlesi malaria has been reported in Malaysia.<ref name="pmid27405869">{{cite journal |vauthors=Bird EM, Parameswaran U, William T, Khoo TM, Grigg MJ, Aziz A, Marfurt J, Yeo TW, Auburn S, Anstey NM, Barber BE |title=Transfusion-transmitted severe Plasmodium knowlesi malaria in a splenectomized patient with beta-thalassaemia major in Sabah, Malaysia: a case report |journal=Malar. J. |volume=15 |issue=1 |pages=357 |date=July 2016 |pmid=27405869 |pmc=4942937 |doi=10.1186/s12936-016-1398-z |url=}}</ref>
*Transfusion-transmitted P. knowlesi malaria has been reported in Malaysia.
 
==Clinical Features==
*The clinical features of Plasmodium knowlesi infection ranges from asymptomatic infection to severe disease.
*Most patients have uncomplicated disease; severe disease occurs in less than 10 % of symptomatic adults.<ref name="pmid23554413">{{cite journal |vauthors=Singh B, Daneshvar C |title=Human infections and detection of Plasmodium knowlesi |journal=Clin. Microbiol. Rev. |volume=26 |issue=2 |pages=165–84 |date=April 2013 |pmid=23554413 |pmc=3623376 |doi=10.1128/CMR.00079-12 |url=}}</ref>
*The [[incubation period]] of P. knowlesi infection is in the range of 3 to 27 days.<ref name="pmid23554413">{{cite journal |vauthors=Singh B, Daneshvar C |title=Human infections and detection of Plasmodium knowlesi |journal=Clin. Microbiol. Rev. |volume=26 |issue=2 |pages=165–84 |date=April 2013 |pmid=23554413 |pmc=3623376 |doi=10.1128/CMR.00079-12 |url=}}</ref>
*Parasites normally appear in the blood several days after the initial temperature rise.<ref name="pmid23554413">{{cite journal |vauthors=Singh B, Daneshvar C |title=Human infections and detection of Plasmodium knowlesi |journal=Clin. Microbiol. Rev. |volume=26 |issue=2 |pages=165–84 |date=April 2013 |pmid=23554413 |pmc=3623376 |doi=10.1128/CMR.00079-12 |url=}}</ref>
===Nonpregnant adults===
====Uncomplicated infection====
*Uncomplicated P. knowlesi malaria is defined as clinical illness with parasitemia <15,000/uL and no features of severe malaria.
*Clinical manifestations of P. knowlesi infection in adults include:
===History and Symptoms===
Clinical manifestations of P. knowlesi infection in adults include:
*Fever and Chills
*Headache
*[[Myalgia]]
*Nausea and Vomiting
*Abdominal pain
*Diarrhea
*Cough
===Physical Examination===
Common physical examination findings of P. knowlesi include:
*Fever of greater than 101F
*[[Tachycardia]]
*[[Tachypnea]]
*[[Splenomegaly]]
*[[Hepatomegaly]]
*Neurologic manifestations are rare in P. knowlesi infection.
*[[Retinopathy]]
====Severe infection====
*Severe P. knowlesi infection occurs when the parasitemia level is >15,000/microL.
*The likelihood of hyperparasitemia correlates with age, with age ≥45 years being the best predictor of hyperparasitemia. Older adults have higher parasitemias and thus are at greater risk of severe disease.
*Clinical manifestations of severe disease include:
**[[Jaundice]]
**[[Acute kidney injury]]
**[[Respiratory distress]]
**[[Shock (medicine)|Shock]]
 
===Children===
*Plasmodium kowlesi infection is uncommon in chlidren.
*Clinical manifestations are similar to those in adults, including rigors, headache, abdominal pain, cough, vomiting, [[arthralgia]], and [[myalgia]].
*[[Thrombocytopenia classification|Thrombocytopenia]] and mild to moderate anemia are also common in childern having P knowlesi infection.
 
===Pregnant women===
*Plasmodium knowlesi infection is rare during pregnancy. only five cases have been reported so far.


==Diagnosis==
==Diagnosis==
*''P. knowlesi'' infections is diagnosed by examining thick and thin blood films in the same way as other [[malaria]]s.   
*''P. knowlesi'' infections is diagnosed by examining thick and thin [[blood films]] in the same way as other [[malaria]]s.   
*The appearance of ''P. knowlesi'' is similar to that of ''[[Plasmodium malariae|P. malariae]]'' and is unlikely to be correctly diagnosed except by using molecular detection assays <ref name="Singh2004">{{cite journal | journal=Lancet | year=2004 | volume=363 | pages=1017&ndash;24 | title=A large focus of naturally acquired ''Plasmodium knowlesi'' infections in human beings | author=Singh B, Lee KS, Matusop A | doi=10.1016/S0140-6736(04)15836-4 }}</ref>
*The appearance of ''P. knowlesi'' is similar to that of ''[[Plasmodium malariae|P. malariae]]'' and is unlikely to be correctly diagnosed except by using molecular detection assays.
*Reporting of P. knowlesi as the more benign P. malariae has been associated with failure to recognize severe malaria and consequent delayed initiation of parenteral therapy, with fatal outcomes.
*Reporting of P. knowlesi as the more benign P. malariae has been associated with failure to recognize severe malaria and consequent delayed initiation of parenteral therapy, with fatal outcomes.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*P. knowlesi malaria should be suspected in the setting of febrile illness after exposure to regions where P. knowlesi malaria is endemic.
*P. knowlesi malaria should be suspected in the setting of febrile illness after exposure to regions where P. knowlesi malaria is endemic.
*The approach to diagnosis of P. knowlesi malaria consists of microscopy to guide immediate clinical management, followed by confirmatory testing with PCR.
*The approach to diagnosis of P. knowlesi malaria consists of microscopy to guide immediate clinical management, followed by confirmatory testing with [[Polymerase chain reaction|PCR]].<ref name="pmid29902183">{{cite journal |vauthors=Herman LS, Fornace K, Phelan J, Grigg MJ, Anstey NM, William T, Moon RW, Blackman MJ, Drakeley CJ, Tetteh KKA |title=Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure |journal=PLoS Negl Trop Dis |volume=12 |issue=6 |pages=e0006457 |date=June 2018 |pmid=29902183 |pmc=6001954 |doi=10.1371/journal.pntd.0006457 |url=}}</ref>
*PCR is the gold standard diagnostic tool with high sensitivity and specificity.<ref name="pmid19812279">{{cite journal |vauthors=Imwong M, Tanomsing N, Pukrittayakamee S, Day NP, White NJ, Snounou G |title=Spurious amplification of a Plasmodium vivax small-subunit RNA gene by use of primers currently used to detect P. knowlesi |journal=J. Clin. Microbiol. |volume=47 |issue=12 |pages=4173–5 |date=December 2009 |pmid=19812279 |pmc=2786678 |doi=10.1128/JCM.00811-09 |url=}}</ref>
*[[Polymerase chain reaction|PCR]] is the gold standard diagnostic tool with high sensitivity and specificity.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Microscopy is a sensitive tool for the detection of level of parasitemia and to know the life cycle stages of Plasmodium knowlesi.
*Microscopy is a sensitive tool for the detection of level of parasitemia and to know the life cycle stages of Plasmodium knowlesi.
*Microscopy can not be used for the differentiation of different species of Plasmodium , as the blood stages of P. knowlesi resemble P. malariae and the ring stages resemble P. falciparum.<ref name="pmid25272973">{{cite journal |vauthors=William T, Jelip J, Menon J, Anderios F, Mohammad R, Awang Mohammad TA, Grigg MJ, Yeo TW, Anstey NM, Barber BE |title=Changing epidemiology of malaria in Sabah, Malaysia: increasing incidence of Plasmodium knowlesi |journal=Malar. J. |volume=13 |issue= |pages=390 |date=October 2014 |pmid=25272973 |pmc=4195888 |doi=10.1186/1475-2875-13-390 |url=}}</ref>
*Microscopy can not be used for the differentiation of different species of Plasmodium , as the blood stages of P. knowlesi resemble P. malariae and the ring stages resemble [[Plasmodium falciparum|P. falciparum]].<ref name="pmid29902183">{{cite journal |vauthors=Herman LS, Fornace K, Phelan J, Grigg MJ, Anstey NM, William T, Moon RW, Blackman MJ, Drakeley CJ, Tetteh KKA |title=Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure |journal=PLoS Negl Trop Dis |volume=12 |issue=6 |pages=e0006457 |date=June 2018 |pmid=29902183 |pmc=6001954 |doi=10.1371/journal.pntd.0006457 |url=}}</ref>
*Patients in endemic regions of P. knowlesi malaria with microscopy findings resembling P. malariae should be treated for P. knowlesi infection.
*Patients in endemic regions of P. knowlesi malaria with microscopy findings resembling P. malariae should be treated for P. knowlesi infection.
*Rapid diagnostic tests (RDTs) are useful for excluding P. falciparum infection but have low sensitivity for detection of P. knowlesi infection, especially at the low parasite densities commonly causing clinical disease.<ref name="pmid23345297">{{cite journal |vauthors=Barber BE, William T, Grigg MJ, Piera K, Yeo TW, Anstey NM |title=Evaluation of the sensitivity of a pLDH-based and an aldolase-based rapid diagnostic test for diagnosis of uncomplicated and severe malaria caused by PCR-confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax |journal=J. Clin. Microbiol. |volume=51 |issue=4 |pages=1118–23 |date=April 2013 |pmid=23345297 |pmc=3666806 |doi=10.1128/JCM.03285-12 |url=}}</ref>
*Rapid diagnostic tests (RDTs) are useful for excluding [[Plasmodium falciparum|P. falciparum]] infection but have low sensitivity for detection of P. knowlesi infection, especially at the low parasite densities commonly causing clinical disease.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref> <ref name="pmid30353400">{{cite journal |vauthors=Mukkala AN, Kwan J, Lau R, Harris D, Kain D, Boggild AK |title=An Update on Malaria Rapid Diagnostic Tests |journal=Curr Infect Dis Rep |volume=20 |issue=12 |pages=49 |date=October 2018 |pmid=30353400 |doi=10.1007/s11908-018-0655-4 |url=}}</ref>


==Treatment==
==Treatment==
''P. knowlesi'' infection responds well to treatment with [[chloroquine]] and [[primaquine]].<ref name="Singh2004"/>
*All adults with known or suspected P. knowlesi infection should be admitted to hospital for management, because of the significant risk of severe disease at relatively low parasitemia and the risk of developing complications after commencement of treatment.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
===Adults===
====Uncomplicated Infection====
*Treatment of uncomplicated Plasmodium knowlesi infection consists of oral [[Artemisinin]] Combination Therapy (ACT) regimen.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Those patients who can not tolerate oral therapy are offered parenteral therapy.
*Artemisinin Combination Therapy (ACT) regimen is superior to [[chloroquine]] for treatment of drug-resistant P. falciparum and P. vivax malaria found in regions where co-infection can occur.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Use of chloroquine for the treatment of microscopy-diagnosed Plasmodium knowlesi infection may result in inadvertent administration of chloroquine for misdiagnosed P. falciparum or P. vivax infection.
*Combination of Artemether-[[lumefantrine]] is the preferred ACT for treatment of uncomplicated P. knowlesi malaria, because of its excellent efficacy, ability to be tolerated and its wide availability.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Artesunate-[[Mefloquine]] and [[Dihydroartemisinin-Piperaquine|Dihydroartemisinin-piperaquine]] have also been used as ACT for the treatment of uncomplicated plasmodium knowlesi infection.<ref name="pmid28961865">{{cite journal |vauthors=van Schalkwyk DA, Moon RW, Blasco B, Sutherland CJ |title=Comparison of the susceptibility of Plasmodium knowlesi and Plasmodium falciparum to antimalarial agents |journal=J. Antimicrob. Chemother. |volume=72 |issue=11 |pages=3051–3058 |date=November 2017 |pmid=28961865 |pmc=5890772 |doi=10.1093/jac/dkx279 |url=}}</ref>
*[[Chloroquine]] can also be used in the treatment of uncomplicated Plasmodium knowlesi but it is associated with slower parasite clearance times and a higher frequency of anemia than ACTs.
*[[Chloroquine]] total dose is 25 mg base/kg which is administered as 10 mg base/kg orally on first day, followed by 10 mg base/kg orally on second day, and 5 mg base/kg on third day.
*In returned travelers, [[Atovaquone]]-proguanil has been used for the treatment of uncomplicated Plasmodium knowlesi infection.
*In Adult atovaquone-proguanil dose is four adult tabs (250 mg atovaquone/100 mg proguanil) orally once daily for three days.


==<i>Plasmodium knowlesi</i> genome data==
===Severe infection===
* [http://www.genedb.org/genedb/pknowlesi/ GeneDB Plasmodium knowlesi]
*Treatment of severe malaria infection regardless of the specie is parenteral Artisunate.
*Intravenous artesunate should be administered for a minimum of three doses followed by a three day course of oral ACT only if oral intake can be tolerated.
*If intravenous Artisunate is not available then intravenous quinine is an acceptable alternative therapy.
*Those who are treated with intra venous Artisunate should be monitored for delayed hemolytic anemia, with repeat hemoglobin testing at 7 and 14 days after treatment.
====Supportive care====
*Severe Plasmodium knowlesi infection can result in complications like multi organ failure which require intensive supportive care including [[inotropic]] and ventilatory support and [[hemodialysis]] for [[acute kidney injury]].
*There are no clinical guidelines available on the intravenous fluid therapy during plasmodium knowlesi infection, hence Intravenous fluids should be administered conservatively.
*Broad spectrum antibiotics are commonly used in Plasmodium knowlesi infections until the blood cultures are negative.
*Platelets count reach back to normal levels once antimalarial treatment is stated.
===Childern===
*The approach to selection of antimalarial drugs for children with P. knowlesi infection is the same as for adults.
*Dosing of [[chloroquine]] consists of 10 mg base/kg orally immediately, followed by 5 mg base/kg orally at 6, 24, and 48 hours (total dose 25 mg base/kg; maximum total dose 1500 mg base [=2500 mg salt]).<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Dosing of [[atovaquone]] is weight-based (5 to 8 kg: 2 pediatric tabs orally once daily for three days; 9 to 10 kg: 3 pediatric tabs orally once daily for three days; 11 to 20 kg: 1 adult tab orally once daily for three days; 21 to 30 kg: 2 adult tabs orally once daily for three days; 31 to 40 kg: 3 adult tabs orally once daily for three days).<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Oral quinine is also used to treat uncomplicated P. knowlesi malaria in children but it clears the parasite at a slower pace as compared to ACT.
*Intravenous artesunate is warranted for children who do not tolerate oral intake.
*Severe Plasmodium knowlesi infection is rare in childern so there are no definitive guidelines available for its treatment.
===Pregnant women===
*Treatment of uncomplicated Plasmodium knowlesi infection during first trimester is chloroquine.<ref name="pmid30127631">{{cite journal |vauthors=Amir A, Cheong FW, de Silva JR, Liew JWK, Lau YL |title=Plasmodium knowlesi malaria: current research perspectives |journal=Infect Drug Resist |volume=11 |issue= |pages=1145–1155 |date=2018 |pmid=30127631 |pmc=6089103 |doi=10.2147/IDR.S148664 |url=}}</ref>
*Treatment of uncomplicated plasmodium knowlesi infectioin in second or third trimester is oral ACT regimen; chloroquine is an acceptable alternative.
*Pregnants with severe malaria should be treated with intravenous artesunate, regardless of trimester.


==References==
==References==
<references/>


[[Category:Malaria]]
[[Category:Malaria]]


{{protist-stub}}
[[Category:apicomplexa]]
[[Category:apicomplexa]]
[[Category:Malaria]]
[[Category:Malaria]]
<references />

Latest revision as of 20:03, 24 July 2019


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2] Syed Musadiq Ali M.B.B.S.[3]

Plasmodium knowlesi
Scientific classification
Kingdom: Protista
Phylum: Apicomplexa
Class: Aconoidasida
Order: Haemosporida
Family: Plasmodiidae
Genus: Plasmodium
Species: P. knowlesi
Binomial name
Plasmodium knowlesi

Overview

Plasmodium knowlesi is a simian parasite that cause malaria; the natural hosts are macaques. Human cases of Plasmodium knowlesi malaria have been reported throughout the Southeast Asia; most cases have been reported from Malaysia, particularly the eastern Malaysian states of Sabah and Sarawak. this malaria is generally acquired in forest or forest-fringe areas; those at risk include farmers, plantation workers, and individuals undertaking other activities in forested areas. Adult population is commonly affected more than children and the mortality increases as the age increases.

Epidemiology

  • Reports of human P. knowlesi infections are confined to Southeast Asia, particularly Malaysia, but there are also reports on the Thai-Burmese border. A fifth of the cases of malaria diagnosed in Sarawak, Malaysian Borneo are due to P. knowlesi[1]
  • P. knowlesi infection is normally considered an infection of long-tailed (Macaca fascicularis) and pig-tailed (M. nemestrina) macaques, but humans who work at the forest fringe or enter the rainforest to work are at risk of being infected with P. knowlesi. [1]
  • The first case of naturally acquired human infection with P. knowlesi was reported in 1965 in a United States national working in Malaysia.[1]
  • The mosquito Anopheles latens is attracted to both macaques and humans and has been shown to be the main vector transmitting P. knowlesi to humans in the Kapit Division of Sarawak, Malaysian Borneo. Within the monkey population in Peninsular Malaysia,A. hackeri, is believed to be the main vector of 'P. knowlesi' : although'A. hackeri' is capable of transmitting malaria to humans, it is not normally attracted to humans and therefore cannot be an important vector for transmission.

Transmission and risk factors for infection

  • Human-mosquito-human transmission has been demonstrated in the laboratory setting but has not yet been proven to occur in the natural environment.[2]
  • Cases of P. knowlesi in humans have been reported to occur in clusters, affecting individuals of all ages.[2]
  • Transmission is predominantly zoonotic but it appears possible that human-mosquito-human transmission may occur (at least to some degree) in endemic areas.
  • Risk factors for acquiring P. knowlesi infection include:[2]
    • Male gender
    • Age greater than 15 years
    • Sleeping outside
    • Proximity to monkeys in the preceding four weeks
    • Presence of open eaves or gaps in walls
    • Presence of long grass around dwelling
  • Protective factors against P. knowlesi infection in one study included:
    • G6PD deficiency
    • Residual insecticide spraying of household walls
    • Presence of sparse forest or rice paddies around the house
    • Use of bed nets was not protective
  • Children Less than 15 years accounted for only 10 % of all P. knowlesi cases in Sabah, Malaysia, between 2010 and 2014.[2]
  • Transfusion-transmitted P. knowlesi malaria has been reported in Malaysia.

Clinical Features

  • The clinical features of Plasmodium knowlesi infection ranges from asymptomatic infection to severe disease.
  • Most patients have uncomplicated disease; severe disease occurs in less than 10 % of symptomatic adults.[3]
  • The incubation period of P. knowlesi infection is in the range of 3 to 27 days.[3]
  • Parasites normally appear in the blood several days after the initial temperature rise.[3]

Nonpregnant adults

Uncomplicated infection

  • Uncomplicated P. knowlesi malaria is defined as clinical illness with parasitemia <15,000/uL and no features of severe malaria.
  • Clinical manifestations of P. knowlesi infection in adults include:

History and Symptoms

Clinical manifestations of P. knowlesi infection in adults include:

  • Fever and Chills
  • Headache
  • Myalgia
  • Nausea and Vomiting
  • Abdominal pain
  • Diarrhea
  • Cough

Physical Examination

Common physical examination findings of P. knowlesi include:

Severe infection

  • Severe P. knowlesi infection occurs when the parasitemia level is >15,000/microL.
  • The likelihood of hyperparasitemia correlates with age, with age ≥45 years being the best predictor of hyperparasitemia. Older adults have higher parasitemias and thus are at greater risk of severe disease.
  • Clinical manifestations of severe disease include:

Children

  • Plasmodium kowlesi infection is uncommon in chlidren.
  • Clinical manifestations are similar to those in adults, including rigors, headache, abdominal pain, cough, vomiting, arthralgia, and myalgia.
  • Thrombocytopenia and mild to moderate anemia are also common in childern having P knowlesi infection.

Pregnant women

  • Plasmodium knowlesi infection is rare during pregnancy. only five cases have been reported so far.

Diagnosis

  • P. knowlesi infections is diagnosed by examining thick and thin blood films in the same way as other malarias.
  • The appearance of P. knowlesi is similar to that of P. malariae and is unlikely to be correctly diagnosed except by using molecular detection assays.
  • Reporting of P. knowlesi as the more benign P. malariae has been associated with failure to recognize severe malaria and consequent delayed initiation of parenteral therapy, with fatal outcomes.[1]
  • P. knowlesi malaria should be suspected in the setting of febrile illness after exposure to regions where P. knowlesi malaria is endemic.
  • The approach to diagnosis of P. knowlesi malaria consists of microscopy to guide immediate clinical management, followed by confirmatory testing with PCR.[4]
  • PCR is the gold standard diagnostic tool with high sensitivity and specificity.[1]
  • Microscopy is a sensitive tool for the detection of level of parasitemia and to know the life cycle stages of Plasmodium knowlesi.
  • Microscopy can not be used for the differentiation of different species of Plasmodium , as the blood stages of P. knowlesi resemble P. malariae and the ring stages resemble P. falciparum.[4]
  • Patients in endemic regions of P. knowlesi malaria with microscopy findings resembling P. malariae should be treated for P. knowlesi infection.
  • Rapid diagnostic tests (RDTs) are useful for excluding P. falciparum infection but have low sensitivity for detection of P. knowlesi infection, especially at the low parasite densities commonly causing clinical disease.[1] [5]

Treatment

  • All adults with known or suspected P. knowlesi infection should be admitted to hospital for management, because of the significant risk of severe disease at relatively low parasitemia and the risk of developing complications after commencement of treatment.[1]

Adults

Uncomplicated Infection

  • Treatment of uncomplicated Plasmodium knowlesi infection consists of oral Artemisinin Combination Therapy (ACT) regimen.[1]
  • Those patients who can not tolerate oral therapy are offered parenteral therapy.
  • Artemisinin Combination Therapy (ACT) regimen is superior to chloroquine for treatment of drug-resistant P. falciparum and P. vivax malaria found in regions where co-infection can occur.[1]
  • Use of chloroquine for the treatment of microscopy-diagnosed Plasmodium knowlesi infection may result in inadvertent administration of chloroquine for misdiagnosed P. falciparum or P. vivax infection.
  • Combination of Artemether-lumefantrine is the preferred ACT for treatment of uncomplicated P. knowlesi malaria, because of its excellent efficacy, ability to be tolerated and its wide availability.[1]
  • Artesunate-Mefloquine and Dihydroartemisinin-piperaquine have also been used as ACT for the treatment of uncomplicated plasmodium knowlesi infection.[6]
  • Chloroquine can also be used in the treatment of uncomplicated Plasmodium knowlesi but it is associated with slower parasite clearance times and a higher frequency of anemia than ACTs.
  • Chloroquine total dose is 25 mg base/kg which is administered as 10 mg base/kg orally on first day, followed by 10 mg base/kg orally on second day, and 5 mg base/kg on third day.
  • In returned travelers, Atovaquone-proguanil has been used for the treatment of uncomplicated Plasmodium knowlesi infection.
  • In Adult atovaquone-proguanil dose is four adult tabs (250 mg atovaquone/100 mg proguanil) orally once daily for three days.

Severe infection

  • Treatment of severe malaria infection regardless of the specie is parenteral Artisunate.
  • Intravenous artesunate should be administered for a minimum of three doses followed by a three day course of oral ACT only if oral intake can be tolerated.
  • If intravenous Artisunate is not available then intravenous quinine is an acceptable alternative therapy.
  • Those who are treated with intra venous Artisunate should be monitored for delayed hemolytic anemia, with repeat hemoglobin testing at 7 and 14 days after treatment.

Supportive care

  • Severe Plasmodium knowlesi infection can result in complications like multi organ failure which require intensive supportive care including inotropic and ventilatory support and hemodialysis for acute kidney injury.
  • There are no clinical guidelines available on the intravenous fluid therapy during plasmodium knowlesi infection, hence Intravenous fluids should be administered conservatively.
  • Broad spectrum antibiotics are commonly used in Plasmodium knowlesi infections until the blood cultures are negative.
  • Platelets count reach back to normal levels once antimalarial treatment is stated.

Childern

  • The approach to selection of antimalarial drugs for children with P. knowlesi infection is the same as for adults.
  • Dosing of chloroquine consists of 10 mg base/kg orally immediately, followed by 5 mg base/kg orally at 6, 24, and 48 hours (total dose 25 mg base/kg; maximum total dose 1500 mg base [=2500 mg salt]).[1]
  • Dosing of atovaquone is weight-based (5 to 8 kg: 2 pediatric tabs orally once daily for three days; 9 to 10 kg: 3 pediatric tabs orally once daily for three days; 11 to 20 kg: 1 adult tab orally once daily for three days; 21 to 30 kg: 2 adult tabs orally once daily for three days; 31 to 40 kg: 3 adult tabs orally once daily for three days).[1]
  • Oral quinine is also used to treat uncomplicated P. knowlesi malaria in children but it clears the parasite at a slower pace as compared to ACT.
  • Intravenous artesunate is warranted for children who do not tolerate oral intake.
  • Severe Plasmodium knowlesi infection is rare in childern so there are no definitive guidelines available for its treatment.

Pregnant women

  • Treatment of uncomplicated Plasmodium knowlesi infection during first trimester is chloroquine.[1]
  • Treatment of uncomplicated plasmodium knowlesi infectioin in second or third trimester is oral ACT regimen; chloroquine is an acceptable alternative.
  • Pregnants with severe malaria should be treated with intravenous artesunate, regardless of trimester.

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 Amir A, Cheong FW, de Silva JR, Liew J, Lau YL (2018). "Plasmodium knowlesi malaria: current research perspectives". Infect Drug Resist. 11: 1145–1155. doi:10.2147/IDR.S148664. PMC 6089103. PMID 30127631. Vancouver style error: initials (help)
  2. 2.0 2.1 2.2 2.3 Grigg MJ, William T, Drakeley CJ, Jelip J, von Seidlein L, Barber BE, Fornace KM, Anstey NM, Yeo TW, Cox J (August 2014). "Factors that are associated with the risk of acquiring Plasmodium knowlesi malaria in Sabah, Malaysia: a case-control study protocol". BMJ Open. 4 (8): e006004. doi:10.1136/bmjopen-2014-006004. PMC 4156811. PMID 25149186.
  3. 3.0 3.1 3.2 Singh B, Daneshvar C (April 2013). "Human infections and detection of Plasmodium knowlesi". Clin. Microbiol. Rev. 26 (2): 165–84. doi:10.1128/CMR.00079-12. PMC 3623376. PMID 23554413.
  4. 4.0 4.1 Herman LS, Fornace K, Phelan J, Grigg MJ, Anstey NM, William T, Moon RW, Blackman MJ, Drakeley CJ, Tetteh K (June 2018). "Identification and validation of a novel panel of Plasmodium knowlesi biomarkers of serological exposure". PLoS Negl Trop Dis. 12 (6): e0006457. doi:10.1371/journal.pntd.0006457. PMC 6001954. PMID 29902183. Vancouver style error: initials (help)
  5. Mukkala AN, Kwan J, Lau R, Harris D, Kain D, Boggild AK (October 2018). "An Update on Malaria Rapid Diagnostic Tests". Curr Infect Dis Rep. 20 (12): 49. doi:10.1007/s11908-018-0655-4. PMID 30353400.
  6. van Schalkwyk DA, Moon RW, Blasco B, Sutherland CJ (November 2017). "Comparison of the susceptibility of Plasmodium knowlesi and Plasmodium falciparum to antimalarial agents". J. Antimicrob. Chemother. 72 (11): 3051–3058. doi:10.1093/jac/dkx279. PMC 5890772. PMID 28961865.