INTRODUCTION — Plasmodium knowlesi is a simian malaria parasite; the natural hosts are macaques [1]. Human cases of knowlesi malaria have been reported throughout Southeast Asia; the greatest number of cases have been reported from Malaysia, particularly the eastern Malaysian states of Sabah and Sarawak [2].
Human P. knowlesi infection is generally acquired in forest or forest-fringe areas; those at risk include farmers, plantation workers, and individuals undertaking other activities in forested areas [3,4]. Clinical disease occurs more commonly in adults than in children [3-8]; the risk of severe disease increases with age [4,7,9].
Issues related to non-falciparum malaria due to P. knowlesi are reviewed here. Issues related to non-falciparum malaria due to Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae are discussed separately. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)
EPIDEMIOLOGY
Geographic distribution — The first case of naturally acquired human infection with P. knowlesi was reported in 1965 in a United States national working in Malaysia [10]. Subsequently, a large focus of naturally acquired P. knowlesi infections in humans in the eastern Malaysian state of Sarawak was described in 2004 [11]. Following this report, P. knowlesi was found to be widely distributed throughout Sarawak and the other eastern Malaysian state of Sabah as well as in Peninsular Malaysia [12]. The infections occurred in patients who had been diagnosed by microscopy as infected with P. malariae, which is morphologically similar. A map of the predicted risk of P. knowlesi infection throughout Southeast Asia is provided in the figure (figure 1).
The geographic distribution of P. knowlesi reflects that of the simian hosts, the long-tailed macaque (Macaca fascicularis) and pig-tailed macaque (Macaca nemestrina), and the mosquito vector (Anopheles leucosphyrus) [13]. These macaque species have a geographic distribution that extends from India, Bhutan, and Bangladesh eastwards through to the Philippines and southwards to Indonesia. The An. leucosphyrus group mosquitoes have a similar distribution across this region.
Human cases of P. knowlesi have been reported throughout this region, including in Myanmar, Thailand, Cambodia, southern China, Vietnam, Laos, Philippines, Singapore, Malaysia, Brunei, the Andaman and Nicobar Islands in India, and Kalimantan, Aceh and Sumatra, Indonesia [14-20]. An increasing number of cases have also been reported in travelers returning from these regions [20-22].
The greatest number of cases have been reported in Malaysia, particularly in the eastern states of Sabah [5,6,8,23] and Sarawak [4]. In Malaysia, P. knowlesi is the only cause of indigenous human malaria. No case of indigenous malaria from any other species has been reported in Malaysia since 2017; between 2017 and 2022 Malaysia reported over 2500 cases of knowlesi malaria per year (peaking at just over 4000 cases in 2018) [24,25]. Malaysia has thus become the first country to be unable to attain malaria free certification from the World Health Organization (WHO) due to ongoing transmission of zoonotic knowlesi malaria [24].
In 2022, reported cases of knowlesi malaria also increased in Indonesia and Thailand, despite molecular surveillance not yet being routine in these countries. In Indonesia, reported cases of P. knowlesi rose from 5 in 2021 to 87 in 2022, and in Thailand, from 71 in 2021 to 176 in 2022. A total of 10 deaths from P. knowlesi were reported globally in 2022, including 9 in Malaysia and 1 in Thailand; no deaths from any other Plasmodium species occurred in these 2 countries [24].
Transmission and risk factors for infection — Humans are incidentally infected with P. knowlesi when bitten by a mosquito vector that has fed from a macaque reservoir host. Human-mosquito-human transmission has been demonstrated in a laboratory setting but has not yet been proven to occur in the natural environment [26]. Modelling suggests transmission remains zoonotic [27]. Human cases of P. knowlesi have been reported to occur in clusters, with individuals of all ages affected; while transmission is zoonotic, it appears possible that human-mosquito-human transmission may occur (at least to some degree) in endemic areas [28].
Risk factors for acquiring P. knowlesi malaria include [3]:
●Age ≥15 years
●Male sex
●Work involving farming, plantations, or clearing vegetation
●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 malaria in one study included glucose-6-phosphate dehydrogenase (G6PD) deficiency, residual insecticide spraying of household walls, and presence of sparse forest or rice paddies around the house; use of bed nets was not protective [3].
Most clinical cases of P. knowlesi infection occur in adults [4,7,23,29,30]. In Sabah, Malaysia, children <15 years accounted for only 6 percent of all P. knowlesi cases between 2015 and 2017 [8], and in Sarawak, Malaysia, children <10 years accounted for only 1 percent of cases between 2011 and 2019 [4].
Travelers from nonendemic countries have acquired P. knowlesi infection in Malaysia, Thailand, Indonesia, and the Philippines [20-22]. The majority of these cases have occurred in men who have spent time in forested regions. (See "Approach to illness associated with travel to Southeast Asia".)
Transfusion-transmitted P. knowlesi malaria has been reported in Malaysia [31].
Life cycle — Anopheline mosquitoes become infected with P. knowlesi parasites after ingesting sexual-stage parasites from infected macaque monkeys. The life cycle of P. knowlesi infection in humans begins when a female anopheline mosquito injects saliva containing sporozoites during a human blood meal (figure 2). The sporozoites travel through the host's bloodstream to the liver, where they invade hepatocytes, undergo asexual replication, and develop into schizonts. Hepatic schizonts rupture and release thousands of daughter merozoites into the bloodstream, causing fever and an inflammatory response. P. knowlesi does not form latent hypnozoite stages.
Merozoites then invade erythrocytes where they develop into young ring parasites and then trophozoites, which undergo further asexual multiplication to form schizonts, containing numerous merozoites. The infected erythrocyte then ruptures, releasing merozoites, which reinvade uninfected erythrocytes, completing the first erythrocytic replication cycle. Within the erythrocyte, some of the merozoites develop into male and female gametocytes. In nonhuman primates (naturally) and human primates (at least experimentally) these gametocytes are taken up by a female mosquito and undergo sexual replication within the midgut of the mosquito to complete the life cycle.
The erythrocytic phase of the P. knowlesi life cycle lasts 24 hours, which is the shortest duration of any human malaria species. Therefore, patients with P. knowlesi may (but not always) experience daily fever spikes. While high parasitemia may develop rapidly, in most clinical cases, parasitemia at presentation is lower than that seen in malaria from the 48-hour erythrocytic cycle parasites, P. vivax and P. falciparum [7,32].
CLINICAL MANIFESTATIONS — The spectrum of clinical disease due to P. knowlesi infection ranges from asymptomatic infection to severe disease [32]. Most patients have uncomplicated disease. Prospective studies in Malaysia have demonstrated that severe disease occurs in 6 to 9 percent of symptomatic adults, but has not been observed in children [7,29,30]. One retrospective study involving 8473 P. knowlesi cases reported that severe disease occurred in 14 percent of patients; however, the definition of severe disease differed from other studies [4]. Fatal infection can occur, particularly in the setting of delayed treatment [12,23,30,33-35].
The incubation period of P. knowlesi infection is usually 8 to 12 days (range of 3 to 27 days) [36-38]. Parasites normally appear in the blood several days after the initial temperature rise. In a study of experimental mosquito infection, pre-patent periods (time to detectable parasitemia) of 9 to 12 days were reported [26]. In hospital-based studies, the average duration of fever prior to presentation is five days [7,30,39].
Nonpregnant adults
Uncomplicated infection — For purposes of clinical management, uncomplicated P. knowlesi malaria is defined as clinical illness with parasitemia <15,000/uL and no features of severe malaria. (See 'Severe infection' below.)
Clinical manifestations of P. knowlesi infection in adults include fever (100 percent), chills, headache (89 to 92 percent), myalgia (62 percent), nausea (56 percent), abdominal pain (23 to 51 percent), vomiting (24 to 32 percent), diarrhea (8 percent), and cough (35 to 52 percent) [7,30,39,40]. Physical findings include fever, tachycardia, and tachypnea. Splenomegaly and hepatomegaly are present in 6 to 33 percent and 24 to 40 percent of patients, respectively [7,30,39].
Neurologic manifestations are rare in P. knowlesi infection. In the three prospective case series including 674 adults with P. knowlesi infection (including 56 with severe disease), none had unarousable coma or seizures [7,30,39,40]. Case reports of coma or focal neurologic signs have been described [23,30]; however, absence of neuroimaging, lumbar puncture, and other diagnostic workup precluded exclusion of alternative diagnoses.
Retinopathy has been described in association with P. knowlesi infection. In one series including 44 patients with P. knowlesi infection, retinal hemorrhages were observed in 18 percent of cases and were associated with thrombocytopenia [41]. However, the characteristic retinal whitening seen in severe falciparum malaria has not been observed in knowlesi malaria.
Severe infection — Criteria for severe P. knowlesi infection are summarized in the table (table 1) [39,42-44]. Increasing parasitemia is strongly associated with risk of severe disease [7,39,45]. A number of cut-off values have been evaluated to define the parasitemia at which risk of severe disease substantially increases. In a prospective study including more than 400 patients in Sabah, Malaysia, parasitemia >15,000/microL was the best predictor of disease severity (odds ratio 16; negative predictive value 98 percent) [7]. Another study in Sabah demonstrated odds ratios of 11 and 28 for parasitemias >20,000/microL and >100,000 microL, respectively [39], while a study in Sarawak, Malaysia, found a parasitemia cut-off of >35,000/microL to be the best predictor of severe disease (odds ratio 10, negative predictive value 96 percent) [45].
Several studies have demonstrated that the likelihood of hyperparasitemia increases with age [4,7,9]. One study demonstrated that age ≥45 years was the best predictor of hyperparasitemia [7]; another reported that parasitemias were highest in adults age ≥60 years [4]. Older adults have higher parasitemias and thus are at greater risk of severe disease [4,9,39]. Two studies have also reported higher parasitemias in adults with forest-related occupations [4]; one of these studies also reported higher parasitemias in certain ethnic groups [4].
Clinical manifestations of severe disease include jaundice, acute kidney injury, respiratory distress, and shock [14]. Severe acute kidney injury (creatinine >3 mg/dL [265 micromol/L]) has been reported in 18 to 94 percent of adults with severe disease [7,30,33,39,45,46]. Blackwater fever with acute kidney injury has been described [33,39,47]. Respiratory distress is associated with hyperparasitemia and occurs in 7 to 70 percent of patients with severe disease [7,30,33,39,45,46]. Coma has not been reported in prospective studies [32]. Thrombocytopenia may rarely be associated with significant bleeding [7,12,30,39,48,49]. Concurrent gram-negative bacteremia has been observed in severe P. knowlesi infection [33,34]. Rarely, spontaneous splenic rupture can occur, presenting with fever and an acute abdomen [50].
The case-fatality rate of P. knowlesi malaria in the era of artesunate treatment is approximately 0.2 to 0.4 percent [7,8,23,35]. Earlier diagnosis and early use of artesunate therapy is associated with lower case-fatality rates [23,35]. Death due to P. knowlesi infection occurs most commonly in older adults [12,23,30,33-35], and age ≥45 years and female sex have been reported as independent risk factors for death [35]. Patients who are pregnant or have underlying cardiovascular disease and diabetes may also be at increased risk [35]. Thrombocytopenia, acute kidney injury, and hyponatremia have been observed in all reported fatal cases, with the majority also having abdominal pain and metabolic acidosis [12,23,34,35].
Laboratory findings — Routine laboratory investigations include hematologic studies and assessment of renal function, liver function, and acid-base status.
Anemia (hemoglobin <10 g/dL) occurs in 5 to 28 percent of cases [30,39]. Severe anemia (<7 g/dL) has been reported in 1.5 to 1.7 percent of cases overall and in 5 to 29 percent of those with severe malaria [7,30,39].
Thrombocytopenia (platelet count <150 x 103/microL) occurs routinely in P. knowlesi malaria. In three large series including 674 adults hospitalized with knowlesi malaria, thrombocytopenia occurred in 94 percent of cases [7,30,39]; platelet count <50 x 103/microL occurred in 29 to 60 percent of cases [30,39]. Platelet counts generally recover quickly, and bleeding occurs in only 4 to 5 percent of those with severe malaria [30,39]. Hematemesis, however, has been observed in patients with severe disease [12,39,48,51]. Absence of thrombocytopenia has been observed in some asplenic patients, suggesting a role of the spleen in platelet destruction or clearance [31,39,47,51].
White blood cell counts are usually normal; neutrophilia has been observed in severe disease [7,9,39].
Coagulation studies may be abnormal. In one series of patients requiring tertiary hospital admission, including 22 patients with severe disease, significant elevations of the prothrombin and partial thromboplastin times were observed in 32 percent of cases, although none had clinically important bleeding [33].
Acute kidney injury is common, occurring in 19 percent of hospitalized adults in one prospective study [7]. Severe acute kidney injury (creatinine >3 mg/dL [265 micromol/L]) has been reported in 18 to 94 percent of patients with severe malaria [7,30,33,39,45,46]. Metabolic acidosis occurs in 11 to 32 percent of cases requiring tertiary hospitalization [33,39].
Mild elevations of liver transaminases are common [7,30,39]. In two series, hyperbilirubinemia (>2.46 mg/dL [>42 micromol/L]) was observed in 3 percent of hospital presentations and in 53 percent of patients with severe infection [30,39].
Children — P. knowlesi malaria in children is relatively uncommon [4,7,23,29,30]. In one study including 3262 cases in Sabah, Malaysia, between 2015 and 2017, 6 percent occurred in children <15 years [8]. In another study in Sarawak, Malaysia, children <10 years accounted for only 1 percent of 8473 cases between 2011 and 2019 [4].
Children typically present with fever [7,52]. Clinical manifestations are similar to those in adults, including rigors (66 percent), headache (77 percent), abdominal pain (43 percent), cough (34 percent), vomiting (32 percent), arthralgia (27 percent), and myalgia (25 percent) [7]. Thrombocytopenia and mild to moderate anemia are common [7,52]. In one series including 31 children, hemoglobin ≤7 g/dL was observed 7 percent of cases [7]. Parasitemia is usually low [7,14,39].
Severe disease has not been observed in children, and no coma or pediatric deaths have been reported [7,8,23,35,52,53].
Pregnant women — P. knowlesi infection during pregnancy appears to be relatively uncommon [33,35,54]. Adverse maternal and infant outcomes have been described, including maternal death, severe maternal malaria, fetal loss, and low birth weight.
Asymptomatic infection — Asymptomatic infection has been observed in endemic areas among adults and children [4,16,17,55,56]. The proportion of asymptomatic individuals in northeastern Sabah, Malaysia, has been estimated to be up to 7 percent [56].
DIAGNOSIS — P. knowlesi malaria should be suspected in the setting of febrile illness after exposure to regions where P. knowlesi malaria is endemic (figure 1).
The approach to diagnosis of P. knowlesi malaria consists of microscopy to guide immediate clinical management, followed by confirmatory testing with polymerase chase reaction (PCR) in a reference laboratory if feasible. PCR is the gold standard diagnostic tool with excellent sensitivity and specificity [57,58].
Microscopy is a relatively sensitive tool for the diagnosis of knowlesi malaria and may be used to detect all species; it allows determination of parasitemia and the life cycle stages present (table 2). However, microscopy cannot be reliably used for distinguishing P. knowlesi from other species (figure 3) [5,34,59,60]. The blood stages of P. knowlesi resemble P. malariae and the ring stages resemble P. falciparum.
Because P. knowlesi may be indistinguishable from P. malariae on microscopy, patients with exposure to regions where P. knowlesi malaria is endemic and microscopy findings resembling P. malariae should be treated for P. knowlesi infection. (See "Laboratory tools for diagnosis of malaria" and "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Diagnosis'.)
In most febrile patients, parasitemia is generally low [32]. In a large prospective hospital study, median P. knowlesi parasitemia at presentation in adults was 2541 (IQR 478-8585) parasites/microL, lower than that in falciparum (9924/microL) and vivax (3765/microL) malaria [7]. The limit of detection of microscopy is about 20 parasites/microL in expert hands. A study from a region with high-transmission of P. knowlesi identified acutely ill patients with PCR-confirmed parasitemia below the limit of detection of microscopy [61]. Studies are ongoing to determine how commonly this occurs. It is prudent for microscopy to be repeated the following day if clinical suspicion persists. Competent microscopy requires ongoing training and evaluation in addition to proper supplies and equipment.
Rapid diagnostic tests (RDTs) are useful for excluding P. falciparum infection but generally have poor sensitivity for detection of P. knowlesi infection, particularly aldolase-based RDTs and at the low parasite densities commonly causing clinical disease [61-64]. A minority of newer PvLDH-based RDTs have sensitivity of up to 92 percent, but are not widely used [61]. Available RDTs are unable to distinguish P. knowlesi from other non-falciparum species [61-63].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of malaria is outlined separately. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children", section on 'Differential diagnosis'.)
TREATMENT — In general, 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 [30,39]. We are in agreement with Malaysian Ministry of Health Guidelines which require hospital admission for all adults, particularly those >40 years of age [9,39].
Antimalarial selection
Adults
Uncomplicated infection — For clinical purposes, uncomplicated P. knowlesi malaria is defined as clinical illness with parasitemia <15,000 parasites/microL and no features of severe malaria (table 1).
The preferred therapy for treatment of uncomplicated P. knowlesi infection consists of an oral artemisinin combination therapy (ACT) regimen [44,65,66]. Patients unable to tolerate oral intake should be treated with parenteral therapy as described below. Because P. knowlesi is a zoonosis, with no drug selection pressure, thus far drug resistance to ACTs has not been reported [67]. (See 'Severe infection' below.)
ACTs are superior to chloroquine for treatment of drug-resistant P. falciparum and P. vivax malaria found in coendemic regions [68,69]. Given that, in P. knowlesi–endemic areas, P. falciparum and P. vivax are commonly misdiagnosed as P. knowlesi, use of chloroquine for the treatment of microscopy-diagnosed "P. knowlesi" malaria may result in inadvertent administration of chloroquine for misdiagnosed P. falciparum or P. vivax infection [16,17,60]. ACTs for treatment of uncomplicated P. knowlesi malaria are summarized in the table (table 3):
●Artemether-lumefantrine is the preferred ACT for treatment of uncomplicated P. knowlesi malaria, given its excellent efficacy, tolerability, and wide availability [33,39]. In a randomized trial including 123 patients with uncomplicated P. knowlesi infection treated with artemether-lumefantrine or chloroquine, those treated with artemether-lumefantrine had faster parasite clearance (18 versus 24 hours; p = 0.02) [70].
●Other ACTs used successfully for treatment of uncomplicated P. knowlesi malaria include artesunate-mefloquine and dihydroartemisinin-piperaquine. In a randomized trial including 252 patients with uncomplicated P. knowlesi malaria treated with artesunate-mefloquine or chloroquine, those treated with artesunate-mefloquine had faster parasite clearance (18 versus 24 hours), faster fever clearance (11 versus 14 hours), and lower risk of anemia within 28 days (71 versus 83 percent) [29]. Successful use of dihydroartemisinin-piperaquine has been described [71,72].
Alternative drugs for treatment of uncomplicated P. knowlesi malaria include chloroquine [29,42,68] and atovaquone-proguanil [22,73-76]:
●Chloroquine is efficacious for treatment of P. knowlesi infection but has been associated with slower parasite clearance times and a higher frequency of anemia than ACTs [11,29,42,70]. Adult dosing of chloroquine consists of a total dose of 25 mg base/kg administered as 10 mg base/kg orally on day 1, followed by 10 mg base/kg orally on day 2, and 5 mg base/kg on day 3. Minor side effects of chloroquine (including bitter taste, gastrointestinal disturbances, dizziness, blurred vision, and headache) may be alleviated by taking the drug with food. (See "Antimalarial drugs: An overview".)
Hydroxychloroquine, the hydroxyl analogue of chloroquine, has similar properties and activity to chloroquine and in vitro has similar efficacy against chloroquine-sensitive P. falciparum [77]. It is likely to be effective; its use for the treatment of P. knowlesi malaria has not been described.
●Atovaquone-proguanil has been used for the treatment of uncomplicated P. knowlesi malaria in returned travelers, with rapid recovery reported in all cases [73-76]. Adult dosing of atovaquone-proguanil consists of four adult tabs (250 mg atovaquone/100 mg proguanil) orally once daily for three days.
Oral quinine has been used successfully to treat uncomplicated P. knowlesi malaria; however, we do not recommend its use (with tetracycline or doxycycline) as first-line treatment of uncomplicated P. knowlesi malaria, given significantly slower parasite clearance times than with ACT [33].
Successful treatment of uncomplicated P. knowlesi malaria with mefloquine has been described [78,79]. However, treatment failures have been reported in rhesus macaques [80,81]. We are in agreement with the World Health Organization, which favors use of mefloquine as an artemisinin partner drug and discourages mefloquine monotherapy [44].
No molecular evidence of drug resistance in P. knowlesi has been identified to date [15,82-84].
Severe infection
Antimalarial therapy — Initial management of patients with features of severe P. knowlesi malaria (table 1) or with parasitemia >15,000 parasites/microL consists of parenteral therapy [21,43]. Parenteral therapy is also warranted for patients unable to tolerate oral intake. (See 'Severe infection' above.)
Treatment of severe malaria (caused by any species) consists of parenteral artesunate [44]:
●In a retrospective study at a tertiary hospital in Malaysia including 16 patients with severe P. knowlesi malaria treated with intravenous quinine (before intravenous artesunate was available), 31 percent of patients died [33]. In a subsequent prospective study at the same hospital including 38 patients with severe P. knowlesi malaria treated with intravenous artesunate, all patients survived [39]. Following statewide implementation of intravenous artesunate in Malaysia, the case-fatality rate due to P. knowlesi malaria between 2010 and 2014 fell from 9.2 to 1.6/1000 case notifications [23].
●Use of intravenous artesunate for treatment of severe P. knowlesi malaria is also supported by randomized trials among adults and children in Southeast Asia [85] and African children [86] demonstrating reduced mortality with intravenous artesunate compared with intravenous quinine for the treatment of severe P. falciparum malaria.
The optimal approach for treatment of patients with parasitemia >15,000 parasites/microL in the absence of other evidence of severe disease is uncertain. For such patients, we favor at least one dose of intravenous artesunate, given the increased risk of severe malaria associated with moderately high parasite counts.
For patients meeting criteria for severe disease, intravenous artesunate should be administered for a minimum of three doses; dosing is summarized in the table (table 4). Intravenous therapy should be followed by a three-day course of oral ACT once oral intake is tolerated. (See "Treatment of severe malaria".)
If intravenous artesunate is not available, intravenous quinine is an acceptable alternative therapy; dosing is summarized in the table (table 4). (See "Treatment of severe malaria".)
Patients treated with parenteral therapy because of inability to tolerate oral intake (in the absence of other criteria for severe malaria) may be switched from intravenous therapy to a three-day course of oral ACT regimen as soon as oral intake is tolerated.
Supportive care — Severe P. knowlesi malaria may be associated with multiorgan failure requiring intensive supportive care, including inotropic and ventilatory support [33] and hemodialysis for acute kidney injury [33,39].
Intravenous fluids should be administered conservatively [87]. There have been no clinical trials to guide intravenous fluid management in P. knowlesi malaria; our approach is extrapolated from studies of severe P. falciparum malaria in which liberal administration of intravenous fluids has been shown to be deleterious [87,88] and conservative fluid regimens have been shown to be safe [89].
For patients with severe knowlesi malaria, we include adjunctive treatment with acetaminophen (500 to 1000 mg every 6 hours for 72 hours). This approach is supported by a randomized trial including more than 390 patients with severe and non-severe knowlesi malaria; improved renal function was observed among those with severe malaria with hemolysis, and with acute kidney injury who received regularly dosed acetaminophen (creatinine fell by 31 versus 20 percent) [90], as also shown previously in severe falciparum malaria [91].
Empiric broad-spectrum intravenous antibiotics are commonly administered in severe P. knowlesi malaria until blood cultures are negative [39].
Platelet counts generally recover rapidly after commencement of antimalarial treatment [39].
Children — The approach to selection of antimalarial therapy for children with uncomplicated P. knowlesi infection is the same as for adults. (See 'Uncomplicated infection' above.)
Dosing of oral ACT regimens is summarized in the table (table 3). Pediatric 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]). Pediatric 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).
Hydroxychloroquine has similar properties and activity to chloroquine and in vitro has similar efficacy against chloroquine-sensitive P. falciparum [77]. It is likely to be effective; its use for the treatment of P. knowlesi malaria has not been described.
Oral quinine has been used successfully to treat uncomplicated P. knowlesi malaria in children [52]; however, we do not recommend its use as first-line treatment of uncomplicated P. knowlesi malaria, given significantly slower parasite clearance times than with ACT [33].
Use of intravenous artesunate is warranted for children who do not tolerate oral intake [39,85,86]. As soon as oral intake is tolerated, treatment may be switched from intravenous therapy to a three-day course of oral ACT regimen.
Severe disease due to P. knowlesi infection in children has not been described; therefore, there is no experience regarding use of intravenous artesunate for this indication. However, children with severe malaria from any species warrant treatment with intravenous artesunate; further principles for management of severe malaria in children are discussed separately. (See "Treatment of severe malaria".)
Pregnant women — Treatment of pregnant women with uncomplicated P. knowlesi malaria in all trimesters of pregnancy consists of an oral ACT regimen, preferably artemether-lumefantrine given its favorable safety profile [92]; chloroquine is an acceptable alternative if ACTs are unavailable [44] (table 5).
Pregnant women with severe malaria (due to any species) should be treated with intravenous artesunate, regardless of trimester [44]. (See "Treatment of severe malaria", section on 'Pregnancy'.)
If there is any doubt as to the species diagnosis, treatment for P. falciparum infection should be administered [44]. (See "Malaria in pregnancy: Prevention and treatment", section on 'Uncomplicated P. falciparum malaria'.)
Follow-up monitoring — Blood smears should be repeated daily until parasitemia has cleared. Parasite clearance is usually rapid; median parasite clearance times for knowlesi malaria of 18 hours for artemether-lumefantrine and 24 hours for chloroquine have been described [70].
In patients with prior splenectomy, parasite clearance can be prolonged despite clinical improvement [39]. This is due to delayed removal of dead circulating parasites, rather than treatment failure.
Antimalarial drug resistance has not been reported in zoonotic malaria [67]. For patients with recurrent parasitemia due to reinfection, a repeat course of antimalarial therapy should be administered [7].
For patients with severe malaria, careful monitoring including complete blood count, renal and liver function, venous blood gases, and oxygenation saturation should be monitored until end organ dysfunction resolves.
Delayed hemolytic anemia after artesunate therapy of falciparum malaria has been described; it is not known whether this occurs after treatment of knowlesi malaria. For this reason, patients treated with intravenous artesunate should be monitored with repeat hemoglobin testing at 7, 14, and 30 days after treatment [44,93,94]. (See "Treatment of severe malaria".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)
SUMMARY AND RECOMMENDATIONS
●Definition – Plasmodium knowlesi is a simian malaria parasite; the natural hosts are macaques. Human cases of knowlesi malaria have been reported throughout Southeast Asia (figure 1). (See 'Introduction' above.)
●Transmission and risk factors – Humans are incidentally infected with P. knowlesi when bitten by a mosquito vector that has fed from a macaque reservoir host (figure 2). Human P. knowlesi infection is generally acquired in forest or forest-fringe areas; those at risk include farmers, plantation workers, and individuals undertaking other activities in forested areas. Most cases of P. knowlesi infection occur in adults. (See 'Transmission and risk factors for infection' above.)
●Clinical manifestations – The spectrum of clinical disease due to P. knowlesi infection ranges from asymptomatic infection to severe disease. The incubation period of P. knowlesi infection is usually 8 to 12 days. Clinical manifestations of P. knowlesi infection include fever, chills, headache, myalgia, nausea, abdominal pain, vomiting, diarrhea, and cough. Physical findings include fever, tachycardia, and tachypnea; splenomegaly and hepatomegaly are observed in some cases. (See 'Clinical manifestations' above.)
•Uncomplicated infection – Most patients have uncomplicated disease, defined for management purposes as clinical illness with parasitemia <15,000/microL and no features of severe malaria. (See 'Uncomplicated infection' above.)
•Severe infection – Severe disease occurs in a minority of adults but has not been observed in children. Clinical manifestations of severe disease include jaundice, acute kidney injury, respiratory distress, and shock. Criteria for severe P. knowlesi infection are summarized in the table (table 1). (See 'Severe infection' above.)
●Diagnosis – 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 consists of microscopy (to guide immediate clinical management), followed by confirmatory testing with polymerase chase reaction in a reference laboratory (if feasible). Microscopy cannot be reliably used for distinguishing P. knowlesi from other species (figure 3). Therefore, patients with relevant epidemiologic exposure and microscopy findings resembling P. malariae should be treated for P. knowlesi infection. Rapid diagnostic tests are useful for excluding P. falciparum infection but have poor sensitivity for detection of P. knowlesi infection. (See 'Diagnosis' above.)
●Treatment – Adults with known or suspected P. knowlesi infection should be admitted to the 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. (See 'Treatment' above.)
•Uncomplicated infection – For treatment of uncomplicated P. knowlesi infection, we suggest an oral artemisinin combination therapy (ACT) regimen (Grade 2B); regimens are summarized in the table (table 3). (See 'Uncomplicated infection' above.)
•Severe infection
-Initial treatment of severe malaria consists of parenteral therapy. We suggest intravenous artesunate (in areas where intravenous artesunate of reliable quality is readily available) rather than intravenous quinine (Grade 2A); dosing is summarized in the table (table 4). Intravenous therapy should be followed by a three-day course of an oral ACT regimen once oral intake is tolerated. (See 'Severe infection' above.)
-For treatment of patients with parasitemia >15,000 parasites/microL in the absence of other evidence for severe disease, we suggest at least one dose of intravenous artesunate (Grade 2C), given the increased risk of severe malaria associated with moderately high parasite counts. (See 'Severe infection' above.)
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