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
- 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. 
- The first case of naturally acquired human infection with P. knowlesi was reported in 1965 in a United States national working in Malaysia.
- 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.
- Cases of P. knowlesi in humans have been reported to occur in clusters, affecting individuals of all ages.
- 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:
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
- 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
- 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.
- 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.
- The incubation period of P. knowlesi infection is in the range of 3 to 27 days.
- Parasites normally appear in the blood several days after the initial temperature rise.

## 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
- Jaundice
- Acute kidney injury
- Respiratory distress
- 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 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.
- 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.
- PCR is the gold standard diagnostic tool with high sensitivity and specificity.
- 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.
- 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. 

# 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.

## Adults

### Uncomplicated Infection
- Treatment of uncomplicated Plasmodium knowlesi infection consists of oral Artemisinin Combination Therapy (ACT) regimen.
- 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.
- 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.
- Artesunate-Mefloquine and Dihydroartemisinin-piperaquine have also been used as ACT for the treatment of uncomplicated plasmodium knowlesi infection.
- 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 ).
- 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).
- 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.
- 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.