Recent advances in the management of Plasmodium knowlesi infection.

Plasmodium knowlesi (P. knowlesi) has been detected to be the fifth malarial parasite that can cause malaria in human beings. The parasite is known to commonly infect macaque monkeys. The infection is highly prevalent in South-East Asia. It has morphologic similarities to Plasmodium malariae and Plasmodium falciparum. P. knowlesi is known to replicate every 24 h in the human host and hence, causes "quotidian malaria." It causes a wide spectrum of clinical manifestations and sometimes can cause fatal illness. Chloroquine is effective in the treatment of uncomplicated P. knowlesi infection. Severe and complicated P. knowlesi malaria can be managed with artemisinin combination therapy.

INTRODUCTION

Plasmodium knowlesi is a malaria parasite that is found in macaque monkeys. It has been recognized as the fifth Plasmodium species that can cause malaria in human beings. P. knowlesi malaria is primarily a zoonotic infection that is commonly seen in South-East Asia. The parasite is transmitted by the bite of an Anopheles mosquito.

Morphologically, P. knowlesi is similar to the human malaria parasite, Plasmodium malariae. Hence, human infections could not be diagnosed until molecular detection methods for diagnosis were made available. P. knowlesi infections cause a spectrum of illness that can be potentially fatal. However, if they are detected at an early stage, they can be treated easily.

LIFE CYCLE

P. knowlesi has a replication period of 24 h in human erythrocytes and hence may be designated quotidian malaria.[1] This may result in high parasite load in a short period of time. It passes through the stages of merozoite followed by trophozoite and schizont formation. The early trophozoites of P. knowlesi are morphologically similar to Plasmodium falciparum and the other stages resemble those of P. malariae.[2]

Relapses are not seen in P. knowlesi infection due to the absence of hypnozoites in its exoerythrocytic stage.[34]

EPIDEMIOLOGY

P. knowlesi is a parasite of long-tailed and pig-tailed macaques, but human beings entering forests to work are liable to acquire the infection.[56] This parasite is commonly found in countries of South-East Asia such as Malaysia, Thailand, Myanmar and their neighboring countries.[7] Mosquitoes are responsible for the transmission of P. knowlesi infection. They are mainly present in the forest areas.

There has been no report of P. knowlesi infection from India.

VECTORS

The vectors belong to the genus Anopheles, subgenus Cellia, series Neomyzomyia and group Leucosphyrus. Mosquitoes of this group are present in the forests of South-East Asia. Human beings are exposed to these vectors as a result of deforestation.

Anopheles latens and Anopheles cracens are the important vectors that transmit P. knowlesi to humans.[89]

MODES OF TRANSMISSION

There are two modes of transmission of the parasite to humans:

From an infected monkey to human

From an infected human to another human.

CLINICAL FEATURES

P. knowlesi infection usually presents with non-specific symptoms. Males in the age group of 30-60 years are commonly affected. The duration of illness is 3-7 days. The most common symptom is fever with chills and rigors. Fever can be associated with headache, myalgia, malaise and anorexia.

Cough, abdominal pain, nausea, vomiting and diarrhea are the other presenting symptoms of the disease. Symptoms start approximately 11 days after bite by an infected mosquito.[10]

P. knowlesi infection should be suspected in patients with these symptoms in patients engaged in farming activities or working in or near forests in an endemic region. In case of patients residing in non-endemic areas, history of travel to endemic areas should be carefully elicited to ascertain the diagnosis.

High body temperature, tachycardia and tachypnea are the common clinical signs of illness. Hepatosplenomegaly can be present in 15-25% of patients.

The clinical manifestations of severe illness can be summarized as below:

Respiratory distress: This is characterized by an increase in the respiratory rate, non-specific auscultatory findings, drop in oxygen saturation detected by pulse oximetry and radiographic changes of non-cardiogenic pulmonary edema. Respiratory distress can be due to pulmonary edema or metabolic acidosis

Jaundice: There is a rise in serum bilirubin along with liver enzymes due to derangement in liver function

Renal failure: Alteration in kidney function is manifested as oliguria with a rise in serum creatinine level despite appropriate fluid resuscitation

Hypotension: Defined as a systolic blood pressure of 90 mm Hg or below despite adequate fluid resuscitation

Hypoglycemia: Defined as random blood glucose of 40 mg/dl or less.

Thrombocytopenia is a common hematological finding in patients with P. knowlesi infection. However, bleeding manifestations or clinically evident coagulopathy is not found. Due to the non-sequestering nature of P. knowlesi, neurologic findings (common in cerebral malaria due to P. falciparum) such as unarousable coma, seizures and encephalopathy are not seen in the course of the illness.

There are no presenting symptoms or signs that can distinguish P. knowlesi malaria from falciparum or vivax malaria. Though P. knowlesi infection is known to have a benign clinical course, life-threatening complications or death may occur in a minority of cases. The prevalence of complications was 10% and mortality rate due to severe P. knowlesi infection was found to be 2% in one series.[11]

MANAGEMENT

Peripheral blood smear examination of patients with P. knowlesi infection can be misdiagnosed as P. malariae due to the morphologic similarities between the 2 Plasmodium species. Hence, P. knowlesi infection is more likely in a patient with an unusual clinical presentation of P. malariae or in a patient with severe malaria who has morphologically appearing P. malariae on the blood smear.

Molecular detection methods like polymerase chain reaction (PCR) are useful in the confirmation of diagnosis of P. knowlesi infection and in detection of mixed infection. The disadvantage of PCR is that it cannot be used as a rapid diagnostic technique. Furthermore, availability of PCR is limited in many hospitals due to its high cost.

Treatment of uncomplicated P. knowlesi infection

Uncomplicated P. knowlesi infection has been found to be sensitive to conventional antimalarial drugs such as chloroquine, quinine and mefloquine. Primaquine is required for gametocyte clearance. It is given in the dose of 15 mg for 2 days. Chloroquine given in conventional doses (10 mg base/kg body weight, followed by 5 mg base/kg at 6, 24 and 48 h-total dose 25 mg base/kg) has a rapid parasite clearance when compared to vivax malaria as reported from several studies.[1213141516]

Chloroquine is a cheap, effective and well-tolerated antimalarial drug and it is useful in the treatment of uncomplicated P. knowlesi infection in humans.

Treatment of severe P. knowlesi infection

Severe and complicated P. knowlesi infection requires treatment with intravenous quinine. Quinine is given as a loading dose of 20 mg/kg in 10% dextrose solution, which is followed by 10 mg/kg dose 8 hourly for a period of 7 days. The side-effects of quinine are hypoglycemia and cardiac arrhythmias (in patients with a history of cardiac illness).

There are limited clinical studies on the use of parenteral artemisinin derivatives for the treatment of severe P. knowlesi infection in humans. However, a study in rhesus monkeys has found artemisinin to be an effective antimalarial drug.

Artemisinin derivatives have been found to have excellent efficacy against human P. knowlesi strain and it correlates clinically in patients treated with Artesunate, where mortality was not seen after treatment.[17]

A study by William et al. carried out a retrospective analysis of P. knowlesi malaria cases in Sabah, Malaysia and reported that artemether-lumefantrine combination therapy was successful in treating patients. They also noted that intravenous artesunate was effective in treating severe P. knowlesi infection.[18]

Due to a zoonotic mode of transmission of P. knowlesi to humans, there is less likelihood of drug resistance by the parasite. However, P. knowlesi laboratory isolates showed less sensitivity to mefloquine when compared to that of P. falciparum.

This could possibly be due to innate tolerance of P. knowlesi to mefloquine. Hence, there is a strong possibility of treatment failure if mefloquine is used alone or as combination therapy. This has been supported by reports of treatment failure with mefloquine in rhesus monkeys and humans infected with P. knowlesi.[1920]

Larger clinical studies are needed before mefloquine can be used for the treatment or prophylaxis of P. knowlesi malaria.

CONCLUSION

P. knowlesi infection, though less commonly prevalent, can be responsible for severe illness. Chloroquine is an effective antimalarial drug that can be used safely and effectively in uncomplicated P. knowlesi infection. The parasite is highly sensitive to artemisinin group of drugs and they are helpful in the management of severe and complicated illness. Due to the potential resistance of the parasite to mefloquine, it is not useful in the management of P. knowlesi infection.