and vomiting. As disease progresses, parasites replicate to very high levels in the blood likely causing acute kidney injury, jaundice, shock, and respiratory distress. Metabolic acidosis is uncommon, but can occur in particularly severe cases. Unlike P. falciparum malaria, severe P. knowlesi malaria rarely causes coma or severe anemia. Approximately 1-2% of cases are fatal. Diagnosis Malaria is traditionally diagnosed by examining Giemsa-stained blood films under a microscope; however, differentiating P. knowlesi from other Plasmodium species in this way is challenging due to their similar appearance. P. knowlesi ring-stage parasites stained with Giemsa resemble P. falciparum ring stages, appearing as a circle with one or two dark dots of chromatin. Older trophozoites appear more dispersed, forming a rectangular-shape spread across the host cell called a "band-form" that resembles the similar stage in P. malariae. During this stage, dots sometimes appear across the host red blood cell, called "Sinton and Mulligans' stippling". Schizonts appear, similarly to other Plasmodium species, as clusters of purple merozoites surrounding a central dark-colored pigment. Due to the morphological similarity among Plasmodium species, misdiagnosis of P. knowlesi infection as P. falciparum, P. malariae, or P. vivax is common. While some rapid diagnostic tests can detect P. knowlesi, they tend to have poor sensitivity and specificity and are therefore not always reliable. Detection of nucleic acid by PCR or real-time PCR is the most reliable method for detecting P. knowlesi, and differentiating it from other Plasmodium species infection. However, due to the relatively slow and expensive nature of PCR, this is not available in many endemic areas. Loop-mediated isothermal amplification methods of P. knowlesi detection have also been developed, but are not yet widely used. Treatment Because P. knowlesi takes only 24 hours to complete its erythrocytic cycle, it can rapidly result in very high levels of parasitemia with fatal consequences. For those with uncomplicated malaria, the World Health Organization recommends treatment with artemisinin-based combination therapy (ACT) or chloroquine. For those with severe malaria, the World Health Organization recommends administration of intravenous artesunate for at least 24 hours, followed by ACT treatment. Additionally, early drug trials have suggested that combinations of chloroquine and primaquine, artesunate and mefloquine, artemether and lumefantrine, and chloroquine alone could be effective treatments for uncomplicated P. knowlesi malaria. There is no evidence of P. knowlesi developing resistance to current antimalarials. Epidemiology P. knowlesi is the most common cause of malaria in Malaysia, and cases