P. knowlesi: A Newly Recognized Human Pathogen

Abstract & Commentary

By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Synopsis: A sensitive and specific nested polymerase chain reaction (PCR) was used to identify Plasmodium species in blood samples from patients and archival blood films (including 4 cases of fatal malaria originally speciated as P. malariae) in several regions of Malaysia. P. knowlesi infection was confirmed in 27.7% of 960 unselected malaria patients, from 83.7% of 49 patients with microscopically-diagnosed P. malariae infection, and in all 4 patients who died from microscopically-diagnosed P. malariae infection.

Source: Cox-Singh J, et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008;46:165-171.

A nested PCR Method was used to identify and speciate cases of malaria in two regions of Malaysia. This study showed a significant proportion of patients to have been infected with P. knowlesi, a pathogen of Old World macaques and previously rarely recognized in humans. Most importantly, 83.7% of malaria cases which were diagnosed microscopically as P. malariae were found to be due to P. knowlesi. All 4 patients who died from presumed P. malariae infection were shown by PCR analysis of blood smears to have actually been infected with P. knowlesi.


This same group, using an elegant, sensitive, and specific nested PCR, originally reported in 2004 that all infections diagnosed microscopically as P. malariae in Sarawak State, Malaysian Borneo, were actually due to the Old World monkey malaria parasite, P. knowlesi.1 At that time, P. knowlesi was not considered to be a cause of severe human disease. However, during the late 2004-early 2005 time period, four fatal cases of "P. malariae" infection were reported in this same district. In this more extensive follow-up on the study, the group convincingly demonstrated that P. knowlesi infection in humans is widespread in both Malaysian Borneo and Peninsular Malaysia, accounting for approximately one-quarter of all human malaria cases and more than three-quarters of all human cases of malaria which had been diagnosed microscopically as P. malariae.

The finding that all four cases of "fatal P. malariae" infection diagnosed during a 5-month period were actually caused by P. knowlesi is critically important information. Since P. malariae infection in humans generally is associated with low level parasitemia and a benign clinical course, clinicians in endemic areas often take a very relaxed approach to patients with microscopically diagnosed P. malariae infection. However, P. knowlesi infection in the Rhesus monkey is rapidly and predictably lethal and is characterized by daily schizont rupture, high parasite loads, and rapid development of anemia, jaundice, and renal failure. It is clear that a similar fulminant disease course can be seen in human cases of P. knowlesi infection. While P. knowlesi remains susceptible to chloroquine, it is clear that appropriate therapy should be promptly administered.

It is felt that most human cases of P. knowlesi infection in Malaysia still arise from macaque-to-human transmission via an Anopheles mosquito vector. However, gametocytes are present in human cases of P. knowlesi infection, and it is likely that human-to-human transmission can occur as well.


  1. Singh B, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet. 2004;363:1017-1024.