Plasmodium knowlesi: The Newest Human Malaria Parasite

Special Report and Update

By Brian G. Blackburn, MD, and Michele Barry, MD, FACP

Dr. Blackburn is Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Dr. Barry is Senior Associate Dean of Global Health at Stanford University School of Medicine.

Dr. Blackburn reports no financial relationship to this field of study. Dr. Barry is a retained consultant for the Ford Foundation and has received research or grant support from Johnson & Johnson Corporate Foundation, the Doris Duke Foundation, and the National Institutes of Health.

Synopsis: Plasmodium knowlesi, typically a parasite of macaque monkeys, is rapidly emerging as a fifth species of malaria that causes disease in humans. Hundreds of human cases have now been reported from southeast Asia, including several fatalities. P. knowlesi may be more widely distributed than initially appreciated, and appears to cause more severe disease than the other non-falciparum malaria species.

Source: Kantele A, Jokiranta TS. Review of cases with the emerging fifth human malaria parasite, Plasmodium knowlesi. Clin Infect Dis 2011;52:1356-1362.

Malaria continues to be a global scourge, causing more than 200 million annual symptomatic cases and nearly a million annual deaths worldwide.1 For decades, human malaria has been classically attributed to four pathogens, Plasmodium falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum causes the most severe form of malaria, and is responsible for most of the morbidity and mortality on a global basis; P. vivax and P. ovale cause a generally less severe illness, but can cause late relapses; and P. malariae usually causes a low-grade illness and can occasionally persist for years, or even decades.

While more than two dozen Plasmodium species cause malaria in primates, the species specificity of these pathogens has generally been strict. Natural transmission of any Plasmodium species to humans, aside from the four classical "human" malaria species described above, has been quite rare.

P. knowlesi was first recognized in 1931, when it was observed to cause malaria in macaque monkeys; it causes malaria in other monkey species as well. Despite being less species-specific than other Plasmodium spp., it was presumed to infect only non-human primates in the wild. Although nosocomial infection of humans was reported in the 1930s, natural infection of humans with P. knowlesi was unknown until 1965, when a case was reported in a returned traveler who had been to peninsular Malaysia.2

Few naturally acquired P. knowlesi human infections were recognized until a 2004 study examined 208 patients with malaria in Malaysian Borneo who were thought to be infected with P. malariae based on microscopy, but for whom PCR testing for this species was negative. One hundred twenty (58%) of these patients had actually been infected with P. knowlesi, based on PCR testing with new primers specific for this species; the morphological similarities between these two species contribute to this common diagnostic error.3 Multiple similar reports have followed, and retrospective analyses have shown that many cases of malaria, dating back many years in southeast Asia, were in fact due to P. knowlesi.

Transmission of P. knowlesi appears to be zoonotic; cases of natural human-mosquito-human transmission have yet to be described. Although gametocytes (responsible for transmission of malaria from a human host to a mosquito) are formed in human P. knowlesi infections, this occurs only at low levels. In addition, the natural vector mosquitoes (Anopheles leucosphyrus group) for P. knowlesi are forest feeders. Importantly, at least one widely distributed urban vector (Anopheles stephensi) can transmit P. knowlesi,4 suggesting that transmission could become widespread if human-mosquito-human transmission were to occur.

To date, P. knowlesi has been identified as the cause of human malaria in 573 cases within Malaysian Borneo, 90 cases in peninsular Malaysia, 33 cases in Burma, 11 cases in Thailand, 6 in the Philippines, 6 in Singapore, 5 in Vietnam, 2 in Indonesian Borneo, and 1 in Brunei. Of these 727 patients, 8 (1.1%) have been travelers, and 5 (0.7%) have died.

Clinically, P. knowlesi is similar to other malaria species. Non-specific fever and chills are common, as are headache, rigors, malaise, myalgia, cough, and thrombocytopenia; anemia has been uncommon. Overall, 7% of cases have been severe (as determined by WHO criteria), most commonly due to respiratory distress. A small number of patients have developed renal dysfunction, and neurological symptoms have been rare; cerebral malaria has not been reported.

Like P. falciparum, P. knowlesi can infect red blood cells of all ages, resulting in potentially high levels of parasitemia. Of the five species which cause malaria in humans, P. knowlesi has the shortest life cycle (24 hours), enabling potentially rapid progression of disease. Although P. knowlesi may be confused microscopically with P. malariae (the least virulent of the human malaria species), it can cause a severe illness like P. falciparum.

The diagnosis of P. knowlesi often is based on PCR. Although visible by light microscopy, the early trophozoites of P. knowlesi resemble the ring forms of P. falciparum, and its later stages mimic those of P. malariae. Thus, P. knowlesi infection often is misidentified microscopically as P. malariae, or less commonly, P. falciparum. Because P. knowlesi malaria can be life-threatening, this parasite should be suspected when microscopic examination suggests P. malariae, but the patient has either severe disease, high-grade parasitemia, or a recent history of travel to southeast Asian forests. Rapid diagnostic tests have not been validated for the diagnosis of P. knowlesi and currently should be regarded as unreliable for this purpose.

P. knowlesi appears to be susceptible to all anti-malarials; current recommendations are for treatment with chloroquine if a patient is known to be infected with P. knowlesi.5 Because P. knowlesi infection can rapidly become severe, it should be treated promptly, and with drugs appropriate for falciparum malaria if the species identification is based on microscopic examination alone or if co-infection with P. falciparum cannot be excluded with certainty. P. knowlesi does not appear to establish liver hypnozoites nor to cause late relapse based on this mechanism; primaquine treatment thus appears unnecessary.

P. knowlesi appears to be a natural parasite of macaques throughout southeast Asia. The wide distribution of human cases shows that P. knowlesi generally is able to infect humans, unlike the other malaria species that infect non-human primates. Although initially identified only in Malaysian Borneo (and with the majority of reported cases there), it seems likely that P. knowlesi is widely distributed throughout Borneo; the small number of cases reported from the Indonesian side of this island is likely the result of the poorer surveillance and public health capacity of Indonesia relative to Malaysia. The increasing number of recent P. knowlesi cases overall may be a result of ascertainment bias (given the increasing availability of PCR methods to detect P. knowlesi), or of decreasing numbers of other malaria species relative to P. knowlesi, or of increased transmission of P. knowlesi in recent years (although archival blood films argue against this latter possibility). While human-mosquito-human transmission has been reported in experimental settings, this has not yet been observed to occur naturally.6 If natural human-mosquito-human transmission does occur, P. knowlesi could spread more widely in Asia, given that at least one vector species (Anopheles latens) is widely distributed in southeast Asia and the southern Indian subcontinent; another species (An. stephensi) is widely distributed in urban centers and could result in spread to cities. P. knowlesi could become a major human pathogen in such a circumstance, and probably is already more widespread than has been appreciated to date. This emerging infection, perhaps the second-most virulent of what are now five human malaria species, will be important to monitor as cases continue to be reported in the coming years.

References

  1. World Health Organization: World Malaria Report: 2010. Available at: www.who.int/malaria/world_malaria_report_2010/en/index.html. Accessed Sept. 5, 2011.
  2. Chin W, Contacos PG, Coatney GR, et al. A naturally acquired quotidian-type malaria in man transferable to monkeys. Science 1965;149:865.
  3. Singh B, Kim Sung L, Matusop A, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 2004;363:1017-1024.
  4. Coatney GR, Collins WE, Warren M, et al. The primate malarias [original book published 1971] [CD-ROM]. Atlanta, GA: Centers for Disease Control and Prevention; 2003.
  5. Centers for Disease Control and Prevention. Guidelines for Treatment of Malaria in the United States (updated May 18, 2009). Available at: www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf. Accessed Aug. 30, 2011.
  6. Chin W, Contacos PG, Collins WE, et al. Experimental mosquito-transmission of Plasmodium knowlesi to man and monkey. Am J Trop Med Hyg 1968;17:355-358.