Plasmodium knowlesi - Malaria Shared Between Man and Monkeys
Abstract & Commentary
By Mary-Louise Scully, MD
Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA.
Dr. Scully reports no financial relationships relevant to this field of study.
Synopsis: This new study confirms P. knowlesi is a major cause of human malaria in both Malaysian Borneo and Peninsular Malaysia. Clinicians should be aware that high levels of parasitemia in patients with a microscopic diagnosis of P. malariae may in fact be infected with a potentially more lethal P. knowlesi species.
Sources: Cox-Singh J et al. Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clin Infect Dis. 2008;46:165-171. White NJ. Plasmodium knowlesi: The fifth human malaria parasite. Clin Infect Dis. 2008;46:172-173.
Singh and colleagues used a nested polymerase chain reaction (PCR) to determine the geographic distribution of Plasmodium knowlesi- malaria in the human population of Malaysia. Blood samples were obtained from 960 patients hospitalized with malaria in Sarawak hospitals during 2001- 2006, and P. knowlesi DNA was detected in 266 (27.7%) of these patients. These infections had been incorrectly reported as P. malariae, but in fact only four (0.4%) were found to contain P. malariae DNA by PCR. Using the PCR technique 53 (5.5%) of patients were found to have mixed infections including 23 with mixed P. knowlesi infections (19 with P. vivax and P. knowlesi, three with P. falciparum and P. knowlesi, and one patient with P. ovale and P. knowlesi). In addition, when P. malariae archival blood films from other parts of Malaysia were tested, 41 (83.6%) of 49 specimens from Sabah and all five specimens from Pahang were positive for the presence of P. knowlesi DNA. Finally, only P. knowlesi DNA was detected in the archival blood films of four patients who died of what had been presumed to be P. malariae by microscopy.
The clinical and laboratory aspects of the four fatal cases of P. knowlesi revealed that the patients were relatively older (age 39-69 years) and all presented with abdominal pain and fever. All patients had hyperparasitemia and thrombocytopenia. In addition, all fatal cases had significant renal impairment, jaundice, and a clinical picture more typical of severe P. falciparum malaria.
Commentary
P. knowlesi was identified in 1931 and its natural hosts are the long-tailed and pig-tailed macaques (Macaca fascicularis and Macaca nemestrina, respectively). P. knowlesi is predictable and rapidly lethal for the Rhesus monkey, and is known to be infectious to humans by inoculation of blood. P. knowlesi was actually used prior to the penicillin era as pyretic treatment for neurosyphillis. However, this practice was discontinued once it was realized that this infection could become rapidly uncontrollable and fatalities occurred. The potential for this rapid increase in parasite load is present because P. knowlesi has a 24-hour asexual life cycle - the shortest of all the known human and non-human primate malarias. This is distinct from P. malariae infection which is associated with a benign clinical course and a relatively low parasite burden, since P. malariae multiplies much more slowly (every 3 days).1 The trophozoites, schizonts and gametocyte stages of P. knowlesi are morphologically indistinguishable from P. malariae by microscopy.
In 2004, this same group first reported a cluster of human P. knowlesi cases in the rural rainforest of the Kapit division of Sarawak, Malaysian Borneo, that had been initially diagnosed as P. malariae.2 In this earlier study, PCR assay of the blood of 208 people with malaria found that 120 (58%) were positive for P. knowlesi. These patients were ill enough to seek medical care and had more dense parasitemia than would be expected with P. malariae. Most of these patients belonged to the Iban ethnic group and lived in longhouses situated along the Rejang and Balleh rivers. The inhabitants of the area were active either in the logging industry, farming, hunting, or collecting jungle produce such as rattan and bamboo (Figure 1). There was no clustering of cases within local housing communities and a low incidence of childhood infection. This suggested that working in the jungle was a risk factor and that monkey-to-human rather than human-to-human transmission was more likely.
The proposed vector for P. knowlesi transmission appears to be restricted to the Anopheles leucosphyrus group, and in the Kapit division more specifically, Anopheles lateens, a mosquito that prefers a forest-fringe habitat, feeds after dusk, and is equally attracted to humans and monkeys. So far monkey-to-human transmission is thought to be the predominant mode of P. knowlesi transmission. However, P. knowlesi malaria patients in Sarawak were noted to have gametocytes in their blood, making it possible that human-to-human transmission might occur.
The four fatal cases are good evidence that misdiagnosis of P. knowlesi infections can have dire consequences. The authors advise that any case of malaria from this area (and perhaps other Southeast Asian countries) with a high parasitemia and a microscopic diagnosis of P. malariae might actually represent the potentially more lethal malaria parasite, P. knowlesi. The practical implications are that these patients should be managed as if they have P. falciparum infection with early treatment and aggressive supportive care. Thus far, uncomplicated cases of P. knowlesi human malaria still respond to chloroquine.
References:
- White NJ. Sharing malarias. Lancet 2004; 363:1006.
- Singh B., et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings Lancet 2004; 363:1017-1024.
- Cox-Singh J. Plasmodium knowlesi: malaria in humans is widely distributed and potentially life threatening. Clin Inf Dis 2008;46:165-171.
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