New Species of Human Malaria?

By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

SYNOPSIS: Increasingly, Plasmodium species previously identified in monkeys are being identified in the blood of people living in or near areas of infected monkey populations. International travelers also have become infected by simian malaria.

SOURCE: Putaporntip C, Cheng CW, Rojrung R, et al. Non-human primate malaria in travellers. J Travel Med 2023;30:taad135.

Malaria still is a concern for international travelers. Each year, more than 125,000,000 individuals travel across international borders into countries in which malaria is endemic. Approximately 10,000 of these travelers return to their home country harboring a malaria infection. Most malaria in travelers is due to Plasmodium falciparum and P. vivax, but there have been reports of P. knowlesi infection in tourists visiting southern Thailand.

The number of malaria cases dropped 13-fold in Thailand between 2010 and 2021, and there was a strong shift to many more of the reported cases of malaria being due to P. vivax. In 2016, there was just one patient in Thailand with P. knowlesi, but in 2021 there were 72 cases of P. knowlesi malaria in Thailand, mostly in the southern part of the country.

Realizing that the same mosquito vectors that transmit P. knowlesi also transmit other species of malaria between non-human primates, in-vestigators carefully reviewed cases of malaria in the Yala province of southern Thailand in 2021. Their intent was to determine if species of simian malaria other than P. knowlesi might also be infecting humans.

Filter paper spot blood samples were available and studied from 33 of the 178 reported symptomatic cases of malaria in Yala province in 2021. Studied patients were from 9 to 61 years of age; the male-to-female ratio was 1.75:1. The median parasitemia was 3,460 per microliter (range 680 to 49,320). The patients resided near rubber plantations or forests in which macaque monkeys lived.

By microscopy, 29 of the 33 patients were infected by a single malaria species (24 P. vivax, four P. knowlesi, one P. falciparum). Of the four with mixed malaria infections, two had P. vivax and P. inui, and one had P. falciparum and P. cynomolgi. (The other was triply infected with P. falciparum, P. vivax, and P. knowlesi.) More specific genetic testing mostly agreed with the microscopic results but also identified an additional case of combined P. vivax and P. inui infection as well as some other mixed infections of other human malaria species.

P. inui is the most prevalent species causing malaria in monkeys in Thailand. It is transmitted by the same Anopheles vectors that transmit P. knowlesi and is indistinguishable from some other forms of malaria on microscopic exam. It was present in low numbers in the identified human infections, is thought to usually cause relatively benign illnesses, and seems susceptible to chloroquine.

The authors suggested that travelers (and physicians caring for travelers) should be aware of monkey malaria species, especially P. inui and P. cynomolgi. This is particularly relevant since it is not known whether all standard malaria chemoprophylaxis regimens are effective against these forms of simian malaria.

COMMENTARY

Many readers of Infectious Disease Alert were trained to know the four species of Plasmodium that cause malaria in humans: P. falciparum, P. vivax, P. ovale, and P. malariae. We understood that P. falciparum could cause severe malaria and could be resistant to chloroquine. We learned that P. vivax and P. ovale (mostly in West Africa) could remain dormant in the liver to cause symptomatic malaria long after the bite of an infected Anopheles mosquito. We knew that P. malariae was not very common anywhere but, without treatment, caused four-day (rather than three-day) cycles of fever.

More recently trained readers know that P. knowlesi has been recognized as a cause of malaria in monkeys for nearly 100 years but was linked to human malaria only rarely until about 20 years ago. P. knowlesi-parasitized red cells appear microscopically similar to those infected by P. falciparum when in early trophozooite stages but then look more like cells infected by P. malariae when the trophozooites are more mature. Clinically, P. malariae mostly occurs in southeast Asia and can, like P. falciparum, cause either uncomplicated or severe illness.

Experts who follow details of malaria species are aware that there are two distinct types of P. ovale that are morphologically identical, P. ovale wallikeri and P. ovale curtisi. Some experts suggest that these actually are two separate species.¹

If that was not complicated enough, this new report from Thailand suggests that P. inui and P. cynomolgi are expanding their range to also infect humans more commonly. Perhaps soon we will be teaching that there are eight distinct species of Plasmodium that cause human malaria.

Nonetheless, it is not yet clear from the current study that the malaria species P. inui and P. cynomolgi, when affecting humans rather than monkeys, cause significant disease. In fact, the current study only identified these species in individuals who were concurrently infected by other malaria species that, alone, could have accounted for all the patients’ symptoms.

Even in monkeys, P. inui often causes asymptomatic or mild infections; infections can resolve spontaneously.² The incubation period between the bite of an infected mosquito and the onset of infection (in the bloodstream, with or without symptoms) is approximately 30 days.² In monkeys, P. inui often has been found as a co-infector along with other malaria species.² Asymptomatic mono-infections with P. inui have been identified in two young adult humans approximately one month after likely exposure to Anopheles cracens mosquitoes in an area where macaque monkeys often carry P. inui.²

The risk of a human becoming infected with a simian species of Plasmodium is greatest for individuals living in or near a forest that is home to macaque monkeys.^3,4 P. coatneyi and P. cynomolgi also were found in screening tests of humans in Malaysia.³ P. simium is similar to P. malariae and usually infects monkeys in southern Brazil (with some reports of human infection).⁴ P. brasilianum is similar to P. vivax and infects monkeys in Central and South America and was presumptively identified in three humans in Costa Rica.⁴ But, as mentioned in the new paper by Putaporntip and colleagues, tourists can become infected by some species of simian malaria and then can become ill later when in their home countries. If human cases of these other parasitic causes of monkey malaria increase in frequency, we might soon be teaching that there are up to 11 Plasomdium species that cause human malaria.

References

1. Snounou G, Sharp PM, Culleton R. The two parasite species formerly known as Plasmodium ovale. Trends Parasitol 2024;40:21-27.
2. Liew JWK, Bukhari FDM, Jeyaprakasam NK, et al. Natural Plasmodium inui infections in humans and Anopheles cracens mosquito, Malaysia. Emerg Infect Dis 2021;27:2700-2703.
3. Yap NJ, Hossain H, Nada-Raja T, et al. Natural human infections with Plasmodium cynomolgi, P. inui, and 4 other simian malaria parasites, Malaysia. Emerg Infect Dis 2021;27:2187-2191.
4. Chaturvedi R, Biswas S, Bisht K, Sharma A. The threat of increased transmission of non-knowlesi zoonotic malaria in humans: A systematic review. Parasitology 2023;150:1167-1177.