First case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia
© Tanizaki et al.; licensee BioMed Central Ltd. 2013
Received: 22 February 2013
Accepted: 8 April 2013
Published: 15 April 2013
This is the first case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia. In September 2012, a previously healthy 35-year-old Japanese man presented to National Center for Global Health and Medicine in Tokyo with a two-day history of daily fever, mild headaches and mild arthralgia. Malaria parasites were found in the Giemsa-stained thin blood smear, which showed band forms similar to Plasmodium malariae. Although a nested PCR showed the amplification of the primer of Plasmodium vivax and Plasmodium knowlesi, he was finally diagnosed with P. knowlesi mono-infection by DNA sequencing. He was treated with mefloquine, and recovered without any complications. DNA sequencing of the PCR products is indispensable to confirm P. knowlesi infection, however there is limited access to DNA sequencing procedures in endemic areas. The extent of P. knowlesi transmission in Asia has not been clearly defined. There is limited availability of diagnostic tests and routine surveillance system for reporting an accurate diagnosis in the Asian endemic regions. Thus, reporting accurately diagnosed cases of P. knowlesi infection in travellers would be important for assessing the true nature of this emerging human infection.
The first naturally acquired zoonotic infection with Plasmodium knowlesi in a human was reported in 1965 ; thereafter, no such infections were reported for almost 40 years. In 2004, however, Singh et al. reported that natural P. knowlesi infections in humans were common parasite species in Malaysia. Cox-Singh et al. subsequently described that P. knowlesi infections in humans were observed throughout wide areas of Southeast Asia, including Thailand, Myanmar, the Philippines, Singapore and Indonesia. Additionally, 12 cases of P. knowlesi infection in travellers have been reported from non-malaria endemic countries thus far [1, 4–14]. Here, this is the first confirmed case of P. knowlesi infection in a Japanese traveller.
Most P. knowlesi infections are reported in the rural jungle areas of the Malaysia peninsular and in Borneo (Sabah  and Sarawak  province) where both of the infectious hosts (macaque and leaf monkeys) and vectors (Anopheles mosquitoes) predominantly exist. The patient in this case was probably infected with P. knowlesi in the Temengor jungle area as he had not entered any other areas of jungle for four weeks before returning to Japan. Interestingly, the incubation period in this patient was probably over four weeks, which is longer than the nine to 12 day incubation period reported for P. knowlesi. This finding is consistent with a case report for a different traveller who also experienced a long incubation period (>17 days) . Clinical data for P. knowlesi infection in travellers are limited; therefore, more data are needed to determine the correct incubation period for P. knowlesi.
No cases of treatment failure have been reported in travellers treated with anti-malarial drugs such as quinine , doxycycline , mefloquine , atovaquone/proguanil [5, 10, 14], and artemether/lumefantrine . In the present case, mefloquine enabled the patient to recover without any complications. Chloroquine has been usually used for uncomplicated P. knowlesi infection ; however, in recent years, a prospective comparative study suggested that early intravenous artemisinin treatment improved the prognosis in severe cases of P. knowlesi infection . The major risk factors of increasing severity are associated with a high parasitaemia [17, 20] and thrombocytopenia . The risk factors of severity in P. knowlesi infection should be evaluated appropriately, and if necessary, should be considered the intravenous artemisinin treatment as other malaria parasite species .
Microscopic examination of Giemsa-stained blood smears is the gold standard for differentiating Plasmodium species; however, differentiating P. knowlesi from other malaria species is very difficult because P. knowlesi band forms and schizonts of mature trophozoites in P. knowlesi are similar to those of P. malariae, while the ring forms of P. knowlesi early trophozoites are similar to those of P. falciparum[2, 17, 18]. This patient was initially suspected of contracting P. malariae after observing his Giemsa-stained thin blood smear (Figure 1). Although PCR is required to obtain a definitive diagnosis, the spurious amplification of a P. vivax gene using P. knowlesi-specific primers has been reported . In the present study, on the other hand, a P. knowlesi gene was amplified using P. vivax-specific primers . These spurious amplifications were observed when the target gene of PCR was the small subunit rRNA gene  because of the similarity between the DNA sequences of P. knowlesi and P. vivax. Thus, a caution is needed for using this gene to differentiate malaria species by PCR. Indeed, some cases of P. knowlesi infection in travellers have been initially diagnosed as P. ovale or P. vivax by nested PCR; however, these were later confirmed as P. knowlesi by DNA sequencing. Therefore, DNA sequencing is indispensable for final confirmation of P. knowlesi infection.
There is limited access to DNA sequencing procedures for identifying P. knowlesi in endemic areas. Hence, accurate reporting of clinical and epidemiological data should contribute to better understanding of the clinical features of P. knowlesi infection, as well as the true incidence of the disease. Close monitoring of febrile travellers returning from P. knowlesi-endemic areas and complete travel histories (including exposure to areas with wild monkeys) should prompt suspicion of P. knowlesi infection  and a move towards further diagnostic tests. Additionally, greater awareness of the risk of the emerging P. knowlesi problem in travellers is necessary among health care workers in non-endemic countries. Thus, reporting accurately diagnosed cases of P. knowlesi infection in travellers would be important for assessing the true nature of this emerging human infection.
Oral informed consent was obtained from the patient for publication of this case report and any accompanying images after explanation of the report objectives.
The authors are gratefully acknowledge Kanako Komaki-Yasuda, Kazuhiko Yano and Shungo Kano at the Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, Japan for their technical expertise in microscopy, and Satoru Kawai at the Center for Tropical Medicine and Parasitology, Dokkyo Medical University, Japan for technical advice and for designing PCR primers for diagnosis of P. knowlesi. This work was partly supported by funding from the Research on Emerging and Re-emerging Infectious Diseases by the Ministry of Health, Labour, and Welfare, Japan (H24-shinkou-ippan-013).
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