The literature search identified 412 records through 4 different sources: 31 from PubMed, 324 from Science Direct, 51 from WoS, and 6 from google scholar. After removal of the duplicates, the eligibility of the remaining studies (n = 373) was assessed upon their title, abstract, and full text. In total, 355 records were excluded as they did not meet the selection criteria. The reasons for exclusion were mainly non-knowlesi species (41%), experimental studies (22%) and non-malaria studies (18%) (Fig. 2). A total of 18 studies were included into the present qualitative study (Fig. 1).
Plasmodium knowlesi transmission in Indonesia
We systematically reported all the documented human cases of P. knowlesi malaria in Indonesia from published articles. Between 2010 and 2021, a total of 545 P. knowlesi malaria indigenous cases were recorded in Indonesia (Fig. 3). Among these cases, 95.4% (520) were recorded between 2017 and 2021 (Table 1).
Table 1
Plasmodium knowlesi confirmed cases in Indonesia.
Article (ref) | Total number of cases (n) | Cases description |
Figtree et al., 2010 [15] | n = 1 | 1 case exported to Ausstralia from South Kalimantan, PCR diagnosis |
Sulistyaningsih et al., 2010 [16] | n = 1 | 1 case in South Kalimantan, PCR diagnosis |
Ompusunggu et al., 2015 [17] | n = 3 | 1 case in South Kalimantan, PCR diagnosis 2 cases in Central Kalimantan, Microscopic diagnosis confirmed by PCR |
Setiadi et al., 2016 [18] | n = 1a | 1 case in Central Kalimantan, PCR diagnosis |
Herdiana et al., 2016 [20] | n = 20 | 20 cases in Aceh, PCR diagnosis |
Salwati et al., 2017 [19] | n = 1 | 1 case in Jambi, PCR diagnosis |
Lubis et al., 2017 [22] | n = 377 | 377 cases in North Sumatra, PCR diagnosis |
Coutrier et al., 2018 [21] | n = 19b | 19 cases in Aceh, PCR diagnosis |
Herdiana, et al., 2018 [23] | n = 15 | 15 cases in Aceh, PCR diagnosis |
Zohra et al., 2019 [24] | n = 111 | 111 agregated cases 2015–2017 in Aceh |
Ramadhan et al, 2021 [25] | n = 16 | 16 cases in Aceh, PCR diagnosis |
an = 1 case described in [18] was obtained at the same place and date as [17] |
b n = 19 cases described in [21] was obtained at the same place and date as [20]. |
The first case of P. knowlesi reported in 2010 from South Kalimantan Province and exported to Australia was a 39-year-old man infected after working for 18 months in close proximity to the forest [15]. In the same year, another case of P. knowlesi was reported from the same province [16]. Again, in Kalimantan, three (n = 3) cases were positive for P. knowlesi out of 287 malaria cases during the 2013–2014 period: a 28 year old man and a 50 year old man were from Central Kalimantan Province and a 28 year old pregnant woman was from South Kalimantan Province [17, 18].
Several cases occurred in different provinces of Sumatra Island (Fig. 2). From the published literature, In Aceh province, 15 P. knowlesi cases occurred in 2014 [23], 20 cases during 2014–2015 and 16 cases in the 2018–2019 period [20, 21, 25]. In Jambi province, 1 case was collected in 2015 [19]. In North Sumatra province, 377 cases of P. knowlesi were collected in 2015 [22]. A total of 111 aggregated cases occurred in this Aceh province between 2015–2018 [24]. Aceh and North Sumatra provinces may be considered as the hotspots of Indonesian P. knowlesi (Fig. 2).
Diagnosis of P. knowlesi malaria
The first case of natural infection of P. knowlesi in Indonesia reported in 2010 was diagnosed by nested PCR [16]. Plasmodium knowlesi infections reported in 2015 were initially diagnosed as P. vivax by microscopy, before PCR analysis revealed them to be P. knowlesi [17]. In the same sampling area and at the same data collection time, one case of P. knowlesi malaria was reported in North Barito Regency, and was diagnosed by PCR [18]. In Jambi province, one of 34 cases was confirmed as P. knowlesi using nested PCR targeting the Small Subunit ribosomal RNA (SSU rRNA) gene [19]. In Aceh province, 20 positive cases of P. knowlesi, initially diagnosed as P. falciparum, P. vivax, or P. malariae, were identified by nested PCR in 2016. Two years later, 19 cases of knowlesi malaria were reported after detection by PCR in the same place and the same year of data collection [20, 21]. These cases were probably the same as those described in 2016. In 2017, 377 cases of P. knowlesi were identified in Batubara, Langkat, and South Nias regencies, North Sumatra province, using a conventional nested-PCR and a heminested PCR assay based on a conserved region of the gene encoding P. knowlesi–specific schizont-infected cell agglutination variant antigens (SICAvar) [22]. In 2018, 11 cases of P. knowlesi infection were reported in Aceh Province using a nested PCR method that targets the cytochrome b gene and Alu-I enzyme digestion, followed by confirmation using 18S rRNA nested PCR [23]. In 2018–2019 period, 16 cases of PCR confirmed knowlesi malaria were reported in Aceh [25]. Of all published P. knowlesi malaria cases, only two were diagnosed using microscopy (Table 1), confirming the global accuracy of the case definition.
Treatment of P. knowlesi malaria in Indonesia
In Indonesia, the first patient infected with P. knowlesi recovered following treatment with chloroquine-primaquine [16]. Several combinations of treatment have been used including chloroquine followed by primaquine, Artemisinin-based Combination Therapies (ACTs artemether/lumefantrine; artesunate/amodiaquine; dihydroartemisinin/piperaquine) and primaquine. All the above combinations of drugs used in Indonesia led to successful outcomes for P. knowlesi malaria. ACTs appear to be effective against P. knowlesi, while few data are available yet and no clinical and biological therapeutic efficacy study have been prospectively conducted in Indonesia. The Indonesian MoH recommends dihydroartemisinin + piperaquine (DHP) for 3 days + primaquine (0.25 mg/kg on the first day for P. falciparum, and 14 days in case of P. vivax and P. ovale infection) as the first line treatment for uncomplicated malaria. In the case of P. vivax malaria relapse, primaquine levels are increased to 0.5 mg/kg per day. Plasmodium malariae treatment is based on DHP for three days with the same dose. For patients with multi-species infections (P. falciparum + P. vivax/ovale), treatments are applied in accordance with the guidelines for the treatment of single vivax/ovale infections. In case of suspected P. knowlesi malaria, the treatment is same as that of P. falciparum malaria.
Vectors of Plasmodium knowlesi
Of the known P. knowlesi vectors, Anopheles latens, An. balabacensis, An. leucosphyrus, An. introlatus and An. cracens are found in Indonesia (Fig. 3).
Anopheles latens has been found in Central, South and North Kalimantan provinces [34, 35]. Anopheles leucosphyrus is located in all provinces of Sumatra and in all provinces of Kalimantan except Central Kalimantan [34, 36]. Anopheles balabacensis is present in North, South and East Kalimantan, Sumatra (Aceh, Jambi, Bengkulu, Lampung), Riau islands, Java (Central and Yogyakarta), West Nusa Tenggara, and North Sulawesi [34–37], whereas An. introlatus is only found in the provinces of Sumatra [34, 35]. An. cracens is present only in Aceh [35]. Of note, P. knowlesi DNA was detected in an An. balabacensis from Lampung province [37]. Data on P. knowlesi vectors and hosts were extracted from the studies listed in Table 2.
Table 2
Records describing P. Knowlesi vectors and hosts in Indonesia
Records describing P. Knowlesi hosts | Records describing P. knowlesi vectors |
Ompusunggu et al., 2015 [17] | Elyazar et al., 2013 [36] |
Moyes et al., 2016 [40] | Moyes et al., 2016 [40] |
Salwati et al., 2017 [19] | Wibowo et al., 2020 [37] |
Ekawati et al., 2020 [39] | Vythilingam et al., 2021 [35] |
Lempang et al., 2022 [38] | Van de straat et al., 2022 [34] |
Plasmodium knowlesi macaque reservoirs in Indonesia
Long-tailed macaques (Macaca fascicularis), Pig-tailed macaques (Macaca nemestrina), and Banded leaf monkeys (Presbytis melalophos) are the natural hosts of P. knowlesi. In Indonesia, M. fascicularis can be found in all provinces of Sumatra, Kalimantan, Java, Bali Province, West Nusa Tenggara province and East Nusa Tenggara.province (Fig. 4) [38–40], M. nemestrina in all provinces of Sumatra and Kalimantan [38–40], and P. melalophos in all provinces of Sumatra [38, 39]. A study conducted in Jambi province reported in 2017 five M. fascicularis and 1 M. nemestrina among 38 wild macaques infected with P. knowlesi [19] and a study conducted in Central Kalimantan in 2014 reported 3 macaques infected with P. knowlesi [17].