Indonesia is one of the tropical countries in the world still facing a high risk of malaria. Approximately 80% of cities or districts in Indonesia are endemic to malaria, one of which is Papua. Based on the data from Annual Parasite Incidence (API) in 2019, the number of positive cases of Malaria in Papua is 64.03% per 1000 population11. P. vivax malaria still causes significant morbidity in endemic areas. Reactivation of the dormant stage of hypnozoite can cause P. vivax relapse12. A single inoculation by a female Anopheles mosquito can be followed by multiple relapses13.
Plasmodium vivax is capable of undergoing early and frequent relapses. In addition to blood-stage parasite replication, P. vivax has a dormant stage of hypnozoites that can persist in the liver and reactivate to cause relapses weeks or even years later14. This reactivation may be triggered by the host’s inflammatory response to systemic illnesses or parasitic and bacterial infections, but not viral infections15. The estimated ratio of P. vivax relapses to total infections is 76–90% in the Papua New Guinea cohort study and 79% in the Thailand cohort study14. Based on the study conducted by Chu et al., P. vivax parasitemia recurrences, mainly relapses, occurred in 377 from a total of 644 (59%) patients treated with artesunate, chloroquine, or chloroquine-primaquine. A history of the previous malaria was more common in patients with recurrences (61%) than without recurrence (39%). About 90% of all P. vivax recurrences occurred by week 16 following treatment. Primaquine, as the radical cure with an estimated efficacy of 92%, would reduce the risk of relapses and lessen the significant burden of morbidity caused by P. vivax16.
The pathophysiology behind the co-infection of COVID-19 with P. vivax Malaria remains unclear. It is not known whether SARS-CoV-2 infection reduces the immunity that leads to malaria reactivation or if complications from malaria increase the susceptibility to get COVID-1917. Based on the disease course, this patient was suspected of having reactivation of P. vivax infection due to COVID-19 infection. The mechanism that caused the reactivation is still unclear and may be attributed to the cytokine response to COVID-19. There is still a possibility of natural reactivation or reinfection not related to COVID-19 infection that cannot be completely ruled out18. The excessive proinflammatory cytokine response generated in co-infection of COVID-19 and Malaria can lead to a worse prognosis19.
Early symptoms of SARS-CoV-2 infection such as fever, fatigue, and myalgia, similar to those of malaria, can lead to delayed diagnosis, especially in malaria-endemic areas18. In contrast to severe malaria, which is often caused by P. falciparum, where neurological symptoms are predominant and more severe symptoms such as loss of consciousness, signs of focal neurological abnormalities, and severe anaemia can further narrow the diagnosis of malaria. The results of blood tests can also be confusing. Therefore, a diagnostic test for both Malaria and COVID-19 is crucial. The principal diagnosis of malaria to date is the microscopic examination to detect the presence of plasmodium at all stages. However, the sensitivity and specificity of this examination are highly dependent on the examiner’s subjectivity. If a microscopy test is not available, a malaria rapid diagnostic test (RDT) can be an alternative to confirm the diagnosis. Another method using a PCR is more sensitive than microscopy, but the results take too long, so it is rarely used20. Plasmodium spp and COVID-19 have incubation periods that are not much different. For COVID-19, the incubation period reaches 14 days from exposure with a median value of 4–5 days, while for malaria, the incubation period varies from 7 to 30 days20. It is hence essential to gain a thorough anamnesis in differentiating these two diagnoses.
Hypercoagulopathy is common in COVID-19 patients, especially in those with severe disease21. SARS-CoV-2 induces tissue factor expression, a primary initiator of the coagulation cascade, by cytokines produced by inflammatory cells. Moreover, SARS-CoV-2 causes endothelial dysfunction through an angiotensin-converting enzyme-2 (ACE-2) receptor expressed on the surface of vascular endothelial cells and induces neutrophil extracellular traps (NETs) release, which activates the coagulation pathways and platelet22. Abnormal coagulation parameters such as elevated D-dimer and fibrin degradation product levels and prolonged prothrombin time are related to a poor outcome. The most common manifestations of COVID-19 hypercoagulopathy are venous thromboembolism and arterial thrombotic complications, including pulmonary embolism and stroke3. COVID-19 patients are at risk for developing disseminated intravascular coagulation (DIC), pulmonary hemorrhage, and thrombosis8. Thrombocytopenia associated with a higher risk of severe COVID-19 is suspected to be caused by platelet consumption in the lungs and infected hematopoietic stem cells and megakaryocytes23.
Malaria is also strongly associated with a hypercoagulopathy condition through activation of the coagulation cascade triggered by proinflammatory cytokines [e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-6]. The most common coagulopathy condition is microthrombotic complications, besides thrombosis of large vessels, including cerebral venous thrombosis and pulmonary embolism. Thrombocytopenia is a common finding (60–80%) that may be due to impaired coagulation, splenomegaly, bone marrow disorders, antibody-mediated platelet destruction, oxidative stress, and platelet aggregation24. DIC and bleeding are related to high mortality, occurring only in severe malaria. Tissue factors released from damaged vascular endothelial cells and the lysis of activated platelets contribute to the development of a pro-coagulant state similar to the underlying mechanism in COVID-19. Therefore, Plasmodium spp. and SARS-CoV-2 co-infection could lead to severe coagulopathy and worse outcomes than with either infection alone8. In this case, the patient had a high risk of mortality due to hypercoagulopathy condition, which is characterized markedly increased D-dimer levels which was also aggravated by malaria vivax relapse. Regarding this condition, thromboprophylaxis has a crucial role to reduce the risk of thrombotic events.
There were also similar report regarding Malaria and COVID-19 co-infection, as shown in Table 1. The first case report was described by Sardar et al. 19 in Qatar as a possible P. vivax reactivation secondary to COVID-19, similar to the case reports presented by Kishore et al. 18 in India and Shahid et al. 13 in Qatar. Ray et al. reported a case of concomitant infection between malaria vivax and COVID-19 in India without suggesting the possibility of P. vivax re-activation26. However, this report is the first case of malaria vivax and COVID-19 co-infection in Indonesia that discussed the possibility of P. vivax relapse related to COVID-19 with symptoms of prolonged fever and exaggerated hypercoagulopathy.
Table 1
A Literature Review of COVID-19 and Plasmodium vivax Co-infection
No | Author | Country | Year of Publication | Age | Clinical Symptoms | History of P. vivax infection |
1. | Shahid Z et al. 13 | Qatar | 2021 | 55 | Dry cough, high-grade fever, chills, rigors, profuse sweating, lethargy | Documented (1 year before) |
2. | Ray M et al. 26 | India | 2020 | 67 | Fever, shortness of breath | Not documented |
3. | Kishore R et al. 18 | India | 2020 | 10 | High-grade fever, chills, rigors, headache, cold, cough, abdominal pain | Documented (6 months before) |
4. | Sardar S et al. 19 | Qatar | 2020 | 34 | Fever, myalgia, vomiting, right upper quadrant abdominal pain | Not documented (but there was a travel history to Pakistan 3 months before) |
Based on WHO recommendations, in terms of facing challenges caused by the COVID-19 pandemic such as the disruption of the malaria rapid test kits supply, the shortage of health workers and personal protective equipment, as well as the limited facilities of the Intensive Care Unit (ICU), the diagnosis of malaria must always be considered in all cases of fever in malaria-endemic countries20. In this case, considering the differential diagnosis of malaria infection other than SARS-CoV-2 infection can reduce the risk of morbidity and mortality due to delayed and inappropriate treatment.
Various clinical trials to determine the appropriate COVID-19 therapeutic regimen are still ongoing. The massive use of hydroxychloroquine to treat COVID-19 in Malaria endemic areas will further increase the risk of anti-malarial drug resistance19. Artemisinin is a very potent anti-malarial drug and can overcome the problem of resistance to quinolones. Artemisinin is also able to inhibit endocytosis more strongly than chloroquine. Artesunate, a semisynthetic derivative of artemisinin, has lately attracted much attention to be tested as a COVID-19 therapy because of its anti-viral and anti-inflammatory effects through inhibition of Nuclear Factor kappa B (NF-kB) downregulation and protein synthesis in the early stages of viral replication27. Further research is required to study the role of artemisinin in treating COVID-19 and the prognosis of COVID-19 co-infection with malaria.