This is the first report of MIS-C and Plasmodium vivax and falciparum malaria co-infection. By presenting this case, we aimed to draw attention to a rare travel related infection masked by a pandemic infection. Indeed, since the end of 2019, the global outbreak of COVID-19 has spread rapidly posing a major challenge to many healthcare systems around the world [8]. In this situation, co-infections present a unique challenge to clinicians and it is essential to remember that neither co-infection with other pathogens can be ruled out when COVID-19 is confirmed, nor does a positive test for other pathogens completely negate the presence of co-infection with COVID-19.

This is especially true in malaria-endemic areas or among people who have recently returned from malaria-endemic countries. Malaria and COVID-19 can actually presents with fever, myalgia, fatigue, headache, gastrointestinal symptoms, and both can have a negative impact on the course of the other [9, 10]. Furthermore, the diagnosis of malaria is already elusive in a non-endemic country; this difficulty appears to be exacerbated by overlap of symptoms and signs with COVID-19. The similarity in the non-specific symptoms and febrile illness associated with COVID-19 and malaria makes missing a malaria diagnosis in the COVID-19 pandemic highly likely especially in country not endemic for malaria.

In our case, the patient was admitted due to COVID-19 and was found to have a concomitant falciparum and vivax malaria infection whose pattern of over-expressed cytokines overlaps with that of COVID-19. Malaria with severe manifestations may be caused by an elevated proinflammatory response (IL 6, IL 1, and tumor necrosis factor alpha increase during haemolysis from malarial infection). Therefore, coinfection with malaria and SARS-CoV2 may lead to an increased risk of developing MIS-C in paediatric age. Co-infection with a parasite and a virus, in particular, can place a double burden on the body’s immune system. Immune cells may undergo a dilemma of whether to produce a response to eliminate one pathogen or the other and ultimately end up with an exaggerated immune response. MIS-C is a novel dangerous and potentially life-threatening entity associated with a wide range of clinical features including persistent fever, digestive symptoms, rash, bilateral non purulent conjunctivitis, mucocutaneous inflammation signs, and frequent cardiovascular involvement. MIS-C is frequently associated with hemodynamic failure, with acute cardiac dysfunction requiring hemodynamic support in 60 to 75% of cases, sometimes leading to death [11]. We diagnosed our patient with MIS-C due to clinical deterioration characterized by continuous fever, a multisystem organ involvement with elevation of inflammatory markers, despite the clearance of parasitaemia after malaria treatment. Many altered biochemical parameters such as anaemia, thrombocytopenia, elevated bilirubin, CRP, procalcitonin, AST, ALT, ferritin, GGT, IL 6, and reduced sodium and albumin levels can be related to both malaria and MIS-C therefore require proper interpretation (Table 2). In severe malaria, there is generally a decline in red blood cell, haemoglobin, and platelet counts due to sequestration of infected red blood cells caused by the activation of endothelial activation markers and surface adhesion molecules. However, ours was not a case of severe malaria, but rather a case of malaria complicated by MIS-C in fact even SARS-CoV-2 infection is associated with a cytokine cascade and endothelial activation [12,13,14].

MIS-C management has evolved over the course of the pandemic. Current guidelines recommend IVIG and/or corticosteroids as first-line therapy. Other interventions are determined by the disease severity, outcome, and response to initial therapy. Antithrombotic therapy and second-line treatment with several immunomodulatory drugs (interleukin-1 inhibitor, interleukin-6 inhibitor), and other supportive therapeutic agents are used concurrently in these cases [15].

Single case reports of patients with malaria and COVID-19 co-infection have been described by several authors [16,17,18] and a recent systematic review reports concomitant infections of SARS-CoV-2 and malaria, mainly in adults (age range 4–67 years) [6]. There are very few cases of co-infection malaria-COVID described in the child. Adetola et al. described four children with COVID and malaria treated with a full course of anti-malaria medications [19]. Rashmi Kishore et al. reported one case of P. vivax malaria reactivation in an Indian 10-year-old boy suggesting a possible role of COVID-19 in inducing malarial relapse [20]. Although the exact mechanism causing this activation is unknown, the cytokine cascade associated with systemic disease could also induce reactivation of Plasmodium vivax from a previous infection with dormant liver stage parasites or hypnozoites. In our case we can’t say if it was the first malaria vivax infection or a case of malarial relapse because we don’t know if it was her first trip to Africa since she was born in Italy.

In none of the few cases of co-infection described to date COVID-19 has manifested itself in a severe form and required intensive support [21].

Ours is the first severe form of COVID-19 and malaria co-infection in the child due to the establishment of MIS-C. Regarding malaria treatment, the role of anti-malarials, e.g. artemisinin derivates and chloroquine, in the COVID-19 pandemic is complex. Artemisinin derivates, artemisinin-based combination therapy, and chloroquine have all been shown in vitro to be effective against SARS-CoV-2 [22, 23]. Several clinical trials, however, failed to confirm such a beneficial effect [24, 25].