In this study we report the presenting symptoms and outcome of Adult Sudanese patients co-infected with COVID-19 and Malaria who were admitted to two isolation centers in Wad Madani, Sudan. Understanding clinical features and outcome of COVID19 and malaria co-infections is essential for accurate diagnosis and predictability of treatment when a patient develops complications, in order to alleviate symptoms and reduce morbidity and mortality. To our knowledge, this is the first retrospective observational study providing clinical characteristics and outcome of COVID19 and Malaria co-infection in Sudan, and one of the few in the whole literature. We found that the most common symptoms seen on presentation among co-infected participants include: shortness of breath (76.3%) and fever (73.1%). We found the overall mortality among all participants to be 40.4% (n=63).
During this crisis period, a malaria case may be misclassified as COVID-19 due to symptoms that resemble COVID-19 such as fever, difficulty breathing, fatigue, and headaches of acute onset 26. At present, given the alertness occurring at the community, health center, nation, regional, and global levels, it is expected that COVID-19 will remain the main target of suspicion; even though co-infection may be present. Sudan faces a number of other infectious diseases that must not be ignored. COVID-19 places additional strain on the already overburdened and resource-constrained health services, which are struggling to keep in check the high burden of existing infectious diseases and non-infectious diseases, such as malaria -which can be misdiagnosed as COVID-19 if it exhibits similar symptoms. Challenges arise from the fact that people with fever are more likely to be tested for COVID-19 and sent home as a result of a negative result, and conversely, febrile patients may be tested for malaria when they are in fact infected with COVID-19; in other words, a patient may be infected with malaria and COVID-19 at the same time, and diagnosis and treatment of one may cause the other to be missed 26. Malaria has been reported to threaten nearly half of the world's population as of 2018 4. The deadly strain of Plasmodium falciparum malaria poses a challenge because it has the potential to result in severe cases; in Africa, P. falciparum is the most prevalent and deadliest malaria parasite causing the most severe malaria cases overall 27, 28. It’s reported in literature that Malaria infections caused by P. falciparum account for approximately 90% of global Malaria mortality 29, 30. Regarding prevalence of Malaria species in Sudan, the majority (91%) are cases of severe falciparum infection, while P.vivax accounts for 8 (%) cases 31. Overall Malaria incidence in Sudan was 12.4 percent of all diseases that were reported, over 1.8 million cases are detected with a 13 per 10,000 mortality rate in 2019 5 which is considered low in comparison to the mortality rate (4.8 per cent) in 2002 32 .Untreated malaria is a leading cause of illness and death in the developing world due to the further infectiousity among community 33, 34. On the other hand, up to 3.58 susceptible individuals can be infected by a single case of COVID-19 35. Given that both COVID19 or Malaria can cause severe disease, and both are highly infectious; then, co-infection is expected to occur – especially in areas endemic with malaria like Sudan – and it’s expected to be even more fatal than either of the two – COVID19 or Malaria – isolated.
Overall mortality rate of COVID-19 – mono-infection - is approximately 1-14% in international studies, as well as 7.1% in Sudan 36, 37. However, the overall mortality rate of a country is not always representative for every state in that country. The majority of COVID-19 cases are in Khartoum state – the capital of Sudan - where the majority of health facilities are available, yet most of the deaths of the disease have been reported from areas outside the capital 38. Regarding comparison of co-infection mortality rate against mortality rate of COVID-19 isolated-infection; the mortality rate in our study 40.4% ( n=63) – which is done in Gezira state – is comparable to a study done in Al Gadarif state, Eastern Sudan; that showed a high mortality rate of COVID-19 – alone – of 37.5% 39. And regarding comparison with other co-infection studies, the overall mortality among our co-infected participants was 40.4%( n=63), in contrast to a cohort study done in Uganda that showed a mortality rate among COVID-19 and Malaria co-infected patients of only 3% 40.We believe that co-infection has a vital role prompting a high mortality rate due to the increased inflammatory response; also, we assume the mortality rate in our study to be inflated due to other factors; such as the lack of fundamental resources (lifesaving resources and adequate staff). P. falciparum overall mortality is difficult to obtain due to scarcity of data; but as stated in a study, P. falciparum mono-infection overall mortality in Sudan, was approximately 0.13% in 2019 5. It is considered low in comparison with the high mortality of co-infection in our study (40.4%). The substantial disparity in death rates is most likely related to two factors: one being the long history of endemic malaria in Sudan, that gave most of the community the knowledge, awareness and immunity to avoid further severe infection, in addition to the cumulative experience gained by the health staff regarding responding to the infection; the other factor being the enhanced severity of disease during co-infection.
Other COVID19 co-infections have been documented, for instance, the co-infection of Dengue virus and COVID19 has been reported 41. Dengue and Chikinguniya – which are two zoonotic arboviral diseases - are endemic in Sudan, as well as malaria 42,43.Tropical and subtropical countries experience high levels of infection with Dengue virus and Chikungunya virus during the monsoon season, and co-occurrence has been documented 44.Malaria and dengue virus co-infection, as well as Malaria and Chikungunya virus co-infection have been reported in Sudan 43,45.A co-infection with any or all of Malaria, Dengue virus, and Chikungunya virus; with COVID19 is predicted during the rainy season due to favorable breeding conditions for the mosquitoes, at the same time as the COVID19 pandemic could have a significant impact on public health46.
Fever, cough, and lethargy are frequent symptoms of COVID-1947. Malaria symptoms are many; low-grade fever, shivering chills, and muscle pain, as well as gastrointestinal issues in children, are common first complaints. Such symptoms may appear abruptly, followed by heavy sweats, a high fever, and fatigue 48.There is scarcity in data regarding COVID-19 and Malaria co-infection, but a study reported that most of the patients with co-infection had fever as a presenting complaint, while some patients had headaches, difficulty breathing and sore throats on presentation 49. Regarding symptoms among our co-infected patients, we found shortness of breath (76.3%) and fever (73.1%) to be the most prevalent symptoms. Our findings align with a study done in Uganda, where fever (21%, n=70) and shortness of breath (19%, n=70) were the second and fourth most common symptoms among COVID-19 and Malaria co-infected patients, respectively 40.Although both symptoms are considered among the most to occur, there is a substantial difference between the prevalence of occurrence among the two studies. This might be due to the treatment seeking behavior of our patients, as many individuals wait until symptoms arise before seeking treatment.
As a general rule Covid19 complications are mainly attributed to cytokine release syndrome or a cytokine storm. Complications regarding COVID-19 include: Coagulopathy, Cardiovascular complications and acute respiratory failure 50. Severe cases may experience dyspnea and hypoxia within a week of the commencement of the illness, which can lead to ARDS or end-organ failure 51.Acute respiratory distress syndrome produces alveolar damage in the lungs, and the prognosis is worse when COVID-19 is the cause 52.Concerning complications among our co-infected patients, we found the most common to be acute respiratory distress syndrome, in 35.3% (n=156) of patients. This is in contrast to a study where the most common complication among COVID-19 mono-infected patients was acute kidney injury followed by probable acute respiratory distress syndrome in 24.3% (n=73,197) and 18.4% (n=73,197) of patients respectively 53. The greater percentage in our patients could be ascribed to the enhanced severity caused by the synergistic co-infection pathogenicity effects. Regarding Malaria, the most common pathogenic mechanism is the hemolysis of the Plasmodium-infected red blood cell, which releases plasmodium endotoxin, resulting in high levels of tumor necrosis factor (TNF) generation and findings like fever 48. Malaria complications are diverse; the most common include: Cerebral malaria, acute renal failure, pulmonary edema, severe anemia, and bleeding 54. We found Thrombocytopenia to be present in 16% (n=156) of our patients. This is in contrast to a study, where Thrombocytopenia complicated 41.7% (n=12) of COVID-19 and Malaria co-infections 55.This may be attributed to the difference in sample size and further studies are needed to clarify the ambiguity.
In our patients, the overall concentration of total white blood cells was decreased, and C-reactive protein levels were increased. During malaria, white blood cell (WBC) counts are low or normal, a characteristic that is commonly regarded to represent leukocyte localization away from the peripheral circulation to the spleen and other marginal pools, instead of real deficiency or stasis 56.In African studies, serum CRP levels have been linked to parasite burden and consequences in malaria, particularly falciparum malaria 57.In up to 86 percent of severe COVID=19 patients, CRP levels were found to be significantly elevated. CRP levels were much higher in patients with severe disease courses than in mild or non-severe patients, hence it was employed for classification and treatment counseling in severe COVID-19 cases 58.Elevated D-dimer is a known predictor of COVID-19 infection severity; it's linked to an elevated risk of complications - such as deep vein thrombosis and pulmonary embolism - and is one of the most important determinants of severity 59.The most common abnormality seen in patients with COVID-19, according to the literature, is sinus tachycardia. Other abnormalities include supraventricular tachycardias like atrial fibrillation or flutter, ventricular arrhythmias like ventricular tachycardia or fibrillation, various bradycardias, interval and axis changes, and ST segment and T wave changes 60.
Malaria's clinical outcome can be impacted by a wide range of factors, including parasite species, host genetics, innate and acquired immunity, access to adequate treatment, comorbidities, and antimalarial resistance. Infections can lead to various outcomes, such as asymptomatic illness, influenza-like symptoms, and organ dysfunction and death 61.Regarding COVID-19 outcome, extended hospital admission and greater death can be due to multi-organ failure as well as various metabolic disturbances and respiratory insufficiency, in addition to the multi-system involvement 62,63.Older age, neutrophilia, and organ and clotting failure (eg, higher LDH and D-dimer) were all linked to the development of acute respiratory distress syndrome in COVID-19 patients hence death 51.We found acute respiratory distress syndrome to be significantly associated with in-hospital mortality; 63.5% (n= 55) of our patients with acute respiratory distress syndrome died. This is similar to a study where mortality was 52.4% (n=84) among patients with acute respiratory distress syndrome 51.The increased mortality rate is probably due to the increased inflammatory response due to the co-infection. Also, we found length of stay of 5.4 ± 4.3 days to be significantly associated with in-hospital death (P = 0.003); and this is similar to a systematic review where- in terms of overall stay - those who died had a shorter stay than those who were discharged alive 63.
There is a possibility of a higher rate of COVID-19 co-infections during the ongoing pandemic; especially in areas endemic with infectious diseases like Sudan, hence more efforts should be done to raise the awareness of the community regarding both diseases – COVID-19 and Malaria – in addition to emphasis on the possibility of co-infection between COVID-19 and Malaria in specific, or COVID19 and other infectious diseases in general. A greater clinical suspicion of COVID-19 co-infection should be held; obtaining a correct diagnosis of a treatable infection, and identifying the presence of co-infections requires careful investigation, hence, it would be beneficial to provide malaria testing kits to the COVID-19 testing laboratories, thereby reducing missed opportunities for malaria testing. As a crucial component of helping to solve this difficult conundrum, convenient health infrastructure needs to be prioritized; lifesaving resources and an adequate number of qualified health workers are essential. Further research is needed for identification of etiology as well as better understanding of the pathophysiology behind COVID19 and Malaria co-infection.
Our study had several limitations, first, although our careful approach, the retrospective design in itself increased chances of bias; secondly we selectively included patients with COVID-19 and Malaria co-infection only, without including patients infected with COVID-19 or Malaria mono-infection, so our results cannot be directly compared between patients; lastly, due to inconvenience, we were not able to include isolation centers in other states, so findings cannot be generalized. Despite these limitations, our study has strong points, such as the large sample size of co-infected patients, and diagnostic and immunological tests, in addition to comprehensive laboratory, imaging, and ECG diagnostic techniques, among others.