Introduction

The Coronavirus-19 (COVID-19) pandemic has affected every continent worldwide, impacting the lives of people everywhere. Recent data shows that up to two-thirds of all Africans have been infected with SARS-CoV-2 (the virus which causes COVID-19), which is higher than the global average of 45% [1]. Africa was predicted to be one of the continents to be hardest hit by COVID-19, given the higher burden of Human Immunodeficiency Virus (HIV), Tuberculosis (TB), and Malaria, with the addition of an increasing burden of non-communicable diseases [4]. This, however, was not reflected in follow-up studies showing that deaths due to the virus were low, despite high case rates [2]. Factors such as a younger population, undertesting, and different demographics have been utilized to explain the differences in death rates [2]. This suggests that data regarding COVID-19 should, therefore, be interpreted specifically for the African region. Yet, the amount of research conducted in this area by authors who are affiliated with African research institutions remains low, with only 4.3% of authors being affiliated with Africa [3].

Individuals with pre-existing cardiovascular disease are more prone to severe COVID-19 infections, often requiring intensive care unit (ICU) admission and ventilatory support, and having higher mortality rates [4]. The COVID-19 virus enters a cell through the angiotensin-converting enzyme 2 receptor, which may lead to a systemic proinflammatory state and result in an increase in cardiovascular sequelae such as myocarditis, worsening heart failure, acute myocardial infarction, and sudden cardiac death [5]. A previous study looked at a global patient cohort to investigate the association between cardiovascular risk factors and clinical outcomes in patients with COVID-19 [6]. We evaluated whether differences in demographics, age of population, access to healthcare, and other factors may affect the presentation and outcomes of the COVID-19 disease in patients hospitalised in Africa compared with other regions. Adding to this are differences in the cardiovascular disease burden and the underlying epidemiological transitions within sub-Saharan Africa, including rheumatic heart disease and congenital heart disease, amongst others. Therefore, we sought to investigate the cardiovascular outcomes of patients in sub-Saharan Africa to guide policy and preventive measures.

Methods

Details on the study rationale, study design, study population, and patient recruitment were reported in Sliwa et al. [7]. In summary, a multinational prospective cohort study was conducted on adults with confirmed COVID-19, consecutively admitted to various hospitals in low-income countries (LICs), low-to-middle income countries (LMICs), upper-middle-income countries (UMICs), and high-income countries (HICs) [8]. Forty hospitals from 23 countries participated in the study, comprising 4 LICs, 15 LMICs, 8 UMICs, and 13 HICs.

Results

Of the 40 recruiting centres, 9 sites were in Africa (LICs = 4, LMICs = 5). In addition to key study findings, Figure 1 displays participating African countries, which were South Africa (n = 189), Zambia (n = 200), Kenya (n = 151), Nigeria (n = 304), Ghana (n = 79), and Sudan (n = 25). African sites had suboptimal specialist services and advanced care compared to higher income countries (Figure 2).

Of the 5,313 COVID-19 patients enrolled across the 40 sites, 948 (17.8%) were from African sites. Table 1 compares the demographic characteristics of the African and non-African study participants. The African cohort had a significantly younger overall mean age of 55.0 years, compared to 57.5 years in the non-African cohort. The sex distribution was similar in both cohorts, but the proportion of Caucasians in the African cohort was significantly lower than in the non-African cohort (0.5% vs. 18.2%), while the percentage of black participants was much higher (78.4% vs. 1.2%). Mean BMI was very similar across groups.

Table 1 also compares the symptoms and clinical signs between the two cohorts. Presentation with self-reported coughing and tachypnea were similar between the two groups. The African cohort had a significantly higher mean heart rate (94.7 vs. 91.5), and significantly higher systolic (133.7 vs. 128), as well as diastolic (81.3 vs. 77.5) pressures, compared to non-African participants. The African cohort had a higher prevalence of hypertension (48.8% vs. 46.9%), HIV (5.9% vs. 0.3%), and TB (3.6% vs. 0.3%), but a significantly lower rates of diabetes (25.3% vs. 33.4%) and a much lower rate of COVID-19 vaccination rate (0.6% vs. 7.4%).

Table 2 shows laboratory findings between the two cohorts. African participants had a higher WCC and a significantly higher CRP (75.7 vs. 51) than non-African participants. No differences were seen in creatinine, D-dimers, or HbA1c. The African non-survivors seemed to have higher pro-BNP levels (163.7 vs. 130.4), total cholesterol levels (4.3 vs. 3.4), and LDL cholesterol levels (3.3 vs. 1.6), as compared to non-African non-survivors. T wave changes were more common (17.9% vs. 13.8%) and QTc longer (437 ms vs. 413 ms) in the African participants on their admission ECGs. ICU admissions were fewer (19.4 vs. 34.0%) in the African cohort. However, participants in the African cohort had higher rates of cardiac arrest (7.5% vs. 5.1%). Other major adverse events were comparable between the two groups. Rates of pneumonia and ARDS also showed no statistically significant differences. Acute renal injury was more common in African participants (12.7% vs. 7.2%).

Table 3 shows in-hospital outcomes, with death occurring in 17% of admitted African participants, compared to 11.9% in the non-African cohort (p < 0.05). Although 30-day mortality was less in the African cohort, overall mortality was much higher in the African cohort (18.2% vs. 14.2%, p < 0.05).

Tables 4a and 4b show results from crude and adjusted regression analyses for factors associated with in-hospital deaths and overall mortality in patients with COVID-19. Adjusted models accounted for age, sex, BMI, smoking, COVID-19 vaccine status, diabetes, hypertension, COPD, asthma, HIV, and acute renal injury.

In the non-African cohort, participants over the age of 60 showed 3.73 times higher odds of in-hospital death, compared to those younger than 45. The increased odds in the African cohort were not statistically significant. However, regarding overall mortality, both the African and non-African cohorts showed significantly increased odds of death in participants aged 60 or older (OR of 4.03 vs. 4.18 respectively). Interestingly, the non-African cohort showed higher odds of overall mortality, even in participants aged 45–60 compared to individuals younger than 45 years of age.

Being female was associated with lower odds of overall mortality (0.71) in the non-African cohort, as compared to being male. This sex difference was not observed in the African cohort in overall mortality. Vaccination status was associated with a strong protective status in the non-African cohort. It could not, however, be elicited in the African cohort due to very low vaccination rates and poor reporting. This was seen both in the in-hospital deaths and overall mortality analyses.

Diabetes showed a significantly higher risk for in-hospital deaths in both the African and non-African cohorts, but particularly in the African cohort, with adjusted ORs of 3.51 and 1.43, respectively. Regarding overall mortality, the adjusted odds of death were still increased for those with diabetes, although they were slightly less than for in-hospital death. Hypertension was associated with higher odds of death, but only in the unadjusted analyses for both in-hospital and overall mortality. When adjusting for covariates, no significant increase in odds was found. HIV was not associated with a higher risk of in-hospital death or overall mortality. AKI showed the highest increase in odds for in-hospital death, with an odds ratio of 48.12 in the African cohort and 8.27 in the non-African cohort, and similar results for overall mortality.

Table 4c shows the results from regression analyses assessing risk factors associated with major adverse cardiac events (MACE). Age above 60 was associated with higher odds of MACE in the non-African cohort, being 2.82 times higher in the adjusted model. However, no difference in the odds of MACE occurrence was found across age groups in the African cohort. Being female was protective in the non-African cohort, but females in the African cohort had 19.95 times the odds of developing MACE, compared to their male counterparts. Covid vaccination status again showed lower odds of developing MACE in the non-African cohort, but it could not be reported in the African participants. Diabetes was associated with higher odds of developing MACE in the non-African cohort (1.32), but not in the African cohort. Again, acute renal injury was one of the strongest predictors of adverse cardiac outcomes in both cohorts, especially in the African cohort where AKI was associated with 660.55 higher odds of MACE.

Discussion

Our analysis showed important differences comparing the African cohort to the global cohort data. The African cohort had a significantly higher mortality rate and poorer overall access to specialist care.

On the African continent, specialist care was only present in 71% of the hospitals, which was lower than any other continent in the global study. Advanced care, which included echocardiography facilities and catheterization laboratories, was only found in 67% of the hospitals, indicating an under-resourced system. Within the global cohort, the majority of participating sites were of lower-middle or high-income status, whereas the African cohort comprised mostly low or low-middle income groups.

Our findings of higher heart rates on admission, worse prognostic ECG changes, higher rates of AKI, and higher rates of sudden cardiac death among patients hospitalised with COVID-19 in Africa, have noteworthy clinical implications. These findings not only challenge the prevailing notion that COVID-19 was milder among Africans, but also highlight the critical need for healthcare providers and policy planners to prioritize enhancing clinical capacity and critical care resources in regions where patients suffered worse outcomes.

At baseline, the African cohort had slightly higher systolic and diastolic blood pressures, averaging 5 mmHg higher than their non-African counterparts. Prevalence of hypertension has steadily been increasing on the African continent, from 19.7% in 1990 to 30.8% in 2010 [10]. In the African cohort, 48.8% had hypertension as a comorbidity (vs. 46% in the non-African cohort), making it the most common co-morbidity in the African cohort. Hypertension is a major health challenge on the African continent and, while communicable diseases often get a lot of attention, cardiovascular disease is more deadly than cancer, chronic respiratory disease, and diabetes combined. Further, between 2010 and 2019, the African continent had the second highest mortality rate from non-communicable diseases [11, 12]. In-hospital cardiac arrest was also higher at 7.5% compared to 5.1% in the non-African cohort. Interestingly, no clinically meaningful differences were observed in BMI between the two cohort, but the non-African cohort had a higher proportion of obesity (26.8% vs. 13.8% in the African cohort).

Mortality overall was significantly higher in the African cohort at 18.2% (compared with 14.2% in the non-African group). The African cohort has lower ICU admission rates, reflecting a system that had less ICU bed availability, potentially contributing to the higher mortality rate. This was found despite the fact that the case-fatality ratio in Africa for COVID-19 was reported to be lower than on other continents [13]. Our data might indicate that people admitted with COVID-19 tended to be sicker than their non-African counterparts.

Overall, the African cohort had a higher prevalence of AKI (12.7%) compared to the non-African cohort (7.2%). We showed that AKI was highly associated with overall mortality in the African cohort, and that those who had died were 41.7 times as likely to have had AKI compared to survivors. This strong link between AKI and mortality was much weaker in the non-African cohort. The adjusted odds ratio also showed that AKI was a very strong predictor of major adverse cardiovascular events, with an odds ratio of 660 in the African cohort. This strong association was again not reflected in the non-African cohort. Very few studies exist on prevalence of AKI in the African setting versus the global population, and those that have been conducted were small in scale. A systematic review and meta-analysis of chronic kidney disease in sub-Saharan Africa concluded from multiple studies that CKD prevalence was higher, with a reported 15.8 percent prevalence in the African population compared to the global burden of CKD, which stood at 10 percent in [14]. This may suggest a higher burden of renal injury already present in the African population in general. A recent review of the heart diseases in the tropics showed that a genetic mutation protecting individuals from African Trypanosomiasis led to higher rates of kidney disease in the same population [15]. Another explanation may be that patients admitted for COVID-19 in the African setting were generally presenting to healthcare facilities at a more advanced stage of disease. AKI should, however, be seen as a major warning sign and risk factor for mortality and MACE.

T wave changes allude to an abnormality in ventricular repolarisation and have been associated with poorer cardiovascular outcomes [17]. In the African population admitted for COVID-19, T wave changes were more prevalent than in the non-African cohort. A difference in QTc length was also observed when looking at the ECGs between the two cohorts. The risk of adverse cardiovascular events and sudden cardiac deaths were higher in a QTc interval >450 ms in men and >470 ms in women. A study done on abnormal QTc prolongation, as described above, reported that this was an independent predictor of sudden cardiac death and that those with QTc prolongation were at a threefold increase in risk of sudden cardiac death [16]. In the African cohort, ECG findings showed that the population had a significantly longer QTc ratio of 437 ms compared to the global population with 413 ms. This signifies the higher risk of sudden cardiac death. The T wave changes and QTc prolongation could suggest that African patients tended to be admitted with more severe disease.

Strengths and Limitations

A major strength of the present study was our access to complete medical records of all hospital-screened RT-PCR-diagnosed COVID-19 patients. This allowed us to investigate the importance of pre-existing CVD comorbidities on the absolute risk of severe COVID-19 outcomes in an African Cohort and compare this to a non-African cohort.

There are, however, some limitations to our study. As we conducted a sub-analysis of the global study, our sample size was reduced and, therefore, so was the power of our analysis. We were only able to include nine African sites from six African countries and could therefore not make definitive inferences about the African population as a whole. The differences seen between the non-African and African cohorts may not be generalisable to all African countries. Factors that might influence generalizability of our study to the rest of Africa might be variations in patient demographics, healthcare systems, cultural practices, or differences in COVID-19 strains at the time of enrolment.

As by nature of observational study designs, the results prevented us from making definite inferences regarding causality. Given the diverse patient population and ethnic groups included, the p-values, particularly those assessing univariable and bivariable associations, should be interpreted cautiously. In this study, we only recruited hospitalized patients, who were more likely to present with more severe disease.

Conclusion

Although other COVID-19 studies showed that the mortality rate of COVID-19 in Africa was significantly lower than in most WHO regions, this study found a higher overall mortality in hospitalised African patients [18]. Findings such as higher rates of AKI and risks for sudden cardiac death suggest that patients in Africa were admitted with more severe COVID-19 disease that might have influenced a higher in-hospital mortality rate, contributing to the higher overall mortality observed.