Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first emerged in Hubei Province, China in December 2019 (1). Since then, not only has COVID-19 been considered a public health emergency of international concern, but it has been declared a global pandemic (1). COVID-19 is an infectious disease caused by a novel coronavirus that can be transmitted from one infected person to an average of three other people in a population (2). This emerging disease may be epidemiologically similar to severe acute respiratory syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) in the context of its association with environmental and animal factors (3). Authors have suggested individual behavior will be crucial in controlling the spread of COVID-19 where early self-isolation, seeking medical advice remotely unless symptoms were severe, and social distancing was vital (4). Although most infected persons develop mild symptoms, some may develop respiratory failure, arrhythmia, shock, renal failure, cardiovascular injury, hepatic failure, and sometimes death (5). It is now reported that most symptoms occur because of inflammation (5).

At present, there is no approved antiviral treatment; only supportive care may be useful, for example, mechanical ventilation, extracorporeal membrane oxygenation (ECMO) to patients with refractory hypoxemia, or ECMO to patients with refractory hypoxemia (5). The overall Case Fatality Rate (CFR) for COVID-19 worldwide is 3.8% (5). CFR in patients with cardiovascular diseases, diabetes, hypertension, respiratory diseases, and cancers is estimated to be 13.2, 9.2, 8.4, 8.0, and 7.6%, respectively (6). Several studies focusing on factors affecting the mortality of COVID-19 have been published in medical journals (4–6).

Even though most African countries have fragile health systems, the Case Fatality Rate (CFR) for COVID-19 in Africa is surprisingly lower than the global trend (7). Lower positive test rates, a younger population, humid temperatures, and a possibility of a pre-existing immunity are some of the postulated factors associated with this difference since only the most severe cases of COVID-19 get tested and confirmed (7).

Although the SARS-CoV-2 virus predominantly targets the respiratory system, its associated mortality involves multiple organ systems (8). An increasing understanding of the disease throughout the pandemic has reduced hospital mortality rates, especially in well-resourced and high-income countries (9–11). In contrast, hospital mortality remains comparatively high in Africa (12). This has been attributed to the burden of underlying co-morbidities and resource deficits (12). Reports globally have indicated that increasing age (13–15), co-morbidities (cardiovascular diseases and diabetes) (13, 16, 17), and obesity (18, 19) are associated with adverse outcomes. In addition, certain demographic characteristics (14–16, 20) and laboratory parameters (21–23) have as well been associated with the severe form of COVID-19 and increased mortality.

The objective of this study was to identify factors associated with hospital mortality in patients who suffered from COVID-19 at Gulu Regional Referral Hospital in Northern Uganda from March 2020 to October 2021.

The study showed that during the period of study from March 2020, when the COVID-19 was declared a pandemic and Gulu Regional Referral Hospital became a treatment center, 32/664 (4.8%) COVID-19 patients died. Most patients who died were females AOR = 0.220, 95%CI: 0.059–0.827; p = 0.030; had Diabetes mellitus AOR = 9.014, 95%CI: 1.726–47.067; p = 0.010; and with co-morbidities for example cardiovascular diseases, other co-morbidities (hepatitis B, liver failure and HIV and AIDS) AOR = 6.860, 95%CI: 1.309–35.957; p = 0.020 and ages 50 years and above AOR = 2.725, 95%CI: 1.187–6.258; p = 0.018. Similarly, COVID-19 patients who presented with clinical symptoms for example tiredness AOR = 0.059, 95%CI: 0.009–0.371; p < 0.001; general body aches and pains AOR = 0.066, 95%CI: 0.007–0.605; p = 0.020, and loss of speech and movement AOR = 0.134, 95%CI: 0.270–0.660; p = 0.010 died. Nevertheless, most COVID-19 patients treated at the Gulu Regional Referral Hospital were unvaccinated 661/664 (99.5%) against the coronavirus and the recovery rate from the disease was 632/664 (95.2%).

Table 1 shows that most COVID-19 mortality at Gulu Regional Referral Hospital from March 2020 to October 2021 were females 18 (56.3%), age group >50 years 19 (59.4%); no formal education 14 (43.0%), Acholi 25 (78.1%), Catholics 13 (40.6%), Peasant farmers 12 (37.5%) and from Gulu District 15 (46.9%).

In Table 2, factors associated with mortality at bivariate analysis were cough χ² = 10.639; p = 0.000; tiredness χ² = 6.488; p = 0.000; Age (>50 years) χ² = 40.601; p =0.000; no formal education χ² = 39.213; p = 0.000; peasant farmers χ² = 119.828; p = 0.000; general body aches and pains χ² = 75.543; p = 0.000; diarrhea χ² = 10.336; p = 0.001; difficulty in breathing/shortness of breath/chest pain χ² = 96.929; p = 0.000; loss of speech and movement χ² = 113.202; p = 0.001; headache χ² = 9.705; p = 0.002; diabetes mellitus χ² = 51.156; p = 0.000; Other CVDs χ² = 34.819; p = 0.000; hypertension χ² = 10.807; p = 0.000; HIV and AIDS χ² = 6.488; p = 0.011; oxygen saturation at admission (SpO₂) < 80) χ² = 62.074; p = 0.000; duration of hospital stay (0–1 week) 33.235; p = 0.000; Catholics χ² = 28.691; p = 0.000; Gulu district χ² = 21.827; p = 0.040 and females χ² = 7.986; p = 0.005.

In Table 3, the Adjusted Odds Ratios (AOR) of factors associated with mortality among COVID-19 patients treated at Gulu Regional Referral Hospital were; Females AOR = 0.220, 95%CI: 0.059–0.827; p = 0.030; Diabetes mellitus AOR = 9.014, 95%CI: 1.726–47.067; p = 0.010; Tiredness AOR = 0.059, 95%CI: 0.009–0.371; p < 0.001; general body aches and pains AOR = 0.066, 95%CI: 0.007–0.605; p = 0.020; loss of speech and movement AOR = 0.134, 95%CI: 0.270–0.660; p = 0.010; ages 50 years and above AOR = 2.725, 95%CI: 1.187–6.258; p = 0.018 and other co-morbidities AOR = 6.860, 95%CI: 1.309–35.957; p = 0.020.

In Table 4, the female COVID-19 patients were statistically and significantly associated with cardiovascular diseases (χ² = 4.996; p = 0.025) and Chronic Obstructive Pulmonary Diseases (COPDs) χ² = 6.346; p = 0.032, and with close to significant associations with HIV and AIDS (χ² = 3.646; p = 0.056) and Cancers χ² = 3.144; p = 0.076).

The most significant finding from this study was the low mortality rate among COVID-19 patients treated at Gulu Regional Referral Hospital 32/664 (4.8%) (Table 1). This mortality rate was much lower than the average mortality rates reported in Africa (6, 12) but slightly higher than the global average amongst hospitalized patients at 3.8% (6, 24). It may not be apparent to readers to find that several asymptomatic SARS-CoV-2 patients were admitted to the Gulu Regional Referral Hospital COVID-19 treatment Center. It is important to note that at the beginning of the COVID-19 pandemic in March 2020, the Ugandan government policy was that all COVID-19 cases and contacts were mandatorily isolated or admitted to the treatment Center until the SARS-CoV-2 test results became negative. This admission policy which was applied throughout the country on all SARS-CoV-2 test positive was maintained until March 2021, when the government adopted a home-based care approach for managing mild and contact cases of the COVID-19 from home.

We authors suggest the low mortality rates were attributable to the mild nature of the COVID-19 disease and relatively fewer patients admitted to the Gulu Regional Referral Hospital with co-morbidities. This was shown by the clinical presentations in most patients who had oxygen saturation (SpO₂), more than ninety-six (96) at admission, and one-fourth of the patients were asymptomatic (Table 2). Furthermore, the admission of asymptomatic cases may appear strange but at the beginning of the COVID-19 in March 2020 and because of many uncertainties, the Government of Uganda adopted a policy of isolating all cases and contacts to the treatment or general holding centers to reduce contacts of the COVID-19 cases with the general population. This government policy provided additional social protection to the general Ugandan population from cases and contacts of the COVID-19 cases. This may have, in many ways, accounted for the non-exponential spread of the virus in Uganda during the pandemic in 2020 and early 2021.

At the same time, most symptomatic cases were mild, and most presented early to the hospital in the course of the disease (Table 2). In addition, the medical team of the Gulu Regional Referral Hospital CTU must be commended for the remarkable work done over the period in successfully treating over 900 COVID-19 patients in one year and eight months with very low mortality considering the resource scarcity. This could not have been achieved without the dedication and technical expertise of the medical team at the Gulu Regional Referral Hospital CTU. The study, however, identified several risk factors associated with mortality among hospitalized COVID-19 patients in the Ugandan setting. Our study found females, Diabetes mellitus, co-morbidities [cardiovascular diseases, hepatitis B, HIV and AIDS, Chronic Obstructive pulmonary diseases (COPDs), and liver failure], and severe illnesses as shown by symptoms such as tiredness, general body aches, and pains, and loss of speech and movements as the risk factors associated with higher odds of mortality (Table 3). This finding was similarly observed in other studies (6, 13, 16, 17) where co-morbidities and severe symptoms and signs of COVID-19 were associated with mortality. Symptoms such as tiredness, general body aches, and pains, loss of speech and movements were observed in most COVID-19 patients who developed the severe disease and died.

Furthermore, this study found a higher chance of death in COVID-19 patients with Diabetes mellitus (Table 3). Authors have stressed the importance of glycemic control during COVID-19 infections because hyperglycemia may adversely affect pulmonary functions and immune response (25). Studies found that hyperglycemia secondary to Diabetes mellitus leads to immune dysfunction by impairing humoral and cellular functions and the antioxidant systems (26, 27). In addition, studies showed that diabetic patients were more susceptible to nosocomial infections (26, 27). These factors may have contributed to higher chances of death in diabetic patients with COVID-19 (28), which we also observed in our study population.

Also, the age group of 50 years and above 19 (59.4%) were the majority among those who died. It was statistically significant at bivariate analysis in the current study (Age >50 years) χ² = 40.601; p = 0.000 (Table 2) and at the multivariable logistic regression analysis AOR = 2.725, 95%CI: 1.187–6.258; p = 0.018. This finding is consistent with previous studies that showed that the elderly were more likely to suffer from more severe forms of the disease (8, 29, 30). In many studies, the median age of hospitalized patients with a severe form of the COVID-19 ranged from 49 to 56 years (8, 29, 30). This was consistent with reports published globally and comparable to other African studies (12, 31).

Furthermore, we argue that the older age group (>50 years and above) in our study had similarly, a statistically significant association with mortality and increased odds of mortality (Table 3). We note that although all age groups are at risk of contracting COVID-19, older people face a significantly higher risk of developing severe illness if they contract the disease due to physiological changes associated with aging and potential underlying health conditions (32). In addition, there are very few studies that connect the known mechanisms of aging to the pathogenesis of viruses however, we have been persuaded with potential mechanistic explanations as to why COVID-19 advances in some people and not others, especially in older patients, including differences in the immune system, glycation, the epigenome, inflammasome activity, and biological age (32). We argue that the immune system changes in many ways during aging, including a gradual decline in the immune function called immunosenescence, which hampers pathogen recognition, alert signaling, and clearance (32). This is an aging-related phenomenon whereby old or dysfunctional cells arrest their cell cycle and become epigenetically locked into a pro-inflammatory state (32). The aging cells secrete cytokines and chemokines, which appear to promote the severity of the illness due to the COVID-19 (32). In addition, during aging, the other classic immune system change is a chronic increase in systemic inflammation called inflame-aging, which arises from an overactive, yet ineffective alert system that seems to function more (33). These two scenarios have persuaded authors to argue that these phenomena may give plausible explanations for the higher mortality rates of COVID-19 among the elderly population. Furthermore, many studies have confirmed that the elderly and males were at increased risks of mortality due to the diseases (8, 29, 30). This was similarly observed in our study, where the middle-aged persons (>50-year-olds) were the most affected (Table 3).

However, contrary to many studies cited above, most mortalities in our cohort were among females (Table 3). This finding in many ways contrasts with previous results in many countries since the onset of the COVID-19 pandemic in 2019. We have asked questions about this development and still asking more questions about why and how females in Northern Uganda suffered more mortalities from COVID-19 than males (Tables 1, 3). Yet, more males were admitted with the disease than females (Table 3). Also, we found in the statistical analysis that females in Northern Uganda had statistically significant associations with cardiovascular diseases (χ² = 4.996; p = 0.025) and chronic obstructive pulmonary diseases (COPDs) χ² = 6.346; p = 0.032, with close significant associations with HIV and AIDs (χ² = 3.646; p = 0.056) and cancers χ² = 3.144; p = 0.076) (Table 4). Cardiovascular diseases are co-morbidities that lead to severe illness, hospitalization, and death from the COVID-19 (13, 16, 17). Furthermore, we argue that the high prevalence of HIV and AIDs and cancers among females in Northern Uganda may have contributed to the higher mortality rates observed among the female COVID-19 patients in the current study population. Recent studies from Northern Uganda showed a higher prevalence of HIV and AIDS among females in Northern Uganda at 17.1% than males at 8.0% (34). Similarly, most cancer prevalence was higher in Northern Uganda than in the rest of the country, especially breast and cervical cancers which commonly affect females (35). We argue that these four factors (cardiovascular diseases, chronic obstructive pulmonary diseases (COPDs), HIV and AIDs, and cancers) may have singly or collectively contributed to the higher mortality risks of the COVD-19 among females in Northern Uganda. Some scholars and academicians may argue that the higher mortality rates among females seen in this cohort may have resulted from the admission of only severe cases of female COVID-19 patients compared to the males. We found out that the Gulu Regional Referral Hospital practiced unprejudiced admission guidelines, and all patients (males or females) were admitted based on the SARS-CoV-2 positive test results. This has been further confirmed by near equal numbers of the asymptomatic COVID-19 patients (males and females) admitted to the Gulu CTU (Table 2).

In addition, tiredness, cough, diarrhea, difficulty in breathing, shortness of breath, chest pain, headache, general body aches and pains, loss of speech and movement were associated with COVID-19 mortality at Gulu Regional Referral Hospital (Tables 2–4). This finding is supported by many studies that showed that the symptoms and signs were more frequent in SARS cases and cases of death (29–31, 36).

In another study, dyspnea was the main symptom of SARS-CoV-2, a severe COVID-19 disease with more chances of death (36). However, other reported symptoms, such as headache, general body aches, and pains, diarrhea, loss of speech and movements, tiredness, cough, difficulty in breathing, shortness of breath, and chest pain were associated with higher chances of death among this cohort (Tables 2–4). Though, loss of smell and taste, sore throat, rashes on the skin, discoloration of the toes and nails, and runny nose were not statistically associated with death in this current study population (Tables 2, 3). This agrees partly with Patrícia Rezende do Prado et al., who reported dyspnea as the factor associated with COVID-19 death, while cough, fever, and other symptoms were protective factors (36).

Taking these results, it can be concluded that this study analyzed the epidemiological characteristics and mortality risk factors in individuals diagnosed with COVID-19 due to SARS-CoV-2 at Gulu Regional Referral Hospital in Northern Uganda. Our view is that the high-risk groups need special attention, especially the elderly and those with co-morbidities as diabetes mellitus, cancers, HIV and AIDs, cardiovascular diseases, hepatitis B, liver failure, and females with conditions. We, authors suggest special attention to be accorded to COVID-19 patients with dyspnea, general body pains and aches, loss of speech and movement, tiredness, headache, and diarrhea as they seem to develop very severe forms of the disease with many adverse outcomes. In addition, some symptoms that we recorded were more frequent in mild cases of COVID-19 and we propose that they should be elucidated in future studies.

Furthermore, females had more mortality risks in this current study mainly in part due to more comorbidities (cardiovascular diseases, chronic obstructive pulmonary diseases (COPDs), HIV and AIDS, and cancers) (Table 4). We propose that special care be accorded to females who contract COVID-19 to screen out for co-morbidities in the early management phases so that avoidable morbidity and mortality can be made.

This study was a retrospective review of datasets from the COVID-19 medical records at Gulu Regional Referral Hospital from March 2020 to October 2021. The study has limitations on how the Gulu Regional Referral Hospital handled records and record keeping. In addition, vital information, such as weight, height, and BMI of COVID-19 patients, was not recorded due to the emergency handling of the cases at the beginning of the pandemic in March 2020. The missing variables in the Hospital HMIS records got a few files excluded from the participating records for this study. In this, we suggest a need for a prospective or a longitudinal assessment of the COVID-19 cases in the future, ensuring that all data are measured and recorded accordingly.

This data is vital as it is one of the well-documented and completed data for over 664 cases of COVID-19 treated at a regional referral hospital in Uganda. Findings from this study show good clinical practices at the Gulu Regional Referral Hospital despite the logistical challenges faced during the pandemic.

These findings should be cautiously interpreted and generalized to regional referral hospitals in low-resource settings such as Uganda.

The overall Gulu Regional Referral Hospital COVID-19 mortality was 4.8% (32/664). Older age groups (>50 years old), diabetics, females, and those with co-morbidities, severe forms of the disease, and admitted to HDU were significant risk factors associated with hospital mortality. More efforts should be made to offer additional social protection to the most vulnerable population from the general population to avoid preventable morbidity and mortality resulting from COVID-19 in Northern Uganda. Further studies are necessary to understand why females had higher mortality even after adjustments, possibly implying admission selection bias or different accessibility of hospital care for the females which have been clarified by the hospital authorities as equal to everybody irrespective of gender.

EI is a Technical Director at ICAP at the University of Columbia, Sierra Leone; JO is a medical officer and member of the Uganda Medical Association, UMA-Acholi branch, Gulu City, Uganda; CO is a Medical Officer Special Grade, Department of surgery at Gulu Regional Referral Hospital, Gulu City, Uganda; SB is a Medical Officer in the Department of Obstetrics and Gynecology at Gulu Regional Referral Hospital, Gulu City, Uganda; PAp is a Consultant Physician at Gulu Regional Referral Hospital, Gulu City, Uganda; NO is a Lecturer at Gulu University, Faculty of Medicine, Department of Anatomy, Gulu City, Uganda; FO is a senior physician, a public health specialist, and member of Uganda Medical Association, UMA-Acholi branch, Gulu City, Uganda; PL was a senior clinician and public health specialist at St. Mary's Hospital Lacor, Gulu City, Uganda; DA is a senior Consultant Radiologist at the Aga Khan Hospital, Mombasa, Kenya; DO is a public health specialist and District Health officer at Lamwo district local government, Lamwo, Uganda; PAt is a senior Obstetrician and Gynecologist and Medical Superintendent at St. Joseph's Hospital, Kitgum, Uganda; PO is a senior public health specialist and a District Health Office of Amuru district Local Government, Uganda; SO is a senior surgeon and a Medical Superintendent of Ambrosoli Hospital, Kalongo, Agago district local government, Uganda; JO was a senior public health specialist and a District Health Officer of Nwoya district Local Government, Nwoya, Uganda; JL is a Technical Director at the Rhites-N, Acholi, Gulu City, Uganda; DK is a Takemi fellow of Harvard University and a Professor at Gulu University, Faculty of Medicine, Department of Surgery, Gulu City, Uganda.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

The studies involving human participants were reviewed and approved by Gulu Regional Referral Hospital Research and Ethics Committee. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

DK, EI, PL, JNO, JA, JO, and FO participated in designing the study. SB and DK were responsible for data abstraction supervision. EI and DK were responsible for data analysis and interpretation. SB, CO, NA, JO, PAp, PAt, PL, DA, JNO, DO, PO, SO, FD, JA, and DK for writing and revising the manuscript. All authors approved the manuscript.

Most funding for this study was contributions of individual research members of the Uganda Medical Association (UMA) Acholi branch.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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