key: cord-0983101-jgbs0w3s
authors: Sibhat, M. M.; Getnet, M. T.; Chane, W. Z.; Gebeyehu, K. T.; Habtamu, A. S.; Mezgebu, T. A.; Asmare, H. B.; Ambaw, M. M.; Getahun, E. M.
title: Determinants of mortality among COVID-19 patients with diabetes mellitus in Addis Ababa, Ethiopia, 2022: An unmatched case-control study
date: 2022-04-05
journal: nan
DOI: 10.1101/2022.04.04.22273344
sha: 79273e1aa4f64a8ce3f182617defca0870768f13
doc_id: 983101
cord_uid: jgbs0w3s

Introduction: COVID-19 remains one of the leading causes of death seeking global public health attention. Diabetes mellitus is associated with severity and lethal outcomes up to death independent of other comorbidities. Nevertheless, information regarding the determinant factors that contributed to the increased mortality among diabetic COVID-19 patients is limited. Thus, this study aimed at identifying the determinants of mortality among COVID-19 infected diabetic patients. Methods: An unmatched case-control study was conducted on 340 randomly selected patients by reviewing patient records. Data were collected using a structured extraction checklist, entered into Epi data V-4.4.2.2, and analyzed using SPSS V-25. Then, binary logistic regression was used for bivariate and multivariable analysis. Finally, an adjusted odds ratio with 95% CI and a p-value of less than 0.05 was used to determine the strength of association and the presence of a statistical significance consecutively. Results: The study was conducted on 340 COVID-19 patients (114 case and 226 controls). Patient age (AOR=4.90; 95% CI: 2.13, 11.50), severity of COVID-19 disease (AOR=4.95; 95% CI: 2.20, 11.30), obesity (AOR=7.78; 95% CI: 4.05, 14.90), hypertension (AOR=5.01; 95% CI: 2.40, 10.60), anemia at presentation (AOR=2.93; 95% CI: 1.29, 6.65), and AKI after hospital admission (AOR=2.80; 95% CI: 1.39, 5.64) had statistically significant association with increased mortality of diabetic patients with COVID-19 infection. Conversely, presence of RVI co-infection was found to be protective against mortality (AOR=0.35; 95% CI: 0.13, 0.90). Conclusion: Patient age (<65years), COVID-19 disease severity (mild and moderate illness), presence of hypertension, obesity, anemia at admission, and AKI on admission was independently associated with increased mortality of diabetic COVID-19 patients. Contrariwise, the presence of RVI co-infection was found to be protective against patient death. Consequently, COVID-19 patients with diabetes demand untiring efforts, and focused management of the identified factors will substantially worth the survival of diabetic patients infected with COVID-19.

The coronavirus disease 2019 (COVID- 19) pandemic, which is caused by a highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of morbidities and mortalities worldwide (1) (2) (3) . COVID-19 has drawn drastic attention and poses a healthcare threat globally. The devastating effects of the COVID-19 pandemic were highly associated with chronic medical conditions, mainly diabetes mellitus (DM). The estimated global prevalence of diabetes in 2021 was 10.5% (537 million), a 16% (74 million) rise since 2019. The international diabetes federation (IDF) projected that the number of diabetic patients will increase to 11.3% (643 million) by 2030 and 12.2% (783 million) by 2045 (4) . The prevalence of diabetes among COVID-19 patients has been estimated up to 31% (5) .

Diabetes mellitus (DM) is one of the most frequent comorbidities that occurred in patients with coronavirus disease 2019 and is associated with severity and lethal outcomes such as intensive care unit (ICU) admission, invasive ventilation, and death (6) (7) (8) independent of other comorbidities. Furthermore, the presence of typical complications of diabetes mellitus (cardiovascular disease, heart failure, and chronic kidney disease) increases COVID-19 mortality (6, (9) (10) (11) . It has been observed that 1.5% of in-hospital deaths related to COVID-19 occurred in patients with type 1 DM and 31.4% in patients with type 2 DM (9) . Deaths in people with diabetes have more than doubled during the COVID-19 epidemic (9) .

Another study indicates that diabetic patients have almost four times the risk of severe disease and death from COVID-19 (12) . The presence of DM is frequently associated with worse outcomes even among patients presented with mild or no COVID-19 symptoms (13) .

Consequently, with this increased mortality and other public health impacts, numerous reports have been evolved worldwide on the link between COVID-19 and DM, and diabetes management during the COVID-19 pandemic (14) . Predicting worse patient outcomes using poor glycemic control is not an innovation. For instance, fasting blood sugar level was identified as an independent predictor of severity during the 2009 H1N1 influenza pandemic (15) . Due to the deregulation of the immune system, diabetic patients are highly vulnerable to infectious diseases. Irrespective of the previous history of DM, hyperglycemia leads to impaired immune function and increased susceptibility to infections, and has been associated with an increased patient death (16, 17) .

With the high prevalence of diabetes and its devastating public health consequences, it is demanding to understand the unique aspects of COVID-19 infection in people with diabetes.

To control the pandemic, it can be even more significant these days and in the future due to the changes in the lifestyle and healthcare service delivery system. Furthermore, recent studies indicated the need for special considerations in diabetes management among COVID-19 patients (18) . Besides, people with diabetes are more concerned about becoming infected with COVID-19 than people without diabetes (19) . Thus, this study aimed at identifying the determinants of mortality among COVID-19 infected diabetic patients.

An unmatched case-control study was employed by reviewing charts of patients admitted to Addis Ababa COVID-19 care centers from September 2020 to August 2021. Addis Ababa, the capital city of Ethiopia, has three main COVID-19 treatment centers. Millennium COVID-19 care center is the largest and best equipped of all those centers, with a capacity of 1040 patient beds and more than 40 intensive care unit beds. The source population was all COVID-19 patients who died in the center. Patients who died during the specified period were considered the study population. Cases were COVID-19 diagnosed DM patients who died while admitted to the center, whereas controls were COVID-19 patients without a diagnosis of DM and who died in the COVID-19 care center. Medical records without HgA1c and patients with stress hyperglycemia without elevated HgA1c were excluded from the study.

The sample size was estimated using the double population proportion formula by the statcalc program of Epi info software, considering unmatched case-control study assumptions. The parameters used include 95% confidence level, 80% study power, control to case ratio of two, percentage of controls exposed=60%, and an odds ratio of 2.04 (20) that yields 341.

Afterward, 114 cases (diabetic patients) and 228 controls (non-diabetic patients) were incorporated. Cases were selected consecutively, and two respective controls next to the sampled case were included randomly with replacement after confining all death records in their order of medical record number (MRN).

Initially, the lists of one-year death records were sorted out. Among those, medical records of diabetic and non-diabetic patients were further confined separately using a computergenerated system and arranged orderly using their medical record number (MRN). Afterward, data collection was conducted using a pretested and structured extraction checklist from medical records of COVID-19 patients who were died in the treatment center. A one-year data (patient records from September 2020 to August 2021) was used to conduct the study.

The extraction checklist comprised socio-demographic characteristics, disease severity, comorbidities, baseline vital signs, and laboratory findings, as well as COVID-19 management and complication-related questions. Four data collectors and two supervisors were recruited and trained for half-day about the data collection requirements. The completeness of the collected data was cross-checked daily.

After completion of data collection, data were coded and entered into Epi data manager version 4.4.2.2. Then, it was exported to SPSS software version 25 for analysis.

Crosstabulation and explorative analysis was done for data cleaning and to determine the data distribution. Categorical data were described using frequency and percent, and mean with standard deviation (SD) or median with interquartile range (IQR) were applied to describe continuous data based on data distribution. Afterward, bivariate and multivariable analyses were run using the binary logistic regression model. After bivariate analysis, a p-value of 0.25 or less was considered to recruit candidate variables for the multivariate model. The model fitness test was checked using Hosmer and Lemeshow test (p=0.302). Finally, an adjusted odds ratio with a 95% confidence interval was used to report the strength of association, and statistical significance was declared at a p-value of less than 0.05.

It is not applicable for this study since patients were not directly involved. The study was conducted via patient chart review without contacting patients.

Ethical clearance was obtained from Saint Paul's Millennium Medical College institutional review board (IRB). The IRB waived such that the study can be conducted via patient chart review. Then, the chief executive director and the clinical director were communicated about the purpose of the study, and permission was obtained on behalf of patients to access the data.

The study was conducted based on the declaration of Helsinki. Anonymity and confidentiality were attained via coding and aggregate reporting, with no individual patient identifiers collected in the extraction process.

This case-control study was conducted on 114 cases (diabetic patients) and 226 controls (non-diabetic patients) that were died due to COVID-19 diseases. About 37.6% of the study subjects were female, of which 27.3% were diabetics. The mean age was 65 years (SD=13.18) among cases and 68.7 years (SD=13.5) among controls ranging from 30 to 94 years. Half of the cases were above the age of 65years, and it was above 62 years among the controls (Table 1) . . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 5, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 5, 2022. 

After data description, inferential analysis was conducted using the binary logistic regression model. Bivariate analysis was done to determine the association of each explanatory variable to the outcome variable. Then, the multi-collinearity chesk was done, and some variables such as antihypertensive use and pulse rate at baseline were excluded since they have a variance inflation factor (VIF) score of greater than ten. Then, variables that fulfilled the test assumptions and had a p-value of less than 0. 25 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 5, 2022 The mortality rate is even higher among diabetic patients (21) . Several studies conducted in the COVID-19 era also reported a strong association between DM and COVID-19 mortality.

Nevertheless, information regarding the determinants factors that lead to the increased mortality among diabetic COVID-19 patients is limited. Thus, this study aimed at identifying the determinants of mortality among COVID-19 infected diabetic patients.

The odds of death among diabetic patients under 65 years of age were almost five-fold [(AOR=4.90; 95% CI: 2.13, 11.50), p=<0.001] higher than non-diabetic patients in the same age group did. Previous studies showed the association of COVID-19 patients with advanced . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273344 doi: medRxiv preprint age (>65 years). This finding is evidenced in the general population (diabetic and nondiabetic patients) (22, 23) . Conversely, the current study reported that patients younger than 65 years are also at a higher risk of death than those without DM. This association might be rationalized by the immune suppression frequently noted in patients with DM than in the general population. This finding implies the need for similar concerns for all diabetic COVID-19 patients irrespective of age strata.

The study finding also revealed that diabetic patients who were admitted with mild and moderate COVID-19 disease had five times [(AOR=4.95; 95% CI: 2.20, 11.30), p=<0.001] increased chance of mortality compared with non-diabetic patients with the same disease severity. Even though not specific to patients with DM, existing evidence documented high mortality among patients who presented with severe COVID-19 illness (23) . Equally, the current study notified that having DM would raise the risk of mortality even among those admitted with mild and moderate COVID-19 illness. The scientific reason might be that SARS-COV-2 infection may worsen the disease for people with diabetes by suppressing β cell function and exacerbating acute metabolic complications (24 (7, 9, 25, 26) . The pathologic link between mortality of diabetes COVID-19 patients and obesity can be multifactorial. First, obesity can make oxygenation and ventilation more difficult by compromising lung capacity and reserve (27) . It is also documented that obesity is associated with impaired immune function (28, 29) .

Likewise, the odds of death were five times higher among diabetic patients with hypertension comorbidity than those without hypertension [(AOR= 5.01; 95% CI: 2.40, 10.60), p<0.001].

Former studies conducted in China and Nigeria also showed the association of hypertension with increased mortality of COVID-19 patients (30) (31) (32) (33) . The exact pathologic link between hypertension and COVID-19 is unclear yet. Nevertheless, the literature hypothesized a higher affinity of SARS-COV-2 to the angiotensin-converting-enzyme receptor-2 (ACE2), which will accelerate viral binding to the epithelial cells of vital organs such as the lung and cardiac . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273344 doi: medRxiv preprint (34, 35) , resulting in cytokine accumulation in these organs. This increased cytokine concentration (cytokine storm) can lead to acute lung injury, ARDS, and multiple organ failure (36) . Besides, cytokine storm is highly linked with the progression of hypertension (37) which could result in severe inflammatory responses and complications.

Diabetic patients who had anemia at presentation (Hgb<12g/dl) were at advanced risk of mortality compared to those with normal hemoglobin levels [(AOR=2.93; 95% CI: 1.29, 6.65), p=0.010). A prospective study conducted on 1257 Iranian COVID-19 patients reported similar findings (38) . However, studies conducted in China (39) and Italy (40) (44), and a meta-analysis (45) . This scientific link may be explained by the pathophysiologic mechanism of COVID-19 disease itself. The SARS-COV-2 may enter the ACE2 receptor (ACE2 is highly prevalent in the kidney) and cause direct injury to the kidney, increased proinflammatory viral cytokines, and thrombotic events. On the other hand, AKI is highly prevalent in critical patients with hemodynamic instabilities, severe ARDS (requiring high PEEP levels of ventilation), decreased cardiac output, hypervolemia, sepsis, and those who received nephrotoxic drugs (44) . All those conditions are associated with more severe illness and higher mortality. Conversely, poorly controlled diabetes mellitus is also associated with kidney injury (nephropathy), which will worsen patient outcomes. (46) . On the contrary, several studies declared that no significant association exists between these variables (47) (48) (49) . All RVI . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 5, 2022. patients in this cohort were on HAART. Most of the ART regimens were hypothesized to have a therapeutic effect on COVID-19 infection (50) , and some (such as remdesivir) were partially recommended as supportive management modalities for patients with COVID-19 disease (51). Even though remdesivir and other ART drugs are no more recommended for COVID-19 patients by WHO, they were still under investigation in clinical trials and in use by some clinical set-ups. Hence, this might be the possible reason for a better outcome. The variation in the effect and COVID-19 outcome among RVI patients could be due to the variation in the management guideline.

This study has certain limitations. First, it would be nice to run a stratified analysis for each type of DM and differentiate among newly versus known diabetic patients, which is not the case in our study. It did not enable us to see the possible variation in the mortality and factors affecting it among the two groups (newly diagnosed and chronic DM). Second, the retrospective nature of the study would delimit the strength of evidence drawn from the study since data were not collected primarily for research purposes.

This case-control study identified pertinent factors including socio-demographic, disease severity, comorbidities, and complications of COVID-19 that can determine the mortality among COVID-19 infected diabetic patients. Patient age (<65years), COVID-19 disease severity (mild and moderate illness), presence of hypertension, obesity, anemia at admission, and AKI on hospital admission was independently associated with increased mortality of COVID-19 patients with DM. In addition, RVI co-infection was found to be protective against patient death. Consequently, COVID-19 patients with DM require untiring efforts irrespective of age specification and disease severity at admission. Besides, focused management of hypertension and other identified factors will significantly worth the survival of diabetic patients infected with COVID-19. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

New England journal of medicine. 2020. 2. World Health Organization

COVID-19 and Diabetes Mellitus: The Link and Clinical Implications

IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045

Prevalence and impact of diabetes in hospitalized COVID 19 patients: A systematic review and meta analysis

Clinical characteristics and risk factors for mortality of COVID-19 patients with diabetes in Wuhan, China: a twocenter, retrospective study

Body mass index and risk for COVID-19-related hospitalization, intensive care unit admission, invasive mechanical ventilation, and death-United States

Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis

Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and metaanalysis

Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes

Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

COVID-19 vaccination in patients with diabetes mellitus: Current concepts, uncertainties and challenges

Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations

Fasting plasma glucose is an independent predictor for severity of H1N1 pneumonia

Relationship between hyperglycemia and infection in critically ill patients

Electronic laboratory reporting for the infectious diseases physician and clinical microbiologist

Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes & metabolic syndrome

Perceived risk, behavior changes and Health-related outcomes during COVID-19 pandemic: Findingsamong adults with and without diabetesin China

Risk of mortality among inpatients with COVID 19 and type 2 diabetes: National data from Kuwait

<COVID-19 diabetes and death.pdf>

COVID-19 and aging: Identifying measures of severity

COVID-19 disease severity and associated factors among Ethiopian patients: A study of the millennium COVID-19 care center

The lancet Diabetes & endocrinology

Impact of obesity on hospitalizations and mortality, due to COVID-19: A systematic review. Obesity research & clinical practice

Diabesity Associates with Poor COVID-19 Outcomes among Hospitalized Patients

High prevalence of obesity in severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) requiring invasive mechanical ventilation

Changes in nutritional status impact immune cell metabolism and function

T lymphopaenia in relation to body mass index and TNF α in human obesity: adequate weight reduction can be corrective

Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study

COVID-19 and hypertension: What we know and don't know

The Association of Hypertension With the Severity of and Mortality From the COVID-19 in the Early Stage of the Epidemic in Wuhan, China: A Multicenter Retrospective Cohort Study. Frontiers in medicine

Hypertension as an independent risk factor for severity and mortality in patients with COVID-19: a retrospective study

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The lancet respiratory medicine

Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide

Anemia predicts poor outcomes of COVID-19 in hospitalized patients: a prospective study in Iran

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine

Early predictors of clinical deterioration in a cohort of 239 patients hospitalized for Covid-19 infection in Lombardy

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic

Acute kidney injury in COVID-19 patients: an inner city hospital experience and policy implications

Severe acute kidney injury in COVID-19 patients is associated with in-hospital mortality

Acute kidney injury in critically ill patients with COVID-19. Intensive care medicine

Acute kidney injury is associated with severe infection and fatality in patients with COVID-19: A systematic review and metaanalysis of 40 studies and 24,527 patients

HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform. The lancet HIV

Clinical characteristics, risk factors, and incidence of symptomatic coronavirus disease 2019 in a large cohort of adults living with HIV: a single-center, prospective observational study

High HIV prevalence in an early cohort of hospital admissions with COVID-19 in Cape Town, South Africa. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde

Clinical Features and Outcomes of Patients With Human Immunodeficiency Virus With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Effectiveness of Remdesivir, Lopinavir/Ritonavir, and Favipiravir for COVID-19 Treatment: A Systematic Review