Morbidity and mortality outcomes of COVID-19 patients with and without hypertension in Lagos, Nigeria: a retrospective cohort study

Background The current pandemic of coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown epidemiological and clinical characteristics that appear worsened in hypertensive patients. The morbidity and mortality of the disease among hypertensive patients in Africa have yet to be well described. Methods In this retrospective cohort study all confirmed COVID-19 adult patients (≥18 years of age) in Lagos between February 27 to July 62,020 were included. Demographic, clinical and outcome data were extracted from electronic medical records of patients admitted at the COVID-19 isolation centers in Lagos. Outcomes included dying, being discharged after recovery or being evacuated/transferred. Descriptive statistics considered proportions, means and medians. The Chi-square and Fisher’s exact tests were used in determining associations between variables. Kaplan–Meier survival analysis and Cox regression were performed to quantify the risk of worse outcomes among hypertensives with COVID-19 and adjust for confounders. P-value ≤0.05 was considered statistically significant. Results A total of 2075 adults with COVID-19 were included in this study. The prevalence of hypertension, the most common comorbidity, was 17.8% followed by diabetes (7.2%) and asthma (2.0%). Overall mortality was 4.2% while mortality among the hypertensives was 13.7%. Severe symptoms and mortality were significantly higher among the hypertensives and survival rates were significantly lowered by the presence of additional comorbidity to 50% from 91% for those with hypertension alone and from 98% for all other patients (P < 0.001). After adjustment for confounders (age and sex), severe COVID-19and death were higher for hypertensives {severe/critical illness: HR = 2.41, P = 0.001, 95%CI = 1.4–4.0, death: HR = 2.30, P = 0.001, 95%CI = 1.2–4.6, for those with hypertension only} {severe/critical illness: HR = 3.76, P = 0.001, 95%CI = 2.1–6.4, death: crude HR = 6.63, P = 0.001, 95%CI = 3.4–1.6, for those with additional comorbidities}. Hypertension posed an increased risk of severe morbidity (approx. 4-fold) and death (approx. 7-fold) from COVID-19 in the presence of multiple comorbidities. Conclusion The potential morbidity and mortality risks of hypertension especially with other comorbidities in COVID-19 could help direct efforts towards prevention and prognostication. This provides the rationale for improving preventive caution for people with hypertension and other comorbidities and prioritizing them for future antiviral interventions. Supplementary Information The online version contains supplementary material available at 10.1186/s41256-021-00210-6.


Introduction
Globally, there is an ongoing pandemic of Coronavirus disease (COVID- 19), an infectious disease caused by a newly discovered coronavirus called the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [1]. The infection fatality rate (IFR) of this disease has been estimated at a range of around 0.5-1% [2,3], with higher rates among those aged 60 or older [4]. The majority of cases of COVID-19 experience mild to moderate respiratory illness and recover with supportive care. Serious illness is more likely with the elderly and those with underlying comorbidities like cardiovascular disease, chronic respiratory disease, diabetes, and cancer [5,6].
Much earlier in a study in China, where the COVID-19 was first reported, it was found that 48% of patients had a comorbidity, with hypertension being the most prevalent (30%), followed by diabetes (19%) and coronary heart disease (8%) [7]. In a study from Italy, it was reported that COVID-19 deaths were mostly among people with comorbidities (99%), the majority of these were hypertensive (76.5%) [8,9]. Studies have shown that hypertension imposes on those who suffer from it an increased risk of getting infected with COVID-19, experiencing worse symptomatology and complications and a 2-fold risk of dying from the infection. Hypertension was reported to have had a hazard ratio (HR) of 1.70 [95% confidence interval (CI) 0.92-3.14] to 3.05 (95% CI 1.57-5.92) for mortality in some unadjusted epidemiological studies in China [7,10].
High blood pressure is common among people over 60 years of age, the prevalence being nearly as high as two-thirds of this population. Long-term ill health and aging lead to a weakened immune system increasing the susceptibility of people with chronic illnesses to coronavirus infection. Along with the increased risk of infection and worsened outcomes among hypertensives, there is a growing concern that some medications used in the treatment may influence mortality in patients with COVID-19 [11,12]. These medications such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), cause a rise in blood levels of ACE2 [13]. The theory is that the COVID-19 virus infects human cells by forming a bond with ACE2, a requirement for viral entry into host cells [ 14], thus increasing individual susceptibility to infection and propagation of the virus [15]. Several other studies have however found no association between the use of these drugs and the severity of COVID-19 [16].
The epidemiological and clinical characteristics of patients with COVID-19 in terms of the detailed clinical course of illness, risk factors for mortality its spread and even its treatment are still being studied and documented. Understanding the potential effect of hypertension on the risk of mortality from COVID-19 could help clinicians to identify and characterize patients' prognoses at an early stage so as to provide timely intervention. This study, hence, was aimed at assessing the hypothesis that hypertension worsens the morbidity and mortality outcomes of confirmed COVID-19 patients.

Study subjects and design
This retrospective observational study was conducted using data collected from 2075 adult COVID-19 patients (≥18 years of age) consecutively admitted across ten designated isolation and treatment centers and hospitals, with reverse transcription polymerase chain reaction (RT-PCR) test results confirming COVID-19. These patients received care at hospitals or isolation and treatment centers dedicated solely to the treatment of COVID-19, in Lagos, Nigeria from 27 February to 6 July 2020. This study was conducted to include only patients who had been admitted to care at the isolation centers as at the commencement of the study on 6 July 2020. The strategy at that phase of the outbreak was containment, in the attempt to reduce community spread. Therefore, all identified positive cases were admitted to the isolation centers.

Data collection
Patients' data collected on admission included sociodemographic data, details of their medical history and comorbidities, symptoms, severity of symptoms on admission, clinical outcomes and status at the end of the study (recovery, transfer/evacuation or death). Data was collected at the hospital/isolation center using the electronic medical records created specifically for the Lagos State COVID-19 response. Data extracted for the purpose of this study was completely anonymized.

Description of variables
Sociodemographic data included the age, sex, health facility and epidemiological identifier. Details of their medical history were limited to the reported comorbidities. The patients' presenting symptoms were recorded and the severity of symptoms on admission was categorized as mild, moderate, severe, or critical. Asymptomatic patients were categorized as mild, while cases with cough, fever, respiratory rate < 30 breaths per minute and peripheral capillary oxygen saturation (spO2) > 90% were categorized as moderate. Patients who had grunting respiration, respiratory rate > 30 breaths per minute and spO2 < 90% on admission were classified as severe. The patients categorized as critical cases were those in respiratory failure [17].

History of hypertension
The data on comorbidities including hypertension was based on the patient's report of the previous diagnosis prior to the infection with SARS-CoV-2. Those who required antihypertensive medication during hospitalization with no prior prescription were treated with antihypertensives, while those who had been on medications prior to admission, were treated with their usual prescribed medication. These patients were not stratified according to whether or not they were receiving antihypertensive while on admission.

Outcomes
The major outcomes after admission were discharged following recovery or death. Patients still receiving care as of July 6, 2020, who had neither been discharged, transferred nor had died were classified as 'yet undetermined'. Details of follow-up of patients after leaving the hospital or isolation center were not included in this dataset.

Data management and analysis
Data were analyzed using the SPSS version 20 and presented in frequencies and proportions. Descriptive statistics considered means ± standard deviation (SD) for continuous variables that were normally distributed and median ± interquartile range (IQR) for those identified as skewed. Bivariate analyses (Chi-square test (trend and non-trend) and the Fisher's exact test as required) were used in determining associations between variables. Kaplan-Meier survival analysis was done to compare mortality between hypertensives and patients without hypertension. The Cox proportional hazards model was used to quantify the risk of worse outcomes among hypertensives with COVID-19 and adjust for the effect of confounders. p-value < 0.05 was considered statistically significant.

Results
The patients were predominantly less than 40 years of age and about a tenth of them were over 60 years of age. The median age of the patients was 40 (IQR = 32-50) years, and the oldest was 98 years of age. The male to female ratio was 2:1. About a quarter (23.3%) of the patients had at least one comorbidity including hypertension, other cardiovascular (CVS) diseases, diabetes, asthma, HIV, Hepatitis B, cancer, renal disease, sickle cell disease, tuberculosis and other lung diseases, while 17.8% had hypertension alone. Over 50% of them were asymptomatic or mildly symptomatic at the time of admission. Severity on admission ranged between mild to critical and over half of them (56.9%) had mild symptoms; about 2% of them were in critical condition on admission and at the end of the study period, there was about 4% mortality (Table 1).
When the groups were stratified by the presence or absence of hypertension it was found that hypertensive cohorts were significantly older (55.68 ± 12.9 vs 38.68 ± 11.5) and there was an increasing proportion of hypertensives across the age groups (p for trend = 0.001). Both cohorts were proportionately similar in sex distribution. A significant proportion of the hypertensive cohort suffered the worse forms of COVID-19; severe (14.4% vs 3.2%) and critical (6.8% vs 1.0%), compared to the nohypertension cohort (p for trend < 0.001). The time till the endpoint of admission irrespective of outcome was significantly different between both cohorts. The hypertensive group experienced a relatively shorter time on admission before the final outcome, with a median duration of admission shorter for hypertensives than for , respectively). The disease outcome was significantly different between the cohorts; 13.7% of those who were hypertensive died compared to 2.2% of patients without hypertension (p = 0.001) ( Table 2).
There was a statistically significant difference in mortality and survival among hypertensive patients who had hypertension only and those hypertensives with multiple comorbidities. Similarly, the time till the endpoint was significantly different between those who died and those who survived. A higher proportion of hypertensives that had at least one other comorbidity died (27.5%) compared to those who had hypertension alone (8.1%) (P < 0.001). The proportion of hypertensives who died within the first 14 days (21.0%) was higher compared to those whose deaths occurred beyond 2 weeks (2.0%), implying that that death among hypertensives occurred mostly within the first 2 weeks of admission (P < 0.001). A greater proportion (26.4%) of the hypertensives with other comorbidities died within the first weeks of admission compared to those who had hypertension only (16.2%) (P = 0.086), ( Table 3).
The Kaplan-Meier estimates indicated that the COVID-19 survival rate for the patients without hypertension was 94, 91% for patients with hypertension only and 50% for those with hypertension with other comorbidities. The log-rank test indicated that there was a statistically significant difference between the three survival rates (p < 0.001). The unadjusted hazard ratio (HR) indicated that in the risk of death there was a 4-fold increase among hypertensives and a 13-fold increase among hypertensives with additional comorbidities compared to those who were not hypertensive. Collectively, these results suggest that patients in the hypertensive group were less likely to survive (Fig. 1).

Discussion
The coronavirus disease (COVID-19) is relatively new and hence understudied. However, the available data has identified the importance of hypertension in the morbidity and mortality picture of the disease. The age and sex distribution found in this study are similar to the findings of a meta-analysis of the clinical characteristics and comorbidities among 1786 coronavirus patients with a median age of 41 years and a male to female ratio of 1.4: 1 [18]. The same study found a hypertension prevalence of 15.8%, lower than was found in this study (17.8%).
Another study in Wuhan, China found almost a 2-fold higher prevalence [19]. However, in all three studies, the spectrum of comorbidities was the same and hypertension was the most common comorbidity. Reports of increased incidence and severity of COVID-19 have stated that the severity is skewed towards the elderly population who have a higher prevalence of hypertension and are apparently at particular risk of being infected with the SARS-CoV-2 virus [20]. This study found that severity is related to hypertension and that the hypertensive group also experienced a significantly shorter time on admission before the final outcome. This could be explained by the significantly higher proportion of worse disease outcomes (death) among the hypertensives. While there is an overrepresentation of hypertension among hospitalized and critically ill COVID-19 patients, expert reports have expressed uncertainty whether hypertension is more causal or if other confounders such as age and other comorbidities associated with hypertension augment its role [21]. In the current study, adjustment for confounders meant that patients with hypertension were at a greater risk of increased severity and death from COVID-19 as was seen in a much smaller study in Wuhan, China [22]. Meanwhile, even though it was found in another study that there was a significant two-fold higher risk of mortality due to hypertension when compared with patients with no hypertension [16], the current study found in addition, a significant difference in the potential of dying or surviving among hypertensives to be augmented in the presence of at least one additional comorbidity.
To corroborate the finding of this study that hypertension posed a greater risk of death among COVID-19 patients, a study in China reported that chronic hypertension was more frequent among COVID-19 patients who died compared with those who recovered [23]. Also similar to the finding that hypertension had an HR of 3.70 (crude) for death in 369 patients admitted for COVID-19 another study found an HR of 3.05 in 191 hypertensive patients with COVID-19 [19]. Another study, however, found that hypertension has a lower HR of 1.70 for death in 201 patients with COVID-19 [12]. The implications of the findings of this study are that hypertension is disproportionately more frequently found among COVID-19 patients than other comorbidities and that severe COVID-19 disease and a relatively shorter time to death are associated with being hypertensive, especially in patients who have other comorbidities. This study was limited because data on hypertensive medication were not included in the dataset. It would have been useful to consider this because there is currently limited clinical evidence of the influence of antihypertensive medication on the prognosis of COVID-19. Nevertheless, continuing a patient's usual antihypertensive treatment is recommended [24]. Also, the patients in this study were only studied till the end of their stay in the COVID-19 isolation ward. It would have been interesting and beneficial to study the patient beyond the time of discharge.

Conclusion
The role of other comorbidities worsening the severity and outcomes of COVID-19 has been highlighted in this study. This recognition of the potential morbidity and mortality risks of hypertension especially with other comorbidities in COVID-19 could help direct efforts towards prevention and prognostication. This provides the rationale for improving preventive caution for people with hypertension and other comorbidities and prioritizing them for future antiviral interventions. Studies that demonstrate causation would be beneficial as understanding about COVID-19 improvements. Until more information is available to guide the treatment and management of COVID-19 patients with hypertension, it is important to control blood pressure according to current clinical practice guidelines.
Additional file 1: Table S1. Cox regression for risk of death among patients with hypertension compared with patients without hypertension. (adjusting for Age, sex, diabetes mellitus, renal diseases, HIV/HBV co-infection, asthma, other cardiovascular diseases and cancer). Table S2. Distribution of comorbidities in patients with and without hypertension.