Exploring the Clinical Features, Management of Hypertension, and Predictors of Severity in Hospitalized Hypertensive COVID-19 Patients

Background Hypertension significantly contributes to the severity, prolonged hospitalization, the need for intensive care, and mortality of COVID-19 patients. However, the data is still evolving. This study investigated the predictors of severity among hypertensive COVID-19 patients. Methodology This cohort study included 333 hospitalized hypertensive COVID-19 patients at the Indus Hospital, Karachi, Pakistan, from April 2021 to October 2021. The study evaluated the clinical features, antihypertensive therapy, and predictors of severity. A multivariable binary logistic regression model was used to determine severity predictors using IBM SPSS Statistics for Windows, Version 27.0 (Released 2020; IBM Corp., Armonk, NY, USA). Results The majority of hypertensive COVID-19 patients were females (54.7%), aged <65 years (55.8%), and coexisted with diabetes mellitus (56.5%). The independent predictors of severity were male (aOR 2.65, 95% CI, 1.08-6.51; p < 0.033), fever (aOR 3.52, 95% CI, 1.24-9.92; p = 0.017), shortness of breath (aOR 4.49, 95% CI, 1.73-11.63; p = 0.002), oxygen saturation (<90%) (aOR 87.39, 95% CI, 19.15-398.75; p < 0.001), and D-dimer (>0.5 mcg/ml) (aOR 3.03, 95% CI, 1.19-7.71; p = 0.020). Conclusions Our study concluded that males with fever before admission, shortness of breath, lower oxygen saturation, and elevated D-dimer are the predictors of severity among hypertensive COVID-19 patients.


Introduction
COVID-19 was discovered when some patients with pneumonia of unidentified origin were reported in Wuhan, China in late December 2019 [1].In Pakistan, the first laboratory-confirmed case of SARS-CoV-2, subsequently referred to as COVID-19, was reported on February 26, 2020.Following this, an appreciable number of positive cases were reported throughout the country in successive waves.As of August 2, 2023, Pakistan has recorded over 1.58 million positive cases and 30,000 deaths [2].
Pakistan has grappled with five waves of COVID-19, and each wave is driven by different SARS-CoV-2 variants, with a notable difference in the severity of COVID-19 observed during these waves [3].Despite initiating vaccination campaigns in February 2021, many people were hesitant to get vaccinated against SARS-CoV-2 [4], which was influenced by their knowledge and beliefs toward COVID-19 since its outbreak in the region [5].Consequently, vaccination rates remained low in the country, and in 2021, the country underwent the third and fourth waves of SARS-CoV-2, which were characterized by more transmissible SARS-CoV-2 variants such as Delta and Omicron.The Delta variant led to high hospitalization rates, severe illness, increased admission to intensive care units, and fatalities in the country [6].
According to the data from the World Health Organization, approximately 29% of Pakistani people died due to cardiovascular diseases [7].Research indicates that patients with comorbid illnesses may experience

Baseline clinical characteristics of patients
The clinical signs and symptoms of COVID-19 patients are presented in

Baseline laboratory characteristics of patients
The baseline laboratory characteristics of the patients are summarized in Table 3.The result shows that the median total leucocyte count was 11.3 (7.5-15.3)× 10 9 /L, slightly above the normal range's upper limit, and the median percentage of neutrophils was very high, 84.3% (77.6-90.6%),which indicates the immune response to the viral infection or a severe inflammatory response to the virus.In contrast, the median percentage of lymphocytes was 9.2% (4.8-14.5%),and eosinophils 0.1% (0.0-0.3%) were lower than normal.
In terms of blood sugar indicator, the median baseline random blood glucose level and median HbA1C were significantly higher than the normal ranges, 191 (138-278) mg/dL and 6.8% (6.0-8.8%),respectively.These levels indicate poor control of blood glucose levels.

Prescribed treatment during the hospital stay
Antihypertensive therapy for COVID-19 patients with HTN is described in  Based on the antihypertensive treatment scheme, around two-fifths of patients (42.0%) received monotherapy, followed by dual antihypertensive therapy (24.1%), and multiple antihypertensive therapies (15.0%).

Discussion
The COVID-19 pandemic is producing a wide-ranging impact on patients with comorbidities, including HTN.Patients without any history of cardiovascular problems also face palpitations and chest pain complaints after being infected with COVID-19 [15].To better understand the disease in hypertensive patients, it is essential to determine the predictors of severe illness among hypertensive COVID-19 patients.By doing so, the relevant resources can be appropriately allocated to patients with a high-severity risk and for effective disease management.
While considering the clinical endpoint of the disease, the association between demographic characteristics and the severity of COVID-19 patients with HTN was determined.The results did not show any difference in the severity of COVID-19 patients with HTN based on gender, median age, smoking status, COVID-19 vaccine status, and comorbidities.These findings are consistent with a previous study conducted in China [16], which showed no significant association between severity and demographic characteristics with comorbidities in COVID-19 patients.
The clinical presentation of COVID-19 patients with HTN varies with the severity of the cases.However, the current study showed a significant correlation between clinical presentation and severe illness.Moreover, critical patients reported a higher incidence of shortness of breath, fever, productive cough, and chest pain than patients with severe or non-severe illness, supported by a multicenter study from Malaysia [17].In addition, we also found that baseline vital signs, including heart rate, respiratory rate, and oxygen saturation, were also associated with the severity of COVID-19 patients with HTN.Furthermore, COVID-19 patients with HTN had even higher median respiratory and heart rates than the respiratory and heart rates reported by Sim et al. [17].These findings indicate that the SARS-CoV-2 virus mainly affects the respiratory tract and causes lung damage and narrowing of the airway, leading to shortness of breath in severe cases [18], and HTN may further affect the respiratory and cardiovascular systems in patients infected with COVID-19.
Some COVID-19 patients are presented with leukocytosis, associated with neutrophilia, indicating a severe illness [19].However, with the progression of COVID-19, the neutrophil count gradually increases; therefore, neutrophilia may be considered a marker for severe respiratory illness and poor outcomes [20].An increasing neutrophil count was identified as a predictor of severe illness among COVID-19 patients [14].Moreover, Liu et al. identified that the risk of severe or critical illness was higher for patients with neutrophils (>75%), comparable with our results.Neutrophilia reflects the cytokine storm and hyperinflammation associated with the pathogenic mechanism of severe COVID-19, which can lead to collateral tissue damage, exacerbate the severity, and worsen clinical outcomes [21].
In addition, we also found that baseline vital signs, including heart rate, respiratory rate, and oxygen saturation, were also associated with the severity of COVID-19 patients with HTN.The current study observed that oxygen saturation (<90%) was associated with the severity of patients, as reported in a Malaysian study [17].These findings indicate that HTN may further affect the respiratory and cardiovascular systems of patients infected with COVID-19.Another study from the Netherlands also reiterated that severe COVID-19 patients had lower oxygen saturation, confirming our findings [22].However, the hypertensive COVID-19 patients in our study posed an even more severe derangement in oxygen saturation.HTN causes structural and functional changes in arteries by narrowing and stiffening them, which reduces the blood flow and oxygen delivery to various organs, including the lungs.In addition, SARS-CoV-2 primarily affects the lungs; therefore, preexisting HTN can further compromise oxygen saturation.
Recent shreds of evidence demonstrated a clear association of elevated HS-cTnI with the severity of COVID-19 [14,23].Similarly, this study determined that HS-cTnI significantly differed among patients with different severity levels.Patients with critical illness showed the highest values of median HS-cTnI compared to severe and non-severe, reflecting acute cardiac injury due to the direct invasion of SARS-CoV-2 and damage to the myocardium [24].
Research has reported increased D-dimer levels in COVID-19 patients after the onset of inflammation, cell damage, or tissue injury.In addition, elevated D-dimer levels were significantly related to severe illness in COVID-19 patients [25].Liu et al. found that patients with D-dimer >0.5 had more severe illness than those with D-dimer <0.5, which confirms our results [14].It may be attributed to a hypercoagulability state, leading to pulmonary embolism or deep vein thrombosis [26], as SARS-CoV-2 may cause damage to blood vessels and clotting.The risk may also be exacerbated due to coexisting HTN.
COVID-19 can cause lung complications during severe illness.Apart from respiratory complications, it may also lead to cardiac complications due to the invasion of SARS-CoV-2 toward cardiac tissues.However, the severity of these complications can vary depending on the individual's health and COVID-19 severity [14].

Limitations
There are a few limitations to our study.Firstly, being a single-center study, the generalizability of our findings to a larger population may be limited due to the relatively small sample size and non-probability sampling technique, which may potentially introduce selection bias.Secondly, the duration of follow-up was short; therefore, the long-term impact of demographic and clinical characteristics on health outcomes could not be determined.However, only stable patients were discharged from the hospital, which may reduce the risk of bias due to premature discharge and help to ensure that the outcomes observed in our study may represent the broader population of hypertensive COVID-19 patients.Finally, due to the limited sample size, it is possible that some key predictors, such as antidiabetic therapy, may have been missed or not identified sufficiently.Therefore, future studies are warranted to further investigate and validate the predictors in a large population.

Conclusions
Our study determined that fever, shortness of breath, elevated pulse rate, HS-cTnI, D-dimer, and LDH values are the predictors of severity among hypertensive COVID-19 patients.The study's findings can be used to inform public health policies and clinical practice in managing COVID-19 patients with HTN in Pakistan and other similar settings.Therefore, healthcare professionals must prioritize hypertensive patients with COVID-19 and provide adequate monitoring and treatment to improve patient outcomes and prevent complications, including cardiac failure, non-ST elevated myocardial infarction, acute kidney injuries, and ARDS.

TABLE 5 : Health complications of patients during hospitalization (N = 333)
ARDS, acute respiratory distress syndrome

TABLE 6 : Univariable analysis for risk factors of severity (N = 333)
Table7presents the results of the multivariable logistic regression model to identify confounding risk factors for predicting severe illness among hypertensive COVID-19 patients.The variables with a significance of p < 0.05 in univariable logistic regression or relevant to the literature (gender, age, diabetes mellitus, cardiovascular disease, and chronic kidney disease) were analyzed using a backward multivariable logistic regression.The overall significance of the model was confirmed by the likelihood ratio test (X2 = 85.936, p < 0.001), suggesting that the predictors reliably distinguished between severe and non-severe cases.The model explained a moderate amount of the variance, as indicated by the Cox & Snell R Square (R2 = 0.221) and Nagelkerke R Square (R2 = 0.382).The Hosmer-Lemeshow test suggested that the model fits the data well (chi-square = 4.847, df = 7, p = 0.679).