The impact of systemic hypertension on outcomes in hospitalized COVID-19 patients – a systematic review

Background Several observational reports from different parts of the world have shown that systemic hypertension (hypertension) was the single commonest comorbid condition in hospitalized COVID-19 patients. Hypertension is also the most prevalent comorbidity reported among patients who developed severe disease, were admitted to Intensive Care Unit, needed mechanical ventilatory support, or who died on admission. The objective of this systematic review is to study the association between hypertension and specific clinical outcomes of COVID-19 disease which are- development of severe COVID-19 disease, need for admission in the intensive care unit (ICU) or critical care unit (CCU), need for mechanical ventilation or death Methods We searched the PubMed, SCOPUS, and Google Scholar databases up till June 28, 2020 for original research articles that documented the risk factors of mortality in patients with COVID-19 using the PRISMA guideline. Results One hundred and eighty-two articles were identified using pre-specified search criteria, of which 33 met the study inclusion criteria. Only three were prospective studies. Most studies documented hypertension as the most prevalent comorbidity. The association of hypertension with development of severe COVID-19 disease was not conclusive, majority of studies however found an associated with mortality. Conclusion Hypertension affects the clinical course and outcome of COVID-19 disease in many cohorts. Prospective studies are needed to further understand this relationship.


Introduction
Starting from a cluster of acute respiratory infection cases in Wuhan, Hubei Province China in December 2019 infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 1,2 has grown to a pandemic of monumental proportions with 21,259,147 cases and 760,840 deaths as at August 14, 2020 3 leaving in its wake grave economic and social consequences. Initially called 2019 novel coronavirus (2019nCov) on January 3, 2020 after it was identified from thorough put sequencing of broncheoalveolar lavage fluid from a patient, the World Health Organization (WHO) designated it SARS-CoV-2 and gave the name Coronavirus disease-2019  to the clinical condition caused by it on February 11, 2020 4 and declared the disease a pandemic on March 11, 2020 as it rapidly escalated. Early reports from Wuhan about the epidemiology of the disease indicated the high prevalence of comorbid conditions such as systemic hypertension (hypertension), di-abetes mellitus, coronary artery disease, cancer and other chronic illnesses among hospitalized cases of Covid 19. Up to half of admitted patients in some early reports from Hubei province reportedly had comorbidities and this proportion increased to as high as two-thirds in those who developed severe disease requiring Intensive Care Unit (ICU) care or leading to death. 5,6 Several observational reports from different parts of the world -Wuhan, China, Chinese cities other than Wuhan, USA, Italy and Israel, have shown that systemic hypertension was the single commonest comorbid condition in hospitalized Covid-19 patients. [7][8][9][10][11] Hypertension is also the most prevalent comorbidity reported among patients who developed severe disease, needed mechanical ventilatory support, were admitted to ICU or who died on admission. [12][13][14][15] An Italian database reported that up to73% of patients who have died in the pandemic had hypertension. 16,17 This raised multiple questions regarding the impact of hypertension on the clinical course of COVID-19 disease. The objective of this systematic review is to study the association between hypertension and specific clinical outcomes of COVID-19 disease which are-development of severe COVID-19 disease, need for admission in the intensive care unit (ICU) or critical care unit (CCU), need for mechanical ventilation or death.

Methodology Search Strategy
We systematically searched the PubMed, SCOPUS, and Google Scholar database up till June 28, 2020 for articles that documented the risk factors of mortality in patients with COVID-19. We used MeSH key words that included coronavirus, COVID-19, COVID-19 Mortality, systemic hypertension, cardiovascular disease and mortality. In the first round of search, hypertension was variously combined with COVID-19, Coronavirus and coronavirus 2019 while in the second round, it was variously combined with COVID-19 mortality, COVID-19 severity and COVID-19 outcomes. We retrieved all the available literature published in English language on COVID-19 that reported patients' comorbidity profiles and the outcomes in patients with systemic hypertension. The analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 18

Eligibility Criteria Inclusion criteria
This study included only full-length original research articles that were published in English language and in which patients were diagnosed for COVD-19 based on the World Health Organization (WHO) recommendation of positive result of a reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasal and/or throatswab specimens. Only studies of hospitalised patients were included. 19 The primary outcome studied was the prevalence of hypertension recorded in each cohort of patients with COVID-19. The secondary outcomes were the association of hypertension with i. developing severe COVID-19 disease, ii. need for admission in the intensive care unit (ICU) or critical care unit (CCU), iii. need for mechanical ventilation and iv. death.

Exclusion criteria
We excluded systematic or narrative review articles, meta-analyses, letters to the editor which did not report original research, case reports and small case series with less than 20 patients. Publications in languages other than English and research in paediatric patients younger than 18 years of age were also excluded.

Results
The initial search returned 182 publications from PubMed, SCOPUS, and Google scholar. Additional 15 publications were obtained through cross-referencing. 147 publications remained after the removal of duplicates. After screening them for eligibility, 101 records were excluded. The 46 remaining articles were then evaluated for eligibility by assessing their full text. 13 full-text articles were excluded because they were written in other languages than English and some were protocol papers. Thereby, 33 studies with a total of 94,765 patients were included in the final analysis ( Figure 1, Table 1) Majority of the studies reviewed were carried out in China, seven were from centres in Wuhan, while 12 were from other centres outside Wuhan (with two being large multi-centre studies), eight studies were from the USA, four from Italy, one each from Israel and Iran. Because the COVID-19 pandemic evolved very rapidly, most of the early reports from most countries were retrospective studies. In our review, only the study by Cummings et al 14 , Huang et al 20    It is also worthwhile to consider that in some cases, the prevalence of hypertension in cohorts of COVID-19 patients reflected the fact that hypertension is the com-monest comorbid condition in the general population.
In a large Chinese COVID-19 combined in-patient and outpatient database of 20,982 patients, the proportion of self-reported hypertension was 12.6%, which is similar to the population prevalence data of 10.9% in China for self-reported hypertension. 45 The association between hypertension and hospitalization rates for COVID-19 may also be related to the fact that hypertension is a proxy for the presence of other cardiovascular risk factors such as diabetes, coronary artery disease and cerebrovascular disease. 16 Hence, the observed association between hypertension and COVID-19-related hospitalizations is thought to be confounded by the presence of other comorbidities. 16

Hypertension and COVID-19 disease severity
Though all the works in this review did not assess the relationship between hypertension and COVID-19 disease severity, this relationship was explored by a majority of workers.  50 , demonstrated that hypertension was not only associated with but also independently predictive of developing severe COVID-19 disease. Overall majority of studies reviewed either did not show any association between hypertension and disease severity, or showed an association which was not significant on multivariate analysis. Only 3 studies demonstrated that hypertension independently predicted severity of disease. For studies that didn't show hypertension as being independently predictive of disease severity, despite observed association on univariate analysis, the observed association may have been confounded by patient's age and preponderance of male gender in most patient cohorts. Conversely, explanations for the significant predictive relationship of hypertension with development of severe COVID-19 disease on multivariate analysis may be related to immune mechanisms, immune dysregulation and inflammation underlying the pathogenesis of hypertension and the mediation of target organ damage in established hypertension.
It has been suggested that pro-inflammatory immune mechanisms play an important role in the pathogenesis of hypertension. This is supported by the demonstration of increased levels of circulating IgG in the serum of hypertensives. 51,52 Increased numbers of central memory CD8+ T cells, activated CD8+ T cells producing interferon gamma (IFNγ) and tumour necrosis factor (TNF), TH17 cells53 interleukin (IL)-2, IL-6, and IL-754 have also been reported in patients with hypertension. The association of these cytokines with the development of hypertension has been demonstrated in experimental 55 clinical observational 53 , as well as in interventional studies. 54 Noteworthy is the fact that these immune responses can induce kidney injury and also interfere with sodium excretion, further contributing to the elevation of blood pressure. 56 An increase in systemic IL-2, IL-6, and IL-7, granulocyte colony-stimulating factor, C-X-C motif chemokine 10 (CXCL10), chemokine (C-Cmotif) ligand 2 (CCL2), and tumour necrosis factor-α (TNF-α) has been observed in patients with COVID-19.20 Rapid deterioration in COVID-19 patients is associated with a pro-inflammatory cytokine storm. Some of the key mediators of the cytokine storm are these inflammatory mediators which are also elevated in and associated with regulating immune-inflammatory responses in hypertension. 57 However only Suleyman et al subjected their observation to multivariate analysis and found no relationship after controlling for confounders. Other workers such as Huang C et al 20 found no significant association between hypertension and need for ICU care. However, their study is limited by a small sample size of 41. The complete picture of the relationship between hypertension and need for ICU care is hampered by the quality of studies which mostly carried out univariate analysis. The presence of an association between hypertension and death may be accounted for by the effect of immune dysregulation described earlier. It has been described that those processes not only underly the development of hypertension but also contribute to target organ damage. The additive effect of pre-existing cytokine activation and that which is triggered by SARS-Cov-2 may be what predisposes to mortality. Another reason for the association of hypertension with COVID-19 patient mortality may be a synergy of hypertension with myocardial injury and other effects of SARS-Cov-2 on the cardiovascular system which are not frequently assessed. Guo et al 7 showed that myocardial injury (assessed using troponin T) occurred frequently among hospitalized COVID-19 patients and hypertensive COVID-19 patients with myocardial injury accounted for the sub-group of patients with the highest mortality.

Hypertension and the need for mechanical ventilation
The unfolding new information about the relationship between cardiovascular risk factors including hypertension and composite outcomes such as mortality and need for ICU care will be further understood in the future as more information accrues to the scientific world especially through longitudinal reviews.

Limitations
A main limitation of most of the studies reviewed was that self-reporting of hypertension and indeed other comorbidities on admission was used. Under-reporting of comorbidities, stemming from the lack of awareness and/or the lack of diagnostic testing, may contribute to the underestimation of the true strength of association with the clinical prognosis. Under-reporting of comorbidities could also lead to over-estimation of the strength of association with adverse outcomes. In a few of the studies too, some patients, though having met study outcome objectives were still on hospital admission at the time of publication and may have evolving outcomes different from what has been published. However, because the COVID-19 disease is a rapidly evolving public health issue, every stage of data captured will still reflect a part of the complete picture of the disease.

Conclusion
Hypertension is the commonest co-morbidity in hospitalised COVID-19 patients. It is frequently associated with development of severe disease, need for ICU care, need for mechanical ventilation and death. However, the strength of evidence for this relationship is weak as only few studies rigorously control for confounders. In many study cohorts this association may have been influenced by age and gender and presence of other comorbidities. The role of myocardial injury and other effects of the virus on the cardiovascular system in potentiating the effect of hypertension on mortality also requires further study. Since the pandemic is still escalating, well-planned prospective studies are needed to properly define the relationship between hypertension and clinical outcomes.