Is sickle cell disease a risk factor for severe COVID‐19 outcomes in hospitalized patients? A multicenter national retrospective cohort study

Abstract Introduction Studies that examine the association between sickle cell disease (SCD) and COVID‐19 outcomes are lacking. This study aims to determine whether SCD is a risk factor for severe COVID‐19 infection in regard to the requirement of noninvasive ventilation/high flow nasal cannula (NIV/HFNC), mechanical ventilation (MV), or death in hospitalized patients. Methods Retrospective cohort study included COVID‐19 patients admitted to four COVID‐19 treatment facilities in Bahrain between February 24, 2020 and July 31, 2020. All SCD patients with COVID‐19 were included and compared to a randomly selected sample of non‐SCD patients with COVID‐19. Data were collected from the medical records. Multivariate logistic regression models were used to control for confounders and estimate the effect of SCD on the outcomes. Results 1792 patients with COVID‐19 were included; 38 of whom were diagnosed with SCD as well. In the SCD group, one (2.6%) patient required NIV/HFNC, one (2.6%) required MV, and one (2.6%) death occurred. In comparison, 56 (3.2%) of the non‐SCD patients required NIV/HFNC, 47 (2.7%) required MV, and death occurred in 58 (3.3%) patients. Upon adjusting for confounders, SCD had an odds ratio of 1.847 (95% CI: 0.39–8.83; p = 0.442). Conclusion Our results indicate that SCD is not a risk factor for worse COVID‐19 outcomes in hospitalized patients.

The illness caused by the SARS-CoV-2 virus varies in its symptomatology and can range from being asymptomatic [3] to severe illness leading to acute respiratory distress syndrome and eventually, death [4]. Several studies have shown an association between higher rates of hospitalization and severe illness with advanced age, male gender, heart failure, diabetes mellitus (DM), severe asthma, high body mass index, chronic kidney disease, chronic pulmonary disease, and malignancy [5][6][7][8]. Additional factors that are suggestive of more serious COVID-19 complications include admission oxygen saturation of <88%, troponin-I level > 1 ng/mL, C-reactive protein level > 200 mg/L, and D-dimer levels > 2500 ng/mL 6 . COVID-19 has been shown to increase the risk of thromboembolism which can lead to significant morbidity and mortality [9].
Sickle cell disease (SCD) is an inherited group of disorders characterized by the presence of hemoglobin S (HbS), either from homozygosity for the sickle mutation in the beta globin chain of hemoglobin (HbSS) or from compound heterozygosity of a sickle beta globin mutation with another beta globin mutation (e.g., sickle-beta thalassemia).
Hemoglobinopathies, sickle cell disease in particular, are commonly found in the Kingdom of Bahrain [10].
Patients with SCD are at a higher risk of morbidity and mortality.
As per the nature of the disease, they are predisposed to developing thrombotic events. These include vaso-occlusive crises, cerebrovascular accidents, acute sickle hepatic crises, acute hepatic sequestration, and renal disease. Hemolytic crises, aplastic crises, infective episodes, and priapism are also among the complications seen in these patients. This can explain why such patients tend to have a reduced life expectancy when compared to the general population [11,12]. Severe complications such as acute chest syndrome [13] and multiple organ failure [14] might be catastrophic and eventually lead to death.
Mortality rates for SCD patients admitted to intensive care units in Bahrain were 12.7%. This was slightly less than the overall mortality in other centers worldwide which was 17.2% [15].
Critically ill patients can develop cytokine storm, progressive endothelial activation, and disseminated intravascular coagulation resulting in multi-organ failure [16].
Patients with SCD often have multiple comorbidities including chronic lung disease. Viral infection can trigger acute vaso-occlusive crises in SCD patients, especially acute chest syndrome which is associated with high mortality rates [17]. In this setting of multi-organ dysfunction, in particular chronic lung damage, COVID-19 could easily trigger acute chest syndrome and multi-organ failure. Underlying endothelial dysfunction and abnormal expression of procoagulants such as tissue factor could also place SCD patients at a greater risk [18].
Hence, the combination of COVID-19 and SCD is hypothesized to cause an increase in disease severity and mortality. Studies that examine the effect of SCD on COVID-19 outcomes are lacking. Given the morbidity and mortality associated with sickle cell disease patients, it is predicted that these patients might have unfavorable outcomes when infected with the SARS-Cov-2 virus.
This study aims to determine if SCD is a risk factor for severe COVID-19 through comparing severity and outcomes of hospitalized COVID-19 cases.

Objectives
• Compare the odds of noninvasive ventilation, intubation, or death in SCD cases and controls. • Compare the odds of requiring oxygenation on presentation or admission in SCD cases versus controls.

Primary outcome
The primary endpoint was the requirement of noninvasive ventilation, intubation, or death.

Secondary outcome
The requirement for oxygenation on presentation or admission.

Diagnosis
The following methods were used to diagnose COVID-19 and sickle cell disease in our study.

COVID-19
All patients were confirmed to be infected by SARS-

Patient selection
A full list of COVID-19 patients in these study periods and their SCD status was extracted from the electronic medical records. The list was imported into the statistical package. All COVID-19 patients with SCD as indicated in the electronic medical records, were included. A total of 1850 non-SCD patients with COVID-19 were randomly sampled.
Ninety-six patients were excluded due to duplicates, non-hospitalized or due to lack of data. Data were collected for a total of 1754 patients.

Data sources and variables assessed
We obtained data from the national electronic medical records database in Bahrain, "I-SEHA." Since this electronic medical records database stores information as unstructured data, the study partici-

Statistical analysis
The distribution of treatment groups was summarized. Bivariate associations between the sickle cell status groups and the measured patient characteristics were analyzed using chi-square (χ2) tests for categorical variables and t-test for continuous variables. We assessed endpoints and their associations with both groups.
Multivariable logistic regression models were used to estimate the relationships between SCD and the composite primary and secondary

Ethical approval
The protocol and manuscript for this study were reviewed and approved by the National COVID-19 Research Committee in Bahrain and Ethics Committee for this study due to its retrospective and observational nature and the absence of any patient identifying information.

RESULTS
1792 cases were included. During the study period from February 24, 2020 until July 31, 2020; a total of 38 patients diagnosed with sickle cell disease (SCD) were admitted with SARS Cov-2 infection. The outcomes of these patients were compared to a randomly selected control group of 1754 patients diagnosed with SARS Cov-2 during the same study period.
There were a number of significant differences between the two groups (Tables 1, 2, and 3

Primary outcome
The primary outcome of the study is to evaluate the composite outcome of the requirement for ventilation (invasive or noninvasive) or death or mortality (

Secondary outcome
The secondary outcome of the study was the requirement of oxygenation on presentation (

DISCUSSION
In this cohort study, SCD was not observed to be significantly asso-  workers (with the majority being from Asian nationalities) [22]. SCD is a very rare disease within these countries [23,24], and hence this can explain the nationality difference observed. In addition, the majority of expatriate workers are males, and this accounted for the male predominance observed in the non-SCD group [22]. Moreover this difference in gender distribution can be explained by the increased female prevalence of COVID-19 patients with hemoglobinopathies.
A multicenter study by de Sanctis et al [25] and another study by Panepinto et al [26] established increased female prevalence (76.9% and 57%, respectively) of COVID-19 infection among patients with hemoglobinopathies.
Among the comorbidities evaluated in all patients with COVID-19, results demonstrated that almost half of those with SCD were found to have G6PD deficiency in contrast to a minority in the control group.
Some studies claim that G6PD deficiency incidence is more abundant in patients with SCD in comparison to the general population [27]. In addition, many studies have established the association of such inherited diseases due to the high rates of consanguineous marriages in the gulf region [28]. Further research on G6PD and COVID-19 outcomes is required to understand more on the topic.
On a different note, patients in the non-SCD group were found to be mostly comorbid with DM and HTN, this could be attributed to the older age of the population [29]. The higher prevalence of DM and HTN increased the baseline risk of the non-SCD group to develop severe COVID-19 outcomes[5]- [7].
One of the remarkable findings in this study was the significant variation in symptom presentation. Although the majority of patients in both groups did present with cough, SCD patients presented more expressively with fever. This may be attributed to the natural history of the disease where it creates an environment supporting infections [30], although the presence of other causes of fever was not explored in this study.
COVID-19 infection has a broad clinical presentation ranging from asymptomatic to severe forms of respiratory disease which can lead to death [31].

STRENGTHS
The study has several strengths; it involved the majority of hospitals that provided acute care for hospitalized COVID-19 cases in Bahrain.
Furthermore, our study included all SCD cases admitted in the study time period allocated at the involved centers. The data collection process was done manually, hence, all patients' files were reviewed carefully, and all documented details were collected. The study represents the only study conducted in the region to explore the relationship between SCD and COVID-19.

LIMITATIONS
Since the study includes severe COVID-19 disease patients requiring hospitalization, inference on milder COVID-19 infections cannot be drawn from these results. Given the small number of sickle cell disease cases, adjustment of confounders could be limited. Secondly, given the retrospective design, information that was not documented in electronic medical records and was not available for analysis, could be potential confounders. These included time from symptom onset, inflammatory markers, and frequency of admission of SCD patients.
This research did not study other relevant outcomes related to sickle cell disease including hemolysis, vaso-occlusive crisis, and other SCD crises. The genotype of sickle cell disease patient was not stratified as data on that wasn't readily available.

CONCLUSION
Our results showed no significant increased risk of adverse COVID-19 outcome in SCD patients hospitalized with COVID-19 as compared to their non-SCD counterparts. Further studies on this topic with larger samples of SCD cases are warranted in order to have conclusive evidence on SCD and the risk of COVID-19 outcomes.

ACKNOWLEDGMENTS
We would like to express our gratitude toward our colleagues: Abdulla and Amna Mohamed Buheiji who played an essential role in the data collection process related to this paper. Our thanks and appreciation goes to them for their dedication and hard work, and we wish them all the best in the future. We thank all the participants of the study and hope they will lead a long healthy life. We extend our condolences to the families of the lives lost due to COVID-19.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

ETHICS APPROVAL
The study was approved by the National COVID-19 Research and Ethics Committee.

AVAILABILITY OF DATA AND MATERIALS
All the data for this study will be made available upon reasonable request to the corresponding author.