Sickle cell disease patients with COVID‐19 in Guadeloupe: Surprisingly favorable outcomes

Abstract We investigate risk factors for hospitalization and difference between sickle cell syndromes in a cohort of COVID‐19 sickle cell disease (SCD) adult patients managed in the Reference Center of Guadeloupe. We retrospectively collected data of symptomatic SCD adult patients infected with SARS‐CoV‐2 between March and December 2020. Thirty‐eight SCD adult patients with symptomatic COVID‐19 infection were included during the first wave, representing 9.6% of the active patient file at our center. The median age (IQR) was 39 years (24–47). Four patients were obese and two had moderate renal failure. The median duration of symptoms (IQR) was 10 days (5–15). Seventeen (44.7%) patients were hospitalized, including two in intensive care unit (ICU) for acute chest syndrome. An 85‐year‐old SC patient with prostate cancer died. No difference was detected between inpatient and outpatient groups in terms of age, gender, BMI, SCD clinical complications, and in history SCD treatment. There was no difference for severity, hospitalization, length of stay, ICU stay, or death between SS or Sβ°‐thal patients and SC or Sβ+‐thal patients. These overall favorable outcomes among symptomatic patients may be related to the low prevalence of comorbidity known to be linked to the more severe forms of COVID‐19, but also to the prompt coordinated management of SCD patients in the Reference Center.


INTRODUCTION
Sickle cell disease (SCD) is an inherited disorder of hemoglobin (Hb) that predominantly involves individuals of African descent, affecting millions of people in sub-Saharan Africa [1]. In Guadeloupe, a French West Indies Island of 379,710 inhabitants in 2020 of which about 90% are of Afro-Caribbean origin, SCD is the most common genetic disease affecting 1 in 300 newborns, and 11% of the population carries an abnormal β globin gene [2].
To manage SCD patients, a Reference Center has been created within the University Hospital of Guadeloupe since 1990. SCD results from the synthesis of the abnormal Hb S that polymerizes in deoxygenated conditions, leading to the sickling of red blood cells (RBCs).
Sickle RBCs are more rigid, fragile, and therefore prone to disruption [3]. While homozygous HbS disease (SS) is the most common type of SCD and considered as the most severe sickle syndrome, less common types of SCD arise as a result of double heterozygosity between HbS gene and different β-globin gene mutations such as Hb C (SC) or β-thalassemia (Sβ-thal) that share some similar basic pathophysiology processes leading to variable phenotypes. Clinically, SCD is characterized by chronic hemolytic anemia and vaso-occlusive events resulting from abnormal interactions between abnormal RBCs, white blood cells, platelets, and endothelial cells, leading to painful acute vaso-occlusive crisis (VOC), acute chest syndrome (ACS), stroke, and a broad range of acute and chronic complications affecting every organ system [3]. Patients with SCD have increased susceptibility to infections, which is partly due to autosplenectomy resulting from recurrent vaso-occlusive infarcts within the spleen, but involvement of leukocytes functions, cell-mediated immunity, antibody production, alternate complement pathway, and abnormalities of opsonization have also been reported [4][5][6].
Several concerns were raised with the pandemic spread of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The impact of various viruses on SCD clinical course has been described.
It is already known that influenza and dengue outbreaks cause excess morbidity in SCD population who experience increased VOC events and ACS with an increased need for intensive care and exchange transfusions during these viral infections [7][8][9][10]. In addition, SC patients, although exhibiting less severe SCD clinical course, have a higher rate of severe dengue fever and death than those with SS genotype [9,11]. Therefore, SCD patients are considered to be at increased risk of COVID-19 complications with a higher risk of life-threatening ACS. This assumption is based on pulmonary tropism of the virus, impaired immunity and systemic vasculopathy of SCD patients that predispose them to end organ dysfunction, and high risk of thrombosis [12]. There was no systematic screening in our center, thus patients with asymptomatic COVID-19 were not identified. Therefore, the incidence of SARS-CoV-2 infection in the SCD population of Guadeloupe could not be computed.

Data collection and clinical definition
In March 2021, we retrospectively collected in our reference center data of symptomatic adult SCD patients infected with SARS-CoV-2 between March and April 2020 for the first wave and between August and December 2020 for the second wave. In accordance with the declaration of Helsinki, the project was approved by the local Research Ethics Committee and written consent was obtained from each subject. Data were anonymized prior to statistical analysis.

SCD clinical and biological features
Demographic information, genotype, medical history including medical treatment, were collected. The basal level of Hb was obtained at least 2 months after or before any acute complication of the SCD and up to 3 months before presentation with COVID-19 or after blood transfusion. Severe occlusive disease in the previous 3 years was defined by more than two hospitalized VOC or priapism and/or by more than one ACS during this period. VOC was diagnosed as hyperalgesic if pain level was higher than 6 on 10 by numeric pain scale and required high opioid doses. ACS is defined as a new pulmonary infiltrate and some combination of fever, chest pain, and signs and symptoms of pulmonary diseases such as tachypnea, cough, and dyspnea [18].
Co-morbidities known to impact severity of SCD and SARS-CoV-2 infection were reported. Glomerular filtration rate (GFR) was estimated by using chronic kidney disease epidemiology collaboration (CKD-EPI) [19].

Statistical analysis
Quantitative variables were summarized as mean with standard devi- were also compared to those of SC and Sβ + -thal (SC/Sβ + -thal) patients.
All statistical analyses were performed using R 4.1.0. Significance was considered at the level 5%.

Demographic and clinical characteristics
Thirty-eight adult SCD patients with either confirmed or probable COVID-19 infection were included in this study (Table 1). Nasal COVID-19 PCR was performed in 28 cases (74%) and was positive in 26/28 cases. The two patients whose RT-PCR was negative and the 10 patients whose RT-PCR could not be performed exhibited a suggestive clinical history, a positive COVID 19 serological test, and no differential diagnosis.
Thirty-eight symptomatic patients were included, that is, 9.6% of the active file of the SCD center. Twenty-two patients had SS disease, 14 SC disease, one Sβ 0 -thal, and one Sβ + -thal disease. Table 1 shows the demographic, clinical, and biological characteristics of the cohort.

Comparison between inpatients and outpatients
No difference was detected between inpatient and outpatient groups in terms of age, gender, BMI, SCD clinical complications studied as well as in terms of SCD severity of vaso-occlusive complications developed in the previous 3 years (Table 2). There was no difference in history of SCD treatment provided, specific infectious symptoms presented, duration of symptoms or time-delay from symptom onset up to management. However, inpatients had significantly higher neutrophils count median and higher value of CRP than outpatients ( Table 2).
It is worth noting that seven outpatients (33%) but none of inpatients were treated by on angiotensin-converting enzyme (ACE) inhibitors and that hospitalized patients had significantly more VOC and ACS during their COVID-19 than non-hospitalized patients ( Table 2).

DISCUSSION
We and ACS in 28.5% of adults [16]. History of pain was a risk factor of hospitalization (RR, 1.8; p <0.002) and for serious COVID-19 (RR 2.0; p = 0.02) in adults [16], but in this study, the authors categorized serious COVID-19 illness when patient had pneumonia even without hypoxia. In addition, they presented evidences that HU treatment had no effect on hospitalization and COVID-19 severity, but was associated with lower risk of presenting with pain in adults during COVID-19 (RR, 0.9; p = 0.02) [16]. Overall favorable outcomes of our Guadeloupean series are also different from those reported by Minniti et al. [16] in SCD Afro-American individuals for which VOC and ACS were observed in 65% and 50%, respectively, with 75% patients requiring hospitalization and 10.6% patients dying. Likewise, in our cohort, genotypes, diabetes, and BMI were not associated with hospitalization or death in this US study. In contrast, US patients with preexisting kidney disease were more likely to be hospitalized. Among inpatients, their results show that age, pulmonary hypertension, stroke, and cardiac or kidney disease were associated with death. Such associations were not detected in our cohort. However, nearly 30% (27%) of our patients had chronic kidney disease, but kidney injury was not associated in our cohort with COVID-19 severity or hospitalization, or death. It is worthwhile to notice that the proportions of patients with medical history of stroke and cardiac or renal insufficiency were lower in our cohort compared to those reported in the US cohort, and there was no patient with pulmonary hypertension, a complication associated with the highest COVID-19 severity in the US Study [16]. Unlike data reported by Arlet et al. [13], older age is not here associated with a worse prognosis.
HU treatment, transfusion or exchange transfusion, and phlebotomy therapy that are related to a more severe SCD course, did not show any association with the severity or outcome of COVID-19 in our series.
The only patient who unfortunately died was in the low prognostic group, based on risk factors identified in general population.
Symptoms of COVID-19 in our SCD patients do not differ from those of the general population [21], and VOCs or ACS presented by almost half of our patients were not particularly severe, and promptly resolved. Surprisingly, there were very few cases of SARS-CoV-2 pneumonia that probably partly explains this favorable evolution. for those with SCD compared to patients without SCD was no significantly different [23]. In a retrospective multicentric cohort study in Barhrain between February and July 2020, in whom 38 SCD patients were compared to a randomly select sample of non-SCD patients with COVID-19, SCD was not a risk factor for severe COVID-19 outcomes in hospitalized patients [24]. The causes of discrepancy remain largely unknown and deserve further studies. However, it is tempting to speculate that the favorable outcome in our cohort could be related to the absence of comorbidity known to be linked to the more severe forms of COVID-19, associated to early and coordinated management of the SCD patients.
We did not find any predictive factors for hospitalization of SCD These two series did not assess whether these findings were related partly by preexisting comorbidities or through association with other clinical, demographic, or socioeconomic risk factors. Overall, our data suggested that SC were not at higher risk of severe course of COVID-19 than SS patients. However, our study is based on a limited number of symptomatic patients and thus may lack statistical power to identify significant differences between genotypes, or between inpatients and outpatients. Therefore, our finding needs to be confirmed on larger SCD cohorts.

CONCLUSION
Our Guadeloupean series surprisingly shows that SCD patients, regardless of their genotype, may exhibit a mild course with COVID-19. Only 9.6% of active adult SCD patient file exhibited symptomatic SARS-CoV-2 infection that prompted a visit to our medical center. We currently do not know how many patients had asymptomatic CoVID- and ensure appropriate prevention and management. However, our experience has shown the benefits of early and close monitoring of the patients.

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.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
This study was approved by ethical research commission of the Centre Hospitalier Universitaire de la Guadeloupe (Registration number: A41_21_02_08_DREPA-COVID).