Low morbidity and mortality with COVID‐19 in sickle cell disease: A single center experience

Abstract Coronavirus disease 2019 (COVID‐19) is caused by SARS‐CoV‐2 infection, which evolved into a global pandemic within a short time. Individuals with sickle cell disease (SCD) suffer from underlying cardiopulmonary comorbidities and are at risk of severe complications such as pneumonia, acute chest syndrome, thrombosis, stroke, and multiorgan failure. Whether COVID‐19 poses a high risk of morbidity and mortality in SCD patients remains unclear. Patients with SCD and COVID‐19 can present with overlapping clinical features such as respiratory symptoms with ground‐glass infiltrates, hyperinflammatory state, and increased risk of thromboembolism. This highlights the need to maintain a low threshold for testing for COVID‐19 infection among symptomatic and hospitalized SCD patients. We report a case series of nine hospitalized SCD patients diagnosed with COVID‐19 from March 18, 2020 to April 30, 2020 at a tertiary medical center in New York City. The mean age of the study population was 27.9 years, and interval since onset of symptoms and hospital presentation was 1–2 weeks. All patients in our series improved and were discharged home. This limited study shows that SCD patients, who are perceived to be high risk, maybe somehow protected from severe symptoms and complications of COVID‐19 infection.

None of the patients received antiviral therapy or IL-6 inhibitor. About 66% of the patients needed simple blood transfusion support during their hospital admission as summarized in Table 4. Vital signs, radiological features, management, and outcomes are noted in Table 4.
The duration of symptoms before presentation ranged between 1 and 2 weeks. All patients except one showed respiratory parenchymal changes that ranged from subtle hazy appearance to frank infiltrates ( Figure 1). All of them had sickle cell crisis and received hydration and analgesics.
Age matched controls were compared with SCD for clinical outcomes. Fifty-three out of 725 were among those aged 18-40 years. Of these, 19 patients needed ICU admission with four needing intubation.
Four died with mortality of 5.6%. Among the nine SCD patients, only one needed ICU admission without the need for intubation. No deaths were observed, and all were discharged. The average length of hospital stay was slightly longer in SCD (7.1 days) than the age matched control (6.8 days) as summarized in Table 5.

DISCUSSION
Patients with SCD are a unique subset of hematological disease population who are postulated to be at higher risk of developing multiple and severe complications with COVID-19 due to multiple organ derangement due to SCD complications. Data on clinical manifestations of SARS-CoV-2 in SCD is scarce. SCD patients at baseline have anemia, increased risk of infections, and vaso-occlusive crisis (VOC).
Acute respiratory illnesses, in general, are a major cause of mortality and morbidity in SCD due to increased risk of developing pneumonia, pulmonary VOC disease, and acute chest syndrome [6]. Infections are major causes of morbidity and mortality in SCD individuals due to tissue hypoperfusion, functional hyposplenism, disproportionately high inflammatory overload, or hypoventilation [7,8]. Furthermore, viral infections such as H1N1, seasonal influenza, Zika can present with increased virulence in these individuals [9][10][11]. If SARS-CoV-2 viral infection produces such hyperinflammatory response in SCD individuals is yet to be reported. The interplay between symptoms or complications of SARS-CoV-2 in patients with SCD who has anemia at baseline, varying levels of hemoglobin variants such as Hb S, Hb F, iron overload, current or recent exposure to hydroxyurea, other prescription drugs, and underlying lung pathology remains unknown.

PRESENTING SYMPTOMS AND COMPLICATIONS
Reported ARDS incidence with COVID-19 is around 15-33%, but the data on the severity of lung involvement, acute chest syndrome (ACS), ARDS, and other presenting symptoms with COVID-19 in individuals with SCD is limited [12]. Nur et al. reported two patients who presented with ACS, severe back pain, and extremity pain. One patient recovered completely; however, the clinical course for the second individual is not known [13]. In a case series, McCloskey et al.
reported 10 SCD patients from the United Kingdom with favorable outcomes except for one patient for whom morbidity and mortality were attributed to multiple underlying comorbidities [14]. Similarly, Hussain et al. reported four patients with SCD who had favorable outcomes. VOC, musculoskeletal symptoms dominated in these patients with one patient showed predominant gastrointestinal symptoms of nausea, vomiting, and diarrhea [15]. Gastrointestinal (GI) symptoms could be a dominant presenting symptom in 10-15% of COVID-19 cases, rarely patients present with GI only symptoms, without respiratory or hematological manifestations [3,4].

SARS-CoV-2 infection can overlap significantly and a high level of vig-
ilance is needed while providing care to patients with SCD especially during the pandemic period [13]. SARS-CoV-2 binds to angiotensinconverting enzyme-2 (ACE-2) expressed on multiple tissues predominantly in the oral cavity (tongue), lung, heart, kidney, and ileal enterocytes, making them vulnerable to viral injury [16]. ACE-2 activity is also noted in the lymphocytes in the lungs and digestive tract; however, its clinical importance is unclear [16]. COVID-19 patients develop hyperinflammatory response (cytokine storm), which can lead to higher vascular permeability, extensive microthrombi formation leading to multiorgan failure, and death [9]. Similarly, SCD patients can develop multiple pathophysiological changes due to vaso-occlusion, which include inflammation (with increased sickling), hemolysis (with increased adhesion to endothelium), hypoxia, and ischemic reperfusion injury (by reactive oxygen species) [17,18]. Due to the history of multiple transfusions, SCD patients have high ferritin levels, a finding common in severe COVID-19 patients where it serves as a marker of inflammation [19]. It is conceivable that if both pathologies coexist in a patient, an enhanced inflammatory cascade is expected. However, such changes have not been reported and have not resulted in less favorable outcomes among SCD patients with COVID-19.

WHAT AND HOW
It remains to be studied how some of these pathophysiological pathways potentially interact to mitigate adverse effects of COVID-19.

LIMITATIONS
Limitations of our data include the retrospective nature of our data captured in this case series. An alternative explanation of the low risk of complications includes the younger age of patients with SCD, low incidence of HTN, and their low comorbidity disease burden. To further explore this issue of complications with COVID-19, preclinical models and larger clinical studies with more data or registry studies need to be conducted and updated frequently [22]. Such studies can provide knowledge about preventative strategies and risk mitigation for COVID-19 patients. Targeted screening of SCD patients for COVID-19 symptoms is needed to identify the disease at the early stages for prompt monitoring and intervention.

CONFLICT OF INTEREST
The authors declare no conflict of interest.