key: cord-0766310-g3fqj3bx
authors: Yurtsever, Nalan; Nandi, Vijay; Ziemba, Yonah; Shi, Patricia A.
title: Prognostic factors associated with COVID-19 related severity in sickle cell disease
date: 2021-11-17
journal: Blood Cells Mol Dis
DOI: 10.1016/j.bcmd.2021.102627
sha: dfc3e3aa4beb2b6593e8f572ada93af5f4d887be
doc_id: 766310
cord_uid: g3fqj3bx

BACKGROUND: Equipoise exists regarding sickle cell disease (SCD) as a risk factor for COVID-19 disease severity and variables that increase risk of COVID-19 severity in SCD. Given our health system's large SCD patient catchment, we analyzed our own experience in this regard. STUDY METHODS: Retrospective analysis of the clinical course and factors associated with need for hospitalization and ICU admission of SCD patients diagnosed with COVID-19 through the Northwell Health system from March 1 to Dec 31, 2020. RESULTS: Of 1098 patients with SCD, 3.3% were diagnosed with COVID-19. Overall rates of hospitalization, ICU admission, cohort mortality, and in-hospital mortality were 80%, 19%, 2.5%,and 3.1%, respectively. By multivariable analysis, hospitalization risk was decreased by 60% for every 1 g/dL increase in admission Hb. ICU admission risk was increased by 84% as a health care worker; increased by 45% for every 1000/uL increase in admission immature granulocyte count; and decreased by 17% with hydroxyurea use. DISCUSSION: High hospitalization rates are compatible with worsened severity upon COVID-19 infection in SCD compared to the general population. Patients should be placed on hydroxyurea to increase their Hb and perhaps lower their neutrophil counts. Health care workers with SCD may warrant special safety precautions.

There is equipoise as to whether sickle cell disease (SCD) is a risk factor for disease severity with COVID-19. Some studies support that SCD increases risk for COVID-19 disease severity [1] [2] [3] [4] [5] [6] , whereas other studies do not. 7, 8 . Despite possible increased COVID-19 disease severity in SCD, one large study did not show an increased fatality rate in SCD 4 . Patient variables J o u r n a l P r e -p r o o f Journal Pre-proof associated with increased clinical severity of COVID-19 infection in SCD patients include older age 1, 9 , comorbidities 1, [8] [9] [10] , not being on hydroxyurea (HU) 1, 9 , history of stroke 2, 8 and black race 5 .

Non-SCD studies show similar risk factors such as older age 11, 12 , comorbidities 11, 12 , as well as being a health care worker (HCW) 13, 14 . Possible laboratory-based predictors of hospitalization include the following admission values: high C-reactive protein (CRP) 1 , low Hb 1,15,16 , low lymphocyte count 1, 15 , high alanine aminotransferase 1 , increased neutrophil-to-lymphocyte ratio 1, 15 , high immature granulocyte count (promyelocytes, myelocytes and metamyelocytes) 11, 15, 17 , high creatinine 1 , and high direct bilirubin 1 . Possible in-hospital mortality values include high D-dimer 1, 11 , high creatinine levels 1, 9, 11 , high lactate dehydrogenase 1, 11 , and high CRP 11 on admission. Fewer comorbidities may contribute to the better outcome of pediatric patients with COVID-19 infection 9 . In order to add our experience in the prognosis of SCD patients with COVID-19, we analyzed the clinical course and potential variables associated with need for hospitalization and ICU admission in all SCD patients diagnosed with COVID-19

infection throughout the Northwell Health system between March 1 and Dec 31, 2020.

Study: This study was conducted under institutional review board approval at Northwell Health. 

Our study in SCD patients examined their rates of COVID-19 infection and related hospitalization, ICU admission, cohort mortality, and in-hospital mortality. We also performed a MVA of risk factors for COVID-19 related severity, as defined by need for hospitalization or ICU admission. Our symptomatic infection rate was 3.3%, compared to a symptomatic infection rate median of 8.6% in the general U.S. population 22 . Our data contrasts with a meta-analysis finding a higher incidence of COVID-19 infection, but with a wide confidence interval, than in the general population, 2 and may be related to our patients' compliance with COVID-19 mitigation measures such as social distancing (personal observation of one of our SCD physicians, Dr. Shi), as lack of access to care and testing is unlikely given that all patients included in the study had been seen in the year 2020. Interestingly, the sickle genotype distribution of our COVID-19 infected patients was significantly different from the SCD US population distribution. 20 This may be related to SARS-CoV-2 diagnostic bias toward symptomatic patients and is consistent with previous reports 5,21 of higher morbidity or mortality in the SC/Sβ + genotypes. Of note, as previously reported 1 , our patients with SC/Sβ + genotypes were less likely to be on HU than SS/Sβ 0 genotypes (Fisher's exact test, p-value=0.002). While

Journal Pre-proof our 19% ICU admission rate is similar to the U.S. general population rate 23 , our 80% overall hospitalization is higher than the U.S. general population rate of 2% 22 but compatible with previously reported ranges in SCD between 41-76% for hospitalization and 11-20% for ICU 1,3-5,21 . Our higher-end hospitalization rate may reflect a conservative approach with our SCD patients. Also notable however, as reported previously 8, 21 , is that a majority of hospitalizations were for SCD-related rather than COVID-19 related complications, most frequently acute painful episodes. In fact, pediatric patients had no COVID-19 related complications, consistent with previously published milder courses in pediatric SCD patients. 3, 5, 6, 9 Our cohort mortality of 2.5% is on the low end of the 3-10% range in SCD previously reported; 1,4,5,21 higher than the U.S.

general population symptomatic fatality of 1.1% 22 but perhaps not higher when specifically compared to a U.S. black population 4,8 . Our in-hospital mortality rate of 3.1% was lower than the 8% found in a nearby geographic area 8 and again, may reflect a conservative approach to hospitalize our SCD patients.

In regard to risk factors for COVID-19 related severity, the only variable that held up to MVA for the outcome of hospitalization was admission Hb; this is consistent with previous findings of a significant Hb decrease from baseline for SCD patients requiring hospitalization 1 and studies that reported Hb as a strong predictor of COVID-19 related severity or mortality in the general population 16, 24, 25 For the outcome of ICU admission, 3 variables remained significant in the MVA: HCW employment, HU use, and immature granulocyte count on admission. HCW employment has not been previously reported as a risk factor in SCD ICU admission but has been associated with COVID-19 morbidity in the general US population as well as comprehensive meta-analysis. 13, 14 . HU use has been reported to reduce morbidity in SCD in one report 1 but not others. 10, 21 It is biologically plausible that HU might decrease morbidity from J o u r n a l P r e -p r o o f Journal Pre-proof COVID-19 infection due to reduction of coagulation and neutrophil and endothelial cell activation. [26] [27] [28] Finally, the level of immature granulocytes has not been previously reported as a risk factor in SCD ICU admission, but is associated with disease severity and ICU admission in the general population 15 

Clinical predictors of poor outcomes in patients with sickle cell disease and COVID-19 infection

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Plasma microparticles of sickle patients during crisis or taking hydroxyurea modify endothelium inflammatory properties

Hydroxyurea therapy decreases coagulation and endothelial activation in sickle cell disease: a Longitudinal Study

Effects of hydroxyurea on cytotoxicity, inflammation and oxidative stress markers in neutrophils of patients with sickle cell anemia: dose-effect relationship

We thank our SCD patients who were the subjects of this study as well as the health care workers at Northwell Health who took care of them.

The patient who died is highlighted in gray. ‡ Sequestration in peds patient, infarct in adult patient