Impact of SARS‐CoV‐2 infection on pain crisis and acute chest syndrome in patients with sickle cell anemia: A retrospective multi‐cohort study based on US national data from 2020 to 2022

Abstract COVID‐19 infection has been a significant contributor to global morbidity and mortality, especially among those patients with chronic diseases. The Centers for Disease Control and Prevention have classified sickle cell disease (SCD) as a condition that increases the risk of severe illness from COVID‐19 infection. A retrospective study was conducted using the TRiNetX health research network database to identify SCA patients ( HbSS, Sbeta‐thalassemia zero) who had SARS‐CoV‐2 infection over 2 years; these were compared with similar patients who did not have the infection in terms of demographics, pain control, and laboratory parameters COVID‐19 illness impacts [ain crises and ACS, and prior vaccination against influenza and COVID‐19 may represent a protective factor for developing pain crises.

attributable to COVID-19 in the United States as of 2022.The Centers for Disease Control claim that hospitalization and mortality is markedly higher in the 30-39 and 85+ age groups compared to those who are less than 30 years of age.Differences in immune responses between children and adults contribute to the variance in severity and hospitalization rates.Adults have suppressed adaptive immunity and hyperactivity of the innate immune response in severe infections, causing severe inflammation.Conversely, children have a strong immune response from frequent viral infections and live vaccines.They are more likely to gain early control of a SARS-CoV-2 infection and exhibit milder symptoms [4].Adults with end-organ disease (e.g., diabetes, chronic obstructive pulmonary disease, heart failure, and chronic kidney disease) are at increased risk for severe COVID-19 and repeat admissions for complications [5].This finding is mirrored in children eJHaem.2024;5:299-307.
wileyonlinelibrary.com/journal/jha2 299 Six study cohorts (Table S1) were created on the TriNetX USA network by using the query builder function identifying ICD-10 codes of the conditions/diagnostics of interest (SCD, pain crisis, ACS, SARS-CoV-2 infection).Inclusion and exclusion criteria were organized by using the operators AND OR MUST HAVE and CANNOT HAVE incorporated in the same platform.
The inclusion criteria are as follows: • age 1-50 years old; • sickle cell disease (SCD), genotype Hb-SS or Sβ0-thal; • diagnosis of pain crisis or acute chest syndrome; • available report of COVID-19 status (positive/negative) at the same time of the pain crisis/ACS diagnosis, within May 2020 to May 2022.
The exclusion criteria are as follows: • children with SCD and multisystem inflammatory syndrome (MIS-C) as this condition presents weeks after the SARS-CoV-2 infection; • patients with SCD genotype Hb-SC and Sβ+ as these individuals tend to have milder clinical phenotypes, hence less incidence and severity of SCD complications (Baba et al., 2019).
The six created cohorts are pain crisis with/without SARS-CoV-2, ACS with/without SARS-CoV-2, and SARS-CoV-2 without pain crisis/ACS.The SARS-CoV-2 infection had to be reported at the same time the pain crisis/ACS was diagnosed.
All the cohorts were matched for demographic characteristics-age group (<18 years old, ≥18 years old), gender, race, and ethnicitybefore comparing the groups and running statistical analysis; additionally, mutually exclusive diagnosis (ICD-10 codes) were used to capture genuine cases of SCD, pain crisis, ACS, and SARS-CoV-2 infection.
Patient data drawn from TriNetX included demographic characteristics, health insurance status, influenza and COVID-19 vaccination status, level of service, baseline laboratory results, disease modifying drugs use, laboratory outcomes, pain control regimens, procedures (transfusion), and mortality.
Of note, Table S2 presents the description of the study cohorts as well as a study flowchart illustrating how the different cohorts were compared.
To investigate the reason why despite SARS-CoV-2 infection certain SCD patients do not develop pain crisis/ACS, patients with SARS-CoV-2 and pain crisis/ACS were compared to their counterparts (SARS-CoV-2 without pain crisis/ACS).Demographic characteristics (Table 1), baseline laboratory parameters, disease-modifying drug use, and influenza/COVID-19 vaccination status were obtained.All these parameters had to be reported at least 6 months before the diagnosis of (1) pain crisis/ACS with concomitant SARS-CoV-2 or (2) SARS-CoV-2 infection alone (Table 4).Laboratory parameters include hemoglobin and reticulocyte percentage.Disease-modifying drugs include hydroxyurea, voxelotor, L-glutamine, and crizanlizumab.Mean and standard deviation were calculated for age and laboratory values; p-values were determined via two-sample t-tests.Total patient count and proportion were calculated for the other variables.
To investigate the differences in morbidity and mortality of pain crisis/ACS with and without SARS-CoV-2 infection, patients with pain crisis/ACS and SARS-CoV-2 were then compared to their counterparts (pain crisis/ACS without concomitant infection).Demographic characteristics (Table 3), laboratory outcomes, and clinical outcomes were obtained.These parameters had to be reported up to 1-month after the diagnosis of (1) pain crisis/ACS with concomitant infection or (2) pain crisis/ACS alone (Tables 5 ).Laboratory outcomes include hemoglobin, reticulocyte %, leukocyte count, lactate dehydrogenase (LDH), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and ferritin.Clinical outcomes include use of pain regimens (opioids, TA B L E 1 Demographic information of patients with and without pain crises/acute chest syndrome (ACS) and concomitant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.the time frame in which Omicron was identified, the database does not include the subtype of COVID-19 that the patients had, so this information could not be obtained.

SARS-CoV
The primary endpoint of the study is the effect of SARS-CoV-2 infection on the incidence of pain crises and ACS.Secondary endpoints include acuity of care setting, need for disease-modifying therapy, the effect of COVID-19 and influenza vaccination status, transfusion burden, critical lab values, length of hospital stay, and mortality.

RESULTS
After matching, a total of 16,341 patients with sickle cell anemia were identified who met the inclusion criteria for this study.The majority of subjects were adults (19-50 years old), the most common race was African American, and the most common ethnic group was Not Hispanic or Latino.Only 20 patients were identified as not having medical insurance.
Table 1 shows the demographic characteristics of the SCD patients with concomitant SARS-CoV-2 infection and pain crisis or ACS and those without pain crisis or ACS.The cohort with SARS-CoV-2 and subsequent pain crisis had higher use of disease-modifying agents (hydroxyurea, voxelotor, L-glutamine, and crizanlizumab) in the 6 months prior to infection than the cohort without pain crisis (p < 0.0001).The former cohort also had lower baseline hemoglobin levels (9.57± 2.15 vs. 11.5 ± 2.31, p < 0.0001) and significantly lower influenza and COVID-19 immunization rates (p < 0.0001) (Table 3) compared to the group who did not develop the pain crisis.
TA B L E 2 Demographic information of patients with and without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who developed pain crises/acute chest syndrome (ACS).1.99-4.75]).
Differences between the ACS cohort with concomitant SARS-CoV-2 infection versus those without infection are outlined as follows:

Setting of care
The cohort with concomitant SARS-CoV-

DISCUSSION
Due to the limited large-scale data on sickle cell outcomes and complications amidst the COVID-19 pandemic, this study evaluates the impact of SARS-CoV-2 on two SCD-related complications: pain crises and ACS using a large US-based data set.Patients with genotypes Hb-SS or Sβ0-thal, which are considered the more severe forms of SCD, are emphasized [11].The findings of the present study show that SARS-CoV-2 did not increase the risk of pain crisis but did increase the risk of ACS.The former is not consistent with a study by Mucalo et al., which suggests that COVID-19 infection may be a trigger for pain crisis in SCD patients [12].

Mucalo et al. analyzed the US-based SECURE-SCD registry and
identified 750 cases of COVID-19 illness in patients with SCD.Pain crisis and ACS were the most common presenting symptoms (67% and 29% in adults, respectively) followed by nephropathy, overt stroke, and pulmonary hypertension.Note that 40% of children and 60% of adults required inpatient admission, and 6% of children and 9% of adults required ICU level of care.The mortality rate for the total cohort was 2.5%, higher than the present study which had a mortality rate of 0.84% in the pain crisis cohort and 1.61% in the ACS cohort [12].This contrasts significantly with the mortality rate of 10.6% reported in a small prospective study by Minniti et al. [9].
In another study of the SECURE-SCD registry, Panepinto et al.
identified 178 COVID-19 patients with SCD; 6% of patients were asymptomatic, 54% had mild disease, and 40% had moderate to critical disease severity.Sixty-nine percent required inpatient admission and 11% needed ICU level of care [13].Similarly, the prospective study by In our study, COVID-19 vaccination rates were low (less than 20%) in every cohort, yet it demonstrated that previous immunization may have played an important role in preventing pain crises, finding also true for the influenza vaccine [20].Due to the timespan of the study, our data likely include patients who did not have access to COVID-19 vaccines that could potentially underestimate the true benefit of immunizations.Further research regarding the benefits of vaccination in pediatric and adult patients with SCD is a priority to be explored as strategies to increase vaccination rates could be implemented.
Our study has several potential limitations.First, in a retrospective study, data entry and collection methods are not established before study operations [21].This is further complicated in assessments of the TriNetX database because data quality cannot be retroactively

AUTHOR CONTRIBUTIONS
Grace Onimoe conceived the study, contributed to the analysis and interpretation of the data, and wrote the manuscript.Juan Alvarado conceived the study; contributed to the acquisition, analysis, and interpretation of data; and wrote the manuscript.Keval Yerigeri, Anita Boakye, Christina Randolph, and Aparna Roy contributed to the interpretation of data and wrote the manuscript.All authors had full access to all the data in the study.
ensured by investigators.TriNetX provides access to a large data set, but it poses unique limitations.It does not capture individual socioeconomic factors that influence health outcomes.It also collects data when patients present to participating healthcare organizations (HCOs); admissions to other institutions may account for the lower admission rates of this study.Second, participating HCOs are mainly large academic centers, skewing the study population.Third, loss to follow-up is also unaccounted for in data analysis and exclusion criteria[22].These confounding variables are not inconsequential and must be factored in when considering the generalizability of this study's results.Fourth, this study looked exclusively at pain crises and ACS with genotypes Hb-SS or Sβ0-thal, thus ignoring other genotypes in association with COVID-19.Additionally, although the period of the present study does include the Delta and Omicron variants of SARS-CoV-2, our database does not specify which variant each patient had.This study contributes to the field by showing the impact of COVID-19 on SCD-specific outcomes, which is important to understand for patient care, especially as COVID-19 variants continue to unfold.The study also contributes to research and management strategies for sickle cell disease as it reports on the effect of a disease of pandemic propensity (COVID-19) on SCD, hence providing crucial information for practitioners on how to anticipate and plan response in treating these patients.Future directions include patient-by-patient chart review to better understand medical and psychosocial factors influencing health outcomes, exploration of the mental health effects of the pandemic on patients with concomitant SCD and COVID-19, and development of actionable policies and advocacy for COVID-19 vaccination.

Table 2
shows the demographic characteristics of the SCD patients who developed pain crisis or ACS with concomitant SARS-CoV-2 infection and those without the infection.Patients with SCD and concomitant SARS-CoV-2 infection were compared with patients without the infection to determine the outcomes of pain crisis and ACS.The incidence of pain crises with accompanying infection was 34 per 100 patients, while the incidence of ACS with concomitant infection was 27 per 100 patients.SARS-CoV-2 significantly increased the risk of developing ACS (2.57% vs. 1.17% [p < 0.0001], relative risk [RR]: 2.2 [95% confidence interval [CI]: 1.72-2.82]),but not the risk for developing pain crises (4.35% vs. 4.18% [p = 0.71], RR: 1.04 [95% CI: 0.85-1.27]).
Laboratory outcomes of patients with pain crisis/acute chest syndrome (ACS) with and without concomitant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Reported up to 1 month after the diagnosis of pain crisis/ACS with concomitant infection or the diagnosis of pain crisis/ACS alone w/o SARS-CoV-2 infection.