Sickle Cell Trait Associated With Adverse Outcomes Following COVID-19

Some demographic and preexisting medical conditions are associated with adverse outcomes in COVID-19, including chronic kidney disease (CKD), chronic obstructive pulmonary disease, and sickle cell disease (SCD). SCD has two copies of hemoglobin beta sickle alleles (rs334-T). Sickle cell trait (SCT) has one rs334-T and one wild-type allele; SCT affects more than 3 million people in the United States and 300 million people worldwide. Largely considered a benign condition, there are associations between SCT and increased risk for adverse outcomes including chronic kidney disease.

During the COVID-19 pandemic, the Centers for Disease Control and Prevention advised that patients with SCD were highly susceptible to the infection. However, the advice did not extend to individuals with SCT. According to Anurag Verma, PhD, and colleagues, there are few data available on the association between SCT and outcomes in COVID-19.

The researchers conducted an analysis of data from the Million Veteran Program (MVP) to examine the association of SCT with preexisting conditions, severity of COVID-19 outcomes, and conditions post-COVID-19. Results were reported in JAMA Internal Medicine [2-22;182(8):796-804].

A total of 132 577 participants in the MVP had COVID-19 data; mean age at the index date was 64.8 years. Of study participants of African ancestry, 7.8% had the sickle allele (rs334-T), as did 1% of participants of Hispanic ancestry. The researchers conducted ancestry-specific analysis. The primary findings were focused on participants of African ancestry.

The researchers performed a phenome-wide association study (PheWAS) analysis to test for associations between rs334-T and preexisting conditions preceding the COVID-19 pandemic among 658 358 MVP participants. The test identified 31 phecodes with significant association in participants of African ancestry. The most significant association was sickle cell anemia/trait-related condition (phecode: 282.5; odds ratio [OR], 93.17; 95% CI, 78.60-110.44; P=1 ×.10^–300).

There were also associations with conditions related to COVID-19 severity and mortality, including CKD (OR, 1.45; 95% CI, 1.36-1.55; P=1.8 × 10^–28), type 2 diabetes with kidney complications (OR, 1.33; 95% CI, 1.23-1.43; P=3.7 × 10^–13), pulmonary embolism (OR, 1.43; 95% CI, 1.27-1.60; P=1.73 × 10^–9), pulmonary heart disease (OR, 1.30; 95% CI, 1.19-1.42; P=5.3 × 10^–9), and hypertensive kidney disease (OR, 1.19; 95% CI, 1.12-1.26; P=2.77 × 10^–9).

In analyses of the association of the 31 preexisting conditions identified from comorbidity association studies with COVID-19 outcomes among MVP participants of African ancestry, 13 of the conditions were associated with COVID-19 related death. The most significant associations were with kidney disorders such as chronic kidney failure (OR, 1.95; 95% CI, 1.44-2.62; P=9.3 × 10^–7), CKD (OR, 1.94; 95% CI, 1.44-2.62; P=1.2 × 10^–5), and kidney dialysis (OR, 2.07; 95% CI, 1.24-3.45; P=.005).

The researchers examined the association between SCT and four COVID-19 outcomes: (1) susceptibility; (2) hospitalization; (3) severe conditions where patients required ventilator support or admission to the intensive care unit; and (4) COVID-related death. In individuals with African ancestry, there was a statistically significant association between SCT and increased risk of death from COVID-19 (OR, 1.77; 95% CI, 1.13-2.77; P=.01). Meta-analysis of the estimates across two ancestral groups provided more statistical power and a stronger association between SCT and COVID-19-related deaths (OR, 1.77; 95% CI, 1.13-2.77; P=.005).

In contrast, there were no associations between rs33930165-T, an HbC allele with a prevalence of 1.7% among individuals with African ancestry, and any COVID-19 outcomes. Results of association analyses demonstrated that the HbC allele was not associated with the clinical/kidney conditions associated with SCT.

The researchers also investigated the incidence of acute kidney failure and declining kidney function within 60 days of diagnosis of COVID-19 and their interaction with SCT. A total of 31 287 individuals of African ancestry who were tested for COVID-19; 66.8% had stable and normal kidney function, 31% had declining kidney function, and 27.4% had kidney impairments, including acute kidney failure, prior end-stage kidney failure, CKD, chronic kidney failure, or nephrosis within 2 years before the COVIID-19 diagnosis.

Compared with those without SCT, there was a statistically significant increase in postindex acute kidney failure in individuals with SCT (OR, 1.40; 95% CI, 1.09-1.90; P=.02). The interaction model suggested a significant interaction effect of COVID-19 with SCT on acute kidney failure (P=.02). In separate models, following adjustment for preexisting kidney impairment based on International Classification of Diseases codes in stepwise regression analysis or declining kidney function based on primarily laboratory values, the ORs for acute kidney failure remained largely unchanged with a nominally significant P value in all the models.

SCT was significantly associated with death in patients with COVID-19, and those with SCT had a higher risk of acute kidney failure due to COVID-19. Mediation analysis was used to determine how much of the effect of SCT on COVID-19-related death was mediated through acute kidney failure due to COVID-19. On average, 22% (95% bootstrap CI, –3% to 83%) of the total effect of SCT on death related to COVID-19 was mediated through acute kidney failure within 60 days of COVID-19.

The researchers cited some limitations to the study findings, including the MVP participants being predominately male, and the possibility of residual confounding.

In conclusion, the authors said, “In this genetic association study, SCT was associated with increased COVID-19 mortality and a number of preexisting chronic medical conditions in African ancestry individuals. Our findings support the inclusion of SCT as an adverse prognostic factor for COVID-19 and development of SCT-tailored interventions. Our work has broad implications for the detection and clinical management of SCT.”

Takeaway Points

1. Researchers conducted a genetic association study to examine the association of sickle cell trait (SCT) with outcomes in patients with COVID-19.
2. The study cohort included 2729 individuals with SCT and 129 848 who were SCT negative; those with SCT had various preexisting conditions that were associated with adverse outcomes post- COVID-19.
3. The results support including SCT as an adverse prognostic factor for COVID-19.