Clinical outcome and humoral immune responses of β-thalassemia major patients with severe iron overload to SARS-CoV-2 infection and vaccination: a prospective cohort study

Abstract

Background: COVID-19 has raised special concern for patients with β-thalassemia major (β-TM) due to frequent comorbidities, regular blood transfusions, and iron overload. However, the exact implications of COVID-19 for patients with β-TM remain uncertain. We aimed to explore the COVID-19 incidence and severity, and the serological response to SARS-CoV-2 infection and vaccination in patients with β-TM.

Methods: Patients with β-TM (n = 105) and age-matched healthy controls, all individuals of all control groups were health care workers of the hospital, were prospectively enrolled at the haematology department of Al-Shifa hospital in the Gaza Strip from January 1st, 2021 to December 31st, 2021. Data on COVID-19 incidence and severity were analysed, with Alpha, Beta, and Delta SARS-CoV-2 variants dominating at that time. Anti-SARS-CoV-2 IgG antibody levels were measured and compared between study groups.

Findings: Patients with β-TM showed a higher incidence of SARS-CoV-2 infection than the general population (61.9% vs. 7.1%, p < 0.0001). Most patients with β-TM had asymptomatic (70.8%) or mild disease (26.1%), with no fatalities recorded. COVID-19 illness was more severe among female than male patients with β-TM. Anti-SARS-CoV-2 IgG antibodies were significantly higher in symptomatic patients with β-TM than controls post-infection (geometric mean ÷ geometric standard deviation 1299.0 ÷ 3.3 vs. 555.7 ÷ 2.4 AU/mL, p = 0.009) and post-vaccination (8404.0 ÷ 3.9 vs. 2785.6 ÷ 5.0 AU/mL, p = 0.015). Similar responses were observed when comparing splenectomised to non-splenectomised (both asymptomatic and symptomatic) patients with β-TM post-infection (595.4 ÷ 3.9 vs. 280.7 ÷ 3.5 AU/mL, p = 0.005) and post-vaccination (13,778.2 ÷ 3.2 vs. 4961.8 ÷ 4.1 AU/mL, p = 0.045).

Interpretation: This distinctive β-TM cohort exhibited a high susceptibility to SARS-CoV-2 infection but mild disease course. Our findings support favourable serological responses to SARS-CoV-2 infection and to vaccination in patients with β-TM, indicating a potential interplay between iron availability and COVID-19-related immunity.

Funding: This study was funded by Mr. Hosam and Wasim s. El Helou.

Keywords: COVID-19; Humoral immune response; Innate immune function; Iron; Iron chelation; Splenectomy; Vaccination; β–thalassemia major.

Fig. 1

COVID-19 illness severity in β-TM categorised by sex (panel A) and splenectomy history (panel B). (A) COVID-19 illness severity in β-TM cohort (n = 105). Most of the patients (70.8%) remained asymptomatic, while 26.1% experienced mild symptoms, and only 3.1% developed a moderate infection. None of the infected patients with β-TM fell into the severe, critical, or death categories. A significant difference in COVID-19 illness severity between infected male (n = 38) and female (n = 27) patients with β-TM was found (p = 0.013). While the male infected patients with β-TM were predominantly included in the asymptomatic category, the mild category included mostly female patients, and the moderate category was comprised only of female patients. (B) No significant difference in COVID-19 illness severity was found between splenectomised (n = 36) and non-splenectomised patients with β-TM (n = 29) (p = 0.863). Abbreviations: β-TM, β-thalassemia major; COVID-19, coronavirus disease 2019.

Fig. 2

Serum anti-SARS-CoV-2 IgG antibody titres in patients with β-TM and age-matched control groups both 3 months post-infection (Panels A & B) and 3 months post-vaccination (Panels C & D). (A) Symptomatic β-TM (n = 24) showed significantly higher anti-SARS-CoV-2 IgG antibody titres compared to control group A (n = 41) after infection (GM ÷ GSD 1299.0 ÷ 3.3 vs. 555.7 ÷ 2.4 AU/ml, p = 0.009). (B) Post-infection anti-SARS-CoV-2 IgG antibody titres were significantly higher in (asymptomatic and symptomatic) splenectomised (n = 29) compared to non-splenectomised patients with β-TM (n = 25) (GM ÷ GSD 595.4 ÷ 3.9 vs. 280.7 ÷ 3.5 AU/ml, p = 0.005). (C) In comparison to age-matched individuals of control group B (n = 23), previously uninfected vaccinated patients with β-TM (n = 31) had significantly higher anti-SARS-CoV-2 IgG antibody titres (GM ÷ GSD 8404.0 ÷ 3.9 vs. 2785.6 ÷ 5.0 AU/mL, p = 0.015). (D) Among the vaccinated patients with β-TM, splenectomised individuals (n = 16) had a significantly higher anti-SARS-CoV2 IgG titre than non-splenectomised individuals (n = 15) (GM ÷ GSD 13778.2 ÷ 3.2 vs. 4961.8 ÷ 4.1 AU/mL, p = 0.045). Abbreviations: β-TM, β-thalassemia major; GM, geometric mean; GSD, geometric standard deviation; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 3

Serum anti-SARS-CoV-2 IgG antibody titres in β-TM patients after infection, categorised by blood group. Significant differences in post-infection anti-SARS-CoV-2 IgG titres in patients with β-TM, with both asymptomatic and symptomatic COVID-19, according to their underlying blood group types indicate lowest titres in individuals with blood group B (n = 8) (GM ÷ GSD 162.2 ÷ 2.2 AU/ml) and highest titres in blood group O (n = 22) (684.9 ÷ 3.2 AU/ml), followed by blood group AB (n = 2) (397.2 ÷ 2.6 AU/ml), and blood group A (n = 22) (366.4 ÷ 4.7 AU/ml) (p = 0.012). Abbreviations: β-TM, β-thalassemia major; GM, geometric mean; GSD, geometric standard deviation; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.