Management and outcome of COVID-19 in CTLA-4 insufficiency

Abstract

Despite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-β, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.

Graphical abstract

Figure 1.

Timeline of COVID-19 infection in 17 patients residing in the United States. All patients tested positive for COVID-19 via polymerase chain reaction or antigen testing. The duration of symptoms is indicated using rectangles, which are depending on whether they received COVID-19 vaccination. The timing of each SARS-CoV-2 vaccine dose is depicted using triangles. The dotted lines indicate when >95% of COVID-19 cases were caused by Delta (light gray) or Omicron (dark gray) variants, based on the Center for Disease Control variant surveillance data. Patients were grouped based on their vaccination status.

Figure 2.

Autoantibodies against type 1 IFNs. Autoantibodies against IFN-α (A), IFN-β (B), and IFN-ω (C) in patients with CTLA-4 insufficiency and COVID-19 (n = 6), CTLA-4 insufficiency with no COVID-19 (n = 10), healthy controls (n = 18), and patients with APECED (n = 10). One-way analysis of variance and post hoc Tukey tests were used for all comparisons. Nonnormally distributed data were transformed for normality. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.

Figure 3.

Anti-S serologies after vaccination or SARS-CoV-2 infection. Anti-S serologies in 16 patients who had available titers at several time points after SARS-CoV-2 infection or vaccination during the study period. The y-axis for P13 and P16 is shown using a different scale, given the high anti-S titers relative to that of other patients. P16 received tixagevimab/cilgavimab before serologies were drawn.