Abstract
Patients with the monogenic immune dysregulatory syndrome autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene, uniformly carry neutralizing autoantibodies directed against type-I interferons (IFNs) and many develop autoimmune pneumonitis, both of which place them at high risk for life-threatening COVID-19 pneumonia. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target the SARS-CoV-2 spike protein and block entry of SARS-CoV-2 in host cells. The use of bamlanivimab and etesevimab early during infection was associated with reduced COVID-19–associated hospitalization and death in patients at high risk for progressing to severe disease, which led the US Food and Drug Administration to issue an emergency use authorization for their administration in non-hypoxemic, non-hospitalized high-risk patients. However, the safety and efficacy of these mAbs has not been evaluated in APECED patients. We enrolled two siblings with APECED on an IRB-approved protocol (NCT01386437) and admitted them prophylactically at the NIH Clinical Center for evaluation of mild-to-moderate COVID-19. We assessed the safety and clinical effects of early treatment with bamlanivimab and etesevimab. The administration of bamlanivimab and etesevimab was well tolerated and was associated with amelioration of COVID-19 symptoms and prevention of invasive ventilatory support, admission to the intensive care, and death in both patients without affecting the production of antibodies to the nucleocapsid protein of SARS-CoV-2. If given early in the course of COVID-19 infection, bamlanivimab and etesevimab may be beneficial in APECED and other high-risk patients with neutralizing autoantibodies directed against type-I IFNs.
Highlights
Studies seeking to identify risk factors for severe COVID-19 uncovered genetic and acquired defects in type-I IFN pathways in a proportion of patients with life-threatening COVID-19 pneumonia
Laboratory studies were significant for a decreased absolute lymphocyte count (ALC) and elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer (Figures 1D–F), absolute neutrophil count (ANC) (7.74 K/μL), absolute monocyte count (AMC) (0.91 K/μL) (Supplementary Figure 3A), lactate dehydrogenase (LDH) (260 units/L), and fibrinogen (491 mg/dL), while ferritin was normal (83 mg/L)
We found that the patient mounted an immune response to the SARS-CoV-2 nucleocapsid protein by day 16 after symptom onset and, as expected, we detected anti-S antibodies starting the day after administration of bamlanivimab and etesevimab (Figure 3A)
Summary
Studies seeking to identify risk factors for severe COVID-19 uncovered genetic and acquired defects in type-I IFN pathways in a proportion of patients with life-threatening COVID-19 pneumonia. TLR7 variants that were associated with impaired type-I IFN responses were independently reported in a few patients with severe COVID-19 [2]. A separate study showed that ~10% of individuals with severe COVID-19 pneumonia had neutralizing autoantibodies directed to type-I IFNs [3]. The presence of these autoantibodies in patients with critical COVID-19 pneumonia was independently verified in other patient cohorts [4, 5] and was recently shown to be associated with delayed viral clearance during COVID-19 infection [6], underscoring the importance of type-I IFNs in the protective immune response against SARS-CoV-2 [7]. Therapeutic approaches aimed to boost viral clearance and type-I responses have been described in some APECED and other patients with type-I IFN autoantibodies, including administration of IFN-b, remdesivir, and/or plasmapheresis [13, 15,16,17]
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