Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others.

Objective: Although several risk factors have been identified as related to complications from and severity of COVID-19, much about the virus remains unknown. The host immune response appears to affect the outcome of disease. It is not surprising that patients with intrinsic or secondary immune compromise might be particularly susceptible to complications from SARS-CoV-2 infection. Pathogenic loss-of-function or gain-of-function heterozygous variants in nuclear factor-κB2 have been reported to be associated with either a combined immunodeficiency or common variable immunodeficiency phenotype.

Methods: We evaluated the functional consequence and immunologic phenotype of a novel NFKB2 loss of function variant in a 17-year-old male patient and describe the clinical management of SARS-CoV-2 infection in this context.

Results: This patient required a 2-week hospitalization for SARS-CoV-2 infection, including 7 days of mechanical ventilation. We used biologic therapies to avert potentially fatal acute respiratory distress syndrome and treat hyperinflammatory responses. The patient had an immunologic phenotype of B-cell dysregulation with decreased switched memory B cells. Despite the underlying immune dysfunction, he recovered from the infection with intense management.

Conclusions: This clinical case exemplifies some of the practical challenges in management of patients with SARS-CoV-2 infection, especially in the context of underlying immune dysregulation.

Keywords: COVID-19; NF-κB; NF-κB pathway; NF-κB2; SARS-CoV-2; immunodeficiency.

Fig 1

Schematic drawing of the NF-κB2 protein. This represents the protein domains of NF-κB2 for the full-length precursor and the processed p52 protein. The known NF-κB2 variants are listed along with this patient’s variant. A total of 50 patients with 18 variants have been described in the literature. This patient’s variant is p.Ser866Asn in the C-terminal region of the protein.

Fig 2

Immunoblotting for NF-κB2, p52, and phosphorylated p65 (RelA). A, PBMCs from the patient (Pt) and healthy controls 1 to 3 (NC 1, NC 2, and NC3) were stimulated with soluble anti-CD3. Immunoblotting was performed for NF-κB2 precursor (p100) and the processed form (p52), phosphorylated NF-κB2, and phosphorylated p65 (RelA) of the canonical pathway in both stimulated and unstimulated samples. There is a distinct inability to phosphorylate NF-κB2, and the amount of processed p52 protein is substantially reduced in the patient sample following stimulation. B, Densitometric analysis of the immunoblot in (A). C, T-cell blasts were generated from PBMCs by stimulation with anti-CD3 and anti-CD28 with IL-2. Blast cell lysates were analyzed for p100 and p52 of NF-κB2. D, Bar graphs depict the relative expression levels of these proteins normalized to β-actin by densitometry. Compared with in normal controls, there is a small decrease in p100 but a remarkable reduction in the processed form, p52 protein, which correlates with the PBMC data. The extent of decrease in phospho-NF-κB2 and p52 is supportive of a complete deficiency for this variant.

Fig 3

Clinical course of SARS-CoV-2 infection. Key clinical, laboratory, and radiologic parameters are depicted. ALC, absolute lymphocyte count; ALT, alanine transaminase; ANC, absolute neutrophile count; AST, aspartate transaminase; BNP, brain natiuretic peptide; ESR, erythrocyte sedimentation rate; IGIV, intravenous IgG; IGSC, subcutaneous IgG; INR, international normalized ratio; NP, natiuretic peptide; PT, prothrombin time; PTT, partial thromboplastin time; WB, whole blood; WBC, whole blood cell.

Fig E1

Treg cell subset quantitation. The gating strategy for Treg quantitation is depicted for a representative healthy control (HC) and the patient. From CD4⁺ T cells, the frequency (percentage) of CD25^high T cells (CD25^hi), FOXP3⁺ Treg cells, and CD25+CD127^low/– Treg cells were gated by using CD25, FOXP3, and CD127.