Interleukin-7 Reverses Lymphopenia and Improves T-Cell Function in Coronavirus Disease 2019 Patient With Inborn Error of Toll-Like Receptor 3: A Case Report

Abstract

Background: Immunotherapy treatment for coronavirus disease 2019 combined with antiviral therapy and supportive care remains under intense investigation. However, the capacity to distinguish patients who would benefit from immunosuppressive or immune stimulatory therapies remains insufficient. Here, we present a patient with severe coronavirus disease 2019 with a defective immune response, treated successfully with interleukin-7 on compassionate basis with resultant improved adaptive immune function.

Case summary: A previously healthy 43-year-old male developed severe acute respiratory distress syndrome due to the severe acute respiratory syndrome coronavirus 2 virus with acute hypoxemic respiratory failure and persistent, profound lymphopenia. Functional analysis demonstrated depressed lymphocyte function and few antigen-specific T cells. Interleukin-7 administration resulted in reversal of lymphopenia and improved T-cell function. Respiratory function and clinical status rapidly improved, and he was discharged home. Whole exome sequencing identified a deleterious autosomal dominant mutation in TICAM1, associated with a dysfunctional type I interferon antiviral response with increased severity of coronavirus disease 2019 disease.

Conclusions: Immunoadjuvant therapies to boost host immunity may be efficacious in life-threatening severe coronavirus disease 2019 infections, particularly by applying a precision medicine approach in selecting patients expressing an immunosuppressive phenotype.

Keywords: case report; coronavirus disease 2019; immunotherapy; interferons; interleukin-7; toll-like receptor 3.

Figure 1.

Effect of interleukin (IL)–7 on clinical and immunologic variables in critically ill coronavirus disease 2019 patient. A, A test dose of IL-7 (3 μg/kg) was administered followed by three additional doses of 10 μg/kg as indicated by red arrows. IL-7 increased the absolute lymphocyte count (ALC) from ~400 lymphocytes/μL to over 5,000 lymphocytes/μL. Green lines indicate upper and lower limit of normal for ALC; IL-7 was well tolerated and did not show any evidence of worsening lung inflammation as indicated by observing a decreasing Fio₂ (B) and improving oxygen saturation (C). Blue arrows in (B) and (C) indicate day of intubation and extubation. Immunologic function of patient immune effector cells was tested by enzyme-linked immunospot (ELISpot). T-cell interferon (IFN)–γ production was tested in peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3/CD28 before and after IL-7 therapy administration to the patient. 2.5 × 10⁴ PBMCs are plated for T-cell functional assay. Note the dramatic increase in the number of lymphocytes that produce IFN-γ (as represented by number of spot forming units [SFUs]) in upper row after IL-7 therapy (D, top row); severe acute respiratory syndrome coronavirus 2 spike, and nucleocapsid peptide antigens were incubated overnight in patient PBMCs before and after IL-7 therapy. 1 × 10⁵ PBMCs are plated to assess antigen-specific T cells. Note the dramatic increase in the number of IFN-γ–producing lymphocytes (SFU) reacting specifically to the viral antigens after IL-7 (D, second row); innate immune function was tested by ELISpot assay for tumor necrosis factor (TNF)–α in PBMCs stimulated with lipopolysaccharide (LPS). 2.5 × 10³ PBMCs are plated to assess innate immune function. Note the marked increase in the number of TNF-α–producing cells (SFU) after IL-7 (E). CD = cluster of differentiation, Spo₂ = oxygen saturation, NCAP = nucleocapsid protein.