WJNS  Vol.10 No.2 , May 2020
Immunotherapy for the Post-Infectious Sequela of SARS-CoV-2 Infection
Abstract: The SARS-CoV-2 2019 pandemic is creating challenges to the management of post-infectious autoimmunity in childhood and adult Covid-19 cases due to its high case fatality. Nearly all of the agents envisioned to treat Covid-19 illness, including the newly recognized pediatric multi-system inflammatory syndrome, impact post-infectious mechanisms in keeping with the multiplier effect of infection, immunity and inflammation, known as I-Cubed (I3).

The SARS-CoV-2 ([Covid-19.1]) pandemic is proving to be associated with high-case fatalities in both children and adults due to a dysregulated, post-infectious autoimmunity response, analogous to the cytokine storm of severe viral influenza illness [1]. The potentially devastating outcome of uncontrolled post-infectious autoimmunity due to SARS-CoV-2 exposure is more severe and long lasting than the infection itself especially in vulnerable patients, including young children with multi-system inflammatory syndrome (New York State Department of Health, Bureau of Communicable Disease Control. Health Advisory: Pediatric multi-system inflammatory syndrome potentially associated with coronavirus disease (COVID-19) in children. May 6, 2020) and older adults with acute respiratory distress syndrome [2]. Recognizing the importance of a given patient’s immune response to the SARS-Cov-2 exposure, subjects are now being recruited to participate in studies to examine B- and T-cell repertoire and immune responses during the acute and resolved phases of Covid-19 infection at home and in the hospital ( Identifier: NCT04362865).

Four immunotherapeutic approaches are being used to stem the Covid-19 pandemic by targeting the immune system, in keeping with the multiplier effect of infection, immunity and inflammation known as I-Cubed (I3) [3]. The oral antimalarial drug hydroxychloroquine was the first highly publicized agent recognized for its immune-mediated mechanisms of chemotaxis, phagocytosis and superoxide production by neutrophils to inhibit SARS in vitro [4]. It was administered in an open-label non-randomized clinical trial of 20 adults and minors with severe Covid-19 illness with improvement, and later made widely available as prophylaxis [5]. An observational study of 1446 hospitalized adult patients at a New York City hospital with Covid-19 illness did not show a significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32), with similar findings in multiple sensitivity analyses [6]. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed to establish efficacy. A phase IIB study to evaluate the efficacy of hydroxychloroquine and azithromycin to prevent hospitalization and death in symptomatic adult outpatients with Covid-19 caused by SARS-CoV-2 infection has not started recruiting subjects ( Identifier: NCT04358068).

The biological agent remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases that showed in vitro activity against SARS-CoV-2 compassionately treated a cohort of 61 adults patients with improvement in two-thirds [7]. A clinical protocol allowing expanded access to remdesivir ( Identifier: NCT04323761), and several clinical studies have begun recruiting subjects in an randomized, open-label, controlled clinical trial, in collaboration with the World Health Organization (WHO) ( Identifier: NCT04330690). A phase III randomized study comparing the safety and efficacy and antiviral activity of two remdesivir regimens with respect to clinical status is recruiting subjects ( Identifier: NCT04292899). An open label study to evaluate the safety and antiviral activity of remdesivir with moderate Covid-19 compared to standard of care treatment is recruiting subjects ( Identifier: NCT04292730).

Convalescent plasma transfusion of SARS-CoV-2–specific IgG and neutralizing antibodies have been administered in uncontrolled case series to critically ill adult patients with Covid-19 with clinical improvement [8]. These preliminary findings suggest a role for transfusion therapy in the treatment of critically ill patients with COVID-19). A pilot prospective study collecting plasma to measure neutralizing antibodies to SARS-Cov-2 in recovered subjects has not yet starting recruiting participants ( Identifier: NCT04344977).

In retrospect, treatment with 2 grams per kilogram high-dose IVIg therapy administered to 3 adult patients over 4-5 consecutive days in the early stages of clinically apparent SARS-Cov-2 viremia, alone (1 patient) or in association with antiviral and antibacterial antibiotics showed clinical stabilization and were uneventfully discharged from the hospital [9]. Early administration of IVIg is first-line therapy in children with Kawasaki Disease (KD) that appears to be missed or delayed during the Covid-19 pandemic [10], but may also be etiologically related to SARS-CoV-2 infection. A single-center, randomized, open-label, controlled study in Peking China is evaluating the safety of IVIg in conjunction with standard care for severe 2019-nCov pneumonia has not started recruiting subjects ( identifier NCT04261426). However, no similarly available studies have been announced in the US.

An anecdotal prospective analysis of 55 children and adults treated with maintenance (400 mg/kg monthly) and high-dose (2 grams/kg) IVIg therapy to treat diverse acquired and post-infectious autoimmune neurological disorders, found no new cases of SARS-CoV-2 stratified by a single home infusion service via phone interviews at the height of the Covid-19 pandemic (when it would have been impermissible for a nurse to enter the home) [11]. This uncontrolled observation suggests that IVIg therapy may yet have an important role in Covid-19 illness prevention among vulnerable individuals. However, a longer period of follow-up of this cohort will be necessary to confirm these observations, as are further controlled studies to identify the dose and frequency of IVIg treatment to confer prophylactic efficacy.

Cite this paper: S. Younger, D. (2020) Immunotherapy for the Post-Infectious Sequela of SARS-CoV-2 Infection. World Journal of Neuroscience, 10, 117-120. doi: 10.4236/wjns.2020.102013.

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