Preliminary Guidelines for the Use of IVIg during COVID-19

Infection with the severe acute respiratory syndrome novel type-2 novel coronavirus (SARS-CoV-2) responsible for the 2019 coronavirus disease (COVID-19) shows a highly heterogeneous clinical presentation and age affliction in children and adults, ranging from asymptomatic or mild disease to severe involvement, with potentially fatal respiratory failure and multiple organ dysfunction. As susceptibility to severe COVID-19 depends upon comorbid factors including immune competence, optimizing the latter through low-dose supplementation or high dose treatment with immune globulin therapy in those with primary immune deficiency and post-infectious immune sequelae of SARS-CoV-2 and existing autoimmune disorders is essential. There are no existing guidelines hence; this paper provides a framework for considering preliminary guidelines for the use of immune globulin therapy during COVID-19.


Background and Rationale
SARS-CoV-2 infection triggers a dysregulated innate and adaptive immune response accompanied by hyperinflammation known as the cytokine storm [1] during which the viral escapes from innate sensing particularly the interferon I (IFN-I) pathway, with activation of myeloid cells, depletion of T-cells, NK T-cell dysfunction, and hemostatic imbalance with widespread clotting. The most dismal outcome is observed in older patients with excessive comorbid disease [2] who sustain hypoxic and inflammatory brainstem and cerebral insults before succumbing to pulmonary embolism, multiple organ failure, and fatal cardiopulmonary arrest [3], and children affected by multisystem inflammatory syndrome (MIS-C) [4]. Unvaccinated younger adults, ages 18 to 23 years [5] and very young school-aged children, ineligible for vaccination who, promote community spread [6] may suffer worse COVID-19 outcomes when they have at least one underlying medical condition [7]. Other children with established pediatric autoimmune neuropsychiatric disease associated with Group A beta hemolytic streptococcus (PANDAS) and the closely related disorder PANS, triggered by other microbial agents, notably autoantibody-positive and seronegative autoimmune encephalitides (AE) [8] may be vulnerable to post-infectious SARS-CoV-2 hyperimmunity. Clinicians treating severe hospitalized COVID-19 may administer monthly high-dose intravenous immune globulin (IVIg-HD) therapy at doses of 1 -2 grams per kilogram (g/kg) over 3 to 5 days to delay progression and improve mortality of SARS-CoV-2-related illness [9]. However, IVIg-HD therapy may be safely administered and well-tolerated at higher total monthly doses with careful monitoring of serum IgG levels, and renal, liver, bone marrow and clotting parameters. More recently, IVIg-HD has been used in the empiric treatment of post-acute sequela of COVID-19 (PASC) [10]. This disorder is defined by the National Institutes of Health [11] as new or persistent organ-related symptoms lasting longer than one month after initial infection. Vulnerable individuals including those ineligible or hesitant to vaccinate, and pre-existing immune deficiency or autoimmune illness, as well as others recovering from SARS-CoV-2-related exposure with acquired immune deficiencies, may benefit from monthly low-dose (LD) (400 -500 mg/kg) (IVIg-LD) or standard subcutaneous (SC) Ig therapy to restore normal host immunity [12]. Table 1 shows some of the neurological disorders in which Ig therapy has had a treatment role during COVID-19.
The way forward for prospective candidates benefitting from Ig therapy during the COVID-19 pandemic and afterward remains to be charted. This article provides a series of recommendations for clinicians, patients, and lay groups on this subject.

Literature Search Methodology
The search rationale followed a PICO model including children and adults (P) treated with Ig (I): LD or HD and SC or IV for post-infectious SARS-CoV-2-related or incidental immune disorders (C), and the immune modulatory outcome (O) thereof.

Limitations
There is a paucity of literature on the judicious use of IVIg during  and in response to the post-infectious sequelae thereof. Furthermore, the proposed guidelines are not intended to be reflective of its use over or above other established immune modulatory therapies.

Severe COVID-19
Three hundred seventeen (317) reported patients received IVIg therapy for severe hospitalized COVID-19 in 2020, including 174 patients in a multi-center study [13], 119 patients in three single center studies [14] [15] [16], eight patients in two cases series (8 patients) [17] [18], and 17 patients in an open-label randomized clinical trial [19]. Doses ranged from 0.1 to 0.5 g/kg for 3 to 5 days over a month, generally in association with the SOC that included corticosteroids (CS) and antibiotics, antivirals, or interferon therapy. Primary endpoints of reduced 28-day, 30-day and 60-day mortality and prevention or slowing of progression were cited as favorably influenced by the addition of IVIg to the SOC. SARS-CoV-2 encodes one superantigen motif near its S1/S2 cleavage site that might trigger the cytokine storm [21]. As IVIg contains antibodies reactive against SARS-CoV-2 antigens [22], IVIg might inhibit superantigen-mediated T-cell activation, cytokine release and an incipient cytokine storm.

Adult and Childhood Post-Acute Sequelae of SARS-COV-2 (PASC)
The scientific community and healthcare professionals not only face the dilemma of understanding the diverse ways in which SARS-CoV-2 affects the host cells, but also the capability of the virus to exert prolonged organ effects espe-World Journal of Neuroscience cially in the nervous system, after the acute-phase of infection. Affected patients may fail to revert to normal and instead develop new organ symptoms, especially in the nervous system. It is unlikely that the proposed designations, "Covid Long Hauler (LH) and Long Covid" [23] are inclusive or accurate enough to describe this disorder. However, given the magnitude of those affected, and their congregation in self-selected social media and Facebook groups, they may be useful cohorts for future studies. Instead, through its recent launch by the NIH of the SARS-CoV-2 Recovery Cohort and Investigator Consortium [11], it focuses attention on PASC and LHs.

Genetic and Acquired Immune Deficiency
IVIg was first employed to treat immunodeficiencies in the 1950s and is currently licensed for the treatment of primary immunodeficiencies (PIDs) with impaired antibody production, secondary immunodeficiencies with recurrent infections, selective IgG and IgA antibody deficiencies, and proven specific antibody failure (PSAF) [31]. The management of PID and SID includes IVIg therapy to restore serum Ig levels and humoral immunity back to normal. The comparatively high morbidity and mortality in PID and SID should inform public health policy and be communicated to affected and at-risk patients so they can take appropriate actions to reduce their exposure to the virus and have access to IVIg therapy. It remains to be seen whether patients with PID and SID elaborate normal amounts of SARS-CoV-2 IgG and if IVIg prevents or increases that likelihood.

Autoimmunity
It is not known whether incidental treatment of autoimmune diseases (AD) with However, experts agree that from a pathogenesis standpoint, SARS-CoV-2 triggers a vigorous host immune response that appears to be not only crucial for viral clearance, involving both the innate and adaptive immune arms, but also immune changes responsible for post-acute sequelae and long-lasting autoimmune diseases (AD) [36]. However, SARS-CoV-2 is linked to many autoinflammatory disease states that emerge in acute COVID-19 illness, even before they can be properly labeled AD, and benefit from IVIg including Guillain-Barré syndrome (GBS) [37], KD [38] and thrombotic microangiopathy (TMA) with abnormal complement activation [39]. Large epidemiological studies involving case-control studies and prospective cohorts treated with IVIg in the course of COVID-19 illness may illuminate whether it impacts autoinflammatory and AD sequela.
A very recent publication in press at the time of this writing [40] demonstrates PASC in a child with striking similarity to the adult conditionclinically and in its responsiveness to HD-IVIg suggesting a continuum of potentially prolonged post-COVID-19 neurological autoimmunity in the absence of effective treatment.

Conclusion
It is a public health priority to better understand and develop strategies to pre-

Recommendations
While awaiting the results of the NIH sponsored SARS-CoV-2 Recovery Cohort [10], some useful guidelines can be posited in the use of IVIg.
1) IVIg-HD is indicated in all patients acute severe COVID-19 to ameliorate the post-infectious autoimmune cytokine storm and widespread clotting due to complement-mediated TMA.
2) IVIg-HD is indicated in all patients COVID-19 who present with or develop autoimmune disorders such as GBS who would normally be treated in the absence of COVID-19. Readers are referred to https://www.davidsyounger.com for recommendation updates.

Conflicts of Interest
The author declares no conflicts of interest regarding the publication of this paper.