Intravenous immunoglobulins in the treatment of post-COVID: A case-control study.

Dear Editor, The post-COVID syndrome (post-COVID) constitutes a major physical and psychological problem for many subjects after recovery from coronavirus disease 2019 (COVID-19) [1]. Symptoms include fatigue, shortness of breath, myalgia and cognitive dysfunction. They frequently have a deleterious effect on everyday functioning. To date, there is no evidence-based therapy. Since autoimmunity is supposed to contribute to post-COVID, we administered intravenous immunoglobulins (IVIg) as an immunomodulatory approach to patients with severe post-COVID refractory to supportive therapeutic measures. We performed a retrospective case–control study comparing 10 patients who received 3–4 monthly courses of IVIg (0.5 g/kg PrivigenR, CSL Behring, Austria; Group 1) in addition to supportive treatment, 10 patients who were treated with inhaled glucocorticoids (budesonide 2 × 0.2 mg/day, Group 2) and 10 patients who were treated by supportive measures in a specialized post-COVID outpatient clinic (Group 3). Matching of controls was based on severity of symptoms, time since COVID-19 and age. Post-COVID symptoms at baseline and follow-up were retrospectively quantified using a 19-item questionnaire based on the ISARIC COVID-19 follow-up study protocol [2]. Comparison of intraindividual changes in the modified ISARIC score from baseline to follow-up was analyzed using the Kruskal–Wallis test. A detailed description of protocol and statistics is presented in the Supporting Information. The study was approved by the local ethics committee of the Ruhr-University Bochum (reg. number 22–7546). The study population was homogeneous for age, comorbidities and time since SARS-CoV-2 infection. Baseline symptoms were not significantly different except insomnia (more frequent in Group 1). A clinical and epidemiological characterization is presented in Table S1. Median baseline modified ISARIC score was 8 (interquartile range [IQR] 6.5–8.5) in Group 1, 8 (IQR 4.75–10.0) in Groups 2 and 7 (IQR 5.5–7.5) in Group 3. At follow-up, the ISARIC score significantly dropped to 3 (IQR 1.0–3.0, p = 0.021) in Group 1, 7 (IQR 4.75–9.25, p = 0.02) in Group 2 and 6 (IQR 4.0–7.0, p = 0.001) in Group 3 (Fig. 1). The change of score (Δ) was significantly higher in Group 1 (−5.44 ± 2.35; p < 0.001) than in Groups 2 (−0.3 ± 0.82; p < 0.05) and 3 (−0.89 ± 0.93; p < 0.05, Table S1). In addition, a strong effect size (r = 0.825) could be demonstrated for Group 1. All patients from Group 1 reported relief of symptoms, whereas only four patients (40%) of Group 2 and six patients (60%) in Group 3 did so. As presented in Fig. S1, the most prominent improvements after administration of IVIg were observed for listlessness, brain fog and fatigue. A screening for autoantibodies including ANA, ANCA, dsDNA-ab and ENA-6-profile was negative before and after administration of IVIg. Moreover, the treatment with IVIg was not associated with a significant change in the concentration of the following cytokines in a subset of patients: IL-1β, IFN-α2, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23 and IL-33. The present study identifies IVIg as a promising candidate for the treatment of severe post-COVID refractory to supportive measures. Patients receiving IVIg and supportive measures reported a substantially greater relief of symptoms than patients receiving supportive therapy alone. Interestingly, especially the most restrictive symptoms of fatigue, listlessness and brain fog responded well to this approach. With regard to the high physical and psychological stress, the subsequent impairment of daily functioning and the lack of any specific treatment so far, these results are promising. The most probable pathophysiologic mechanisms of post-COVID include virus-specific pathophysiologic changes, sequelae of post-critical illness and immunologic aberrations in response to the acute infection leading to autoimmunity-mediated damage [3]. Thus, several autoantibodies have been identified in acute COVID-19 [4]. IVIg contain a broad spectrum of anti-idiotypic antibodies, which neutralize the deleterious autoimmune antibodies. This mechanism is very attractive in the context of post-COVID because it remediates antibody-mediated autoimmunity without the side effect of systemic immunosuppression. Although this is the first report on the use of IVIg in post-COVID, some data indicate a positive effect of IVIg administration in acute COVID-19. However, data on this issue are sparse and controversial [5]. Notably, IVIg therapy ameliorates symptoms in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well, especially if it was triggered by a viral infection [6]. In this context, post-COVID may be regarded as a SARS-CoV-2-induced CFS. This matched case–control study is limited by its size and its retrospective character. Thus, it is hypothesis-building but does not prove the efficacy of IVIg in post-COVID. The substantial difference between the three groups nevertheless suggests that IVIg might be a candidate approach for post-COVID that requires further evaluation in randomized controlled trials. Open Access funding enabled and organized by Projekt DEAL. The authors received no specific funding for this study. The authors have declared no conflicts of interest. Supplementary Table 1: Clinical characterization of study population. Supplementary Table 2: Individual symptoms at baseline according to the modified ISARIC-Score. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.