An opinion data of almost one hundred international pediatric rheumatologists at the time of peaking COVID-19 pandemic are presented. Due to the rapid evidence evolvement in these unique times may this survey impose slightly outdated. However, the growing body of evidence regarding treatment options in patients with COVID-19 or management strategies of individuals with AID applies still mainly to the adult population. Furthermore, the care for children and adolescent with COVID-19 as well as the approach to the pediatric patients with AID in context of the COVID-19 pandemic remains controversial and only scarce data on changes in health care of pediatric patients with rheumatic diseases are available [
33,
34].
Treatment strategies in pediatric patients with COVID-19
In this survey, remdesivir was the most frequently considered virus-directed drug in pediatric patients (almost 50% support throughout all disease stages). Frequent concurrent choice of remdesivir and/or cytokine blockade and/or corticosteroid therapy points towards possible combination strategies. This opinion is very well in line with later published data on positive clinical effects in a subset of patients with COVID-19 [
35‐
37]. Those findings resulted in an emergency use authorization from the US Food and Drugs Administration (FDA), including children over 12 years of age and/or weighing more than 40 kg [
38], followed by approval in Europe [
39]. Early use during the viral replication stage seems to be most beneficial [
40,
41].
Within the group of immunomodulatory drugs corticosteroid use gained the highest respondents’ support, reaching 35.8% and 81.7% use of oral and intravenous corticosteroids, respectively, for patients in stage III. This view corresponds with "real life" COVID-19 treatment data worldwide [
42] and is underpinned by the findings from the RECOVERY study on use of dexamethasone [
43]. However, a precaution is warranted as the application of dexamethasone in this trial improved outcome only in those on respiratory support [
43].
Cytokine blocking strategy (blockade of IL-1 and IL-6) was the most often chosen treatment option for patients with clinically severe COVID-19 reaching support of 83.6% and 85.5% respondents, respectively, for use in stage III. This is in line with data from case series and individual case reports [
2,
44,
45], at times in combination with high-dose methylprednisolone [
46]. The popularity of anakinra may be based on its great potential to control hyperinflammation, but also its excellent safety profile including use in patients with bacterial sepsis and cytokine storm [
47]. In addition, anakinra as well as tocilizumab are approved for use in cytokine release syndrome (macrophage activation syndrome) from 8 and 24 months of age, respectively.
The most controversial findings in the survey concern HCQ and azithromycin. Results of a small clinical trial at the onset of the pandemic showed enhancement of the clearance effect on SARS-CoV-2 by addition of azithromycin to HCQ therapy [
48]. This controversial study contributed to optimism and broad uncritical endorsement of HCQ and azithromycin in treating COVID-19. However, growing evidence from controlled clinical trials [
49‐
52] did not show conclusive benefit of the therapy. Moreover, cardiotoxicity, namely rhythm disorders, became an increased concern among adult patients [
53,
54]. Currently, HCQ and/or azithromycin are not recommended for treatment of COVID-19. Participants of this survey were rather hesitant about using HCQ and/or azithromycin in COVID-19; however, still around a quarter of them would consider their use in the stage I. The dynamics of opinion change and growing skepticism towards these treatment modalities could be demonstrated when compared to a related, but previous survey that we performed among German-speaking pediatric rheumatologists [
55].
Recently, it has been shown that the immunocompromised state of patients with primary immunodeficiency is not a predominant factor for severe course of COVID-19 [
22]. With exception of deficiency in type I interferon signaling [
22,
56] or presence of autoantibodies against interferons [
57]. Secondary immunodeficiency due to chemotherapy in pediatric patients treated for malignant disease is associated with longer viral clearance; however, with only minimally increased risk of severe course of COVID-19 [
58]. Thus, the current available data do not justify therapy intensification against SARS-CoV-2 infection in all immunocompromised children considered by some of our respondents and support individualized approach.
Approach to pre-existing anti-inflammatory, immunomodulatory and immunosuppressive therapy in patients with AID in the context of COVID-19 pandemic
Support for the continuation of pre-existing immunomodulatory and/or immunosuppressive therapy in patients with AID without proven COVID-19 documented in the survey is in line with recommendations of the American College of Rheumatology (ACR) [
30] as well as the European societies [
31,
59] published after closure of this survey.
In the case of an incipient COVID-19 disease, almost all respondents were in favor of continuing ongoing therapy with HCQ and subcutaneous or intravenous immunoglobulins for the underlying rheumatological disease. In fact, there is no evidence for a disadvantage of these drugs in the context of COVID-19 [
60]. The majority of colleagues would also continue a pre-existing oral steroid therapy, however, reduce higher dosages beyond 2 mg/kg/d. The ACR recommends continuation of long-term steroid therapy taking into account the risk of potential adrenal cortex insufficiency (with a pre-treatment period of > 14 days) [
30]. The majority of respondents argued against immediate termination of IL-1 or IL-6 inhibition. Discontinuation of a short-acting IL-1-targeted therapy such as anakinra, carries the risk of a rebound phenomenon of the underlying (systemic) rheumatic or inflammatory diseases. Moreover, it may trigger a macrophage activation syndrome, a complication was also observed in some COVID-19 patients [
61]. Data supporting continuation of IL-1-blockade during mild COVID-19 has been recently published: a mild course of the infection was shown in three children and one adult treated for autoinflammatory disease with IL-1-targeted therapy [
62]. After recovery from the infection two out of the three pediatric patients suffered from an increased autoinflammatory activity. Those flares were presumably due to the underlying disease and not related to the IL-1-targeted therapy [
62].
A large number of respondents favors a continuation of dapsone, mycophenolate, leflunomide, methotrexate, azathioprine and calcineurin-inhibitors, possibly administered in reduced dosages. Presumably, antiproliferative drugs would be continued for fear of a severe relapse, e.g. in connective tissue diseases and vasculitides. In COVID-19 patients-receiving ongoing immunomodulating/suppressive drugs, close monitoring of blood count changes, liver and kidney toxicity and, parameters such as IgG, IgM and CD4 T-cell numbers are justified [
63].
The majority of respondents would pause TNF-alpha inhibitors and IL-12/23-inhibitors in COVID-19 patients. As in other virus infections, this is a standard approach for patients with inactive juvenile (psoriatic) arthritis due to the fast effect at restart of TNF-alpha inhibitors post-infection. Moderate-to-highly immunosuppressive agents with long half-lives such as cyclophosphamide, anti-CD20 and anti-BAFF antibodies, CTLA-4 IgG would be omitted or discontinued [
1].
The data published after closure of the survey do not show substantially increased risk of infection or severe course of COVID-19 in AID patients-receiving immunosuppressive and/or biologic treatment [
64‐
66]. A possibly less stringent approach regarding the long-term immunomodulatory therapy than suggested from our respondents might be required.