1,261
Views
2
CrossRef citations to date
0
Altmetric
Editorial

The Role of Anti-IL-1 Treatment in MIS-C Patients

, , , &
Pages 1-5 | Received 05 May 2021, Accepted 11 Nov 2021, Published online: 26 Nov 2021

1. INTRODUCTION

Since the beginning of the COVID-19 pandemic with the first cases reported in December 2019 in the city of Wuhan, it was clear that the pediatric population had low susceptibility to SARS CoV-2 infection as children developed mild or no symptoms in most cases.

However, at the end of April 2020, the British National Health Service and the Italian Society of Pediatrics issued a warning about an apparent rise in the number of hospitalized children suffering from a systemic inflammatory syndrome characterized by high fever and multi-organ involvement frequently requiring intensive care support [Citation1–4].

In the early phases of the pandemic, this inflammatory syndrome was associated with Kawasaki syndrome (KS) due to the sharing clinical findings as prolonged fever, mucocutaneous manifestations and frequent cardiac involvement. Subsequent data from epidemiological and clinical observations during the furthermore period suggested some differences: a remarkable frequency in African and Hispanic ethnic groups, a higher average age of onset and the presence of gastrointestinal symptoms sometimes so severe as to simulate a surgical emergency. However, the cardiac involvement has shown peculiar characteristics, as it is more often associated with myocardial damage, ventricular dysfunction, hypotension, and poor perfusion [Citation1–4].

In most cases, the children affected by this inflammatory syndrome showed a negative nasopharyngeal swab for the SARS-CoV-2 viral genome, whilst elevated serum antibody titers. Additionally, all the reported cases developed the disease about 4–5 weeks later on the peak of COVID-19 pandemic in the related geographic area. These observations suggested that this hyperinflammatory state derived from a post-infectious condition and presented an immune-mediated pathogenesis, with the ability to induce a huge cytokine storm [Citation4].

With the increase in the number of cases, the World Health Organization (WHO), the United States Centers for Disease Control and Prevention (CDC) and the Royal College of Pediatrics and Child Health (RCPCH) worked out a specific case definition of this syndrome [Citation5–7] (). Adopting the WHO definition, we refer to this condition as Multisystemic Inflammatory syndrome in children (MIS-C).

Table 1. Diagnostic criteria of hyper-inflammatory syndrome related to SARS-CoV-2 infection in children

The overall percentage of SARS-CoV-2 infected children developing MIS-C is unknown. However, the number may be underestimated since many cases, especially in the first wave of the pandemic, may have been undiagnosed as infectious disease tests for SARS CoV-2 were not available or not performed. According to CDC data updated to 4 October 2021 in the United States, 5217 confirmed cases and 46 MIS-C related deaths were recorded [Citation8]. Most MIS-C cases involved children and adolescents of age between 5 and 13 years old, with an average age of 9 years: 61% of reported cases occurred in subjects with Hispanic or Afro-Caribbean descent (1,444 cases) and 98% of cases tested positive for SARS CoV-2 on nasopharyngeal swab or for antibodies in serum. More than the half (60%) of patients were male [Citation8].

2. MIS-C TREATMENT

Due to the changing body of currently available evidence, MIS-C management is continuously updated and several recommendations have been issued including the Pediatric Inflammatory Multisytem Syndrome temporally associated to SARS- CoV-2 infection (PIMS-TS) National Consensus Management of the English study group [Citation9], the American College of Rheumatology (ACR) guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV‐2 [Citation10] and the diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics [Citation11].

As the available data refer to single case reports or case series and randomized controlled studies are not available, all recommendations derive from clinical practice and from the principles of management of similar hyperinflammatory syndromes in pediatric age. As primary statement, the leading role of a multidisciplinary team composed of specialists in infectious diseases, immunology, rheumatology, cardiology, and pediatric intensive care for the management of the MIS-C patients, has been advocated [Citation9–11].

A step-up therapeutic approach with the use of an immunomodulatory treatment has been proposed, suggesting the recourse to intravenous immunoglobulins and glucocorticoids, as first and second line agents, respectively [Citation9–11]. The type of therapy and its initiation should be modulated according to the patient’s clinical condition at the first evaluation. Children in critical conditions at onset could benefit of a precocious start of therapy and a more aggressive approach even if the full diagnostic process is not still completed [Citation9–11]. In case of refractory disease, the expert panel seems to agree on the need to promptly introduce a biological therapy, although a clear consensus on the drug of choice is not yet been achieved [Citation9]. During the first pandemic wave, the scales seemed to be tipping equally in favor of tocilizumab (TCZ) and anakinra since TCZ was adopted in 69 patients and anakinra in 80 cases. Furthermore, 17 and 2 children received infliximab and rituximab, respectively. The overall efficacy of biological treatment was 96.3% (data available in 82 patients) [Citation12].

However, the ACR guidelines and the Italian recommendations suggest a preferable recourse to anakinra, the recombinant Interleukin-1 (IL-1) receptor antagonist [Citation10,Citation11]. Anakinra the recombinant IL-1 receptor antagonist was the first anti-IL-1 agent employed in clinical practice. Since blood levels significantly drop within few hours after discontinuation, it became a manageable drug with a remarkable safety profile.

IL-1 overproduction was firstly demonstrated to have a predominant pathogenic role in autoinflammatory diseases, a heterogeneous group of disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform. The use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions, such as cryopyrinopathies, mevalonate kinase Deficiency and colchicine-resistant Familial Mediterranean Fever, as well as in nonhereditary inflammatory diseases, such as refractory KS, systemic-onset juvenile idiopathic arthritis and adult Still disease [Citation13].

Similar to autoinflammatory diseases, there were evidence of inflammasome hyper-activation also in MIS-C. It has been hypothesized that viral strains with specific mutations might be able to induce higher levels of NLRP3 (nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3) inflammasome activation and might result in MIS-C in genetically susceptible children [Citation14].

As regards genetical susceptibility, haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, has been hypothesized as risk factor for MIS-C in two children. Moreover, a hemizygous deleterious defects in XIAP (X-linked inhibitor of apoptosis), and CYBB, (cytochrome b-245, beta subunit) were identified and validated in two MIS-C patients respectively. These children with defects in SOCS1, XIAP, or CYBB exhibited an inflammatory immune cell transcriptome even after MIS-C recovery [Citation15].

We reviewed the available data on MIS-C patients who were treated with anti-IL-1 therapy from the start of the pandemic until 15 April 2021. Anakinra adoption for the treatment of MIS-C has been reported in 41 papers: 13 case reports and 28 case series for a total number of 1,002 patients of which 122 undergoing anakinra therapy (3,4,) (). However, data regarding the criteria for the initiation of therapy are rarely available as well as the extent and duration of previous immunomodulatory therapy. Moreover, the dosage, the route of administration and the duration of anakinra therapy are rarely specified [Citation3,Citation4] (). Taking into account a possible publication bias (unsuccessful treatments are rarely reported), anakinra proved efficacy in 83 out of 85 of the patients for whom outcomes data were available, achieving a rate of response of 97.6%.

Table 2. Studies reporting the use of anakinra therapy in MIS-C patients

3. EXPERT OPINION

In our clinical experience, we reserved an early use of intravenous anakinra for the treatment of MIS-C patients reporting an acute severe cardiac dysfunction at onset. Anakinra was adopted as first-line therapy and administered as continuous intravenous infusion at 10 mg/kg/day (maximum dose 400 mg/day) in association with immunoglobulins and intravenous steroids in 5 patients with MIS-C showing values of left ventricular ejection fraction (LVEF) <40%. At median time of 24 hours (range 12–36 h) from starting anakinra therapy, all patients restored a LVEF>55% together with a progressive reduction in the troponin and N-terminal pro B-type natriuretic peptide values. A reduction in inotropic support to discontinuation was achieved within the first week of treatment with anakinra in all 5 patients [Citation15].

These results seem to suggest that an aggressive and early immunomodulatory approach to MIS-C patients showing a significant cardiac dysfunction from the onset of disease may obtain a faster recovery as quickly damping the cytokine storm. To further confirm this hypothesis, Belhadjer et al. recently observed a reduction in the median time to the recovery of LVEF in 22 MIS-C patients treated with a combination of immunoglobulin and intravenous methylprednisolone versus the group that received immunoglobulins only (18 patients), 2.9 versus 5.4 days, respectively. Thus, the addition of corticosteroids seems to be associated with a shorter time to recovery of cardiac function in MIS-C patients [Citation16]. In this perspective, the combination of anakinra with immunoglobulins and steroids could produce a synergistic effect ensuring an even more rapid recovery of cardiac function, as observed in our patient group [Citation15]. Nonetheless in our cohort the recovery time of heart function appeared faster compared to that reported in the cohort treated with steroids and immunoglobulins [Citation16], it is not possible to exclude that the combination therapy with steroids and immunoglobulins rather than the use of anakinra itself is responsible for this fast clinical improvement.

As regards administration route, the adoption of intravenous infusion for anakinra may be preferable in case of hemodynamic instability and signs of peripheral perfusion. The switch to subcutaneous route might be considered after reaching stable conditions [Citation15].

As suggested by the ACR Consensus, despite the clinical improvement, immunomodulatory therapy should be continued for at least 2–3 weeks until suspension to prevent a rebound of the inflammatory state. In this perspective, anakinra may be adopted as maintenance therapy during the MIS-C subacute phase and act as a steroid-sparing drug [Citation10]. Otherwise, anakinra treatment, except for local reactions at the injection site, is associated with an excellent safety profile [Citation17].

In conclusion, as the cardiac dysfunction onset is a life-threatening condition, together with the current recommendations to use the immunomodulatory therapy for treatment failure cases of IVIG and/or steroids, in children with rapid and significant impairment of LVEF, a step-down immunomodulatory approach may be considered an additional valuable option. This strategy might add chances to prevent further progression and/or the onset of sequalae over time. Even if deriving from a limited number of patients, the available data regarding the effectiveness of anakinra for the treatment of MIS-C certainly appear encouraging and anakinra currently represents the most widely adopted biologic drug in the treatment of this condition.

However, data comparing efficacy between anakinra and other biologics as well as between anakinra and the combination of immunoglobulins and steroids for MIS-C treatment are lacking. Furthermore, data comparing different anakinra dosages and routes of administration both in the acute phase and as maintenance therapy are not available. Further evaluation is needed in randomized trials to confirm these first results and to better define and stratify the optimal treatment strategies for MIS-C patients, according to different patients’ risk classes.

However, at the present, since a life threatening disease, anakinra seems a valuable option in this childhood clinical setting, to be considered from the beginning when life threatening cardiac disfunction abruptly appears.

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper is not funded.

References

  • Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607–1608. S0140-6736(20) 31094-1.
  • Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771–1778.
  • Pouletty M, Borocco C, Ouldali N, et al. Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort. Ann Rheum Dis. 2020;79(8):999–1006.
  • Whittaker E, Bamford A, and Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS- CoV-2. JAMA. 2020;324(3):259–269.
  • Royal College of Paediatrics and Child Health. Guidance: paediatric multisystem inflammatory syndrome temporally associated with COVID-19. [cited 2021 Oct 10]. Available from: https://www.rcpch.ac.uk/resources/guidance-paediatric-multisysteminflammatory-syndrome-temporally-associatedcovid-19
  • World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19. [cited 2021 Oct 19]. Available from:https://www.who.int/publications-detail/multisystem-inflammatorysyndrome-in-children-and-adolescents-withcovid-19
  • Centers for Disease Control and Prevention. Emergency preparedness and response: health alert network. [cited 2021 Oct 10]. Available from: https://emergency.cdc.gov/han/2020/han00432.asp
  • Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome (MIS-C). [cited 2021 Oct 10]. Available from: https://www.cdc.gov/mis-c/cases/index.html
  • Harwood R, Allin B, and Jones CE, et al. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID- 19 (PIMS-TS): results of a national Delphi process. Lancet Child Adolesc Health. 2020;(2):133–141.
  • Henderson LA, Canna SW, and Friedman KG, et al. American college of rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS–CoV‐2 and hyperinflammation in pediatric COVID‐19: version 1. Arthritis Rheumatol. 2020;72(11):1791–1805.
  • Cattalini M, Taddio A, and Bracaglia C, et al.; Rheumatology Study Group of the Italian Society of Pediatrics. Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics. Ital J Pediatr. 2021;47(1):24.
  • Mastrolia MV, Maccora I, and Marrani E, et al. Biological drugs in paediatric COVID-19 infection: what patients, which drug, how much and how long. Clin Exp Rheumatol. 2021;39(3): 697–699 .
  • Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6(4):232–241.
  • Bukulmez H. Current understanding of Multisystem Inflammatory Syndrome (MIS-C) Following COVID-19 and its distinction from kawasaki disease. Curr Rheumatol Rep. 2021;23(8):58.
  • Chou J, Platt CD, Habiballah S, et al. Taking on COVID-19 Together Study Investigators. Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C). JACI. 2021;148(3):732–738.e1.
  • Mastrolia MV, Marrani E, and Calabri GB, et al. Fast recovery of cardiac function in PIMS-TS patients early using intravenous anti-IL-1 treatment. Crit Care. 2021;25(1):131.
  • Belhadjer Z, Auriau J, Méot M, et al. Addition of corticosteroids to immunoglobulins is associated with recovery of cardiac function in multi-inflammatory syndrome in children. Circulation. 2020;142(23):2282–2284.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.