|Ahead of print
Immunotherapies in pediatric neurology during the COVID-19 pandemic: A pragmatic approach
Chaithanya Reddy, Chandana Bhagwat, Arushi Gahlot Saini
Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||07-Jul-2020|
|Date of Decision||17-Feb-2021|
|Date of Acceptance||24-Mar-2021|
|Date of Web Publication||11-Oct-2021|
Arushi Gahlot Saini,
Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Immunotherapy is an important treatment modality for several pediatric neurology conditions. The immunosuppressive therapies may predispose to a heightened risk of infection and fatal consequences. The paper aims to examine the immunological effects of various commonly used immunomodulators and their associated risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Immunotherapies may exhibit different effects at the different stages of coronavirus disease 19 (COVID-19) pathogenesis. Conventional immunosuppressive therapies appear to produce less favorable results or may aggravate the risk of infection, especially during the primary response phase. Whereas immunomodulators such as inhibitors of pro-inflammatory cytokines, antagonists of complement activity, and those drugs which decrease viral-neutralizing antibodies levels seem to have beneficial effects during the secondary hyper inflammation phase of infection. However, adequate clinical data is yet to be available for most of the immunotherapies. Based on the emerging evidence, the authors attempt to draw some conclusions of practical importance on the applications of different immunomodulators for children with pediatric neurological disorders in the COVID-19 pandemic.
Keywords: Applications, COVID-19, immunomodulators, immunotherapy, neurology, pediatric
| Introduction|| |
Being child neurologists, we have to consider immunotherapies, sometimes as a first-line, in many clinical conditions, viz. autoimmune encephalitis and demyelination disorders. A similar situation prevails in many other subspecialties, mainly pediatric rheumatology, pediatric nephrology, and pediatric dermatology. Conventionally, immunosuppressive therapies pose a high risk of infection and may result in fatal consequences. Therefore, because of the ongoing coronavirus disease 19 (COVID-19) pandemic, clinicians around the globe are now more cautious in initiating and continuing these medications even in patients with clear medical indications. The paper aims to examine the immunological effects of various commonly used immunomodulators and their associated risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection.
| COVID-19 and the Stages of Infection|| |
The objective fulfills better if we understand the various stages of the COVID-19. The initial primary inflammatory response phase begins with the ACE2 receptor-mediated cell entry of the virus, mainly involving respiratory epithelial cells. Extensive intracellular viral replication causes cytopathic effects and cellular apoptosis by inducing abnormal protein synthesis and dysfunction. Meanwhile, synthesized viral neo-proteins, through various pathways activated by toll-like receptors, stimulate innate immune cells, and release several pro-inflammatory mediators chiefly TNF-a and IL-1. Besides protecting both infected and healthy cells, interleukins activate the adaptive immune system mainly T-cells and promote de-differentiation of T-cell to CD4 and CD8 subsets. CD8-T cells, along with NK-cells, kill infected cells and help to control the viral spread. To conclude, the purpose of the primary response phase is to restrict viral activity.
In some patients, the primary phase may switch over to the most fulminant secondary inflammatory response phase, which is dominated by a cytokine storm (IL-1, IL-6, IL-8, IL-12, TNF-a) and robust tissue invasion of leukocytes. Viral neutralizing antibodies, though they have no significant role in the early phase of infection due to the absence of memory B-cells, play a dominant role in the secondary stage by causing accumulation of inflammatory cells and production of matrix metalloproteinase, leukotrienes, and interleukins. Also, complement activation through antibody-mediated pathways triggers the generation of chemokines (C5a), which increases the pulmonary damage by enhancing further the infiltration of inflammatory cells (monocytes and neutrophils). Importantly, interleukins like IL-8 negatively regulate protective T-cells. They facilitate SARS-CoV2 to evade the host defensive mechanisms, infect more cells, and to re-initiate a new sequence of events. Thus, the hallmark of the secondary inflammatory response phase is that the chain of immunological reactions may act viciously to cause cell apoptosis, the exuberant release of cytokines, and organ failure.
| Immunotherapies and Risk of COVID-19 Infection|| |
By understanding the pathophysiological mechanisms underlying the different phases of SARS-CoV2, now we are wiser to take out some assumptions. Immunomodulators seem to have beneficial effects during the secondary hyper inflammation phase. Such drugs of great importance may include inhibitors of pro-inflammatory cytokines at various levels, antagonists of complement activity, and those drugs which decrease the levels of viral-neutralizing antibodies. On the other side, conventional immunosuppressive therapies appear to produce less favorable effects or may aggravate the risk of infection, especially during the primary response phase because the latter need the co-ordinated interplay between innate and adaptive immune systems to contain the viral activity. In conclusion, the specific drug-related immunological effects and the stage of viral infection are the key factors deciding whether the particular immunotherapy is beneficial or detrimental in a patient infected with SARS-CoV2.
Here, we discuss some specific groups of immunomodulatory drugs of relevance to our day-to-day child neurology practice [Table 1]. Drugs that primarily act by interfering with DNA synthesis, viz. azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil (MMF) usually carry a higher risk of infection as well as infection-related adverse events due to the long-term risk of severe leukocytopenias associated with them. Of which, MMF needs a special mention here. In vitro studies have shown the antiviral properties of MMF against MERS-CoV. Though maintenance MMF therapy does increase the risk, it may be used as an antiviral agent in acute viral infections. Likewise, monoclonal antibodies (mAbs) against CD20 antigens, namely rituximab is likely to risk of infection. Rituximab treatment needs repeated pulse applications and leads to severe depletion of B-cells, chronic hypogammaglobulinemia, and the risk of long-term neutropenias. However, mAbs specifically tocilizumab, as a receptor antagonist for pro-inflammatory cytokine IL-6, seems to have a low risk of infection. Also, it may show beneficial effects in the secondary response phase because IL-6 is the chief inflammatory mediator of the cytokine storm. Results from several reports and non-randomized clinical trials revealed the favorable outcomes of tocilizumab treatment in patients infected with SARS-CoV2., Similarly, accumulating evidence is supporting that mAbs targeting the complement activation such as eculizumab, and other cytokine targeted drugs such as cyclosporin A, an inhibitor of pro-inflammatory interleukin (IL-2) transcription, do not cause the increased risk of infection.,, Besides, cyclosporin A also exhibited anti-corona virus properties in a few in vitro studies.
|Table 1: Considerations for several immunotherapies during the COVID-19 pandemic|
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At this stage, it is worth considering two well-established broad-spectrum immunotherapies, namely intravenous immunoglobulins (IVIG) and glucocorticosteroids (GCS). IVIG having pleiotropic immunological properties may show beneficial effects on the secondary inflammatory response phase of the infection. Importantly, reduction of viral neutralizing antibodies, neutralization of abnormal complement activity, and suppression of pathogenic T-cell subsets might favor the use of IVIG in such patients., However, it is not appropriate to conclude currently because of the lack of an adequate number of studies in COVID-19. On another side, GCSs have shown to have anti-inflammatory activities at multiple levels by inhibiting the migration of immune cells from lymphoid tissues, inducing T-cell apoptosis, downregulating the transcription of pro-inflammatory cytokines (IL-1, IL-2), and also by restricting the leukocyte movement across the blood–brain barrier. Previous studies revealed that pulse therapies are associated with a significant risk of viral infection. Both bacterial and viral infection risk increases with steroids at maintenance doses. Nevertheless, experience with GCSs in patients with SARS-CoV2 is limited. Hopefully, the undergoing clinical trials may provide enough evidence regarding the safety and beneficial aspects of GCSs and IVIG in these patients.
| Practical Considerations|| |
The adequate clinical data related to the SARS-CoV2 infection is not available for most of the immunotherapies except for IL-6 antagonists. Based on the emerging evidence, we attempt to draw some conclusions of practical importance on the applications of different immunomodulators for children with pediatric neurological disorders in the COVID-19 pandemic.
Children at risk and the COVID-19 pandemic
DNA synthesis inhibitors (azathioprine, methotrexate, cyclophosphamide) are associated with a higher risk of infection. So, dose-reduction strategies could be a suitable option in stable children on maintenance therapy. MMF or cyclosporine A are better alternatives if there is an indication to start the treatment. Rituximab only if a clear recommendation exists. However, repeated pulse therapy needs to be guided carefully by serial CD-19 B-cell count. Eculizumab and tocilizumab can be initiated and continued safely for children. IVIG may be safe, as there is no evidence of a high risk of infection that exists so far. Intravenous GCSs pulse regimens require a consideration of the risk–benefit ratio. Abrupt discontinuation of any maintenance immunotherapy is strongly discouraged as it might lead to life-threatening disease exacerbations and may increase the requirement for hospital admission, which further increases the risk of infection.
Children and acute onset SARS-CoV2 infection
The therapeutic effect of DNA synthesis inhibitors may last for several weeks after the discontinuation. So, consideration must be given for the stoppage of these medications until infection subsides. It might be necessary to suspend the treatment with rituximab and other pulsed immune therapies such as IV steroids temporarily. The recommendation of stress doses to the patients on maintenance steroids is advisable. Available data ensure the safety to continue cyclosporin A, eculizumab, and tocilizumab, particularly in patients with a refractory infection. There is no consensus opinion regarding the IVIG applications. But therapy can be considered if a strong clinical indication exists such as Guillain–Barré syndrome.
| Conclusion|| |
At last, we conclude that immunotherapies are unavoidable treatment modalities for several child neurology conditions. The specific drug-related effects on the immune system and the phase of viral infection are the key factors deciding whether the particular immunotherapy is beneficial or detrimental in a patient infected with SARS-CoV2. However, the clinical data are not available for most of the immunotherapies. Thus, future studies are needed to address the several aspects related to the initiation and continuation of the different immunomodulators in these patients.
Financial support and sponsorship
Conflicts of interest
The authors have no conflict of interest.
| References|| |
Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virol Sin 2020;35:266-71.
Zhu J, Mohan C. Toll-like receptor signaling pathways–therapeutic opportunities. Mediat Inflamm 2010;2010:781235.
Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol 2009;83:3039-48.
Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al
. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight 2019;4:e123158.
Stankiewicz JM, Kolb H, Karni A, Weiner HL. Role of immunosuppressive therapy for the treatment of multiple sclerosis. Neurotherapeutics 2013;10:77-88.
Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson RF, et al
. Interferon-β and mycophenolic acid are potent inhibitors of middle-east respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014;95:571-7.
Tesfa D, Palmblad J. Late-onset neutropenia following rituximab therapy: incidence, clinical features and possible mechanisms. Expert Rev Hematol 2011;4:619-25.
Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy 2016;8:959-70.
Luna G de, Habibi A, Deux JF, Colard M, d’Alexandry d’Orengiani ALPH, Schlemmer F, et al
. Rapid and severe Covid-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with tocilizumab. Am J Hematol 2020;95:876-8.
Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents 2020;55:105954.
Wang R, Xiao H, Guo R, Li Y, Shen B. The role of C5A in acute lung injury induced by highly pathogenic viral infections. Emerg Microbes Infect 2015;4:e28.
Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, et al
. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio 2018;9:e01753-18.
Bonifati DM, Angelini C. Long-term cyclosporine treatment in a group of severe myasthenia gravis patients. J Neurol 1997;244:542-7.
de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RWAL, et al
. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. J Gen Virol 2013;94(Pt 8):1749-60.
Ichiyama T, Ueno Y, Hasegawa M, Niimi A, Matsubara T, Furukawa S. Intravenous immunoglobulin inhibits NF-kappab activation and affects fcgamma receptor expression in monocytes/macrophages. Naunyn Schmiedebergs Arch Pharmacol 2004;369:428-33.
Basta M, Van Goor F, Luccioli S, Billings EM, Vortmeyer AO, Baranyi L, et al
. F(ab)’2-mediated neutralization of C3A and C5A anaphylatoxins: a novel effector function of immunoglobulins. Nat Med 2003;9:431-8.
Gold R, Buttgereit F, Toyka KV. Mechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders. J Neuroimmunol 2001;117:1-8.
Le Page E, Veillard D, Laplaud DA, Hamonic S, Wardi R, Lebrun C, et al
; COPOUSEP investigators; West Network for Excellence in Neuroscience. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet 2015;386:974-81.
Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-barré syndrome associated with SARS-cov-2 infection: causality or coincidence? Lancet Neurol 2020; 19:383-4.