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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 102-105

Successful use of tocilizumab in the treatment of multisystem inflammatory disease of childhood refractory to intravenous immunoglobulin and glucocorticoids


Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Pune, Maharashtra, India

Date of Submission15-Oct-2020
Date of Decision14-Nov-2020
Date of Acceptance01-Dec-2020
Date of Web Publication10-Mar-2021

Correspondence Address:
Dr. Guruprasad Hassan Shankar
Department of Pediatrics, Bharati Vidyapeeth Medical College, Pune Satara Road, Pune - 411 043, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPCC.JPCC_162_20

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  Abstract 


Multisystem inflammatory syndrome in children (MIS-C) is one of the many challenges thrown by the ongoing SARS CoV-2 pandemic. A high index of suspicion is warranted for the diagnosis of MIS-C as presenting features overlap with Kawasaki disease and toxic shock syndrome. The treatment guidance is empirical with consideration of intravenous immunoglobulin (IVIG) and glucocorticoids. However, treatment of refractory MIS-C remains eluded. We describe here a 7-year-old boy with MIS-C refractory to IVIG and pulse methylprednisolone who responded to interleukin-6 inhibition using tocilizumab.

Keywords: COVID-19, interleukin-6, Kawasaki disease, SARS-CoV-2


How to cite this article:
Oswal JS, Sarangi B, Shankar GH, Sharma V. Successful use of tocilizumab in the treatment of multisystem inflammatory disease of childhood refractory to intravenous immunoglobulin and glucocorticoids. J Pediatr Crit Care 2021;8:102-5

How to cite this URL:
Oswal JS, Sarangi B, Shankar GH, Sharma V. Successful use of tocilizumab in the treatment of multisystem inflammatory disease of childhood refractory to intravenous immunoglobulin and glucocorticoids. J Pediatr Crit Care [serial online] 2021 [cited 2021 Apr 20];8:102-5. Available from: http://www.jpcc.org.in/text.asp?2021/8/2/102/311055




  Introduction Top


The uncertainties from lack of evidence-based guidance in the pathogenesis, diagnosis, and management of multisystem inflammatory syndrome in children (MIS-C)[1] imply that physicians often need to extrapolate therapeutic approaches from limited information and understanding of the pathogenesis and rely on observational data while navigating through potentially life-threatening clinical situations.

Due to the temporal association with the pandemic, MIS-C is presumed to be a para/postinfectious phenomenon related to COVID-19 driven by hyperinflammation. The partial overlap between Kawasaki disease (KD) and toxic shock syndrome has led to intravenous immunoglobulin (IVIG) being the first line of therapy, along with glucocorticoids.[2] However, guidance about the use of biologics in refractory disease is very limited. In view of similarities between the cytokine storm syndrome of COVID19 and the cytokine release syndrome associated with chimeric antigen receptor-T (CAR-T) cell therapy, a rationale for interleukin-6 (IL6) directed blockade has been drawn.[3] We hereby report a 7-year-old boy (weight = 25 kg) with MIS-C refractory to IVIG and pulse methylprednisolone who responded to IL-6 inhibition using tocilizumab.


  Case Report Top


A 7-year-old boy was presented with high-grade intermittent fever of 2-day duration accompanied by abdominal pain and vomiting for a day. He was referred to us with worsening symptoms, difficulty in breathing, and lethargy. He had tested positive for COVID-19 by reverse transcription real-time polymerase chain reaction (RT-PCR) 3 weeks prior but had remained asymptomatic. On arrival, he was found to be in hypotensive shock (heart rate = 142/min, respiratory rate = 26/min, and blood pressure –82/42 mmHg) going on to require fluid resuscitation (up to 20 ml/kg of crystalloid) and dopamine infusion along with high flow nasal oxygen to alleviate his work of breathing. On evaluation, his laboratory parameters showed a rise in all acute phase reactants (C-reactive protein, procalcitonin, ferritin, fibrinogen, and D-dimer) with no organ dysfunction [Table 1]. Considering the differential diagnosis of a gut source sepsis, a broad-spectrum antibiotic was also added. Blood cultures however remained sterile and fever persisted with the continued requirement of vasoactive drugs. Following the added exclusion of tropical infections using multiplex PCR and a positive SARS CoV-2 IgG antibody test, immunomodulation was initiated 48 h after admission as repeat inflammatory markers showed no change in CRP and worsening procalcitonin.
Table 1: Laboratory parameters

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On day 3, pulse methylprednisolone (at 10 mg/kg/day) was started to which he transiently responded by being afebrile with no further hemodynamic deterioration for 24 h. However, by day 4, he developed bilateral nonpurulent conjunctivitis with edema of hands and feet and a morbilliform rash over palms and soles while abdominal pain persisted. Echocardiography revealed a left ventricular ejection fraction of 55% and coronary dilatation with mildly elevated Z-score (2.67) of the left main coronary artery (LMCA). Considering an incomplete KD scenario with coronary involvement, elevated inflammatory markers, and no microbiological evidence of bacterial infection along with a positive COVID-19 antibodies, criteria for MIS-C were fulfilled and IVIG infusion (at 2 g/kg) was given over 12-h duration while low-molecular weight heparin (LMWH) and oral aspirin in anti-inflammatory dose were added. His response remained partial with persistence of intermittent fever and abdominal pain, while over the next 24 h, he developed progressive abdominal pain and distension with sluggish bowel sounds. A computed tomography (CT) scan of the abdomen with contrast showed dilated large bowel loops without any transition point. Serial inflammatory markers indicated worsening of CRP levels, with a slight reduction in procalcitonin and similar D-dimer levels. Hemodynamics deteriorated again in the form of a vasoplegic shock with wide pulse pressure requiring fluids and noradrenaline infusion which stabilized the clinical condition. At this stage, IL-6 levels were done and found to be elevated (190 pg/ml). Due to nonresponse to IVIG over the next 48 h and 4 days of pulse methylprednisolone in the presence of high IL-6 [Figure 1], 8 mg/kg of tocilizumab was administered which he tolerated without any adverse effects. The response noted was very satisfactory with cessation of fever spikes within 4 h postinfusion. The child was off high flow nasal oxygen within the next 24 h while noradrenaline and dopamine infusions were tapered over the next 48 h. Abdominal pain and distension also subsided after 48 h of tocilizumab administration. Repeat IL-6 after tocilizumab increased as anticipated (355 pg/ml) which started reducing after a week with normalization of other inflammatory markers.
Figure 1: Trends in IL-6 levels in relation to the timing of treatment modality

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Aspirin was reduced to antiplatelet dose after 48 h of afebrile period while LMWH was stopped with normalization of D-dimer levels. He was discharged after 11 days of hospitalization on oral prednisolone (at 1 mg/kg/day) and antiplatelet dose of aspirin. Echocardiography at 2 weeks showed mild ectasia of the left anterior descending coronary artery and LMCA Z-score of 2.82. Serial IL-6 levels showed a reduction and normalization over 3 weeks. Repeat echocardiography after another 4 weeks showed Z-scores <2 for all coronary arteries with resolution of ectasia of left anterior descending coronary artery.


  Discussion Top


The epidemiological link between MIS-C and SARS CoV-2 has not been established. However, an individual timeline, as in this case, of being positive for COVID-19 by RT-PCR and 3 weeks later presenting with criteria fulfilling MIS-C strengthens the epidemiologic link between the two. Observational studies across the globe have reported fairly consistent clinical and laboratory presentations for MIS-C,[4] encompassing a febrile illness in relatively older children with gastrointestinal (GI) manifestations, shock, cardiac involvement, elevated inflammatory markers, and relatively more frequent coronary involvement.

GI manifestations in MIS-C are often nonspecific. Reported findings in abdominal CT[5] often involve the right iliac fossa with mesenteric inflammation and lymphadenopathy, bowel wall thickening, and may mimic acute appendicitis. Clinically, an intestinal obstruction type of presentation with distension, abdominal pain, diffuse tenderness, and bilious aspirates with dilated large bowels on CT, as found in our case, has not been described commonly. These manifestations may represent the effects of GI vasculitis.[6]

IL-6 is a multifunction cytokine secreted by neutrophils, monocytes, and macrophages during the inflammatory response. It has a wide range of biological activities in various target cells and regulates immune responses, acute phase reactions, hematopoiesis, and bone metabolism.[7] It is important to understand, however, that the cytokine profile of COVID-19 is multi-pronged, including tumor necrosis factor-alpha, granulocyte colony-stimulating factor, interferon–gamma, and IL-1 beta.[8] Therefore, IL-6-targeted therapy should not be indiscriminately used in any sick patient with active COVID-19 infection or a COVID-19-related illness such as MIS-C but should be carefully considered in refractory clinical scenarios with significant elevation of levels at the time of treatment.

Treatment guidance is based on recommendations for the treatment for KD, with IVIG being first-line therapy. Resistance to IVIG is defined as persistence of fever 24 h posttherapy.[9] While IV methylprednisolone pulse forms part of the second-line treatment, as the child had already received the same, tocilizumab was considered.

The effect that the timing of initiation of immunomodulation has on the outcome is not known. Even with early presentations and a high degree of suspicion, it may not be possible to start glucocorticoids prior to ruling out sepsis and IVIG due to cost considerations. Acute-phase reactants being elevated in both sepsis and hyperinflammation, the presence of KD like features may serve to shift the balance to the hyperinflammatory side. Tocilizumab, a humanized monoclonal antibody targeting the IL-6 receptor, has been used to treat cytokine-release syndrome (a side effect of CAR-T cell immunotherapy) which is found to have similar manifestations as COVID-19-induced respiratory disease.[3] Further, elevated IL-6 has been associated with a hypercoagulable state[10] which is typical of severe COVID-19 infection. For these reasons, IL-6-targeted treatment may be theoretically useful in COVID-19-related disease. At this stage of the pandemic, however, clear evidence is not available on indications and outcomes of tocilizumab. Free serum IL-6 levels often increase after tocilizumab administration because IL-6R-mediated consumption of IL-6 is inhibited by the unavailability of tocilizumab-free IL-6R.[11] As the inflammatory state resolves, IL-6 levels again reduce and normalize. This pattern was observed in our case.

Specific adverse effects have to be monitored for upon initiation of tocilizumab including anaphylactic reactions, increased risk of secondary bacterial infection, re-activation of latent TB, hepatotoxicity, neutropenia, thrombocytopenia, and intestinal perforation.[3]

Tocilizumab may be beneficial in a subset of children with MIS-C who are refractory to the currently proposed therapy using steroid and IVIG. Elevated IL-6 levels in the presence of persistent fever and multiple organ support may validate the indication for using tocilizumab. Objective evidence for frequent justifiable use of tocilizumab in the form of randomized controlled trials remains awaited.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C). Available form: https://www.cdc.gov/mis-c/hcp/20. [Last accessed on 2020 Jun 06].  Back to cited text no. 1
    
2.
Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395:1607-8.  Back to cited text no. 2
    
3.
Alzghari SK, Acuña VS. Supportive treatment with tocilizumab for COVID-19: A systematic review. J Clin Virol 2020;127:104380.  Back to cited text no. 3
    
4.
Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-coV-2. JAMA 2020;324:259-69.  Back to cited text no. 4
    
5.
Hameed S, Elbaaly H, Reid CEL, Santos RMF, Shivamurthy V, Wong J, Jogeesvaran KH. Spectrum of Imaging Findings at Chest Radiography, US, CT, and MRI in Multisystem Inflammatory Syndrome in Children Associated with COVID-19. Radiology 2021;298:E1-10. doi: 10.1148/radiol.2020202543.  Back to cited text no. 5
    
6.
Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: Prospective observational study. BMJ 2020;369:m2094.  Back to cited text no. 6
    
7.
Nishimoto N, Kishimoto T. Interleukin 6: From bench to bedside. Nat Clin Pract Rheumatol 2006;2:619-26.  Back to cited text no. 7
    
8.
Jain S, Sharma SK. Rational use of tocilizumab in COVID-19. Ann Rheum Dis. 2020 Jul 31:annrheumdis-2020-218519. doi: 10.1136/annrheumdis-2020-218519.  Back to cited text no. 8
    
9.
Research Committee of the Japanese Society of Pediatric Cardiology, Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease. Guidelines for medical treatment of acute Kawasaki disease: Report of the research committee of the Japanese society of pediatric cardiology and cardiac surgery (2012 revised version). Pediatr Int 2014;56:135-58.  Back to cited text no. 9
    
10.
Levi M. Tocilizumab for severe COVID-19: A promising intervention affecting inflammation and coagulation. Eur J Intern Med 2020;76:21-2.  Back to cited text no. 10
    
11.
Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and castleman disease. Blood 2008;112:3959-64.  Back to cited text no. 11
    


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