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CASE-BASED REVIEW
Ahead of print publication  

Infliximab in treatment of refractory multisystem inflammatory syndrome in children with severe cardiac dysfunction


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

Date of Submission23-Jan-2021
Date of Acceptance25-Mar-2021
Date of Web Publication08-May-2021

Correspondence Address:
Bhakti U Sarangi,
Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Pune - 411 043, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_21_21

  Abstract 


Multisystem inflammatory syndrome in children (MIS-C) has emerged as one of the several challenges thrown by the ongoing severe acute respiratory syndrome-coronavirus 2 pandemic. Although diagnostic criteria of MIS-C have now been established to raise the clinical suspicion for the condition, the Kawasaki disease (KD)-like phenotype of MIS-C presents with additional therapeutic dilemmas. The treatment guidance till date remains empirical with consideration of intravenous immunoglobulin (IVIG) and glucocorticoids. However, treatment of cases refractory to the current conventional therapy with respect to biologics remains uncertain. We describe here, an 8-year-old boy with MIS-C (KD-like phenotype) with severe cardiac dysfunction refractory to IVIG and pulse methylprednisolone who responded to tumor necrosis factor-α inhibition using infliximab.

Keywords: Intravenous immunoglobulin, Kawasaki disease, methylprednisolone, severe acute respiratory syndrome-coronavirus 2



How to cite this URL:
Shankar GH, Oswal JS, Sarangi BU, Walimbe A, Markal P, Badarayan KV. Infliximab in treatment of refractory multisystem inflammatory syndrome in children with severe cardiac dysfunction. Indian J Rheumatol [Epub ahead of print] [cited 2021 Jun 18]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=315681




  Introduction Top


Multisystem inflammatory syndrome in children (MIS-C) is now recognized to be a postviral severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) inflammatory disease, with a clinical syndrome of fever, inflammation, multiorgan involvement, and evidence of or link to SARS-CoV-2 infection. Due to the overlap with Kawasaki disease (KD)-like phenotype, treatment protocols have focused on standard KD therapies.[1] However, the degree of inflammation in MIS-C is found to be significantly higher than KD and on occasion refractoriness to intravenous immunoglobulin (IVIG) and corticosteroids is observed. The guidance in the use of biologic response modifiers in these clinical scenarios is limited. IL1, IL6 inhibition, and tumor necrosis factor-α (TNF-α) blockade are under study. We, hereby, report an 8-year-old boy with MIS-C with features like KD and significant cardiovascular dysfunction who was refractory to IVIG and pulse methylprednisolone and responded dramatically to infliximab.


  Case Report Top


An 8-year-old boy presented to us with moderate grade intermittent fever for 7 days duration followed by abdominal pain, vomiting, and an erythematous rash all over the body for 2 days before admission. Having received intravenous (IV) antibiotics (ceftriaxone and doxycycline) and fluid resuscitation (upto 20 ml/kg of crystalloid) for hypotensive shock at a primary health center outside, he was referred to us as features of shock persisted. On arrival, he was lethargic and had features of distributive shock (heart rate – 152/min, respiratory rate (RR) – 36/min, blood pressure – 66/42 mmHg) with bilateral nonpurulent conjunctivitis and a generalized rash. He went on to receive another 20 ml/kg of crystalloid and 5 ml/kg of colloid (5% albumin), followed by IV infusion of noradrenaline (upto 0.3 mcg/kg/min) and vasopressin (@0.0005 IU/kg/min) as features of distributive shock persisted. Bedside functional echocardiography also showed impaired myocardial contractility with left ventricular ejection fraction (LVEF) of 40% following which adrenaline infusion was also added. Due to the progressive increase in work of breathing despite high flow nasal oxygen, persistent metabolic acidosis, and escalating hemodynamic support, he was mechanically ventilated. Broad-spectrum antibiotics (ceftriaxone and doxycycline) were continued. His laboratory evaluation revealed an elevation of all acute phase reactants (C-reactive protein [CRP], procalcitonin, ferritin, fibrinogen, and D-dimer) with thrombocytopenia, hypoalbuminemia, raised cardiac enzymes (proBNP), and no other organ dysfunction as shown in [Table 1]. Blood and urine cultures remained sterile and he tested negative for a panel of tropical infections using multiplex-polymerase chain reaction. With the constellation of persistent fever, conjunctivitis, rash, and gastrointestinal symptoms presenting in shock with biochemical evidence of hyperinflammation and a positive SARS-CoV-2 immunoglobulin G antibody test, the diagnosis of MIS-C (Kawasaki disease-like phenotype) was made on day 2 of admission. Immune modulation was initiated the same day with pulse IV methylprednisolone therapy (@10 mg/kg/day), followed by IVIG @2 gm/kg on day three. Oral aspirin was also added in anti-inflammatory dose. The response remained transient with a temporary reduction in fever, acidosis, and requirement of hemodynamic support. He was weaned off mechanical ventilation to and extubated on day 4. However, within 24 h of extubation, he worsened clinically with recurrence of hypotensive shock. Bedside echocardiography revealed a worsening LVEF (20%–25%) with the presence of pericardial effusion and no coronary dilatation. The chest radiograph showed bilateral nonhomogenous opacities. Repeat laboratory investigations showed a reduction in CRP and procalcitonin levels with a significant rise in D-dimer and cardiac enzymes (proBNP). Inotropic support was initiated in the form of IV adrenaline and dobutamine infusions and he was re-intubated. Low-molecular-weight heparin (LMWH) was also added while therapy for congestive heart failure (CHF) was initiated in the form of diuretic (IV furosemide), after-load reducing agent (oral enalapril), and oral digoxin in maintenance doses. The cultures of blood and endotracheal secretions remained sterile. Interleukin-6 (IL-6) levels were marginally raised [Table 1]. Considering MIS-C with KD-like phenotype refractory to current conventional therapy with 5 days of IV methylprednisolone and IVIG with significant cardiovascular dysfunction and near-normal IL-6 levels, it was decided to give IV infliximab. On day 5 of admission, IV Infliximab infusion was given @5 mg/kg over 4 h. The response noted was immediate and dramatic with cessation of fever within 2 h of infusion with the reduction in inotrope requirement over the next 24 h. Repeat chest radiographs showed clearing of lung fields. Ventilatory support was weaned and he was extubated successfully on day eight of stay. Serial inflammatory markers showed a reducing trend including D-dimer levels with a concurrent decrease in pro-BNP levels and objective evidence of improved LVEF on echocardiography as seen in [Figure 1] and [Figure 2]. Aspirin was reduced to antiplatelet dose after 48 h of afebrile period while LMWH was stopped with normalization of D-dimer levels. Therapy for CHF was also de-escalated. He was discharged after 11 days of hospital stay with normalization of all inflammatory markers on oral prednisolone, aspirin, digoxin, and enalapril. LVEF at the time of discharge was 55% with no evidence of coronary dilatation.
Table 1: Laboratory investigations

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Figure 1: Trends in proBNP and D-dimer levels

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Figure 2: Trends in CRP levels

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  Discussion Top


A KD-like phenotype is seen in approximately 40% of children presenting with MIS-C.[1] Although a significant overlap of features is noted between the two illnesses, some differences include an older age of presentation, significantly higher levels of inflammatory marker elevation, more frequent need for intensive care unit care and vasopressor support, and greater incidence of coronary artery involvement in MIS-C.[2] However, until a solid evidence base is available to instruct on the manner of immune modulation in this relatively new disease, the first-line therapy continues to be derived from standard KD treatment strategies, namely IVIG and corticosteroids.[3] The requirement of a second dose of IVIG has been reported in 12.8%–62.5% of patients in different series.[4],[5] Further on, the choice of immunomodulatory drugs devolves to more targeted medication. MIS-C and KD share two major elements in the pathophysiology-endothelial damage and upregulation of the interleukin-1 (IL-1) β pathway.[6] IL-1 also has an important role in the pathogenesis of coronary artery aneurysms in KD. For this reason, IL-1 blockade seems to be an appropriate first choice biologic response modifier in MIS-C. Upon activation of IL-1 β, and through paracrine mechanisms, there is a downstream increase in expression of IL-6, IL-8, TNF-α, IL-10, IL-1RA, and CXCL10.[7] The other options hence include IL-6 antagonism as well as TNF-α blockade. The subset of patients likely to benefit in these situations may be selected by elevated levels of the respective inflammatory markers at this stage after initial therapies. IL-1, however, mostly remains in the microenvironment and measured levels may not directly reflect the degree of pathway upregulation.[6] Furthermore, anakinra is not available locally, hence it could not be used in our patient. IL-6 levels were not significantly elevated in our case; therefore, tocilizumab was not considered.

Infliximab is a human and mouse chimeric monoclonal antibody that specifically blocks TNF-α with high affinity and inhibits the binding of TNF-α to its receptor. A meta-analysis of 16 studies of infliximab efficacy in the treatment of KD showed that infliximab decreased the incidence of CAA, the nonresponse rate, and the incidence of adverse events.[8] Myocarditis is an integral component of KD and may be more common than coronary artery abnormalities.[9] Reports of a child on infliximab therapy for inflammatory bowel disease found to lead to a milder phenotype of MIS-C,[10] and another received the same for both severely active Crohn's disease and MIS-C and reported good outcome.[11] Case series have reported usage of infliximab as one of the biologics without information on individual outcomes.[2],[12]

Cardiac manifestations are frequent in MIS-C with acute myocardial dysfunction as manifested by a decreased ejection fraction being the most common finding.[13] At least 50% of patients present in shock which is distributive/cardiogenic or both as in this case, presumably due to the cytokine storm. Levels of cardiac-specific markers like troponin I and T as indicators of direct cellular injury to the myocardium, and Pro-BNP, secreted primarily from cardiac myocytes in the ventricles in response to wall tension and stretching are highly valuable in evaluating the presence and severity of cardiac involvement as well as monitoring response to therapy. Significant elevations of BNP also may imply the severity of myocardial interstitial edema and vasculopathy.[6] In addition to these markers, the elevation of D-dimer levels also may reflect vasculopathy. In MIS-C with low ejection fraction, LMWH should be considered.[14]

While the initial hemodynamic instability requiring three inotropes resolved with first-line treatment, cardiac inflammation persisted as evidenced in the clinical deterioration and by the worsening Pro-BNP values eventually leading to pulmonary edema and reintubation. Pericardial involvement was noted through the presence of effusion. TNF-α being shown to be an important regulator of inflammation-mediated cardiac injury[15] with evidence of the efficacy of its blockade in refractory KD[16] led to its consideration in this case with near-immediate and sustained response being observed, in both clinical and laboratory parameters.

In conclusion, TNF-α blockade may be a promising target for consideration in refractory MIS-C and merits further study as well as the relative efficacy and choice of different biologic response modifiers.

Declaration of patient consent

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

Acknowledgments

The authors would like to acknowledge the Pediatric Intensive Care Team and Pediatric Rheumatology team at Bharati Hospital and Research Centre, Pune.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MB, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334-46.  Back to cited text no. 1
    
2.
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. 2
    
3.
Harwood R, Allin B, Jones CE, Whittaker E, Ramnarayan P, Ramanan AV, 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 2021;5:133-41.  Back to cited text no. 3
    
4.
Pouletty M, Borocco C, Ouldali N, Caseris M, Basmaci R, Lachaume 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;79:999-1006.  Back to cited text no. 4
    
5.
Godfred-Cato S, Bryant B, Leung J, Oster ME, Conklin L, Abrams J, et al. COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020. MMWR Morb Mortal Wkly Rep 2020;69:1074-80.  Back to cited text no. 5
    
6.
McMurray JC, May JW, Cunningham MW, Jones OY. Multisystem inflammatory syndrome in children (MIS-C), a post-viral myocarditis and systemic vasculitis – A critical review of its pathogenesis and treatment. Front Pediatr 2020;8:626182.  Back to cited text no. 6
    
7.
Dinarello CA. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev 2018;281:8-27.  Back to cited text no. 7
    
8.
Lu Z, Wang F, Lv H. Efficacy of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis. Exp Ther Med 2021;21:15.  Back to cited text no. 8
    
9.
Pilania RK, Jindal AK, Bhattarai D, Naganur SH, Singh S. Cardiovascular involvement in Kawasaki disease is much more than mere coronary arteritis. Front Pediatr 2020;8:526969.  Back to cited text no. 9
    
10.
Meredith J, Khedim CA, Henderson P, Wilson DC, Russell RK. Paediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2 [PIMS-TS] in a Patient Receiving Infliximab Therapy for Inflammatory Bowel Disease. J Crohns Colitis. 2021;15:687-691.  Back to cited text no. 10
    
11.
Dolinger MT, Person H, Smith R, Jarchin L, Pittman N, Dubinsky MC, et al. Pediatric Crohn disease and multisystem inflammatory syndrome in children (MIS-C) and COVID-19 treated with Infliximab. J Pediatr Gastroenterol Nutr 2020;71:153-5.  Back to cited text no. 11
    
12.
Felsenstein S, Willis E, Lythgoe H, McCann L, Cleary A, Mahmood K, et al. Presentation, treatment response and short-term outcomes in paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS). J Clin Med 2020;9:3293.  Back to cited text no. 12
    
13.
Alsaied T, Tremoulet AH, Burns JC, Saidi A, Dionne A, Lang SM, et al. Review of cardiac involvement in multisystem inflammatory syndrome in children. Circulation 2021;143:78-88.  Back to cited text no. 13
    
14.
Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, 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;72:1791-805.  Back to cited text no. 14
    
15.
Howerton E, Tarzami ST. Tumor necrosis factor-alpha and inflammation-mediated cardiac injury. J Cell Sci Ther 2017;8:268.  Back to cited text no. 15
    
16.
Hur G, Song MS, Sohn S, Lee HD, Kim GB, Cho HJ, et al. Infliximab treatment for intravenous immunoglobulin-resistant Kawasaki disease: A multicenter study in Korea. Korean Circ J 2019;49:183-91.  Back to cited text no. 16
    


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