Treatment failure with IVIG in a case of multisystem inflammatory syndrome in children, managed by Tocilizumab

Abstract

Coronavirus disease (COVID-19) in children, so far, was thought to be a benign condition. However, in the later half of April 2020, a novel syndrome in children and adolescents was first described presenting with a hyperinflammatory state with or without circulatory shock termed as "multisystem inflammatory syndrome in children" (MIS-C). Most of these children had COVID-19 infection in recent past, or exposure to confirm or suspected cases. Hallmark of this syndrome is cytokine storm evidenced by elevated inflammatory markers, and hence immunomodulatory therapy has been the mainstay of treatment. Majority of cases responded to intravenous immunoglobulin (IVIG) or corticosteroids or both for their anti-inflammatory and antibody-mediating effects. We report a young adolescent boy with MIS-C who failed to respond to adequate dose of IVIG and steroid, and later recovered successfully with tocilizumab, an IL-6 receptor inhibitor as a second line therapy.

Full text

Treatment failure with IVIG in a case of multisystem
inflammatory syndrome in children, managed by Tocilizumab
Fahmida Zabeen1, M Quamrul Hassan2, Tahera Nazrin3, Badrun Nessa4
1Consultant, Department of Paediatrics, Evercare Hospital Dhaka
2Senior Consultant, Department of Paediatrics, Evercare Hospital Dhaka
3Clinical and Interventional Paediatric Cardiologist, Evercare Hospital Dhaka
4Senior Registrar, Evercare Hospital Dhaka
First author: Fahmida Zabeen, Co-First author: M Quamrul Hassan
Corresponding author: Fahmida Zabeen, fahmida.zabeen@hotmail.com
Abstract:
Coronavirus disease (COVID-19) in children, so far, was thought to be a benign condition.
However, in the later half of April 2020, a novel syndrome in children and adolescents was first
described presenting with a hyperinflammatory state with or without circulatory shock termed as
“multisystem inflammatory syndrome in children” (MIS-C). Most of these children had COVID-19
infection in recent past, or exposure to confirm or suspected cases. Hallmark of this syndrome
is cytokine storm evidenced by elevated inflammatory markers, and hence immunomodulatory
therapy has been the mainstay of treatment. Majority of cases responded to intravenous
immunoglobulin (IVIG) or corticosteroids or both for their anti-inflammatory and antibody-
mediating effects. We report a young adolescent boy with MIS-C who failed to respond to
adequate dose of IVIG and steroid, and later recovered successfully with tocilizumab, an IL-6
receptor inhibitor as a second line therapy.
Keywords: Coronavirus disease, multisystem inflammatory syndrome in children, cytokine storm,
intravenous immunoglobulin, tocilizumab.
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread
around the world from the time when it was first identified in China in December 2019.1,2 Among
initial reports from China on Corona Virus Disease 19 (COVID-19) in paediatric age group, very
few have sporadically described critically ill children.3 Most children with this disease are

asymptomatic or exhibit a mild upper respiratory illness, and recover within 1 to 2 weeks.4
However, reports have begun to emerge of multiple system involvement with circulatory shock
and systemic inflammation that has presented predominantly in children with COVID-19. The first
such report was from the United Kingdom involving a cohort of 8 children with evidence of severe
inflammation and Kawasaki disease-like features.5 Thereafter, similar reporting continued from
Italy describing 10 children, and from France and Switzerland describing 35 children.6,7 On 14
May, the US Centers for Disease Control and Prevention (CDC) formally termed this entity as
multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 and
introduced a case definition.8
Epidemiologic evidence implicates SARS-CoV-2 as the likely cause of the newly recognized MIS-
C, even though causation has not yet been established. The occurrence of clusters of MIS-C
cases in places that have been heavily impacted by COVID-19 such as Italy, the UK, and New
York City, is highly suggestive of an association to infection with SARS-CoV-2. While the
incidence of MIS-C is uncertain, it appears to be an uncommon complication of COVID-19 in
children. In one report, the estimated incidence of laboratory-confirmed SARS-CoV-2 infection in
individuals less than 21 years old was 322 per 100,000 and the incidence of MIS-C was 2 per
100,000.9
CDC data on tracking reports of MIS-C cases shows strong evidence of its linkage with COVID-
19. Almost all (98 %) cases were positive for antigen or antibody of SARS Cov-2.8 The majority
of published cases with this syndrome were positive for serologic testing for SARS-CoV-2 (60/69,
87%) and less commonly positive for RT-PCR testing from nasopharyngeal swab (23/70, 32%),
which suggests that this syndrome may be post-infectious rather than related to acute early
infection.10 The clinical presentation of MIS-C includes fever with severe illness, and the
involvement of two or more organ systems, along with laboratory evidence of inflammation and
laboratory or epidemiologic evidence of SARS-CoV-2 infection.8 Laboratory findings include
lymphopenia, hypoalbuminaemia, elevation in serum troponin, liver enzymes, D-dimer, and S.
Ferritin. C-reactive protein and ESR are also elevated, along with cytokines elevation such as
tumor necrosis factor alpha, interleukin (IL)-4, IL-6, and IL-10.11
Specific immunomodulatory therapy depends on the clinical presentation of this severe illness.
The goals of treatment for MIS-C are to reduce systemic inflammation and restore organ function,
in order to decrease mortality and reduce the risk of long-term sequelae, such as the development
of coronary artery aneurysm (CAAs) or persistent cardiac dysfunction.10 Overall, children will

survive this hyperinflammatory condition with IVIG administration, steroids, a multidisciplinary
team of relevant healthcare providers, and in few cases immunomodulatory agents.12 In a very
few reported cases where IVIG response was unsatisfactory, Interleukin-6 inhibitors, an
immunomodulatory agent was found beneficial while given during the cytokine storm associated
with COVID-19.13 We report a case of MIS-C from a tertiary care hospital (Evercare Hospital
Dhaka), from Capital Dhaka, Bangladesh, who was successfully treated with IL-6 inhibitor
(Tocilizumab), as a second line therapy after failed treatment with adequate dose of IVIG and
steroid.
Case report
A 10 years 10 months old previously healthy boy was admitted through emergency room with the
complaints of high-grade fever (maximum peak 106oF) for 2 days, repeated vomiting, severe
abdominal pain and dry cough. Both his parents and he were positive for SARS - CoV - 2 RT PCR
nasopharyngeal swab test three weeks prior to this illness. At that time, he had fever (102oF for
about 2.5 days) with mild cough, which was managed conservatively at home.
On arrival, the boy was febrile with temperature 104oF, sick looking, mildly tachypneic with normal
oxygen saturation. His heart rate was 128 beats/min and he was normotensive with BP 90/60 mm
of Hg. His chest was clear on auscultation, abdomen was soft with diffuse tenderness, and bowel
sound was normal. Skin survey was normal and no signs of meningism were noted. Investigations
on admission showed, neutrophilic leukocytosis and lymphopenia, slightly raised CRP and SGPT.
His SARS -CoV- 2 (RT PCR) test came negative and chest radiograph was normal. Ultra-
sonogram of whole abdomen showed trace free fluid. On suspicion of sepsis, Inj. Amoxycillin with
Clavulanic acid was started empirically. On the following day, he also developed new symptom
of intermittent delirium with irritability and complained of getting smell in everything around. After
36 hours of admission, on day 4 of illness, as there was no change of clinical condition, repeat
investigations were done, which revealed thrombocytopenia and markedly raised inflammatory
markers including S. Ferritin, D-Dimer, LDH and ESR. He also had low S. albumin, proteinuria
and normal Troponin-I (1.9 ng/ml). Multisystem inflammatory syndrome in children (MIS-C) has
been suspected and inj. Methylprednisolone (2 mg/kg/day) 12 hourly IV was added in treatment.
Next day, his general condition further deteriorated with continued high fever along with cough
induced vomiting and persisting abdominal pain. Repeat investigations revealed persisting
lymphopenia, markedly raised C-reactive protein (127 mg/L), raised Procalcitonin, normal Widal

Titre, further increasing D-Dimer & high Fibrinogen level (717.2 mg/dl) with negative septic
screen. 2D Colour doppler echocardiography (Fig.-1) revealed medium aneurysmal dilation of
coronary arteries [LMCA (Z- score +5.95) and LAD (Z -score +5.26)] with irregular and distorted
vascular wall and electrocardiogram (EKG) showed sinus tachycardia. Our patient fulfilled the
CDC case definition of MIS-C.8 We have started IVIG (1.5 gm/kg) continuous infusion over 24
hours. Antibiotic was switched to Meropenem. Inj. Enoxaparin S/C and low dose Aspirin were
also started. He became afebrile day after IVIG infusion and started showing general wellbeing.
His cough as well as vomiting and abdominal pain also subsided.
However, 72 hours after IVIG infusion (on Day 9 of illness), his fever recurred with increasing
peak along with excessive dry cough, anorexia and repeated vomiting. His ESR further raised
along with raised inflammatory markers, and he also developed hyponatraemia. On day 11 of
illness, 48 hours after new onset fever, he also developed macular rash on both palms, bilateral
conjunctival injection (Fig.-2) and erythematous throat with mildly tender left cervical
lymphadenopathy. His blood pressure and oxygen saturation remained within normal range.
Antifungal Tab. Fluconazole was added. His subsequent lab test showed very low S. Albumin,
further rising inflammatory markers with markedly high CRP, D-DIMER as well as ESR. His 2nd
set of septic screen also came negative and repeat chest radiograph also revealed normal. On
day 13 of illness, Inj. Tocilizumab (8 mg/kg) single dose was infused. Shortly after the infusion, 2
hours later, his fever subsided and there was significant improvement of wellbeing along with
resolution of cough and vomiting. Four days after Tocilizumab infusion, investigations were
repeated and yielded normal Lymphocyte count, improving CRP and ESR, near normal
Procalcitonin and normal D-Dimer (Fig.-3). He developed thrombocytosis (455 10^9/L), further
rising S. Ferritin & SGPT (422 IU/L). 2-D echo (Fig.-1) before discharge revealed reduction in
aneurysmal dilation of LMCA (Z- score +3.13) and LAD (Z- score +3.38) with irregular vascular
wall. He was discharged in vitally stable state after 15 days of hospital stay with advice of tapering
oral steroid and low dose Aspirin. All his relevant laboratory tests during admission and
subsequent follow up are shown in the Table-I and trend of inflammatory markers during hospital
stay in (Fig.-3). He attended follow-up visits in outpatient clinic after 1, 3 and 6 weeks of discharge,
where he was found vitally stable with normalization of his inflammatory markers, but he had
persisting small aneurysmal dilatation of LMCA and LAD with irregular vascular wall in 2-D
Echocardiogram even at 3 weeks after discharge. On further follow up, at 7 weeks, all coronary
arteries became normal.

1st 2D-Echocardiogram showing medium
aneurysmal LMCA dilation on Day 5 of illness
2nd 2D-Echocardiogram showing small aneurysmal
LMCA dilation on Day 15 of illness
Fig.-1 1st and 2nd Echocardiogram images showing aneurysmal dilation of coronary arteries with irregular
and distorted vascular wall
Conjunctival Injection
Palmer rash
Fig.-2 Changes in eyes and hands on day 11 of illness
Table-I Laboratory findings during hospital stay and follow-up
Laboratory test
During Hospitalization 1
st
F-up 2
nd
F-up
Day of illness/specific treatment
1
4
5
IVIG
7
10
13
Tocilizumab
14
17
24
56
TLC 10^9/L (normal: 5-13) 13.93 7.71 6.42 4.65 9.67 14.82 15.59 12.97 6.13
Absolute Neutrophil count 10^9/L (norm al: 2-7) 12.79 6.37 5.74 3.18 8.23 12.96 11.3 9 3.71
Absolute Lymphocyte count 10^9/L (normal: 1-3) 0.87 1.13 0.61 0.97 0.85 1.34 3.31 3.68 1.83

Platelets 10^9/L (normal 150-400) 161 139 165 244 292 284 4.55 319 257
CRP mg/L (normal <3.3 ) 5.2 127 70.9 53.7 178 162 28.6 <2.9
Procalcitonin ng/ml (normal <0.05 ) 0.75 2.97 0.7 0.38 0.14
ESR mm in 1st hour 80 121 134 110 41 11
Ferritin ng/ml (12-140) 148 239 349 454 796 259 86
D-Dimer Microgm/L (<500) 462 2314 2646 1618 1422 1917 923 305 184
Fibrinogen mg/dl (180-350) 717 358
LDH U/L (normal <250) ) 264 194
Troponin ng/mL, (normal 3-17) 1.9
SGPT IU/L (normal 14 -63) 73 50 75 44 422 140 64
S. Albumin gm/dl (normal 3.5 – 5) 3.3 2.9 2.2 2.6 3.3
S. Sodium mmol/L (normal 135-145) 135 136 130 134 136
Urine Protein Trace Trace NIL
Aerobic C/S blood No growth No growth
Aerobic C/S urine No growth No growth
Fig.-3 Trend of Inflammatory markers with effect of IVIG and Tocilizumab during Hospital stay
Discussion
Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe inflammatory
condition that has been reported in previously healthy pediatric patients having SARS-CoV-2
exposure.14 Evidence supporting an underlying link with SARS CoV- 2 includes a strong historical
association with Covid-19 activity, diagnosis of SARS-CoV-2 infection through RT-PCR or
antibody testing in most patients, and hyper inflammatory manifestations like Covid-19 infected
Tocilizumab
IVI
IVIG

adults.15-17 We report a previously healthy boy, who fulfilled the CDC case definition8 of MIS-C
and was positive for SARS-CoV - 2 RT PCR nasopharyngeal swab test three weeks prior to his
illness. MIS -C is speculated to be a delayed immunological phenomenon associated with
inflammation (stage III hyperinflammation phase) following either symptomatic or asymptomatic
COVID infection.10
There is resemblance between MIS-C and atypical Kawasaki disease (KD); however, there are
some noticeable clinical differences, such as presentation at older age, a higher frequency of
gastrointestinal symptoms on presentation, and a higher rate of cardiac involvement in MIS-C.6-
8,18
Our reported case had several systemic involvements including Cardiac, Gastrointestinal,
Hematological, Hepatic and Nervous system. He presented very early within 2 days of illness,
and we could record the evolution of clinical and laboratory features. His brief mucocutaneous
manifestations with cervical lymphadenitis resembling features of Incomplete KD developed late
in the disease course on 11th day of illness during second peak of febrile episode.
Current management of MIS-C emphasizes on supportive care and treatment of the underlying
inflammatory process to reverse organ dysfunction and prevent further complications. Although
there are no specific therapies approved by the U.S. Food and Drug Administration (FDA) for this
condition, several agents are being used in different clinical trials and under institutional protocols
based on their clinical benefit in similar conditions.8,18 Stepwise immunomodulatory treatment in
MIS-C is recommended with intravenous immunoglobulin (IVIG) and/or glucocorticoids as first
line agents. This immunomodulatory approach is the most commonly used treatment reported to
date in patients with MIS-C.5-7,19-24We have seen brief positive clinical response in our patient after
treatment with IVIG and Steroid. But after 3 days of IVIG infusion, his fever recurred along with
clinical deterioration and rapidly rising inflammatory markers. Verdoni et al6, reported that, the KD
cases who presented during the COVID-19 pandemic showed high rate of IVIG resistance, as
compared to that in a past cohort of KD patients, suggesting a role for glucocorticoids in MIS-C.
In case of patients not responding or partially responding to IVIG and/or Steroid, alternative
agents have been used in different centers. Considering the cytokine release syndrome as the
important contributor to severe inflammation in some patients with MIS-C.25 American College of
Rheumatology guidance recommended anakinra (Interleukin-1 antagonist) in patients with MIS-
C who are refractory to IVIG and/or glucocorticoids.26

This recommendation is based on the relative safety of anakinra in pediatric patients with
hyperinflammatory syndromes even with active infection, and the outcomes mentioned in the
literature in some of MIS-C patients. 13,14,24,27-30 IL-6 is an important cytokine in this inflammatory
process and a few studies suggest that CS is certainly correlated with disease severity. 31 IL-6 is
a proinflammatory cytokine that is involved in T-cell activation, immunoglobulin secretion
induction, acute-phase protein synthesis initiation in liver, and stimulation of hematopoietic
precursor cell proliferation and differentiation.32 Assuming the relationship between increased IL-
6 levels and negative outcomes in COVID-19, IL-6 neutralization with tocilizumab can be a
potential treatment option.16,33,34 This monoclonal antibody blocks IL-6-mediated signaling by
competitively binding to both soluble and membrane-bound IL-6 receptors, and it is approved by
the US FDA for treating Cytokine release syndrome (CRS).6
Our reported patient was declared as treatment failure with IVIG and was labeled as an IVIG
refractory case of MIS-C. We chose Tocilizumab (IL-6 inhibitor) empirically as the second line
treatment considering role of IL-6 in cytokine storm, as Anakinra (IL-1 inhibitor) is not available
in commercial market, and we lack laboratory facility for doing IL-6 assay. He demonstrated
quick and significant as well as sustained clinical remission and improvement in laboratory
parameters after treatment with Inj. Tocilizumab.
Children’s Hospital of the King’s Daughters (CHKD) protocolized tocilizumab for patients with
continued fever for 24 hours after IVIG and/or steroids or moderate to severe presentation. They
recommended a single dose of tocilizumab 12 mg/kg IV in patients less than 30 kg and 8 mg/kg
IV (Max: 800 mg) in patients 30 kg or more and mentioned the typical response time within 48 to
72 hours.35 We have used 8 mg/Kg single dose in our patient. In 3 New York City tertiary care
children’s hospitals, (n = 33; age 2 months to 20 years), Kaushik S and colleagues treated 12
(36%) patients with tocilizumab along with IVIG or Methylprednisolone. Tocilizumab was given to
patients with high IL-6 concentrations.36 In another 3 systematic reviews of MIS-C patients (n =
662 to 783), interleukin-6 inhibitors were administered to 6% to 6.5% of patients. Sixty-eight to
seventy one percent of patients were in the intensive care unit and there was 1.5% to 1.7%
mortality rate.37-39 In an observational study (n = 27; median age 6 years) by Torres JP and
colleagues, tocilizumab was administered to 2 patients with suspected cytokine storm syndrome
with no mortality.40

Fourteen percent of patients among 186 MIS-C cases reported to receive tocilizumab or
siltuximab in addition to IVIG and other therapies. Eighty percent of patients were in the
critical care unit and 20% received mechanical ventilation.14 Gruber C et al., reported in a
case series of 8 patients with median age 11.5 years, all patients received 1 to 3 doses of
tocilizumab within 1 day of admission. Seven of the 8 patients also received IVIG. Markers of
inflammation, coagulopathy and cardiac injury normalized rapidly in all patients.41
For Tocilizumab use, there is risk of GI perforation, hepatotoxicity and infusion-related reactions.
32 In our experience while managing the case, tocilizumab was well tolerated. Tocilizumab is
much cost effective than that of IVIG. Our reported case showed rapid drop in his later raised
CRP and D-dimer, and lymphopenia as well as thrombocytosis soon corrected within 4 days
following intravenous Tocilizumab. We have seen, Ferritin, ESR and later raised SGPT took
time to normalize, which we are not considering markers for immediate treatment success.
Nozawa T et. al. 42, reported Coronary-Artery Aneurysm in Tocilizumab-Treated Children with
Kawasaki’s Disease. In our case, on further follow up upto 6 weeks, there was no significant
adverse effects like worsening of coronary artery aneurysm or fare of infection associated with
Tocilizumab use. Rather, we have seen normalization of coronary arteries at 6 weeks follow up
visit.
MIS-C patients who require treatment with steroids, irrespective of the dose, frequently require a
gradual tapering over 2–3 weeks to avoid rebound inflammation.26 For our patient, we continued
oral steroid with gradual taper over 3 weeks after discharge, and we also did not experience any
such rebound inflammation.
Conclusion
Though IVIG and steroid are so far widely used effective first line agents to treat severe MIS-C,
failure to treatment can happen which may take about 72 hours to be evident. Predictors for
treatment failure of MIS-C with IVIG need to be studied further. In this case report, Tocilizumab,
the IL-6 inhibitor, has been safely and successfully used in an adolescent as second line
therapy. Considering this experience of safety, quick recovery response and relatively cheaper
option, use of Tocilizumab as a second line agent instead of repeat use of costly IVIG may be
considered. If it is proved safe in larger study, it can be considered as even a first line
therapeutic agent in treating MIS-C.

Authors’ Contribution
Fahmida Zabeen: Conceptualization, treating the patient, collecting data, writing manuscript
M Quamrul Hassan: Conceptualization, treating, review and editing, supervision
Tahera Nazrin: Echocardiography, review
Badrun Nessa: Collecting data, reference collection, review
Acknowledgement
Research and Ethics committee, Evercare Hospital, Dhaka for approval. CEO, Evercare Hospital
for permission to publish. The patient and his parents for their permission to publish.
Conflict of interest: Authors declared that there was no conflict of interest
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