Journal of The Association of Physicians of India ■ Vol.

69 ■ February 2021 43

original article

Itolizumab Treatment for Cytokine Release Syndrome in

Moderate to Severe Acute Respiratory Distress Syndrome Due to
COVID-19: Clinical Outcomes, a Retrospective Study
Vishal Gore1*, Dinesh P Kshirsagar2, Shreepad M Bhat3, Khalid I Khatib4, Bhavna Mansukhani 5

mortality of 0.7 million. 1 About 15-20%

Abstract of the infected patients develop severe
hypoxemia and require hospitalization2
Background: Hyperinflammation, hypercoagulation and multi-organ dysfunction
and may progress to life-threatening
are life-threatening complications needing immediate attention in moderate-to-
complications such as acute respiratory
severe COVID-19 patients. We present our real world experience with Itolizumab, a
distress syndrome (ARDS), systemic
repurposed immunomodulatory monoclonal antibody, administered in COVID-19
hyperinflammation, vascular hypo-
patients. responsiveness, increased endothelial
Methodology: Data from 25 confirmed moderate-to-severe COVID-19 patients, permeability, hypercoagulation and
with high levels of pro-inflammatory markers and pulmonary function worsening multi-organ dysfunction. 3 ARDS may
on best supportive care and Itolizumab were included in this analysis. Patients lead directly to respiratory failure and
requiring invasive mechanical ventilation were excluded. Clinical parameters is reported to be the cause of death in
(oxygen requirement) and laboratory parameters (ferritin, interleukin [IL]-6, 70% and cytokine storm in 28% of fatal
C-reactive protein [CRP] and absolute lymphocyte count [ALC]) were studied pre- COVID-19 cases.
and post-treatment. Average total length of stay in hospital and ICU, percentage of T-cells play a crucial role in viral
patients requiring ICU admission and average time taken for weaning off oxygen clearance and regulate the activation,
for all patients were also reported. proliferation, and effector functions
Results: All Patients were in the range of 30-78 years of age, with majority of a wide range of immune cells for
being male (76%). Most prevalent comorbid conditions were diabetes (64%) and the maintenance of self-tolerance and
homeostasis. 4 However, studies have
hypertension (28%). Median IL-6 value showed a decline by 85.4%. Significant
shown that high serum concentration
reduction in median CRP (86.96%) and Ferritin (55.61%) was observed post-
of IL-2, IL-2R, IL-6, IL-7, IL-8, IL-10,
Itolizumab compared to pre-dose values. Median ALC improved from 1605 cells/
GM-CSF, IP-10, MCP1, MIP1a and
mm3 (pre-dose) to 2462.5 cells/mm3 (post-dose). Average recovery time, defined
TNF-α has been reported in moderate
as time from Itolizumab infusion to discharge was 9.28 ± 4.04 days. Average t o s e ve r e l y i l l C O V I D - 1 9 p a t i e n t s
duration of hospitalization and ICU admission was 14.24 ± 4.15 and 8.27 ± 4.47 admitted to the ICU, 5-7 suggesting an
days, respectively, with 76% patients recovered and discharged. Median oxygen immune dysregulation and brewing of
saturation improved from 88 % (pre-dose) to 96 % (post-dose). All patients a cytokine storm.
were weaned off oxygen within Avg + SD : 6.53 ± 2.09 days post-Itolizumab
CD6 is a transmembrane glycoprotein
treatment. One and two point reduction in ordinal scale was observed in 88%
associated with modulation of T-cell
and 76% patients, respectively. Three patients (12%) did not show improvement activation, proliferation, differentiation
in ordinal sore of which two patients died because of complications due to and trafficking. 8 It is expressed on
pre-existing comorbidities. The all-cause mortality of 8%; was considered not mature T-cells, thymocytes, B1a
related to Itolizumab. One infusion related event reported abated with infusion lymphocytes and CD56+ NK cells but
period extension. not on T-regulatory cells 9 and serves as
Interpretation and Conclusion: A single dose of Itolizumab accelerated recovery a key checkpoint in regulating T effector
in adult patients with COVID-19 by controlling immune hyperactivation. The cells that are crucial to autoimmune
clinical improvement was demonstrated by reduction in inflammatory markers, responses. 10 The binding of CD6 to
weaning off oxygen, reduced length of hospital stay and improvement of ordinal a c t i va t e d l e u k o c y t e c e l l a d h e s i o n
score. Itolizumab was well tolerated and when administered in the early phase molecule (ALCAM), a ligand of CD6
of the inflammatory cascade is an efficient therapeutic option for treatment of expressed on antigen-presenting cells,
cytokine release syndrome in moderate to severe COVID-19 patients. leads to T cell activation, proliferation,
differentiation and survival. 10

Introduction 1
Consultant Physician and Intensivist, Shri Markandeya Solapur Sahakari Rugnalaya & Research Centre Niyamit and Chandan
Neuro Sciences (CNS) Hospital, Solapur, Maharashtra; 2Consultant Physician, Chandan Neuro Sciences (CNS) Hospital, Solapur,

S
Maharashtra; 3Professor and HOD, 4Professor, 5Intern, Department of Medicine, Smt. Kashibai Navale Medical College, Pune,
ince the SAR-CoV-2 (COVID-19)
Maharashtra; *Corresponding Author
outbreak, the number of confirmed Received: ; Accepted:
cases have exceeded 21 million with a
44 Journal of The Association of Physicians of India ■ Vol. 69 ■ February 2021
Itolizumab is a non-depleting
anti-CD6 humanized IgG1 monoclonal
antibody that inhibits the activity
and trafficking of T effector cells by
selectively targeting CD6-ALCAM
pathway.11 Late immunotherapy strategy
to administer immunomodulatory
agents, such as Itolizumab, can reduce
the hyperinflammatory syndrome, also
called Cytokine Release Syndrome
(CRS), associated with COVID-19
complications.
Itolizumab is approved in India
for chronic plaque psoriasis 12 and is
being evaluated in other immuno-
inflammatory disorders such as
rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, uncontrolled
asthma, lupus nephritis and acute graft-
versus-host disease. Across studies and
populations, Itolizumab is found to be
safe and well tolerated. 12-18 Previous
studies have also demonstrated
that Itolizumab downregulates
T-cell activation, proliferation and
subsequent production of various pro-
inflammatory cytokines such as IL-6,
TNF, IFNγ, IL-17 and IL-1. 8, 19
Considering the paucity of clinical
therapeutic alternatives for COVID-19
complications, we recommend
treatment of COVID-19 related
hyperinflammation using existing
therapies with proven safety profiles
to address the immediate need. Our
experience presented here is based
on the hypothesis that Itolizumab
treatment with its immunomodulatory
mechanism of action would control
CRS and further reduce morbidity
and mortality in moderate to severe
COVID-19 patients.
Patients and Methods
We constituted an observational
cohort in order to collect information
about the impact of adding anti-CD6
monoclonal antibody, Itolizumab to
the best supportive care in hospitalized
patients on clinical course of COVID
-19, recovery time and survival status.
We included confirmed COVID-19 cases
from 5 th June 2020 up until August 22 nd
2020 from two centers; 21 patients from
Shri Markandeya Solapur Sahakari
Rugnalaya & Research Centre Niyamit
and CNS Hospital Sholapur and 4
patients from Kashibai Navale Medical
College, Pune. The main inclusion
criteria were a confirmed diagnosis of
COVID-19, age > 18 years and inpatient
admission with SPO2 < 94%. The main
exclusion criteria was patients on
invasive mechanical ventilator.
Data was extracted on demographics,
personal medical history, comorbidities
(like diabetes, hypertension, deep vein
thrombosis, and hypothyroidism),
presenting symptoms, concomitant
medications and for outcomes from the
hospital’s medical records. Outcomes
included recovery time from hospital
admission to day of discharge,
average total length of stay during
hospitalization and ICU admission,
improvement in ordinal scores, average
time taken for weaning off oxygen and
mortality rates. All clinical outcomes
were monitored until day of discharge.
For COVID-19 diagnosis, specimens
were obtained by nasopharyngeal and
oropharyngeal swabs under aseptic
operation and tested with real-time
reverse transcription polymerase chain
reaction (rRT-PCR) assay. COVID-19
p o s i t i ve c o n f i r m e d p a t i e n t s we r e
administered standard of care such
as antivirals (remdesivir/favipiravir ),
hydroxychloroquine, anticoagulants
and steroids as per the hospital protocol.
Based on the clinical assessment of
patients at hospitalization, oxygen
supplementation by nasal cannula,
non-rebreather mask (NRBM), bilevel
positive airway pressure (BiPAP) or
pressure-controlled ventilation (PCV)
was initiated. If the condition of patients
deteriorated, they were intubated and
put on invasive mechanical ventilator
as per the hospital protocol. Patients
who were hospitalized and needed
o x y g e n s u p p o r t we r e i n c l u d e d i n
this observational cohort, while
those requiring invasive mechanical
ventilation were excluded.
Pa t i e n t s ( N = 2 5 ) w h o d i s p l a ye d
high levels of pro-inflammatory
markers and showed deterioration
in spite of best supportive care were
administered single dose of 1.6 mg/kg
Itolizumab infusion over a period of
5-6 hours. A premedication of 100 mg
Hydrocortisone and 30 mg Pheniramine
(i.v) was given 30 minutes prior to
Itolizumab infusion.
Clinical parameters such as oxygen
saturation, oxygen supplementation
and changes in laboratory investigations
(ferritin, IL-6, C-reactive protein [CRP],
absolute lymphocyte count [ALC])
were recorded prior to and post
Itolizumab administration. IL-6 levels
were evaluated by electrochemical
luminescence method. Ordinal
s c a l e d e ve l o p e d b y W o r d H e a l t h
Organization (WHO) 20 was used to
measure the clinical improvement.
Average time to recovery, defined
as time from Itolizumab infusion to
discharge, average total length of
stay during of hospitalization or ICU
admission and average time taken for
weaning off oxygen for all patients,
were calculated.
The study was conducted in
compliance with good clinical practice
guidelines on clinical research and data
protection.
D e s c r i p t i ve s t a t i s t i c s wa s u s e d
to summarize the data; Baseline
demographics and clinical
c h a r a c t e r i s t i c s we r e e x p r e s s e d a s
mean ± standard deviation (SD) or
the median (min, max) for continuous
numerical variables and the frequency
(percentage) for categorical variables.
In data analysis, N represents the
number of patients with available
values, excluding the missing data.
Results
The age of the patients ranged from
30 to 78 years (mean 52.04 years; Table 1).
Seven patients (28%) were ≥ 60 years of
age. Majority of the patients were male
(76%). Patient’s comorbid conditions
included diabetes (64%), hypertension
(28%), deep vein thrombosis (4%)
and hypothyroidism (4%). About
24% patients reported having both
diabetes and hypertension, and 24%
patients reported no comorbidities.
Out of the 25 patients admitted to the
hospital, 17 patients data was available
on presenting complaints, while all
patients had complaints of difficulty in
breathing, 11(64.71%) presented with
fever and cough.
All patients were on non-invasive
ventilation: 36% on NRBM and 36%
o n B i PA P , 1 6 % p a t i e n t s o n n a s a l
cannula and 12% patients on pressure-
controlled ventilation (PCV). For
outcome analysis in form of clinical
and laboratory parameters last follow
up values were considered as post dose
values.
Nineteen patients were discharged
with recovery rate of 76% and average
recovery time of 9.28 ±4.04 days. The
average total length of stay during of
hospitalization was 14.24 ± 4.15 days,
data of four patients was censored as
 Journal of The Association of Physicians of India ■ Vol. 69 ■ February 2021 45

Table 1: Baseline characteristics and

demographics
Variable Percentage
(Number / Value) (%)
Baseline Characteristics
Total Number of 25 100
patients
Age
Data Available 23 92
(N)
Mean ± SD 52.04 ± 10.68 -
Range 30-78 -
(Min-Max)
(years)
Gender
Data Available 25 100
(N)
Male 19 76
Female 6 24
Symptoms & Comorbidities
Symptoms Fig. 1: Changes in SpO2 levels pre and post Iolizumab infusion
Data available 17 68
(N)
Fever 11 64.71
Cough 11 64.71
Dyspnoea 17 100
Comorbidities
Patients with 16 64
DM
Patients with 7 28
HTN
Patients with 6 24
Both DM and
HTN
Patients with 1 4
DVT
Patients with 1 4
Hypothyroidism
Patients with no 6 24
comorbidities
they were lost to follow up and two
patients died. The all-cause mortality
was 8%.
Fig. 2: Changes in Ferritin Levels pre and post Itolizumab infusion
Among the 25 patients, 44% required
ICU admission during hospitalization
with average total length of stay of 8.27
+ 4.47 days in ICU.
Median SpO2 levels improved
from 88% (pre-dose) to 96% after
administration of Itolizumab along
with best supportive care (Figure 1).
The average time taken from Itolizumab
infusion to weaning off from the oxygen
was 6.53 ± 2.09 days. Three patients
(12%), of which two died and one of
the four censored patients did not show
any improvement in ordinal score.
The remaining three of the censored
patients showed at least one point
reduction in ordinal score but were lost
to further follow up.
A significant decrease in pro-
inflammatory biochemical parameters
such as ferritin, IL-6 and CRP was
observed after treatment with Fig. 3: Changes in IL-6 Levels pre and post Itolizumab infusion
 46 Journal of The Association of Physicians of India ■ Vol. 69 ■ February 2021

Itolizumab. The median ferritin levels

from pre- dose 829 (12, 2103) improved
to post- dose 368 (180, 966) ng/mL with
reduction of 55.61 % (Figure 2). The
IL-6 levels median from pre-dose 113
(48, 645) to post-dose 16.5(4.2, 44.3) pg/
mL with reduction of 85.4%. (Figure 3).
The CRP levels median from pre-dose
46 (13, 300) to post-dose 6 (0.6, 25)
mg/L with reduction of 86.96% after
treatment with Itolizumab (Figure 4).
The median pre-dose ALC was 1605
cells/mm 3 . These levels eventually
improved to 2462.5 cells/mm 3 post
treatment with Itolizumab.
Out of 25 patients, 3-point, 2-point
and 1-point reduction on the ordinal
s c a l e we r e o b s e r ve d i n 6 8 % , 7 6 %
and 88% patients, respectively. The
cumulative and patient wise changes
in ordinal score and time to recovery
Fig. 4: Changes in CRP Levels pre and post Itolizumab infusion
during hospitalization is illustrated in
100.0% Figures 5 and 6, respectively.
90.0% Best supportive care for all
80.0% patients included anticoagulants, low
Percentage of patients

70.0% molecular weight heparins- enoxaparin

60.0% (100% of patients), short course of
50.0% steroids-methylprednisolone (96%
40.0% patients) antivirals -remdesivir or
30.0% favipiravir (80% of patients) and
20.0% hydroxychloroquine (20% of patients).
10.0%
A single case of infusion related
0.0%
Pre Infusion 3Days Post 7Days Post 14Days Post reaction was reported of grade 1 severity
Baseline (N=25)
(N=25) Infusion (N=25) Infusion (N=24) Infusion (N=23) presented with fever, chills and rigors.
Ordinal Score 5 56.0% 92.0% 48.0% 12.5% 8.7% The patient received symptomatic
Ordinal Score 4 16.0% 4.0% 44.0% 29.2% 4.4% treatment with pheniramine 30mg i.v
Ordinal Score 3 28.0% 4.0% 4.0% 37.5% 8.7% and paracetamol. The rate of infusion
Ordinal Score 2 0.0% 0.0% 0.0% 16.7% 73.9% was slowed down to 25 ml/hour for the
remaining infusion.
Fig. 5: Cumulative Change in Ordinal Score
The first patient who died was a
58-year-old male who had presented
with symptoms of fever, cough, and
dyspnea in the past 10 days. He had a
history of diabetes. On admission, his
SpO2 was 69%, IL-6 was 645 pg/mL,
ferritin was 488 ng/mL, LDH was 612
U/L, TLC was 3800 cells/mm 3 and CRP
was 14.2 mg/L. He was initiated on
BiPAP FiO2 100% (SpO2 88%). On day
2, he continued on BiPAP (SpO2 90%)
and received Itolizumab infusion (1.6
mg/kg). On day 3 of hospitalization, an
improvement in clinical and laboratory
parameters was observed with SPo2
of 96%, TLC 11800 cells/mm 3, CRP 12.7
mg/L and IL-6 44 pg/mL. He continued
on BiPAP 100% FiO2. On Day 4, SpO2
was 94%, FiO2 80% and Chest X-ray
showed slight improvement. On Day
5, SpO2 was 89% and the patient had a
Fig. 6: Time to Recovery and Changes in Ordinal Score in all patients

sudden Cardiac arrest and died in spite
of CPR administration.
The second patient who died was a
78-year-old male who had presented
with recent fracture of right femur
and had a history of diabetes and
hypertension. On admission, his SpO2
was 80% and was initiated on BiPAP.
His pre-dose IL-6 level was 422 pg/
mL, CRP was 110 mg/L, LDH was 1570
U/L and ferritin was 1500 ng/ml. He
received Itolizumab infusion (1.6 mg/
kg) on Day 3. He weaned off BiPAP
7 days post Itolizumab infusion and
shifted to high flow nasal cannula. On
Day 10, the patient had pulmonary
embolism and atrial fibrillation and
was again put on BiPAP. His condition
however, deteriorated and he died
on Day 14. Both these events were
considered not related to Itolizumab.
Discussion
COVID-19 is rapidly spreading
worldwide, sending billions of people
into lockdown as hospitals struggle
to cope. Efforts to identify new drugs
that could help treat COVID-19
are underway. However, new drug
development is impractical in the face
of the current global pandemic. An
effective alternative is repurposing an
existing drug with known safety profile
and showing effectiveness in managing
COVID-19 complications. Itolizumab,
approved in India in December 2012
for treating chronic plaque psoriasis,
12
with its novel immune-modulating
anti CD6 mechanisms is showing
p r o m i s e i n a d d r e s s i n g t h e s e ve r e
immuno-inflammatory complications
experienced by COVID-19 patients.
I t h a s r e c e n t l y r e c e i ve d a p p r o va l
for restricted emergency use for the
treatment of cytokine release syndrome
in moderate to severe ARDS in patients
with COVID-19. 21 We administered
Itolizumab to patients who exhibited
high levels of pro-inflammatory
markers and showed deterioration
in spite of being provided the best
supportive care.
In COVID-19 infections, recovery
and fatality rates vary between
demographic groups, with certain
comorbidities associated with a higher
risk. 22-24 Age, gender and comorbid
conditions are considered as risk
factors for severe COVID-19 illness,
complications, and death. As per the
systematic review and meta-analysis by
Journal of The Association of Physicians of India ■ Vol. 69 ■ February 2021
Li J et al. (2020), the pooled mean age
was 60 years among those with severe
disease. 23 Case fatality was highest
i n p e r s o n s a g e d ≥ 8 5 ye a r s ( r a n g e
10%–27%) followed by those aged 65-84
years (3%–11%) among the confirmed
cases in USA. 24 Other than older age,
u nderl y i n g m edi c a l c om orb i di ti es
such as diabetes, hypertension,
malignancy and immunosuppression,
and male sex have been the identified
biological vulnerabilities for more
severe COVID-19 outcomes. 22,24 In the
current study, majority of the patients
administered Itolizumab were male and
the age of the patients ranged from 30
to 78 years. Diabetes and hypertension
were the most frequently reported
comorbidities. Two patients who died
in this observational cohort both were
elderly with 58 years and 78 years of
age, both had diabetes and in addition,
second patient had hypertension.
During the course of inflammatory
diseases, increase in ferritin production
h a s b e e n o b s e r ve d . 2 5 T h i s m a y b e
due to ferritin secretion caused by
the macrophages or due to several
inflammatory stimuli including
cytokines such as IL-6 which can induce
f e r r i t i n s y n t h e s i s . 25 I n t e r e s t i n g l y ,
an elevation in IL-6 levels has been
r e p o r t e d w i t h t h e a g g r a va t i o n o f
t h e C O V I D - 1 9 d i s e a s e . 26 T h u s ,
hyperferritinemia is considered
associated with inflammatory states
in COVID-19 infection. As per a recent
retrospective study with 150 confirmed
COVID-19 cases, a significant difference
in ferritin and IL-6 levels were observed
between the non-survivor group and
the survivor group (p < 0.001). 27 CRP
is a non-specific acute-phase protein
induced by IL-6 and the levels increase
rapidly and significantly during acute
inflammatory responses.28,29 Individuals
w i t h C R P l e ve l s   >   4 1 . 8   m g / L we r e
mo r e l i k el y t o d evel op C O V ID- 1 9
complications. 30 Elevated levels of
all these parameters suggest that the
mortality seen in severe COVID-19 cases
with ARDS might be due to the virus-
activated cytokine release syndrome.
Two patients who died in this study
also had high levels of IL-6 and Ferritin
at baseline. This cytokine storm is
characterized by a marked increase in
interleukins and tumor necrosis factor
that promotes lymphocyte apoptosis. 31,
32
A lymphocyte count <1.0 × 109/L has
been associated with severe COVID-19
disease. 33 During the disease course,
47
e va l u a t i o n o f p a r a m e t e r s s u c h a s
ferritin, IL-6, CRP and lymphocyte
count may help identify patients at risk
of respiratory failure, help in triage
planning and prompt intervention
in order to improve outcomes. After
administration of Itolizumab, a
reduction in important indicators of
disease severity such as ferritin, IL-6
and CRP levels were observed in the
current set of patients. An improvement
in lymphocyte count was also observed.
The severity of COVID-19 disease
ranges from asymptomatic infection to
severe illness characterized by ARDS.
SpO2 level, in particular, is an important
parameter to determine the need for
admittance to ICU. Depending on the
disease severity and clinical assessment
of patients at hospitalization, oxygen
supplementation by nasal cannula,
NRBM, BiPAP or PCV was administered
to all patients directly at hospital
admission. An improvement in oxygen
saturation (96% SpO2) and patient’s
clinical status (2 or 3 points reduction
on WHO ordinal scale) 20 was observed
post Itolizumab administration in
majority of the patients. The patients
were weaned off oxygen within an
average of 6.53 days post Itolizumab
administration with majority of the
patients getting discharged 14 days
(median) post hospitalization.
The median time to recovery,
defined as time from Itolizumab
infusion to discharge, was 8 days. In
previous studies, median length of
hospitalization among survivors has
been observed to be 10 to 13 days 34-36
and the median time to recovery with
remdesivir has been seen to be 11
days. 37 The median and mean length of
stay for the 11 patients admitted in the
ICU was 8 and 8.27 days, respectively in
our study, as compared to the median
length of stay for 15 days (Suleyman G
et al, 2020) and mean length of stay for
18.4 days (Turacotte JJ et al, 2020). 38, 39
Depending on the study and
characteristics of the patient population,
a mortality rate of 39% to 72% has been
reported among patients admitted to
ICU with COVID-19 complications. 5, 36,
40, 41
In the current study, two patients
died on Day 5 and Day 14 (one due
to sudden cardiac arrest and another
due to pulmonary embolism and
atrial fibrillation, who got admitted
w i t h f r a c t u r e f e m u r ) ; w h i c h wa s
considered not related to Itolizumab
administration. The all-cause mortality
 48 Journal of The Association of Physicians of India ■ Vol. 69 ■ February 2021
in the current study was observed
to be 8%. A single event of infusion
related reaction related to Itolizumab
administration was reported which
wa s a b a t e d w i t h t h e e x t e n s i o n o f
infusion period. The patient received
symptomatic treatment and completed
the infusion.
One limitation of this study is the
occurrence of missing data, which
can be considered acceptable in this
pandemic situation, as it is very difficult
to record repeated observations and
assessments while the hospital battles
w i t h m a n a g i n g t h e e ve r - g r o w i n g
numbers of COVID-19 patients.
Conclusion
A single dose of Itolizumab
accelerated recovery in adult patients
with COVID-19 by controlling
immune hyperactivation. The clinical
improvement was demonstrated by
reduction in inflammatory markers,
weaning off oxygen, reduced length
of hospital stay and improvement of
ordinal score. Itolizumab was well
tolerated and when administered in
the early phase of the inflammatory
cascade is an efficient therapeutic
option for treatment of cytokine
release syndrome in moderate to
severe COVID-19 patients. Randomized
controlled clinical trials in large patient
population can further validate these
findings.
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