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\begin{document}

\title{Outcome of using Intravenous Immunoglobulin (IVIG) in critically ill
COVID-19 patients': a retrospective, multi-centric cohort study}



\author[1]{Mohammadreza  Salehi}%
\author[2]{Mahdi Barkhori Mehni}%
\author[3]{Mohammadmehdi Akbarian}%
\author[1]{Samrand Fattah Ghazi}%
\author[1]{Nasim Khajavi Rad}%
\author[4]{Omid Moradi Moghaddam}%
\author[3]{Saeed reza Jamali Moghaddam}%
\author[4]{Masoumeh Hosseinzadeh Emam}%
\author[1]{Sayed Hamidreza Abtahi}%
\author[4]{Maryam Moradi}%
\author[3]{Fereshteh Ghiasvand}%
\affil[1]{Imam Khomeini Hospital Complex}%
\affil[2]{Tehran University of Medical Sciences School of Medicine}%
\affil[3]{Tehran University of Medical Sciences}%
\affil[4]{Iran University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\selectlanguage{english}
\begin{abstract}
Abstract Background: To access the effect of Intravenous immunoglobulin
(IVIG) in critically ill corona virus disease 2019 (COVID-19)
patients. Method: In this retrospective matched cohort study, records of
three tertiary centers with large number of COVID-19 admissions were
evaluated and used. Based on treatment options, patients were divided
into two groups, standard COVID-19 treatment (109 patients) and IVIG
treatment (74 patients) patients. Also, the effect of IVIG in different
dosages was evaluated. Patients with IVIG treatment were divided into
three groups of low (0.25 gr/kg), medium (0.5 gr/kg), and high (1
gr/kg) dose. Data analysis was performed using independent t-test and
One-way analysis of variance (ANOVA) to compare the outcomes between
two groups, including duration of hospitalization, intensive care unit
(ICU) length of stay, and mortality rate. Result: The duration of
hospitalization in the IVIG group were significantly longer than
standard treatment (13.74 days vs. 11.10 days, p\textless{}0.05). There
was not a significant difference between the two groups in ICU length of
stay, number of intubated patients and duration of mechanical
ventilation (P\textgreater{}0.05). Also initial outcomes in IVIG
subgroups were compared separately with the standard treatment group.
The results indicated that only the duration of hospitalization in the
IVIG subgroup with medium dose is significantly longer than the standard
treatment group (P\textless{}0.01). Conclusion: Using IVIG is not
beneficial for COVID-19 patients based on no remarkable differences in
duration of hospitalization, ICU length of stay, duration of mechanical
ventilation and even mortality rate.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Novel coronavirus disease 2019 (COVID-19) pandemic has become a global
concern since 2019. By August 2021 more than 4,300,000 people have been
sacrificed by this disease{[}1{]}.

No definitive treatment has been found, so it makes sense to consider
the effects of possible treatments on the disease. One of these possible
treatments is Intravenous Immunoglobulin (IVIG), which has been reported
to have contradictory effects in previous studies{[}2, 3{]}.

The IVIG is a plasma-derived drug that was first used to treat some
immune deficiencies{[}4{]}. It has been used as an adjunct therapy in
the management of some infections. Among viral infections, this
treatment has been used to prevent and treat various viruses such as
influenza, viral hepatitis, rabies, measles and severe acute respiratory
syndrome~(SARS){[}5{]}. Studies have revealed that IVIG can be effective
in the treatment of severe acute viral pneumonia such as influenza and
para-influenza pneumonia{[}6, 7{]}. Antigen clearance and immune system
modulation are increase by IVIG {[}8{]}. Due to the mechanism, safety
and efficacy of this treatment in previous viral infections, some
centers have utilized it in severe cases of COVID-19 infection. Despite
its efficacy, this treatment is expensive and has various side
effects{[}9{]}. Thus, the effectiveness and safety of this intervention
in COVID-19 infection is debatable. Based on several studies IVIG
administration in COVID-19 patients is controversial{[}9, 10{]}.

In this study we intend to investigate the efficacy of adding IVIG to
the standard regimen of COVID-19 infection in outcome measures such as
duration of hospitalization, mechanical ventilation, and intensive care
unit (ICU) length of stay and mortality rate.

\textbf{2. Materials and Methods}

This retrospective study was conducted on COVID-19 patients in Imam
Khomeini hospital complex, Rasul-e Akram and Ziaeian hospitals in
Tehran, Iran.

\emph{2.1. Participants}

In this study, a total of 202 patients who were admitted to between
February 2020 to December 2020 were reviewed. These patients were
treated with standard methods or IVIG added to standard care. Inclusion
criteria were COVID-19 confirmation with real-time polymerase chain
reaction~(PCR), significant pulmonary findings compatible with
radiographic imaging and critically ill patients in ICU.

Critically ill patients were those with less than 90\% oxygen saturation
level with Non-rebreather mask, those who needed noninvasive ventilation
(NIV) or intubation. Exclusion criteria were age under 18 years old,
pregnancy, patients with incomplete data, non-ICU patients, those who
participated in other clinical trials or received nonstandard treatment
due to national or regional protocol and those who received less than
five grams of IVIG.

\emph{2.2. Study arms and treatment plans}

After carefully reviewing the COVID-19 patients records based on the
hospital information database, and finally considering the inclusion and
exclusion criteria, 183 patients were divided into two groups; 109
patients have received standard treatment and 74 patients have received
IVIG (Figure1).

In this study, epidemiological, demographic, clinical, laboratory data,
management, and outcomes of patients were obtained. Finally, the
outcomes include mortality rate, duration of hospitalization, mechanical
ventilation and ICU length of stay were analyzed and compared between
two groups.

The standard treatment group regimen was oral Hydroxychloroquine (HCQ)
400 mg daily for 5 days plus Atazanavir/Ritonavir (300/100) daily for
ten days. IVIG treatment was divided into three groups of low, medium
and high dose (0.25, 0.5 and 1 gr/ kg) during 3-5 consecutive days in
addition to standard care.

\emph{2.3. Ethical considerations}

The study was approved by the Institutional Review Board of Tehran
University of Medical Sciences and exempted from written informed
consent \textbf{{[}} IR.TUMS.VCR.REC.1399.390{]}.

\emph{2.4. Measurements and statistical analysis}

Distribution of age, sex, initial clinical symptoms and on admission
vital signs were compared between the two groups. Mortality rate,
duration of hospitalization, mechanical ventilation and ICU length of
stay were also evaluated.

The results were analyzed using SPSS v.25.0 software. Chi-square tests
were performed to evaluate the difference in qualitative data.
Shapiro-Wilk test was performed to assess the normality of data
distribution. To compare the differences in the quantitative variables
of groups, the independent t-test and One-way analysis of variance
(ANOVA) was carried out. Values with p\textless{}0.05 were considered
statistically significant.

\textbf{3. Results}

Based on the inclusion and exclusion criteria, 183 ICU admitted COVID-19
patients were included in the study, of which 109 (59.6\%) were males
and 74 (40.4\%) were females, with an average age of 62.71 (\emph{+}
15.46) years old. The patients were divided between standard treatment
(comprising 109 patients) and IVIG treatment groups (comprising 74
patients) based on their treatment method.

\emph{3.1. Clinical and laboratory findings}

The clinical characteristics of patients (case and control group) are
shown in Table I. Based on the results there were no significant
differences between the two groups in demographic data, vital sign on
admission, clinical features, laboratory tests and even risk factors. (P
\textgreater{}0.05).

\emph{3.2. Primary and secondary outcome}

Primary outcomes including mortality rate, duration of hospitalization,
ICU length of stay and duration of mechanical ventilation were compared
in the two groups (Table II).

According to the primary outcomes the duration of hospitalization was
longer in the IVIG group (P\textless{}0.05). Two groups were not
significantly different in ICU length of stay, number of intubated
patients, duration of mechanical ventilation and mortality rate
(P\textgreater{}0.05).

Patients in the IVIG treatment group were divided into three groups;
low, medium and high dose of IVIG (0.25, 0.5 and 1 gr/kg). Accordingly,
33.8\% of the cases received low dose, 43.2\% medium dose and 23\% high
doses (Table III). In these groups, mortality rate, duration of
hospitalization, ICU length of stay and duration of mechanical
ventilation were compared using analysis of variance (ANOVA) for
Continuous scores and chi-square (\selectlanguage{greek}χ\selectlanguage{english}2) for stratified scores. The LSD
post hoc test was also used to determine the location of the
discrepancy. ANOVA test results are listed in Table III along with the
results which are significantly different between the two groups.

There are no significant differences among three groups of IVIG
treatment in primary outcomes as indicated in Table III.
(P\emph{\textgreater{}} 0.05). The comparison between IVIG groups and
standard treatment is summarized in Table IV. Based on the results, the
duration of hospitalization was longer in the medium dose IVIG group (p
\textless{} 0.01).

Finally, 165 patients were divided into five subgroups based on
intubation as shown in Table V. Eighteen out of 183 patients were
excluded due to the lack of data.

Mortality rate was not significantly different between IVIG and standard
treatment groups in both intubated and non-intubated subgroups.
Mortality rate in subgroups one and four was 0\% and the result of
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test between subgroups three and five showed no
statistical difference (p-value = 0.731 and \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} =
0.393).

\textbf{4. Discussion}

There have been different studies so far with different results about
effect of IVIG on COVID-19 patients. But clear results have not been
obtained {[}2, 3, 11{]}. Hence in this study, the therapeutic effects of
IVIG on the confirmed COVID-19 cases were examined and the previous
valuable results of related articles were reviewed.

Based on a randomized clinical trial on 84 patients, 52 patients
received a treatment regimen including hydroxychloroquine, lopinavir /
ritonavir and supportive care, plus 400~mg/kg IVIG daily for three days,
but 32 patients received the same regimen without IVIG. Addition of IVIG
to the standard treatment of critically ill COVID-19 patients could not
decrease the duration of hospitalization, mechanical ventilation or
mortality rate. In this study Tabarsi et al. found that duration of
hospitalization was significantly longer in IVIG treatment group{[}2{]}.
In our study we also found that the duration of hospitalization in the
medium dose subgroup of IVIG was longer than control group and no
positive effects were obtained on duration of mechanical ventilation and
mortality of patients. Many studies have shown that IVIG administration
reduces mortality in patients with COVID-19, but increases
hospitalization time instead of standard COVID-19 treatment {[}12,
13{]}.

In a multicenter retrospective cohort study on 325 patients (174
patients in the case group who received IVIG and 151 patients in the
control group), 28-day and 60-day mortality were the primary outcomes.
Subgroup analysis showed that 28-day mortality in patients with critical
type was improved compared to the control group and in these critically
ill patients, IVIG reduced the inflammatory response and improved some
organ functions, but the length of hospital stay and overall duration of
the disease was increased{[}11{]}. In another study, IVIG administration
in the first 48 hours of hospitalization reduced mortality, length of
stay, length of stay in the ICU, and duration of mechanical ventilation
compared to IVIG administration after 48 hours of hospital
admission{[}9{]}. Herth et al. retrospectively evaluated the clinical
courses of 12 COVID-19 patients who received IVIG at various stages of
their disease, including within the first 72 h of clinical presentation,
after initiation of mechanical ventilation, and after prolonged
ventilation and ICU stay. Patients in this study received 0.2 or 0.5
g/kg/d of IVIG for 1 to 4 days. Early IVIG administration in viral phase
of COVID-19 infection can decrease the duration of hospitalization, ICU
length of stay, duration of mechanical ventilation and even mortality
rate rather than late administration {[}9, 14, 15{]}.

In our retrospective matched cohort study, we examined 183 patients with
severe covid-19 infection who were admitted to the ICU. Seventy-four
(40/4 \%) patients were included in the case group and received IVIG in
addition to the standard treatment, but 109 (59/6 \%) patients in the
control group received only standard treatment. On admission vital
signs, clinical signs, laboratory data, and risk factors did not differ
significantly between the two groups. Primary outcomes in our study
were, duration of hospitalization, ICU length of stay, duration of
mechanical ventilation and mortality rate. The results showed that the
duration of hospitalization in the IVIG group (13.74 days) was
significantly longer than the standard treatment group (11.10 days)
(\emph{p-value} = 0.041), But there were no significant differences
between the other primary outcomes (P\textgreater{}0.05).

Another question that was examined in this study was the impact of the
time, dose and period of IVIG prescription on its effectiveness. For
this purpose, patients with IVIG treatment were divided into three
subgroups of low, medium and high dose. Then the primary outcomes of
mortality rate, duration of hospitalization, ICU length of stay and
mechanical ventilation were compared between these subgroups, but no
significant differences were obtained. Also, initial outcomes were
compared separately with the standard treatment group. The results
indicated that only the duration of hospitalization in the IVIG subgroup
with medium dose is significantly longer than standard group, and in
other cases these differences were non-significant. These findings were
consistent with the results of Tabarsi et al{[}2{]}. So, in this study,
it can be concluded that, the use of IVIG method in COVID-19 treatment,
is not preferable to its standard treatment.

Difficulty in patient matching and the difference timing in IVIG
administration were the limitations in our study which should be
overcome by conducting RCT studies with a large statistical population.

\textbf{5. Conclusion}

Using IVIG is not beneficial for COVID-19 patients based on no
remarkable differences in duration of hospitalization, ICU length of
stay, duration of mechanical ventilation and even mortality rate.

\textbf{Funding:} This study was approved and supported by Tehran
University of Medical Sciences.

\textbf{Competing interests:} The authors declare that they have no
competing interests.

\textbf{Ethical approval:} This project was approved by the
Institutional Review Board of Tehran University of Medical Sciences
{[}IR.TUMS.VCR.REC.1399.390{]}

\textbf{References}

1. https://www.worldometers.info/coronavirus/., August 17, 2021

2. Tabarsi, P., S. Barati, H. Jamaati, S. Haseli, M. Marjani, A. Moniri,
et al., \emph{Evaluating the effects of intravenous immunoglobulin
(IVIg) on the management of severe COVID-19 cases: a randomized
controlled trial.} International immunopharmacology, 2021. \textbf{90} :
p. 107205.

3. Mohtadi, N., A. Ghaysouri, S. Shirazi, E. Shafiee, E. Bastani, T.
Kokhazadeh, et al., \emph{Recovery of severely ill COVID-19 patients by
intravenous immunoglobulin (IVIG) treatment: A case series.} Virology,
2020. \textbf{548} : p. 1-5.

4. Kaveri, S., M. Maddur, P. Hegde, S. Lacroix-Desmazes, and J.
Bayry,\emph{Intravenous immunoglobulins in immunodeficiencies: more than
mere replacement therapy.} Clinical \& Experimental Immunology,
2011.\textbf{164} : p. 2-5.

5. Ferrara, G., A. Zumla, and M. Maeurer, \emph{Intravenous
immunoglobulin (IVIg) for refractory and difficult-to-treat
infections.}The American journal of medicine, 2012. \textbf{125} (10):
p. 1036. e1-1036. e8.

6. Liu, X., W. Cao, and T. Li, \emph{High-dose intravenous
immunoglobulins in the treatment of severe acute viral pneumonia: the
known mechanisms and clinical effects.} Frontiers in immunology,
2020.\textbf{11} : p. 1660.

7. Kanjilal, S. and M.J. Mina, \emph{Passive immunity for the treatment
of influenza: quality not quantity.} The Lancet Respiratory Medicine,
2019. \textbf{7} (11): p. 922-923.

8. Nimmerjahn, F. and J.V. Ravetch, \emph{Anti-inflammatory actions of
intravenous immunoglobulin.} Annu. Rev. Immunol., 2008. \textbf{26} : p.
513-533.

9. Xie, Y., S. Cao, H. Dong, Q. Li, E. Chen, W. Zhang, et
al.,\emph{Effect of regular intravenous immunoglobulin therapy on
prognosis of severe pneumonia in patients with COVID-19.} The Journal of
infection, 2020. \textbf{81} (2): p. 318.

10. Liu, J., Y. Chen, R. Li, Z. Wu, Q. Xu, Z. Li, et
al.,\emph{Intravenous immunoglobulin treatment for patients with severe
COVID-19: a retrospective multi-center study.} Clinical Microbiology and
Infection, 2021.

11. Shao, Z., Y. Feng, L. Zhong, Q. Xie, M. Lei, Z. Liu, et
al.,\emph{Clinical efficacy of intravenous immunoglobulin therapy in
critical ill patients with COVID-19: a multicenter retrospective cohort
study.} Clinical \& translational immunology, 2020. \textbf{9} (10): p.
e1192.

12. Farrokhpour, M., N. Rezaie, N. Moradi, F.G. Rad, S. Izadi, M. Azimi,
et al., \emph{Infliximab and intravenous Gammaglobulin in hospitalized
severe COVID-19 patients in intensive care unit.} Archives of Iranian
medicine, 2021. \textbf{24} (2): p. 139-143.

13. Gharebaghi, N., R. Nejadrahim, S.J. Mousavi, S.-R. Sadat-Ebrahimi,
and R. Hajizadeh, \emph{The use of intravenous immunoglobulin gamma for
the treatment of severe coronavirus disease 2019: a randomized
placebo-controlled double-blind clinical trial.} BMC infectious
diseases, 2020. \textbf{20} (1): p. 1-8.

14. Herth, F.J., G. Sakoulas, and F. Haddad, \emph{Use of intravenous
immunoglobulin (Prevagen or Octagam) for the treatment of COVID-19:
retrospective case series.} Respiration, 2020. \textbf{99} (12): p.
1145-1153.

15. Pourahmad, R., B. Moazzami, and N. Rezaei, \emph{Efficacy of
plasmapheresis and immunoglobulin replacement therapy (IVIG) on patients
with COVID-19.} SN Comprehensive Clinical Medicine, 2020: p. 1-5.

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