Evaluation of the Efficacy and Safety of Intravenous Immunoglobulin (IVIG) in Moderate-to-Severe Hospitalized COVID-19 Patients: A Randomized, Open-Label Parallel-Group Study

Purpose Since February 2020, the world has been overwhelmed by the SARS-CoV-2 outbreak, and several patients suffered interstitial pneumonia and respiratory failure requiring mechanical ventilation, threatening the capability of healthcare systems to handle this amount of critical cases. Intravenous immunoglobulins (IVIG) possess potential immunomodulatory properties beneficial for COVID-19 patients, yet evidence supporting IVIG as adjunctive therapy remains sparse. This study evaluated the outcomes of adjunctive IVIG with the standard of care (SoC) in moderate-to-severe COVID-19 patients. Methods This randomized study included 59 moderate-to-severe COVID-19 patients with known comorbidities. One arm (n = 33) received high-dose IVIG (400 mg/kg/day) within 48 hours for five days alongside SoC, while the other arm (n = 26) received SoC, comprising steroids, enoxaparin, and remdesivir. The primary endpoint was clinical improvement, as measured by the National Early Warning Score 2 (NEWS2) and discharged/death proportions. Secondary outcomes included IVIG safety, hospitalization duration, changes in oxygen saturation, inflammatory markers, IgG titer, CTSS (CT severity score), and radiological findings. Results There was an improvement in the NEWS2 at the end of treatment in the IVIG arm (5.67 vs. 5.96). A significant absolute effect improvement (Day 1 vs. Day 9) was seen in serum LDH, D-dimer, hs-CRP, IL-6, CTSS, procalcitonin, respiratory rate, and chest radiographic findings. SARS-CoV-2 IgG titer increased significantly in the IVIG arm. There was a statistically significant reduction in mortality in the IVIG group (5 vs. 10). Conclusion IVIG was a safe and effective adjunctive therapy to SoC treatment in moderate-to-severe COVID-19 patients needing ventilatory support. Furthermore, studies are required to validate our findings. This trial is registered with CTRI/2021/05/033622.


Introduction
Since February 2020, the world has been overwhelmed by the SARS-CoV-2 virus outbreak, and several patients sufered interstitial pneumonia and respiratory failure requiring mechanical ventilation, threatening the capability of healthcare systems to handle this amount of critical cases.Severe COVID-19 illness may be more than a cytokine storm, acting with more complex mechanisms involving innate and cellular immune responses [1].
Unfortunately, there are a few validated therapies to prevent or treat the severe acute respiratory distress syndrome (ARDS) caused by this novel virus.Tus, the case fatality rate in patients admitted to ICU is exceptionally high.Terefore, along with maintaining vital functions through supportive treatment, efective therapies for COVID-19 are urgently needed.
Immunoglobulins (Ig) have pleiotropic efects on the infammatory-immune response, including toxin scavenging, microbial phagocytosis, anti-infammatory efects, and antiapoptotic actions on immune cells.Immunoglobulin may have a role in the early phases of COVID-19 by reducing the viral burden and scavenging or downregulating the production of high infammatory mediators.In the late phases, especially in ICU patients with secondary bacterial infections, IVIG may have an essential synergic activity in the empowerment of antibiotic efcacy and in supporting overt immune dysfunction [2].
Although the multifaceted immunomodulant properties of IVIG could beneft COVID-19 patients, clinical data supporting adjunctive therapy with IVIG in these patients are few and limited only to the use of standard polyclonal IVIG [3][4][5].Te crucial role of endogenous immunoglobulins in host response and the robust experience in immunocompromised and septic patients make adjunctive therapy with IVIG attractive in COVID-19, particularly in hospitalized patients with severe respiratory failure.A structured consensus identifed the rationale for the use of IVIG therapy in these patients with immune paralysis for preventing secondary infections and in patients with septic shock caused by nosocomial infections [6].
At Lok Nayak Hospital, New Delhi, we conducted a study on moderate-to-severe hospitalized COVID-19-positive cases needing ventilatory support.Te study's primary objective was to study the efcacy of intravenous immunoglobulin (IVIG) drug therapy on moderate-to-severe COVID-19 patients.Te second objective was to evaluate the safety of IVIG when used in moderate-to-severe hospitalized COVID-19 patients.

Study Design and Population.
Tis was a single-center, randomized, open-label, parallel-group, comparative trial study conducted at Lok Nayak Hospital, New Delhi, to evaluate the efcacy and safety of intravenous immunoglobulin (IVIG) in hospitalized patients with COVID-19 between mid-May 2021 and October 2021.
59 moderate-to-severe laboratory-confrmed reverse transcriptase-polymerase chain reaction (RT-PCR) COVID-19-positive subjects were recruited as per the Ministry of Health and Family Welfare (MoHFW) criteria, which defned moderate illness as an adolescent or adult with the presence of clinical features of dyspnea and/or hypoxia, fever, and cough, including SpO2 ≤94% (range: 90-94%) on room air and respiratory rate more or equal to 24 breaths per minutes [7].
Similarly, severe illness was defned as an adolescent or adult with clinical signs of severe pneumonia plus one of the following: respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% on room air [7].
Clinical data were collected using a structured proforma and then subjected to appropriate statistical analysis.A written informed consent was obtained from all the study participants after explaining the study procedure and the benefts and risks of participation.In severe COVID-19 patients, written consent was taken from their legal guardians.Privacy and confdentiality of data were maintained.

Inclusion and Exclusion Criteria
Inclusion criteria are as follows: (1) Laboratory-confrmed (RT-PCR) COVID-19-positive subjects of moderate-to-severe illness category as per the abovementioned criteria were included.(2) Age 18 to 65 years Exclusion criteria are as follows: (1) Subjects with known hypersensitivity to immunoglobulin, (2) History of deep vein thrombosis (DVT), (3) Pulmonary embolism (PE), (4) Tromboembolic stroke or other thrombotic events, (5) Pregnant females, and (6) Active participants in another research treatment study are to be excluded.

Sample Size Estimation.
To the best of our knowledge, it was a frst-of-its-kind pilot study; hence, a convenience sample of 40 patients (20 patients at least per group) was taken.Adjusting for 20% dropouts, approximately 24 patients per group, at least 48 patients were to be enrolled in the study.

Methodology.
Seventy eligible patients were screened for the study as per the inclusion and exclusion criteria, as shown in Figure 1.
Eight patients were excluded due to involvement in other studies (n � 3) or refusal to give written informed consent (n � 5).Sixty-two patients were available for the allocation to the groups.
Sixty-two available study subjects willing to provide written informed consent were divided into two treatment arms: the frst treatment arm (IVIG group) with 35 moderate-to-severe COVID-19-positive subjects treated with standard-of-care (SoC) treatment plus intravenous immunoglobulin (IVIG) drug at 400 mg/kg/day for fve days and the second treatment arm (SoC group) with 27 moderate-to-severe COVID-19-positive subjects treated with SoC as per the guidelines, as shown in Fig. 1.Te IVIG was initiated within 48 hours of hospital admission and given as a slow infusion (initially started with 0.5 mL/kg/h and gradually titrated to a maximum of 2 mL/kg/h) along with adequate hydration.

2
Canadian Journal of Infectious Diseases and Medical Microbiology Subjects underwent simple randomization via open labeling, where each study subject was allocated to IVIG (intervention) and S-SoC groups using computer-generated codes.Patients were allocated to diferent groups depending on odd or even numbers through a simple random number generation in the Excel sheet.
Te SoC treatment included steroids per guidelines for 5-10 days and remdesivir in severe cases for 5-10 days as per the need for mechanical ventilation.IV methylprednisolone 0.5 to 1 mg/kg and 1 to 2 mg/kg IV in two divided doses were given for 5-10 days in moderate and severe patients, respectively [7,8].A per-protocol analysis was done wherein all the allocated subjects were interviewed and underwent detailed clinical history, including demographic details; history of COVID-19 vaccination; pre-existing medical conditions, such as hypertension, diabetes, tuberculosis, heart or liver, or kidney disease or any allergic reaction; and examination as per a structured proforma.For severe  Canadian Journal of Infectious Diseases and Medical Microbiology patients, a relevant history was obtained from their legal guardian.National Early Warning Score 2 (NEWS2) and routine vitals, including BP (blood pressure), respiratory rate, pulse rate, random blood sugar, and oxygen saturation via pulse oximeter, were measured on the admission of every patient.Tese vitals were monitored subsequently throughout the hospital stay for every patient.Furthermore, study subjects underwent a baseline routine laboratory analysis including serum infammatory markers (hs-CRP, D-dimer, ferritin, and IL-6), IgG titer (the presence of antibodies against SARS-CoV-2), bedside chest radiograph, and an HRCT (high-resolution CT) scan of the chest, and a CTSS was calculated based on a defned radiological criterion [9].
NEWS2 was calculated using respiratory rate, oxygen saturation, systolic blood pressure, heart rate, level of consciousness, and temperature.Te score was then calculated, and two points were added in case of supplemental oxygen need [10].
As per Government of India guidelines, patients were discharged after ten days of symptom onset if symptoms resolved within three days and saturation above 95% was maintained for the next four days (without oxygen support) [11].
Tirty-three patients in the IVIG study group and 26 in the SoC group completed the entire study and were analyzed concerning the outcome parameters.Two patients in the IVIG group and one in the SoC group dropped out midway through the study due to a patient/attendant requesting transfer or LAMA (leave against medical advice).

Outcome Variables
2.5.1.Te Primary Outcome.Te primary outcome was to study the efcacy of intravenous immunoglobulin (IVIG) drug therapy on moderate-to-severe COVID-19 patients in terms of clinical improvement as measured by improvement in the NEWS2 at the end of treatment.

Te Secondary Outcome.
Te secondary outcome was to evaluate the safety of IVIG when used in moderate-tosevere COVID-19 patients and to study the change in oxygen saturation by pulse oximetry, all-cause mortality until the duration of hospital stay, average number of days of hospitalization, change in infammatory markers, IgG titer, CTSS score, and radiological fndings between the IVIG and SoC treatment groups.

Statistical Method.
Te data were compiled and analyzed using MS Excel (R) Ofce 365, GraphPad Prism 8.4.2, and SPSS version 25.Descriptive statistics were presented as proportions/percentages for categorical variables and mean and standard deviation for continuous data variables.Fisher's exact test/Chi-square test was used to compare proportions (categorical variables).Continuous variables were analyzed using the Mann-Whitney test/Student's t-test (independent group/unpaired data) and Wilcoxon sign-rank test/paired t-test (for paired data) based on the normality of the data.A P value of ≤0.05 was considered signifcant.

Demographic and Clinical Parameters.
A total of 59 subjects completed the study."Te average age and gender distribution across the two groups were similar with no signifcant diference statistically, as shown in Table 1."Both the groups were similar in comorbidity profle, clinical severity scoring, CT-based severity scoring, and NEWS2 at the baseline (Day 1).Apart from pulse rate and SpO2 levels at baseline, all other disease-related parameters were similar across the two groups.Tus, the demography parameters showed no signifcant diference between the two groups.

Laboratory Parameters.
Laboratory profles of the patients comparing Day 1 and Day 9 values have been tabulated in Table 2.It was seen that the IVIG group had a signifcant change in the P/L ratio, neutrophil, and lymphocyte proportion as compared to baseline.Similar trends were not seen in the SoC group.Te rest of the hematological and biochemical parameters were comparable between Day 1 and Day 9. Te serum infammatory marker (LDH, hs-CRP, IL-6, procalcitonin, and D-dimer) levels also signifcantly improved in the IVIG and SoC groups.However, the extent of improvement, as suggested by the mean of difference assessment (absolute efect), as shown in Figure 2 It was further seen that the serum IgG levels on Day 9 increased signifcantly compared to baseline in the IVIG group (6.58 vs 3.59 μg/ml at baseline).A slight increase was seen in the SoC group (4.88 vs 4.53 μg/ml), but the absolute efect was much higher in the IVIG group [2.99 (95% CI: 2.05 to 3.92) vs 0.350 (95% CI: −0.61 to 1.31)] (P value <0.0001).

Chest Radiograph Profle.
Te fndings suggested that there was a signifcant improvement in the chest radiograph fndings in the IVIG group on Day 9 in terms of the proportion of patients with GGO (87.88% vs. 100% at baseline), central (24% vs. 48% at baseline) and peripheral lung infltration (87% vs. 100% at baseline), basal area involvement (78% vs. 96% at follow-up), and pleural efusion (9% vs. 39% 4 Canadian Journal of Infectious Diseases and Medical Microbiology  Te trend was signifcant for the SoC group and was very close to signifcance in the IVIG group.Vital parameter change is shown in Figure 3. Similarly, the IVIG group signifcantly improved the CTSS (17.97 on Day 9 vs 21.67 on Day 1).A slight decrease in the CTSS was seen in the SoC group, but the trend was insignifcant (−0.540 in the SoC group vs −3.70 in the IVIG group).
Additionally, the NEWS2 declined signifcantly across both groups.Te extent of improvement was the same across both groups (−1 in IVIG vs −0.96 in SoC).Te mean of efect between Day 1 and Day 9 showed no signifcant diference between the groups [−1.00 (−1.88 to −0.11) in IVIG vs. −0.96(−1.54 to −0.37) in SoC].
Te mortality was signifcantly lower in the IVIG group compared to the SoC group (15.1% vs 38.4%).Te average duration of hospital stay was signifcantly higher in the SoC group (25 days) compared to the IVIG group (18 days).Tis diference was signifcant statistically (P < 0.0001).

. Discussion
Te lack of an efective antiviral agent and adequate vaccination coverage during the Delta wave (B.1.617.2) of COVID-19 in India complicated the situation and called for further intensifcation in the research.As per an Indian study, the Delta COVID-19 wave had been associated with a higher case fatality rate, afecting younger individuals and more rampant hospitalization, subsequently overburdening healthcare facilities [12].In parallel with developing new agents, studying the efcacy of existing therapeutic options with an acceptable safety profle was prudent.Te intravenous immunoglobulin (IVIG) administration represented such an example [13].In the COVID-19-related multisystemic infammatory syndrome in children and adolescents, the Ministry of Health, Government of India, has considered intravenous immunoglobulins as the frst line of treatment [14].Hence, this randomized, open-label parallel-group study was conducted in Lok Nayak Hospital, New Delhi, from mid-May to October 2021 to evaluate the efcacy and safety of intravenous immunoglobulin (IVIG) in moderate-to-severe hospitalized COVID-19 patients.
Te present study enrolled a population of moderate-tosevere hospitalized COVID-19-positive cases needing ventilatory support for evaluating adjuvant therapy with IVIG and the standard of care (SoC).Studies have found that early   Canadian Journal of Infectious Diseases and Medical Microbiology administration of IVIG (within three days) during the COVID-19 infection has improved patient recovery and survival rates [15][16][17].IVIG was within 48 hours after hospitalization in the present study.Evidence also suggests that high-dose IVIG (0.3-0.5 g per kg weight for fve doses) with combined corticosteroids could have a better outcome and may be considered valid and safe immunotherapy in COVID-19 patients [18].Comparing the baseline demographic and clinical characteristics of the patients, it was, however, seen that the pulse rate was higher and SpO2 levels were lower in the SoC group, which might suggest that more clinically severe patients were a part of the SoC group   Canadian Journal of Infectious Diseases and Medical Microbiology that could imply the overall outcomes, but given the fact that CTSS and clinical severity grade-based distribution was similar across the two groups, diference was unlikely to have a signifcant clinical impact on outcomes.
4.1.Anti-Infammatory or Immunomodulatory Role.Te overall efects of adding IVIG in our study could be attributed to its anti-infammatory and immunomodulatory properties.Tere was a statistically signifcant reduction in the serum infammatory marker levels (LDH, hs-CRP, IL-6, procalcitonin, and D-dimer) in the IVIG group, as shown in Figure 2.More strikingly, the absolute fall in the serum D-dimer [405 (95% CI: −727.18 to −82.81) ng/mL vs. 200 (95% CI: −685.13 to 283.95) ng/mL] and serum LDH levels [235 (95% CI: −336.24 to −133.89)U/L vs. 124 (95% CI: −243.76 to −4.23) U/L] was seen more in the IVIG group than SoC group on Day 9. Similarly, the extent of improvement in the chest radiography fndings, as shown in Table 3, on Day 9 was signifcant in the IVIG group in terms of the proportion of patients with GGO, central and peripheral lung infltration, basal area involvement, and pleural efusion as compared to Day 1.Moreover, the CTSS fell by −3.70 (95% CI: −5.22 to −2.17) in the IVIG group vs −0.540 (95% CI: −2.46 to 1.38) in the SoC group.Te absolute change in the respiratory rate was signifcant in the IVIG group as compared to the SoC group on Day 9 compared to Day 1 (Table 4).Tis refected the additional anti-infammatory role of IVIG compared to the SoC, as seen on Day 9. A retrospective cohort study also reported a signifcant decrease in serum CRP and ferritin levels on Day 6 following IVIG therapy for fve days [19].Similar efects have also been found in other studies [20].Literature shows that these immunomodulatory efects of IVIG come through the blockage of intact Fcc receptors on the immune cells, downregulating the infammatory cytokines like IL-6 and TNF-alpha and inhibiting the complement cascade [21][22][23].
IVIG comprises human immunoglobulins, predominantly IgG, pooled from thousands of healthy plasma donors who have recovered after viral infections.It contains neutralizing antibodies against microbial infections in improved patients from various infections.In addition, neutralizing antibodies, autoantibodies, and natural antibodies are found in prepared IVIG [24].Our study found that SARS-CoV-2-specifc IgG titer was signifcantly higher in the IVIG group on Day 9 than SoC.Díez, J in their study supports the presence of anti-SARS-CoV-2 cross-reacting antibodies in the IVIG preparations, where a cross-reactivity of IVIG products with SARS-CoV-2, SARS-CoV, and MERS-CoV was found using ELISA test on the available IVIG preparations [25].Also, IVIG preparations have been shown to contain antibody reactivity against the SARS-CoV-2 S1 protein [25].Moreover, in IVIG preparations created during the pandemic year, Schwaiger, J in their study showed a substantial rise in the concentration of specifc neutralizing antibodies against SARS-CoV-2 [26].

Efect on Clinical Profle.
A study conducted by Ina Kostakis and colleagues supports the national and international recommendations for the use of NEWS or NEWS2 for the assessment of acute illness severity in hospitalized patients with COVID-19 [27][28][29][30].A study by Marius-Myrstad and colleagues found that the NEWS2 at hospitalization predicted severe disease and in-hospital mortality and was superior to other clinical risk scores like qSOFA, SIRS criteria, and CRB-65 score in COVID-19 patients [31].Similarly, another study found that the NEWS was more sensitive in predicting in-hospital mortality, early bacterial infection, and ICU admission than SIRS and qSOFA [32].Hence, assessing the change in the NEWS2 was used as the primary outcome of our study.
Te clinical improvement measured by improvement in the National Early Warning Score 2 (NEWS2) at the end of treatment did not show a statistically signifcant diference, as the extent of improvement was the same across both groups (−1 in IVIG vs −0.96 in SoC).However, a study by Reynaga E and colleagues showed a rapid improvement in NEWS, reaching a minimum value by 14 days post-IVIG administration in fve subjects with a medium risk of ARDS and a mid-to-high NEWS [33].Te efect of the IVIG on the NEWS2 could have been more substantial if a larger samplesized study population had been assessed.
Moreover, in our study, there was better control of respiratory rate in the IVIG group as shown by the absolute change in the respiratory rate in the IVIG group as −5.47 (95% CI: −7.35 to −3.58) compared to the SoC group on Day 9 as compared to Day 1.Similarly, the CTSS score fell signifcantly by −3.70 (95% CI: −5.22 to −2.17) in the IVIG group vs −0.540 (95% CI: −2.46 to 1.38) in the SoC group.A case series of fve patients who received IVIG showed improved pulmonary involvement after fve days [23].Te study by Zhou et al. documented a reduction in pulmonary shadows in 36 cases out of 40 who received IVIG and steroids [34].
Te SpO2 improvement was seen across both the groups, and the extent of improvement was comparable across both the groups (95% CI: 1.70 in SoC vs 1.56 in the IVIG group).Tis again highlights that IVIG is essential in combating the disease process by having an immunomodulatory or antiinfammatory efect in COVID-19 patients.Once the multifaceted efects of IVIG alter the pathology, one could see the more pronounced efect in the overall outcome in terms of duration of hospital stay and mortality.An improvement in SpO2 values after IVIG treatment in COVID-19 patients has also been validated in multiple other studies [16,23,34,35].Similarly, in another case study report, the oxygen saturation level was above 96% after six days of IVIG treatment without oxygen support [17].

Efect on Outcome.
Te number of hospitalization days was signifcantly lower (18 days vs 25 days) in the IVIG arm; similarly, the number of deaths (15% vs 38%) in the IVIG study arm was considerably less than in the SoC arm.Conversely, the number of subjects discharged at the end of our study was 84.85% in the IVIG group compared to the standard-of-care group (61.54%).Similar results were reported by a randomized, open-label study by Raman et al. in moderate COVID-19 patients [36].However, they reported mild-to-moderate adverse reactions following IVIG infusion, which were not encountered in our study.Similarly, a retrospective study from China involving 58 severe critically ill COVID-19 patients showed that early institution of IVIG within 48 h of admission to ICU was associated with a reduction in mechanical ventilation use, shortened ICU duration, and ICU and hospital stay, and improved 28-day survival [15].
Furthermore, it was found that severe ARDS was the primary cause of mortality among the study subjects in our study.Few other studies have also found adverse efects like thromboembolism [37,38] and acute kidney injury [39] with IVIG, which could have led to increased mortality.Keeping a slower IVIG infusion rate, along with hydration and enoxaparin use as per MoHFW criteria, might have avoided these adverse efects in our study [7,8].Moreover, no secondary infections were seen in the IVIG group, as serum procalcitonin and TLC levels were within the normal range.Tis could also point toward the anti-infammatory and antiinfectious nature of the IVIG.Moreover, in the present study, IVIG was used with other recommended therapeutic options available as per the norms, such as methylprednisolone and remdesivir, based on the severity of COVID-19 infection.Te overall efect of these therapies could have resulted in benefcial outcome.
On the other hand, a retrospective, multicenter cohort study assessing the outcome of IVIG in critically ill COVID-19 patients found no remarkable diferences in hospitalization, ICU length of stay, duration of mechanical ventilation, and even mortality rate [40].A multicenter, double-blinded, placebo-controlled, and phase 3 trial involving moderate-to-severe COVID-19 ARDS showed that IVIG did not improve clinical outcomes at Day 28 and showed an insignifcant increase in adverse events [41].Yet, another randomized controlled trial involving 84 severe COVID-19 patients IVG (400 mg/kg, IV, daily for three days) was given to 52, and 32 were in the control group.Te study did not support the benefcial efects of IVIG in combination with hydroxychloroquine and lopinavir/ritonavir SARS-CoV-2 patients, as improvement in the mortality rate, radiographic changes, and the need for mechanical ventilation was not evident; however, a positive relationship was found between early IVIG initiation and the length of the ICU and hospital stay [42].Tis again highlights the importance of using IVIG earlier during COVID-19 infection, as seen in our study.
It is evident that IVIG use in COVID-19 has been associated with a mixed response [43,44]; however, our study found the early institution of IVIG to be a safe and efective adjunctive therapy in moderate-to-severe COVID-19 infection.Furthermore, as a pilot study, our study provides valuable inputs on assessing the role of adjunctive IVIG over SoC on the NEWS2 among hospitalized moderate-to-severe COVID-19 patients.However, much larger trials are needed to validate the study's fndings.Given the immune system redundancies, IVIG appears to ofer global, multifaceted mechanisms of immunomodulation to counteract the immune dysregulation (i.e., "cytokine storm") seen in severe COVID-19 infection.

Limitations of the Study.
Te main limitation of our study was that we could not rule out the possible advantages of IVIG monotherapy in treating COVID-19 since ethical concerns prevented us from including a control group without any treatment.Additionally, the sample size of our study was relatively small, which may limit the generalizability of our fndings.Our study was conducted during the peak of Delta wave, and hence, more patients were enrolled to achieve a greater sample size initially.However, as the study progressed, the Delta wave subsided suddenly with nearly no infow of patients resulting in a disproportionate allocation of patients among the treatment groups, potentially impacting the balance between the subgroups.Moreover, had we used block randomization, a discrepancy in the study subjects between the groups could have been avoided.Additionally, our trial was conducted in an open-label manner, lacking blinding, which may have infuenced the interpretation of the results.Moreover, the study could have been more meaningful if we had included a follow-up of the patients to assess the long-term efects of IVIG.Furthermore, the cost and limited accessibility of IVIG therapy in resource-poor settings raise concerns about the feasibility of implementing our fndings in clinical practice.Finally, we recognize the need for more extensive clinical studies to validate our fndings and provide more robust evidence regarding the efcacy and safety of IVIG therapy in treating COVID-19.

Conclusions
To conclude, IVIG was found to be a safe and efective therapy adjunctive to SoC treatment in moderate-to-severe hospitalized COVID-19 patients needing ventilatory support.Te study consolidates the previous fndings of the promising role of the addition of IVIG to the standard of care.Te clinical diference was appreciated through the anti-infammatory efects of IVIG in most of the severity outcomes as well as the outcome profle with an overall improvement in the reduction of NEWS2, CT severity score, infammatory markers, duration of hospital stay, deaths, and improvement in respiratory rate, SpO2 values, and IgG titers from the baseline.Furthermore, large-scale studies are needed to validate our fndings.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Follow- Up Figure 1 :
Figure 1: Study fow diagram of randomized controlled trial.

Figure 2 :
Figure 2: Showing mean of diference assessment (absolute efect) between the IVIG and SoC groups.

Figure 3 :
Figure 3: Showing vital parameters outcome in the IVIG and SoC group.

26 moderates to severe COVID-19 positive subjects
, was higher in the IVIG group.Serum D-dimer levels were seen to fall by 405 (95% CI: −727.18 to −82.81) ng/ml in the IVIG group vs 200 (95% CI: −685.13 to 283.95) ng/ml in the SoC group.Similarly, serum LDH levels reduced by 235 (95% CI: −336.24 to −133.89)U/L compared to 124 (95% CI: −243.76 to −4.23) U/L in the IVIG group.Te change in the level of serum IL-6, D-dimer levels, and procalcitonin was not signifcant in the SoC group but was signifcant in the IVIG group.

Table 2 :
Laboratory parameters.Te outcome profles of the patients have been tabulated in Table 4.It was observed that a signifcant improvement was seen in the respiratory rate in the IVIG group (19.86 vs 25.33 per minute at baseline) compared to the SoC group.Te absolute change in the respiratory rate was signifcant in the IVIG group: −5.47 (95% CI: −7.35 to −3.58).Te SoC group had no signifcant change in the respiratory rate on Day 9 compared to Day 1. Te respiratory rate was almost similar, with no clinically noticeable change.SpO2 improvement was seen across both the groups, with the extent of improvement comparable across both the groups [(95% CI: 1.70 in SoC vs 1.56 in the IVIG group)].
at baseline) on Day 9 compared to that at the start of therapy initiation.suchtrendswereseen in the SoC group (Table3).3.4.Outcome Parameters.

Table 3 :
Chest radiograph fndings and their comparison between groups.