Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Immunoglobulin G has an anti-inflammatory effect through the modulation of T helper 1 and T helper 2 cytokine and cytokine antagonist production. IVIg has been shown to reduce circulating IL-1β, increase levels of IL-1 receptor antagonists and inhibits TNF-α mediated cytotoxicity in patients with other inflammatory conditions.1  In COVID-19, IVIg has a potential role in regulating the initial phase of the host inflammatory response. It has been proposed that IVIg should be given between the seven to 14 days of illness during the pulmonary stage to regulate the immune system and inhibit the formation of the systemic hyperinflammatory state.2  Several case reports have described the successful use of IVIg in the recovery of COVID patients with severe disease.3-7

The incidence of adverse effects on the use of IVIg has ranged from 3 to 87% and this wide variation maybe due to the rate of infusion, immunoglobulin brand, patient risk factors and study design variations. Immediate adverse effects include flu like symptoms; dermatologic lesions such as urticaria, papules, eczema, lichenoid dermatitis and desquamation; arrythmia, hypotension and transfusion related acute lung injury which carries a high mortality. Delayed adverse effects of IVIg are thrombotic events (stroke, myocardial infarct), neurological disorders, renal

Should IVIg be used in the treatment of COVID-19?

impairment, hematologic disorders, electrolyte disturbance and transfusion-related infection.8

Surviving sepsis campaign guidelines suggest against the routine use of IVIg in critically ill adults with COVID-19. (Weak recommendation, low-quality evidence).9 Clinical Practice Guideline for Sepsis and Septic Shock in Adults in the Philippines 2020 also does not recommend the use of standard polyclonal intravenous immunoglobulins in sepsis and septic shock. (Strong recommendation, high quality evidence).10

OBJECTIVE

This rapid review systematically summarizes the current available evidence on the efficacy and safety of intravenous immunoglobulin G (IVIg) in the treatment of COVID-19 patients.

METHODS

We searched MEDLINE, CENTRAL, Clinicaltrials. gov, and Chinese Clinical Trial Registry up to September 2020. WE also searched MedRXIV, BioRXIV, COVID-19 CORe Portal.

Articles were selected based on the research question: Should intravenous immunoglobulin G be used in the treatment of COVID-19?

We appraised the cohort study using the guide questions from the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Cohort Studies.

Characteristics of Included Studies

We found no completed clinical trials on the efficacy of Intravenous Immunoblobulin G among COVID-19 patients.

There were three retrospective cohort studies that were all conducted in China. An observational study11 published as a letter to the editor described the outcome of 58 COVID-19 patients with severe pneumonia who were given IVIg <48 (n=30) or >48 hours (n=28) from admission. All were treated according to WHO guidelines. In addition, according to the patient’s condition, low molecular heparin anticoagulation was given and Thymosin was administered if the absolute lymphocyte count was still < 0.5 ×10 9 /L after IVIg. They reported an improved outcome among the patients given IVIg <48 hours. The study measured the outcomes in a valid and reliable way with sufficient time to followup (28 days). However, the baseline characteristics of the two groups (IVIg <48 or >48 hours) were not described, specially the presence of co-morbidities that may affect the outcome. No strategies were mentioned that dealt with the confounding biases from the treatment regimen given to both groups. The statistical analysis was also not stated.

Another study12 enrolled 109 COVID positive patients with (n=53) and without (n=56) ARDS. Both groups were given antibiotics, antivirals, glucocorticosteroids and IVIg

therapies and followed up until clinical outcomes were recorded. The exposures were measured in a valid and reliable way. However, due to the retrospective nature of the study, a systematic selection bias is present. The baseline features of the two groups showed that there were more patients with ARDS who had diabetes, cerebrovascular disease and chronic kidney disease.The confounding factors were not addressed. The results, therefore of the the treatment should be interpreted with caution.

A third study13 included 325 patients with severe and critical type of COVID illness, 174 of whom were given IVIg and 151 were not. There was a significant difference in the baseline characteristics of the two groups. Exposures were measured in a valid and reliable way. Signifcant confounding factors including age, sex, comorbidities and laboratory parameters were addressed in the statistical analysis. However, since this was a multicenter retrospective study, the treatment protocol in terms of dose and timing of IVIg may have differed as well as the care of patients that could have affected the outcome. Other medications that were given to the patients were not discussed. Evaluation of effect of immunoglobulin was based on clinical manifestation rather than direct cellular and molecular assessment, including viral load and lymphocyte activation.

RESULTS

There were four case report / case series on the use of IVIg in COVID positive patients. The first successfully treated three COVID positive adults with severe disease during the early stage of clinical deterioration.3 Another described the recovery of ten COVID-19 patients who were given short term moderate dose corticosteroids and IVIg.4 A third case series administered high dose IVIg in five severely ill COVID positive patients in whom standard treatment has failed.5  There was also a report of three COVID patients who were Tocilizumab resistant but responded with steroid pulse treatment and IVIg.6  A 42-year-old Italian woman was also effectively treated with IVIg for severe COVID pneumonia.7

There were three retrospective cohort studies on the use of IVIg in COVID-19 patients. The first investigated 58 COVID positive with severe pneumonia. Patients given IVIg <48 hours from admission had significantly shorter length of ICU and hospital stay, required less mechanical ventilation and had increased 28 day survival time as compared to those given IVIg >48 hours.11 In this report, 35 patients survived and 23 died (7 in <48 hours, 16 in >48 hours). In another study, the survival of 53 COVID positive patients with ARDS was not improved with antivirus, corticosteroids and IVIg treatment.12 And a third study showed no significant difference in the 28- and 60-day mortality between the IVIg and non-IVIg groups.13 Subgroup analyses of patients with severe [RR>30/min; or resting SPO2 ≤ 90%; or PaO2/FiO2 ≥ 300mmHg] and critical type [presence of respiratory failure,

shock or multiorgan failure] of illness showed significant reduction in the 28-day mortality in those with critical illness who were given IVIg. There was also significant reduction in the 28-day and 60-day mortality with IVIg dose >15 g/day and in the 60-day mortality if IVIG is given in the early stage (≤7 days from admission).

Ongoing studies

We found eight registered clinical trials14-21 investigating the efficacy of intravenous immunoglobulin G in the treatment of COVID-19 patients (Table 1).

Recommendations from other guidelines

The NIH COVID-19 treatment guidelines22, Infec- tious Diseases Society of America23, CDC24 and the Philippine Society of Allergy, Asthma and Immunology25 presently do not recommend the routine use of intravenous immunoglobulin G in the treatment of COVID-19 patient until we have more evidence based on clinical trials

CONCLUSION

There is conflicting evidence on the use of Intravenous Immunoglobulin G on COVID-19 patients with severe disease. There are ongoing clinical trials on the use of intravenous immunoglobulin G in severe COVID patients. Result of these trials are needed before any recommendation is made. Surviving sepsis campaign guidelines suggest against the routine use of IVIg in critically ill adults with COVID-19.

Declaration of conflict of interest

No conflict of interest.

REFERENCES

1.Dourmishev LA, Guleva DV, Miteva LG. Intravenous immunoglobulins: mode of action and indications in autoimmune and inflammatory dermatosis. Int J Inflam. 2016; 2016:3523057. doi: 10.1155/2016/3523057.

2.Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virol Sin. 2020 Jun; 35(3):266-271. doi: 10.1007/s12250-020- 00207-4.

3.Cao W, Liu X, Bai T, Fan H, Hong K, Song H, et al. High dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with Coronavirus Disease 2019. Open Forum Infect Dis. 2020 Mar; 7(3):ofaa102. doi: 10.1093/ofid/ofaa102.

4.Zhou ZG, Xie SM, Zhang J, Zheng F, Jiang DX, Li KY, et al. Short-term moderate-dose corticosteroid plus immunoglobulin effectively reverses covid-19 patients who have failed low-dose therapy [Internet]. 2020 [cited 2020 Mar]. Available from: https://www. researchgate.net/publication/339743438_Short-Term_Moderate- Dose_Corticosteroid_Plus_Immunoglobulin_Effectively_Reverses_ COVID-19_Patients_Who_Have_Failed_Low-Dose_Therapy

5.Mohtadi N, Ghaysouri A, Shirazi S, Ansari S, Shafiee E, Bastani E, et al. Recovery of severely ill COVID-19 patients by intravenous immunoglobulin (IVIG) treatment: a case series. Virology. 2020; 548:1-5. https://doi.org/10.1016/j.virol.2020.05.006

6.Sheianov MV, Udalov YD, Ochkin SS, Bashkov AN, Samoilov AS. Pulse therapy with corticosteroids and intravenous immunoglobulin in the management of severe tocilizumab-resistant COVID-19: a report of three clinical cases. Cureus. 2020 Jul;12(7):e9038. doi: 10.7759/ cureus.9038.

Should IVIg be used in the treatment of COVID-19?

7.Lanza M, Polistina GE, Imitazione P, Annunziata A, Di Spirito V, Novella C, et al. Successful intravenous immunoglobulin treatment in severe COVID-19 pneumonia. IDCases. 2020; 21:e00794. doi: 10.1016/j.idcr.2020.e00794

8.Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy.Front Immunol.2018; 9:1299.doi: 10.3389/fimmu.2018.01299

9.Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020 May; 46(5):854-887. doi: 10.1007/s00134-020-06022-5

10.Clinical Practice Guidelines for Sepsis and Septic Shock Task Force 2020. Clinical Practice Guideline for Sepsis and Septic Shock in Adults in the Philippines 2020. Unpublished.

11.Xie Y, Cao S, Dong H, Li Q, Chen E, Zhang W, et al. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect. 2020 Aug; 81(2):318- 356. doi: 10.1016/j.jinf.2020.03.044.

12.Liu Y, Sun W, Li J, Chen L, Wang Y, Zhang L, et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. medRxiv preprint. 2020. doi: https://doi.org/10.1101/20 20.02.17.20024166

13.Shao Z, Feng Y, Zhong L, Xie Q, Lei M, Liu Z, et al. Clinical efficacy of intravenous immunoglobulin therapy in critical ill patients with COVID-19: a multi-center retrospective cohort study. medRxiv preprint. 2020. doi:https://doi.org/10.1101/2020.04.11.20061739

14.A Randomized, Open-label, Controlled, Single-center Study to Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Patients With Severe 2019- nCoV Pneumonia [Internet]. Led by Peking Union Medical College Hospital. [cited 2020 Jun]. Available from: https://clinicaltrials.gov/show/NCT04261426

15.Comparison between the efficacy of intravenous immunoglobulin and convalescent plasma in improving the condition of patients with COVID-19: A randomized clinical trial [Internet]. Led by Birjand University of Medical Sciences Iran. [cited 2020 Apr]. Available from: https://www.irct.ir/trial/47212

16.To evaluate the effectiveness of intravenous immunoglobulin (IVIG) for the treatment of COVID-19-induced cytokine storm [Internet]. Led by Tabriz University of Medical Sciences in Iran. [cited 2020 Apr]. Available from: https://www.irct.ir/trial/47014

17.Evaluation of the efficacy of intravenous immunoglobulin (IVIg) in patients with severe COVID-19 (Before intubation phase) who have not responded to treatment with the standard three-drug protocol (hydroxychloroquine / chloroquine + lupinavir / ritonavir + ribavirin) [Internet]. Led by Mashhad University of Medical Sciences. [cited 2020 Apr]. Available from: https://www.irct.ir/trial/46811

18.Polyvalent Immunoglobulin in COVID-19 Related ARds (ICAR) [Internet]. Led by Centre Hospitalier St Anne Paris, France. [cited 2020 Sep]. Available from: https://clinicaltrials.gov/ct2/show/NCT0 4350580?id=NCT04264858+OR+NCT04350580+OR+NCT042614 26&draw=2&rank=1&load=cart

19.Study to Evaluate the Safety and Efficacy of High Dose IVIG in Hospitalized Participants With Coronavirus Disease (COVID-19) [Internet]. Led by Instituto Grifols, S.A. 2020 [cited 2020 Jun]. Available from: https://clinicaltrials.gov/show/NCT04432324.

20.OCTAGAM 10% Therapy in COVID-19 Patients with Severe Disease Progression [Internet]. Led by Octapharma. [cited 2020 Nov]. Available from: https://clinicaltrials.gov/ct2/show/NCT04400058

21.Study of Standard of Care Plus Intravenous Immunoglobulin (IVIG) Compared to Standard of Care Alone in the Treatment of COVID-19 Infection [Internet]. Led by Octapharma USA. [cited 2020 Jun]. Available from: https://clinicaltrials.gov/show/NCT04411667.

22.NIH COVID 19 treatment guidelines [Internet]. [cited 2020 Dec]. Available from: https://www.covid19treatmentguidelines.nih.gov/

23.Infectious Diseases Society of America [Internet]. [cited 2020 Jun]. Available from: https://relief.unboundmedicine.com/relief/view/ Coronavirus-Guidelines/2355057/all/Infectious_Diseases_Society_ of_America_Guidelines_on_the_Treatment_and_Management_of_ Patients_with_COVID_19

24.CDC [Internet]. [cited 2020 Dec]. Available from: https://www.cdc. gov/coronavirus/2019-ncov/hcp/therapeutic-options.html

25.A Review of Immunomodulators as Therapeutic Interventions for Moderate to Severe COVID 19 Infections Version 2.0 [Internet]. May 10, 2020 [cited 2020 May]. Available from: https://bit.ly/ PSAAIImmunomodulatorsVer2

Appendix 1. Characteristics of ongoing clinical trials

	No.	Clinical Trial ID / Title	Status	Start and estimated	Study design	Country	Population	Intervention	Comparison
				primary completion date				Group(s)	Group(s)
	1	NCT04261426	Not yet	February 10, 2020	Randomized	China	COVID-19	IVIg	Standard Care
			recruiting		Open Label
		A Randomized, Open-label, Controlled,		April 30, 2020	Parallel
		Single-center Study to Evaluate the Efficacy of			Controlled
		Intravenous Immunoglobulin Therapy in Patients			Clinical Trial
		With Severe 2019-nCoV Pneumonia14

Outcomes

Clinical Improvement based on the 7 point scale Lower Murray lung injury score

28 day mortality

Duration of mechanical ventilation Duration of hospitalization

Proportion of patients with negative RT-PCR results Proportion of patients in each category of the 7 point scale Proportion of patient with normalized inflammation factors Frequency of adverse drug events

Frequency of serious adverse drug events

	No.	Clinical Trial ID / Title	Status	Start and estimated	Study design	Country	Population
				primary completion date
	6	NCT04432324	Not yet	June 2020	Phase 2	Spain	COVID-19
		Study to Evaluate the Safety and Efficacy of	recruiting	July 2020	Clinical Trial
					Randomized
		High Dose IVIG in Hospitalized Participants
		With Coronavirus Disease (COVID-19)			Parallel
		https://clinicaltrials.gov/show/NCT04432324, 2020 |			Assighment
		added to CENTRAL: 30 June 2020 | 2020 Issue 0619

Intervention Comparison

Group(s) Group(s)

IVIgStandard

Medical

Treatment

Outcomes

Primary Outcome [Up to Day 29]

%of Participants Dying or Requiring ICU Admission

%of Participants Who are Dependent on High Flow Oxygen Devices or Invasive Mechanical Ventilation

Secondary Outcomes [up to 29 days]

Change from Baseline in National Early Warning Score (NEWS)

Time to Clinical Response as Assessed by: NEWS ≤ 2 Maintained for 24 hours Time to Hospital Discharge

Duration of ICU Stay. Oxygen Use, Mechanical Ventilation Time to Sustained Normalization of Temperature

% of Participants with Normalization of Fever

Number of Participants who Develop Acute Respiratory Distress Syndrome (ARDS) Length of Time to Clinical Progression

%of Participants in Each Severity Category of the 7-point Ordinal Scale (time frame: Day 15 and Day 29)