Clinical Efficacy of Intravenous Immunoglobulin Therapy in Critical Patients with COVID-19: A Multicenter Retrospective Cohort Study

  1. Ziyun Shao
  2. Yongwen Feng
  3. Li Zhong
  4. Qifeng Xie
  5. Ming Lei
  6. Zheying Liu
  7. Conglin Wang
  8. Jingjing Ji
  9. Liu Huiheng
  10. Zhengtao Gu
  11. Zhongwei Hu
  12. Lei Su
  13. Ming Wu
  14. Zhifeng Liu

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Abstract

Importance

Coronavirus disease 2019 (COVID-19) has become pandemic, causing more than 1.5 million infections and over ten-thousands of deaths in a short period of time worldwide. However, little is known about its pathological mechanism, and reports on clinical study on specific treatment are few.

Objective

The purpose of this study is to determine the clinical efficacy of intravenous immunoglobulin (IVIG) therapy in COVID-19 patients.

Design, setting and participants

This multicenter retrospective cohort study enrolled 325 adult critical COVID-19 patients, including severe type and critical type, according to the clinical classification defined by National Health Commission of China, in 8 government designated treatment centers in China from Dec 23, 2019 to Mar 31, 2020. Demographic, clinical, treatment, and laboratory data as well as prognosis were extracted from electronic medical records.

Exposure

IVIG was exposure factor.

Main outcomes and measures

Primary outcomes were the 28-day and 60-day mortality, and secondary outcomes were the total length of in-hospital and the total duration of the disease. Meanwhile, the parameters of inflammation responses and organ functions were measured. The risk factors were determined by COX proportional hazards model. The subgroup analysis was carried out according to clinical classification of COVID-19, IVIG dosage, and timing.

Results

In the enrolled 325 patients, 222 (68%) were severe type and 103 (32%) were critical type; 42 (13%) died in 28-day within hospitalization, and 54 (17%) died within 60-day; The death in 60-day includes 6 (3%) severe type patients and 48 (47%) critical type patients. 174 cases were used IVIG, and 151 cases were not. Compared with the baseline characteristics between two groups, the results showed that the patients in IVIG group presented higher Acute Physiology and Chronic Health Evaluation (APACHII) score and Sequential Organ Failure Assessment (SOFA) score, higher plasm levels of IL-6 and lactate, and lower lymphocyte count and oxygenation index (all P <0.05). The 28-day and 60-day mortality were not improved with IVIG in overall cohort. The in-hospital stay and the total duration of disease were longer in IVIG group ( P <0.001). Risk factors were clinical classifications (hazards ratio 0.126, 95% confidence interval 0.039-0.413, P =0.001), and using IVIG (hazards ratio 0.252, 95% confidence interval 0.107-0.591, P =0.002) with COX proportional hazards model. Subgroup analysis showed that only in patients with critical type, IVIG could significantly reduce the 28-day mortality, decrease the inflammatory response, and improve some organ functions (all P <0.05); and application of IVIG in the early stage (admission≤7 days) with a high dose (>15 g/d) exhibited significant reduction of 60-day mortality in the critical type patients.

Conclusions and Relevance

Early administration of IVIG with high dose improves the prognosis of critical type patients with COVID-19. This study provides important information on clinical application of the IVIG in treatment of SARS-CoV-2 infection, including patient selection and administration timing and dosage.

Key points

Question

Intravenous immunoglobulin (IVIG) was recommended to treat critical Coronavirus disease 2019 (COVID-19) patients in a few reviews, but the clinical study evidence on its efficacy in COVID-19 patients was lacked.

Finding

In this multicenter cohort study that included 325 adult critical patients from 8 treatment centers, the results showed that early administration (admission ≤ 7 days) of IVIG with high dose (> 15 g/d) improves the prognosis of critical type patients with COVID-19.

Meaning

This study provides important information on clinical application of IVIG in treatment of SARS-CoV-2 infection, including patient selection, administration timing and dosage.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.04.11.20061739: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the Research Ethics Commission of General Hospital of Southern Theater Command of PLA (HE-2020-08) and the requirement for informed consent was waived by the Ethics Commission.
    Consent: The study was approved by the Research Ethics Commission of General Hospital of Southern Theater Command of PLA (HE-2020-08) and the requirement for informed consent was waived by the Ethics Commission.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variable, noninfectious causes, etc.; (2) Women who are pregnant or breast-feeding; (3) Researchers consider unsuitable.

    Table 2: Resources

    Antibodies
    SentencesResources
    The data collection period was from December 2019 to March 2020, and the data cutoff date was April 3, 2020. Inclusion Criteria: (1) Adult aged >=18 years old; (2) Laboratory (RT-PCR) confirmed SARS-COV-2 infection in throat swab and/or sputum and/or lower respiratory tract samples; or conformed plasma positive of specific antibody (IgM or/and IgG) against SARS-COV-2; (3) In-hospital treatment ≥72 hours; (4) Meet any one of the following a-c criteria for severe type or d-f criteria for critical type: (a) Respiratory rate >=30/min; or (b) Rest SPO2<=90%; or (c) PaO2/FiO2<=300 mmHg; or (d) Respiratory failure and needs mechanical ventilation; or (e) Shock occurs; or (f) Multiple organ failure and needs ICU monitoring; Exclusion Criteria: (1) Exist of other evidences that can explain pneumonia including but not limited to influenza A virus, influenza B virus, bacterial pneumonia, fungal pneumonia
    SARS-COV-2; (3
    suggested: None
    IVIG represents the human Immunoglobulin for intravenous injection, which is a liquid preparation containing human immunoglobulins made from normal human plasma, containing IgG antibody with broad-spectrum anti-viral, bacterial, or other pathogens.
    anti-viral, bacterial,
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analysis was performed using the SPSS Windows version 11.0 statistical package (SPSS Inc, Chicago, IL), P values (two-tailed) below 0.05 were considered statistically significant.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There are some limitations in present study. Firstly, the cases from these eight clinical centers may still lack sufficient representativeness. Secondly, the dose and timing of IVIG administration in each center may not be exactly consistent. And thirdly, limited by the clinical workload and situation, the evaluation of immunoglobulin effect is mainly based on the clinical manifestations, rather than direct cellular and molecular assessment, including viral load and lymphocyte activation. With the progression in recognition of COVID-19, large cases randomized control studies and more developed evaluation systems are needed to confirm the efficiency of IVIG on COVID-19 treatment. In conclusion, the present study is the first clinical research evaluating the efficiency of IVIG treatment to critical COVID-19 patients. The data demonstrate that early application of high dose IVIG can improve the prognosis of COVID-19 patients with critical type. This study provides important information on clinical application of IVIG in treatment of SARS-CoV-2 infection, including patient selection and administration timing and dosage.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.04.11.20061739v2 on medRxiv
  3. Version published to 10.1101/2020.04.11.20061739v1 on medRxiv
  4. Version published to 10.1002/cti2.1192