Dear Editor,

Corona Virus Disease 2019 (COVID-19) is a highly contagious disease that has caused outbreaks across the globe. As of May 21, 2020, a total of 5,027,732 confirmed COVID-19 cases have been reported in 188 countries, with an average mortality of 6.54%¹1. Johns Hopkins University. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Baltimore: Johns Hopkins University; 2020. [cited 2020 May 21]. Available from: https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6
https://gisanddata.maps.arcgis.com/apps/... . The current relationship between COVID-19 disease severity and immune function status is unclear. As far as we know, this study is the first meta-analysis to compare immune status and immunoglobulin efficacy in severe vs. non-severe patients with COVID-19.

An extensive electronic search of PubMed, Embase, and Cochrane Library was conducted without date limitations (until May 6, 2020), using the keywords “COVID-19”, “2019-nCoV”, “SARS-CoV-2”, “Novel Coronavirus”, “Feature”, “Immune”, etc. Two authors independently screened articles, assessed qualities, and performed data extraction. Any discrepancies during these steps were regularly resolved by consulting with a third reviewer. Severe COVID-19 infection was defined as severe pneumonia, acute respiratory distress syndrome (ARDS), treatment with mechanical ventilation or intensive care unit (ICU), and/or death. Dichotomous variables were estimated with Odd Risks (OR) and 95% confidence interval (CI). Continuous data (using mean and standard deviation - SD) were compared and the mean difference (MD) was calculated with 95% CI, and a P-value <0.05 was considered statistically significant. The random-effects model was used if I²2. Cai Q, Huang D, Ou P, Yu H, Zhu Z, Xia Z, et al. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. Allergy. 2020;75(7):1742-52.. >50%. The publication bias was evaluated by visual inspection of the funnel plot. Our meta-analysis was carried out using Review Manager software version 5.3 (Cochrane Collaboration).

Nineteen studies ²2. Cai Q, Huang D, Ou P, Yu H, Zhu Z, Xia Z, et al. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. Allergy. 2020;75(7):1742-52..

3. Chen Q, Zheng Z, Zhang C, Zhang X, Wu H, Wang J, et al. Clinical characteristics of 145 patients with corona virus disease 2019 (COVID-19) in Taizhou, Zhejiang, China. Infection. 2020;1-9.

4. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. Bmj. 2020;368:m1091.

5. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine. 2020;382(18):1708-20.

6. Li Q, Zhang J, Ling Y, Li W, Zhang X, Lu H, et al. A simple algorithm helps early identification of SARS-CoV-2 infection patients with severe progression tendency. Infection. 2020;1-8.

7. Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 2020;55:102763.

8. liu lei GJ-y. Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing-China. medrxiv. 2020.

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14. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA internal medicine. 2020;180(7):1-11.

15. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory medicine. 2020;8(5):475-81.

16. Zhang G, Hu C, Luo L, Fang F, Chen Y, Li J, et al. Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China. Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology. 2020;127:104364.

17. Zheng S, Fan J, Yu F, Feng B, Lou B, Zou Q, et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. Bmj. 2020;369:m1443.

18. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.

19. Cao M, Zhang D, Wang Y, Lu Y, Zhu X, Li Y, et al. Clinical Features of Patients Infected with the 2019 Novel Coronavirus (COVID-19) in Shanghai, China. medRxiv. 2020. - ²⁰20. 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. 2020. were enrolled in our analysis. All studies originated from China and involved 4,011 confirmed COVID-19 patients in total. The incidence of combined immune diseases before the diagnosis of COVID-19 was not significantly associated with an enhanced risk of severe COVID-19 (OR: 1.69, 95% CI: 0.61-4.71, P=0.31). Immune globulin A (IgA) and immune globulin G (IgG) were found to be increased in COVID-19 patients in the severe group [IgA: MD=0.21, 95%CI (0.01, 0.41), P=0.04; IgG: MD=0.74, 95%CI (0.22, 1.26), P=0.005]. Immune globulin M (IgM) was not found to be correlated with the severity of COVID-19 (MD: -0.02, 95% CI: -0.11, 0.08, P=0.73). Our study revealed that a decrease in the mean cluster of differentiation (CD)3, CD4 and CD8 was significantly associated with an increased likelihood of severity [CD3: MD=-282.2, 95%CI (-481.28, -83.13), P=0.005; CD4: MD=-199.57, 95%CI (-329.68, -69.46), P=0.003; CD8: MD=-85.83, 95%CI (-116.46, -55.20), P<0.0001]. Immunoglobulin therapy is significantly more effective in severe COVID-19 patients (OR: 6.25, 95% CI: 3.01-12.99, P<0.0001). Based on a visual inspection of the funnel plots, no evidence of publication bias was found. More details of our meta-analysis are presented in Figure 1 .

FIGURE 1
META-ANALYSIS RESULTS OF THE OUTCOMES: (A) THE INCIDENCE OF COMBINED IMMUNE DISEASES BEFORE THE DIAGNOSIS OF COVID-19; (B) IGA; (C) IGG; (D) IGM; (E) CD3; (F) CD4; (G) CD8; (H) IMMUNOGLOBULIN THERAPY.

This meta-analysis provides evidence that hypoimmune states could be associated with a more severe form of COVID-19, and that immunoglobulins are more effective against severe COVID-19. Our results are consistent with some previous descriptive reviews²¹21. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection: a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727-32.

22. Kadkhoda K. COVID-19: an immunopathological view. mSphere. 2020;5(2):e00344-20. - ²³23. Jawhara S. Could intravenous immunoglobulin collected from recovered coronavirus patients protect against COVID-19 and strengthen the immune system of new patients? Int J Mol Sci. 2020;21(7):2272. . In addition, this study has important clinical implications. First, it can potentially help in disease assessment as the COVID-19 pandemic continues to affect multiple countries. Second, it reminds us of the relevance of early initiation of immunoglobulin therapy, which is effective in improving the prognosis of severe and critical type patients.

This study has its limitations. First, most of the studies included are retrospective and lack a prospective design. Second, some of the outcomes in this study had a high I2 value, which represents heterogeneity. This might be explained by the small sample size, limited data, and different patient populations.

Based on our results, a hypoimmune status might be an important sign of COVID-19 severity, guiding clinicians to identify severe patients earlier and faster and alerting clinicians that immunoglobulins have better efficacy in critically ill patients. Further, more high-quality literature is needed to better support this conclusion.

Acknowledgments

The National Natural Science Foundation of China (No. 81370494 and No. 31471330) funded this manuscript.

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