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. 2020 Nov 20;31(4):e2195. doi: 10.1002/rmv.2195

A systematic meta‐analysis of immune signatures in patients with COVID‐19

Kun Liu 1, Tong Yang 2, Xue‐Fang Peng 2, Shou‐Ming Lv 2, Xiao‐lei Ye 2, Tian‐Shuo Zhao 3, Jia‐Chen Li 2, Zhong‐Jun Shao 1, Qing‐Bin Lu 3,✉, Jing‐Yun Li 2,✉, Wei Liu 2,3,✉
PMCID: PMC7744845  PMID: 34260780

Summary

Currently severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) transmission has been on the rise worldwide. Predicting outcome in COVID‐19 remains challenging, and the search for more robust predictors continues. We made a systematic meta‐analysis on the current literature from 1 January 2020 to 15 August 2020 that independently evaluated 32 circulatory immunological signatures that were compared between patients with different disease severity was made. Their roles as predictors of disease severity were determined as well. A total of 149 distinct studies that evaluated ten cytokines, four antibodies, four T cells, B cells, NK cells, neutrophils, monocytes, eosinophils and basophils were included. Compared with the non‐severe patients of COVID‐19, serum levels of Interleukins (IL)‐2, IL‐2R, IL‐4, IL‐6, IL‐8, IL‐10 and tumor necrosis factor α were significantly up‐regulated in severe patients, with the largest inter‐group differences observed for IL‐6 and IL‐10. In contrast, IL‐5, IL‐1β and Interferon (IFN)‐γ did not show significant inter‐group difference. Four mediators of T cells count, including CD3+ T, CD4+ T, CD8+ T, CD4+CD25+CD127‐ Treg, together with CD19+ B cells count and CD16+CD56+ NK cells were all consistently and significantly depressed in severe group than in non‐severe group. SARS‐CoV‐2 specific IgA and IgG antibodies were significantly higher in severe group than in non‐severe group, while IgM antibody in the severe patients was slightly lower than those in the non‐severe patients, and IgE antibody showed no significant inter‐group differences. The combination of cytokines, especially IL‐6 and IL‐10, and T cell related immune signatures can be used as robust biomarkers to predict disease severity following SARS‐CoV‐2 infection.

Keywords: antibody, COVID‐19, cytokines, disease severity, innate immunity, meta‐analysis

Abbreviations

ARDS

acute respiratory distress syndrome

CLIA

chemiluminescence immunoassay

COVID‐19

coronavirus disease 2019

CSS

Churg–Strauss syndrome

DCs

dendritic cells

ELISA

enzyme‐linked immunosorbent assay

ICU

intensive care unit

IFN

interferon

Ig

immunoglobulin

IL

interleukins

IQR

interquartile range

MERS

Middle East respiratory syndrome

MMFI

multiple microsphere flow immunofluorescence

NK cell

natural killer cell

NOQAS

Newcastle–Ottawa Quality Assessment Scale

PD

programmed cell death protein

PD‐L

programmed cell death protein ligand

PRISMA

preferred reporting items for systematic reviews and meta‐analyses statement

SARS

severe acute respiratory syndrome

SD

standard deviation

SMD

standardized mean difference

TNF‐α

tumour necrosis factor‐α

1. INTRODUCTION

Currently, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) transmission has been on the rise in the worldwide range, with more than 32,000,000 cases and more than 990,000 deaths documented to 28 September 2020. Intensive efforts have been put forward to study the clinical process and outcome of the disease. 1 Predicting outcome in coronavirus disease 19 (COVID‐19) remains challenging, and the search for more robust methods continues. A broad range of signs and symptoms have been investigated in COVID‐19 to predict the disease outcome, while showing divergent results.2, 3, 4, 5, 6 Inclusion more specific biomarkers is urgently needed to develop a robust algorithm. Previous studies have suggested that lymphocytopenia and inflammatory cytokine storm are typical abnormalities in infections caused by highly pathogenic coronavirus, such as SARS and MERS.7, 8 Similarly, numerous studies on COVID‐19 patients have reported a decrease in peripheral blood lymphocyte count and an increase in serum inflammatory cytokines,9, 10, 11, 12 which is suggested that the inflammatory factors may be the main reason for adverse progression and poor treatment response in COVID‐19, but mostly proposed from small sample studies. 13 If these biomarkers are validated in a large patient cohort, their incorporation into algorithms might prove sufficiently sensitive and specific to be clinically useful, particularly when they can be related to the disease outcome.

In the current study, we attempted to address these issues by conducting a systematic meta‐analysis using the pooled data for the immune indicators that were evaluated at early disease and among patients with various disease severity. The inclusion of various studies allowed more statistical power for a holistic view of SARS‐CoV‐2‐induced immune mediators among patients with different disease severity, and across various geographic locations. This will also help to identify the immune signatures that better distinguish the development of COVID‐19 outcome.

2. MATERIALS AND METHODS

2.1. Protocol registration

This systematic review was not registered. The format of the review used the preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) (Table S1), and addressed the following question: ‘Are the immune mediators different in severe and non‐severe groups of COVID‐19 patients?’ according to PICOS (P—Patient, Problem or Population; I—Intervention; C—Comparison, control or comparator; O—Outcome; S—Study design) (Table S2).

2.2. Search strategy and study selection

We performed a comprehensive systematic review and meta‐analysis to identify the associations of immune cells, cytokines and the severity of COVID‐19. Identification of relevant existing literature was performed by an online search in PubMed, Web of Science and EMBASE, for studies published from 1 January 2020 to 15 August 2020. The MESH headings (keywords) searched were ‘nCoV’ or ‘coronavirus’ or ‘SARS‐CoV‐2’ or ‘COVID’ and ‘cytokine’ or ‘immunological or ‘immunity’ or ‘Cellular immunity’ or ‘T cell’ or ‘B cell’ or ‘NK cell’ or ‘antibody’. In addition, the same search strategy was applied to the database of bioRxiv and medRxiv for the unpublished studies (Table S3). Two reviewers (TY and XFP) independently screened the list of titles and abstracts, and the full text of chosen manuscripts related the immune mediators. Disagreements on which manuscripts to include during both title and abstract screen, and the subsequent full‐text analysis, were discussed until a conclusion was reached with two other reviewers (SML and KL).

2.3. Inclusion and exclusion criteria

All studies evaluating individual measurement of immunological indicators in predicting severe infection (as measured by disease severity criteria, or ICU admission or fatal/survived) were included. All studies of any design, from any time since the outbreak started were eligible. To avoid selection bias, no subjective quality criteria were applied to the studies for inclusion. The immunological signatures that were measured at the acute phase of infection were used, and if there was more than one evaluation for the same patient, only the first test results were used. Only those immune signatures investigated in at least three papers were used in the subsequent analysis. Exclusion criteria included the following: (1) Case reports of individual patients, literature reviews, nonhuman studies, editorials, comments, expert opinions or articles with number of patients ≤10; (2) Studies of exclusively paediatric or pregnant patients, due to the varying presentation of the disease in these groups and (3) Studies without adequate baseline information, such as age, sex or geographic region.

2.4. Data extraction

All the search results were evaluated according to the PRISMA statement. 14 From each study, various details including the baseline information of study population (age, sex, interval from disease onset to hospitalization, intervals from disease onset to the sample collection, study areas), the number of patients in each study group, the measured immunological indicators and their test methods and the definitions used to measure outcome, were extracted into Microsoft Excel. These details are presented in Table 1. The Newcastle‐Ottawa Quality Assessment Scale (NOQAS) was used to assess the quality of the studies included in the meta‐analysis and performed by two reviewers (TY and XFP) with a third reviewer (SML) consulted in case of discrepancy.

TABLE 1.

Characteristics of the association studies included in the meta‐analysis

Author Publish date Country Journal Detection method Patients group Sample size Mean ± SD or IQR
Severe No‐severe Severe No‐severe
IL‐2 (unit: ng/L)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 9.48 ± 4.87 6.7 ± 4.42
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry and ELISA Severe/no‐severe 69 11 2.69 ± 0.14 2.51 ± 0.16
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 4.2 (4.0–4.4) 3.8 (3.6–4.3)/3.7 (3.5–4.0)
Shi et al. 17 2020/3/16 China medRxiv – Severe/no‐severe 25 31 5.12 ± 1.64 4.47 ± 0.29
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 1 (0.8–1.9) 1 (0.7–2.0)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.52 (0.33–0.66) 0.36 (0.22–1.23)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐sever 69 135 4.06 (3.28–4.09) 3.55 (3.38–3.65)
Wei et al. 21 2020/4/29 China J Med Virol CLIA Severe/no‐severe 121 131 2.8 ± 0.7 9 ± 53.4
2.9 ± 0.9
Zhu et al. 22 2020/4/22 China Int J Infect Dis Flow cytometry Severe/no‐severe 16 111 0.90 (0.47–1.60) 0.93 (0.55–1.73)
IL‐2R (unit: ng/L)
Chen et al. 23 2020/2/4 China Chinese Medical Association ELISA Severe/no‐severe 14 15 902 ± 51/1185 ± 80 631 ± 37
Chen et al. 24 2020/3/27 China J Clin Invest CLIA Severe/no‐severe 9 7 1209.33 ± 421.86 448.97 ± 186.35
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 1189.0 (901.0–1781.0) 566.5 (448.0–858.3)
Li et al. 26 2020/3/23 China medRxiv – Death/no‐death 26 108 1166.5 (898.8–1788.5)/1076.5 (671.8–1699.5) 571.5 (353.0–821.8)/454.5 (270.3–563.0)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 757 (528.5–1136.3) 663.5 (473.3–862.8)
Liu et al. 27 2020/4/10 China Viral Immunol Severe/no‐severe 30 46 1451 (879–2768) 579 (429–1432)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 7 27 5.00 (5.00–25.88) 5.00 (5.00–5.00)
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 766 (595–1050) 546 (455–743)
1026 (378–1260)
Hou et al. 30 2020/5/4 China Clin Exp Immunol CLIA Severe/no‐severe 221 168 833.33 ± 620.21 666.77 ± 334.12
250.23 ± 750.12
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 2 27 1729.50 (1277.25–2181.75) 529.00 (385.00–754.50)
Wang et al. 32 2020/6/1 China Am J Respir Crit Care Med – Death/no‐death 133 211 1098 (721–1512) 716 (458–954)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 905.08 ± 441.45 787.88 ± 313.40
1077.16 ± 551.21
IL‐4 (unit: ng/L)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 3.49 ± 1.27 2.90 ± 1.28
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry and ELISA Severe/no‐severe 69 11 2.02 ± 0.10 1.88 ± 0.24
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 4.5 (4.1–4.8) 4.2 (3.8–4.9)/4.1 (3.8–4.6)
Shi et al. 17 2020/3/16 China medRxiv – Severe/no‐severe 25 31 1.42 ± 0.27 1.47 ± 0.2
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 1.8 (1.4–1.8) 1.8 (1.2–1.8)
Wan et al. 34 2020/2/10 China Br J Haematol MMFI Severe/no‐severe 21 102 1.83 ± 0.1849 1.69 ± 0.07049
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.11 (0.00–0.42) 0.24 (0.10–0.48)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 4.30 (4.01–4.60) 3.75 (3.70–3.85)
Wei et al. 21 2020/4/29 China J Med Virol CLIA Severe/no‐severe 121 131 2.3 ± 0.8 2.6 ± 1
8.4 ± 20
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 10 30 3.25 ± 0.81 1.49 ± 0.22
Zhu et al. 22 2020/4/22 China Int J Infect Dis Flow cytometry Severe/no‐severe 16 111 1.99 (1.26–2.73) 1.87 (1.43–2.55)
IL‐6 (unit: ng/L)
Cai et al. 36 2020/4/2 China Allergy – Severe/no‐severe 58 240 38.8 (22.7–57.2) 12 (6.4–19.7)
Chen et al. 23 2020/2/4 China Chinese Medical Association ELISA Severe/no‐severe 14 15 52 ± 11/108 ± 12 34 ± 7
Chen et al. 24 2020/3/27 China J Clin Invest CLIA Severe/no‐severe 9 7 72.39 ± 71.64 18.66 ± 15.80
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 72.0 (35.6–146.8) 13.0 (4.0–26.2)
Gao et al. 37 2020/4/10 China J Med Virol Severe/no‐severe 15 28 36.1 (23–59.2) 10.6 (5.13–24.18)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 29.42 ± 41.34 12.47 ± 22.05
Li et al. 26 2020/3/23 China medRxiv – Death/no‐death 26 108 48.4 (12.6–154.1)/65.1 (11.3–154.1) 4.2 (1.9–16.4)/3.3 (1.4–16.7)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry and ELISA Severe/no‐severe 69 11 36.52 ± 5.54 2.61 ± 0.65
Mo et al. 38 2020/3/16 China Clin Infect Dis – Severe/no‐severe 85 70 64 (31–165) 23 (9–57)
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 9.93 (8.58–11.92) 5.78 (5.10–7.19)/6.03 (5.39–7.93)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 25.2 (9.5–54.5) 13.3 (3.9–41.1)
Ruan et al. 39 2020/3/3 China Intensive Care Med – Death/no‐death 68 82 13.47 ± 15.89 6.78 ± 8.78
Shi et al. 17 2020/3/16 China medRxiv – Severe/no‐severe 25 31 445.83 ± 204.85 312.61 ± 24.27
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 24.2 (11.6–47.0) 21.6 (8.7–57.2)
Wan et al. 34 2020/2/10 China Br J Haematol MMFI Severe/no‐severe 18 45 37.77 ± 7.801 13.41 ± 1.84
Wu et al. 9 2020/3/13 China JAMA Intern Med – ARDS/no‐ARDS 84 117 7.39 (5.63–10.89) 6.29 (5.36–7.83)
Xiao et al. 40 2020/2/27 China Acta Acad Med Mil Tert – Severe/no‐severe 36 107 15.29 ± 4.54/28.06 ± 8.38 6.21 ± 1.04
Xu et al. 41 2020/3/8 China medRxiv – Severe/no‐severe 25 44 14.8 (7.5–45.3) 5.9 (2.8–10.9)
Zheng et al. 42 2020/3/17 China Cellular & Molecular Immunology – Severe/no‐severe 6 10 28.3 ± 22.64 50.94 ± 31.13
Zhou et al. 43 2020/3/9 China Lancet – Death/no‐death 54 137 11 (7.5–14.4) 6.3 (5.0–7.9)
Liu et al. 27 2020/4/10 China Viral Immunol Severe/no‐severe 30 46 29.1 (2–89.3) 7.1 (2.79–25.7)
Sun et al. 44 2020/5/8 China J Am Geriatr Soc – Death/no‐death 121 123 75.2 (35.2–162.9) 12.7 (3.3–41.5)
Fan et al. 45 2020/4/19 China Metabolism Death/no‐death 4 15 195 (127–280) 12 (4–18)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 18.15 (5.91–49.24) 2.21 (0.83–13.22)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 57.33 ± 111.5/116.47 ± 141.9 24.69 ± 39.72
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 154.55 ± 315.11 9.21 ± 10.12
Dong et al. 46 2020/5/29 China Transbound Emerg Dis – Severe/no‐severe 53 94 21.85 (11.77–38.68) 8.54 (3.52–17.29)
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 33.22 ± 31.90/34.09 ± 26.47 5.26 ± 1.25/14.17 ± 11.37
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 7 27 22.88 (18.90–27.76) 9.50 (1.79–18.09)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 14.3 (7.8–11.6) 14.0 (7.2–15.3)
Li et al. 48 2020/5/19 China JCI Insight CLIA Severe/no‐severe 26 43 24.6 (17.9–45.0) 8.4 (5.7–15.9)
Wei et al. 21 2020/4/29 China J Med Virol CLIA Severe/no‐severe 121 131 150.7 ± 449.2 64.6 ± 137.7
57.4 ± 105.6
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 27.1 (11.8–60.0) 13.2 (3.8–23.1)
32.8 (17.8–62.6)
Hou et al. 30 2020/5/4 China Clin Exp Immunol CLIA Severe/no‐severe 221 168 16.9 ± 25.32 67.71 ± 56.33
25.35 ± 33.15
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 10 30 44.51 ± 12.45 7.06 ± 3.55
Burian et al. 49 2020/5/18 Germany J Clin Med – ICU/no‐ICU 12 25 103.9 ± 43.6 51.7 ± 65.6
Gayam et al. 50 2020/7/16 USA J Med Virol – Death/no‐death 132 276 84.5 (53.3–205) 53.1 (23.9–97.4)
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 43.8 (20.1–62.6) 3.9 (2.2–9.6)
Xu et al. 52 2020/6/13 China Zhonghua Wei Zhong Bing Ji Jiu Yi Xue – Severe/no‐severe 30 125 75.85 ± 37.64 19.16 ± 10.53
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 4 27 22.88 (18.90–27.76) 9.50 (1.79–18.09)
Xie et al. 53 2020/6/13 China Circ J – Severe/no‐severe 24 38 14.1 (4.3–26.7) 5.0 (4.3–8.2)
17.5 (8.4–27.9) 6.7 (4.2–9.3)
Morrison et al. 54 2020/7/3 USA J Autoimmun – Death/no‐death 16 22 47.5 (15.5–82) 12 (5–32)
Wang et al. 55 2020/3/24 China Int J Infect Dis – Severe/no‐severe 25 100 39.80 (23.75–60.6) 16.80 (5.55–29.7)
Zheng et al. 56 2020/3/27 China Int J Infect Dis – Severe/no‐severe 21 34 64.3 (3.8–439) 27.6 (3.6–280)
Wang et al. 57 2020/3/15 China J Infect – Death/no‐death 65 274 93.8 (35.9–182.3) 10.5 (4.9–18.8)
Wang et al. 32 2020/6/1 China Am J Respir Crit Care Med – Death/no‐death 133 211 61.1 (29.9–132.2) 10.8 (2.7–37.4)
Chen et al. 58 2020/4/17 China Clin Infect Dis – Severe/no‐severe 27 21 5.8 (3.1–16.9) 10.4 (3.8–31.0)
64.0 (25.6–111.9)
Liu et al. 59 2020/7/31 China Ann Intensive Care – Death/no‐death 157 1033 31.9 (11.1–1487.0) 13.2 (7.7–366.2)
Arunachalam et al. 60 2020/8/11 China and USA Science Flow cytometry Severe/no‐severe 18 4 41.89 ± 68.33 9.87 ± 5.74
Wei et al. 61 2020/4/16 China J Infect – Severe/no‐severe 30 137 36.20 (16.25–59.90) 15.40 (5.05–28.90)
Zhu et al. 22 2020/4/22 China Int J Infect Dis Flow cytometry Severe/no‐severe 16 111 24.11 (1.14–54.37) 3.82 (2.19–9.87)
Shi et al. 62 2020/4/23 China medRxiv – Severe/no‐severe 46 88 23.0 (7.2–49.7) 5.7 (5.0–9.9)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 11.30 (4.34–28.43) 14.60 (4.21–22.30)
17.40 (7.18–50.20)
Pereira et al. 64 2020/4/24 USA Am J Transplant – Severe/no‐severe 27 41 32 (11–90) 18 (5–45)
IL‐8 (unit: ng/L)
Chen et al. 23 2020/2/4 China Chinese Medical Association ELISA Severe/no‐severe 14 15 20 ± 16/30 ± 16 16 ± 11
Chen et al. 24 2020/3/27 China J Clin Invest CLIA Severe/no‐severe 9 7 61.62 ± 73.07 24.74 ± 26.86
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 28.3 (18.7–72.1) 11.4 (7.8–20.2)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 49.74 ± 76.59 18.19 ± 16.24
Li et al. 26 2020/3/23 China medRxiv – Death/no‐death 26 108 22.0 (14.0–28.4)/27.6 (14.1–64.9) 9.3 (6.4–18.6)/9.4 (5.7–15.9)
Liu et al. 27 2020/4/10 China Viral Immunol Severe/no‐severe 30 46 21.5 (5–125.6) 8.66 (5.41–17.5)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 18.4 (11.3–28.4) 13.7 (8.9–21)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 7 27 29.05 (14.35–56.75) 9.40 (6.55–15.85)
Li et al. 48 2020/5/19 China JCI Insight CLIA Severe/no‐severe 26 43 13.1 (11.4–15.9) 7.8 (6.4–10.4)
Hou et al. 30 2020/5/4 China Clin Exp Immunol CLIA Severe/no‐severe 221 168 32.21 ± 34.88 29.78 ± 43.11
55.99 ± 78.34
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 4 27 29.05 (14.35–56.75) 9.40 (6.55–15.85)
Wang et al. 32 2020/6/1 China Am J Respir Crit Care Med – Death/no‐death 133 211 28.3 (14.7–59.1) 12.5 (6.9–20.8)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 32.58 ± 23.79 36.55 ± 54.97
57.23 ± 61.01
IL‐10 (unit: ng/L)
Chen et al. 23 2020/2/4 China Chinese Medical Association ELISA Severe/no‐severe 14 15 11.0 ± 9.2/11.4 ± 2.6 8.0 ± 3.2
Chen et al. 24 2020/3/27 China J Clin Invest CLIA Severe/no‐severe 9 7 10.93 ± 2.10 6.67 ± 2.65
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 12.8 (8.8–19.6) 5.0 (5.0–8.4)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 19.38 ± 37.95 5.51 ± 4.31
Li et al. 26 2020/3/23 China medRxiv – Death/no‐death 26 108 4.9 (4.0–10.0)/8.3 (4.9–17.0) 4.9 (4.0–4.9)/4.9 (4.0–4.9)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry and ELISA Severe/no‐severe 69 11 5.48 ± 0.48 3.06 ± 0.16
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 6.54 (5.96–7.44) 4.93 (4.25–5.55)/4.78 (4.28–5.51)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 6.6 (5.0–11.3) 5 (5.0–7.0)
Shi et al. 17 2020/3/16 China medRxiv – Severe/no‐severe 25 31 25.43 ± 12.71 19.21 ± 1.89
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 6.7 (3.3–8.2) 4.3 (3.0–8.1)
Wan et al. 34 2020/2/10 China Br J Haematol MMFI Severe/no‐severe 21 102 4.59 ± 0.3777 2.464 ± 0.08506
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 30.25 (15.57–67.13) 24.79 (16.64–36.92)
Liu et al. 27 2020/4/10 China Viral Immunol Severe/no‐severe 30 46 7.32 (<5–11.23) 5 (<5–5.87)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 5.23 (3.31–10.64) 2.34 (1.16–4.41)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 10.16 ± 4.96 36.55 ± 54.97
23.85 ± 26.57
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 14.28 ± 16.92 4.52 ± 3.71
Dong et al. 46 2020/5/29 China Transbound Emerg Dis – Severe/no‐severe 53 94 4.50 (3.91–5.45) 4.51 (3.48–6.23)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 7 27 22.00 (14.73–60.00) 5.00 (5.00–7.90)
Wei et al. 21 2020/4/29 China J Med Virol CLIA Severe/no‐severe 121 131 4.3 ± 1.7 3.9 ± 1.8
5.6 ± 3.6
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 7.25 (6.20–8.05) 6.37 (5.71–6.67)
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 6.4 (5.0–10.4) 5.0 (5.0–8.1)
8.0 (5.0–15.1)
Hou et al. 30 2020/5/4 China Clin Exp Immunol CLIA Severe/no‐severe 221 168 7.28 ± 3.71 13.88 ± 12.95
9.18 ± 8.52
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 10 30 7.45 ± 2.64 0.91 ± 0.7
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 4 27 22.00 (14.73–60.00) 5.00 (5.00–7.90)
Wang et al. 32 2020/6/1 China Am J Respir Crit Care Med – Death/no‐death 133 211 10.5 (5.9–18.5) 2.5 (2.5–7.0)
Zhu et al. 22 2020/4/22 China Int J Infect Dis Flow cytometry Severe/no‐severe 16 111 6.41 (3.24–11.02) 3.13 (2.15–4.57)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 8.52 (4.90–15.80) 5.00 (4.90–7.16)
9.56 (5.14–14.80)
TNF‐α (unit: ng/L)
Chen et al. 23 2020/2/4 China Chinese Medical Association ELISA Severe/no‐severe 14 15 10.8 ± 6.5/10.1 ± 1.5 8.3 ± 1.9
Chen et al. 24 2020/3/27 China J Clin Invest CLIA Severe/no‐severe 9 7 10.93 ± 3.30 7.56 ± 1.85
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 11.8 (8.6–17.6) 7.9 (6.7–9.6)
Li et al. 26 2020/3/23 China medRxiv – Death/no‐death 26 108 13.0 (8.3–23.3)/21.3 (13.2–28.9) 7.3 (5.6–9.4)/5.7 (3.8–7.9)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry and ELISA Severe/no‐severe 69 11 2.26 ± 0.15 2.11 ± 0.10
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 2.98 (2.76–3.41) 2.85 (2.51–3.35)/2.89 (2.55–3.28)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 8.7 (7.1–11.6) 8.4 (6.9–10.4)
Shi et al. 17 2020/3/16 China medRxiv – Severe/no‐severe 25 31 1.23 ± 0.30 0.93 ± 0.20
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 12.2 (12.2–54.4) 19.7 (2.5–67.5)
Wan et al. 34 2020/2/10 China Br J Haematol MMFI Severe/no‐severe 21 102 2.948 ± 0.4432 4.077 ± 1.588
Zheng et al. 42 2020/3/17 China Cellular & Molecular Immunology – Severe/no‐severe 6 10 97.06 ± 30.88 202.94 ± 70.59
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.1 (0.00–0.24) 0.10 (0.10–0.26)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 10.16 ± 2.94 10.34 ± 3.12
13.26 ± 14.02
Dong et al. 46 2020/5/29 China Transbound Emerg Dis – Severe/no‐severe 53 94 2.07 (1.81–2.22) 2.18 (1.93–2.35)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 7 27 23.00 (9.65–44.23) 7.60 (5.65–9.00)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 2.98 (2.63–3.11) 2.50 (2.44–2.73)
Li et al. 48 2020/5/19 China JCI Insight CLIA Severe/no‐severe 26 43 7.4 (6.7–8.7) 5.0 (4.8–6.08)
Wei et al. 21 2020/4/29 China J Med Virol CLIA Severe/no‐severe 121 131 5.5 ± 6.1 5.6 ± 6.6
3.2 ± 2
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 9.3 (7.6–11.6) 8.1 (6.8–9.8)
9.3 (6.8–11.1)
Hou et al. 30 2020/5/4 China Clin Exp Immunol CLIA Severe/no‐severe 221 168 10.41 ± 4.73 9.03 ± 4.11
4.48 ± 8.13
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 10 30 1.74 ± 0.4 0.91 ± 0.49
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 4 27 23.00 (9.65–44.23) 7.60 (5.65–9.00)
Wang et al. 32 2020/6/1 China Am J Respir Crit Care Med – Death/no‐death 133 211 10.7 (7.5–15.9) 8.2 (6.1–10.2)
Arunachalam et al. 60 2020/8/11 China and USA Science Flow cytometry Severe/no‐severe 18 4 7.11 ± 1.65 5.66 ± 2.94
Zhu et al. 22 2020/4/22 China Int J Infect Dis Flow cytometry Severe/no‐severe 16 111 1.48 (1.39–1.74) 1.35 (1.12–1.73)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 94.09 ± 20.40 72.01 ± 20.96
IL‐5 (unit: ng/L)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 13.61 ± 12.57 12.62 ± 12.75
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 2.22 (2.11–2.33) 2.16 (2.07–2.22)/2.13 (2.05–2.18)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 2.27 (2.12–2.35) 2.39 (2.30–3.05)
IL‐1β (unit: ng/L)
Chen et al. 23 2020/2/4 China Chinese Medical Association ELISA Severe/no‐severe 14 15 5.0 ± 1.1/6.2 ± 2.4 5.5 ± 1.9
Chen et al. 24 2020/3/27 China J Clin Invest CLIA Severe/no‐severe 9 7 5.32 ± 0.96 5 ± 0.21
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 1.16 ± 0.54 1.40 ± 1.52
Li et al. 26 2020/3/23 China medRxiv – Death/no‐death 26 108 4.5 (4.0–4.9)/4.9 (4.2–4.9) 4.9 (4.0–4.9)/4.9 (4.7–4.9)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 5 (5.0–5.0) 5 (5.0–5.0)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 4.90 (4.90–5.42)/4.90 (4.90–5.61) 4.90 (4.90–5.21)
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 10 30 1.65 ± 0.38 0.85 ± 0.14
Li et al. 48 2020/5/19 China JCI Insight CLIA Severe/no‐severe 26 43 9.9 (6.0–18.3) 7.5 (6.8–8.7)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 7 27 5.00 (5.00–25.88) 5.00 (5.00–5.00)
Liu et al. 27 2020/4/10 China Viral Immunol – Severe/no‐severe 30 46 5.69 (<5–11.6) 5 (<5–10.1)
Hou et al. 30 2020/5/4 China Clin Exp Immunol CLIA Severe/no‐severe 221 168 6.43 ± 3.01/10.71 ± 6.02 5.57 ± 2.13
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 4 27 5 (5–25.88) 5 (5–5)
Wang et al. 33 2020/4/23 China JCI Insight – Severe/no‐severe 35 30 6.48 ± 3.83/5.32 ± 0.63 6.11 ± 2.92
IFN‐γ (unit: ng/L)
Huang et al. 1 2020/1/24 China Lancet – ICU/no‐ICU 13 28 16.062 ± 20.752 0.849 ± 5.472
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry and ELISA Severe/no‐severe 69 11 2.49 ± 0.18 1.87 ± 0.09
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 3.99 (3.61–4.44) 3.76 (3.53–4.19)/3.64 (3.38–4.07)
Shi et al. 17 2020/3/16 China medRxiv – Severe/no‐severe 25 31 5.27 ± 1.91 4.9 ± 0.85
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 9 (5.7–24.3) 12.2 (5.8–37.9)
Wan et al. 34 2020/2/10 China Br J Haematol MMFI Severe/no‐severe 21 97 6.904 ± 1.247 5.132 ± 0.8413
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 86.37 (47.01–255.91) 80.06 (36.63–129.08)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.58 (0.11–1.69) 0.66 (0.11–1.57)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 3.8 (3.8–3.93) 3.93 (3.51–4.61)
Wei et al. 21 2020/4/29 China J Med Virol CLIA Severe/no‐severe 121 131 2.9 ± 4.5 2.5 ± 1.1
9.5 ± 24.7
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 10 30 13.48 ± 4.84 0.87 ± 0.72
Zhu et al. 22 2020/4/22 China Int J Infect Dis Flow cytometry Severe/no‐severe 16 111 1.93 (1.25–2.29) 1.24 (0.93–1.57)
IgA (unit: g/L)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 2.18 (1.84–3.68) 2.38 (1.85–3.04)
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 2.4 (1.6–3.3) 2.1 (1.6–2.8)
Han et al. 67 2020/3/24 China Aging (Albany NY) – Severe/no‐severe 24 23 3.08 ± 1.08 1.01 ± 0.64
Liu et al. 68 2020/2/16 China EBioMedicine – Severe/no‐severe 13 27 2.4 ± 0.6 2.2 ± 0.8
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 1.97 (1.55–2.41) 1.90 (1.41–2.52)
1.93 (1.30–2.39)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 2.26 (1.57–2.89) 2.14 (1.66–2.71)
Fu et al. 69 2020/4/22 China medRxiv Death/no‐death 14 71 3.30 (1.68–4.50) 2.55 (1.81–3.01)
He et al. 20 2020/4/14 China J Clin Virol Severe/no‐severe 69 135 2.10 (1.43–2.85) 1.84 (1.45–2.44)
IgG (unit: g/L)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 12.4 (10.9–13.8) 11.8 (10.3–13.6)
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 12.3 (10.1–14.5) 11.3 (9.3–13.0)
Han et al. 67 2020/3/24 China Aging (Albany NY) – Severe/no‐severe 24 23 12.50 (9.82–15.20) 11.05 (9.34–12.53)
Liu et al. 68 2020/2/16 China EBioMedicine – Severe/no‐severe 13 27 11.5 ± 2 10.8 ± 2
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 12 (10–14) 12 (11–16)/13 (11–15)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 11.7 (9.53–13.8) 11.85 (10.13–13.40)
Fu et al. 69 2020/4/22 China medRxiv Death/no‐death 14 71 12.20 (10.60–14.30) 10.00 (11.70–13.40)
He et al. 20 2020/4/14 China J Clin Virol Severe/no‐severe 69 135 13.4 (10.5–16.5) 11.6 (9.9–13.8)
IgM (unit: g/L)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 0.86 (0.68–0.99) 0.96 (0.69–11.24)
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 1.0 (0.7–1.4) 1.0 (0.7–1.4)
Han et al. 67 2020/3/24 China Aging (Albany NY) – Severe/no‐severe 24 23 1.01 ± 0.36 1.01 ± 0.44
Liu et al. 68 2020/2/16 China medRxiv – Severe/no‐severe 13 27 1.1 ± 0.3 1.1 ± 0.5
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 1.05 (0.74–1.52) 1.16 (0.74–1.36)/1.20 (0.96–1.86)
Qin et al. 10 2020/3/12 China Clin Infect Dis – Severe/no‐severe 286 166 0.9 (0.69–1.28) 1.02 (0.77–1.37)
Fu et al. 69 2020/4/22 China medRxiv Death/no‐death 14 71 0.93 (0.72–1.16) 0.86 (0.67–1.09)
He et al. 20 2020/4/14 China J Clin Virol Severe/no‐severe 69 135 0.94 (0.66–1.22) 1.11 (0.86–1.38)
IgE (unit: IU/mL)
Han et al. 67 2020/3/24 China Aging (Albany NY) – Severe/no‐severe 24 23 36.00 (0.00–103.5) 0.00 (0.00–33.98)
Liu et al. 68 2020/2/16 China EBioMedicine – Severe/no‐severe 13 27 43.9 (27–105.5) 26.5 (12.8–76.1)
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 28.0 (17.3–58.0) 17.5 (17.3–98.2)/32.2 (17.3–65.0)
He et al. 20 2020/4/14 China J Clin Virol Severe/no‐severe 69 135 30.85 (17.3–68.9) 21.9 (17.3–84.3)
CD3+T cells count (unit: cells/μL)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 411.0 (198.0–537.0) 801.0 (561.5–1087.0)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 294.0 (169.3–415.3) 640.5 (588.3–789.5)
Diao et al. 70 2020/5/1 China Front Immunol – ICU/no‐ICU 43 212 261 (157–457) 652 (351–977)
Han et al. 67 2020/6/24 China Aging (Albany NY) – Severe/no‐severe 24 23 378.10 ± 142.33 973.46 ± 298.92
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 461.6 ± 264.7 663.8 ± 291.3
Shi et al. 17 2020/3/12 China medRxiv Flow cytometry Severe/no‐severe 25 19 738 ± 512.15 1073.38 ± 464.14
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 269.0 (158.0–410.0) 504.5 (262.0–918.8)
Wu et al. 9 2020/3/13 China JAMA Intern Med – ARDS/no‐ARDS 84 117 446.50 (231.00–633.75) 633.00 (467.00–846.00)
Xu et al. 41 2020/3/8 China medRxiv Flow cytometry Severe/no‐severe 25 44 306 (185–464) 734 (445–1036)
Zeng et al. 71 2020/3/8 China medRxiv Flow cytometry ICU/no‐ICU 65 113 503 ± 187 1056 ± 191
Zheng et al.(a) 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 530.25 ± 255.417 1245.105 ± 619.531
Zheng et al.(b) 11 2020/3/19 China Cell Mol Immunol – Severe/no‐severe 13 55 583.94 ± 328.97 857.66 ± 737.83
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 427.86 ± 253.74 571.23 ± 270.10
259.85 ± 155.97
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 707.55 ± 538.45 1047.17 ± 481.21
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 305 (198–525) 1066 (804–1321)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 378 (258–576) 991 (740–1154)
Shi et al. 73 2020/5/14 China Diabetes Care – Death/no‐death 47 259 266.5 (173.8–579.8)/297.0 (139.0–433.0) 706.0 (491.5–1004.5)/657.5 (431.0–1035.3)
Liu et al. 74 2020/5/13 China Clin Chim Acta Flow cytometry Severe/no‐severe 105 49 358.15 (73.71–1019.43)/511.78 (120.54–1739.49) 512.03 (118.69–1746.61)
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 522.57 ± 318.73/464.67 ± 339.68 1210.75 ± 408.81/808.97 ± 371.22
Liu et al. 59 2020/7/31 China Ann Intensive Care – Death/no‐death 157 1033 367 (267–409) 647 (468–991)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 339.50 (217.50–524.25) 609.00 (410.00–905.00)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 593.00 (412.00–725.00) 894.50 (662.75–1192.00)
287.50 (240.50–528.50)
CD4+T cells count (unit: cells/μL)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 198.0 (116.0–340.0) 468.0 (309.5–679.5)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 177.5 (104.0–249.8) 381.5 (255.0–451.0)
Diao et al. 70 2020/5/1 China Front Immunol – ICU/no‐ICU 43 212 198 (100–279) 342 (192–559)
Han et al. 67 2020/6/24 China Aging (Albany NY) – Severe/no‐severe 24 23 230.50 ± 86.68 610.15 ± 178.30
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 285.1 ± 168.0 420.5 ± 207.8
Shi et al. 17 2020/3/12 China medRxiv Flow cytometry Severe/no‐severe 25 19 384.72 ± 270.99 616.62 ± 294.09
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 139.0 (72.0–206.0) 288.5 (142.5–504.0)
Wan et al. 34 2020/2/10 China Br J Haematol – Severe/no‐severe 21 102 263.2 ± 28.83 451.3 ± 23
Wu et al. 9 2020/3/13 China JAMA Intern Med – ARDS/no‐ARDS 84 117 234.00 (136.75–398.00) 371.00 (283.00–572.00)
Xu et al. 41 2020/3/8 China medRxiv Flow cytometry Severe/no‐severe 25 44 201 (127–251) 422 (244–593)
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 329 (200.25–438.5) 559.5 (377–784)
Zeng et al. 71 2020/3/8 China medRxiv Flow cytometry ICU/no‐ICU 65 113 290 ± 87 599 ± 163
Zheng et al. 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 140.798 ± 336.375 416.618 ± 622.589
Zhou et al. 75 2020/3/17 China Ann Palliat Med Aggravation/no‐aggravation 5 12 377.2 ± 229.6 698.2 ± 267.4
Fan et al. 45 2020/4/19 China Metabolism Death/no‐death 4 15 168 (108–250) 416 (172–557)
Liu et al. 27 2020/4/10 China Viral Immunol Severe/no‐severe 30 60 125 (60–107) 462 (239–636)
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 392.27 ± 267.42 612.83 ± 296.34
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 257.86 ± 129.48/270.11 ± 162.75 689.38 ± 251.29/436.8 ± 225.08
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 199 (128–325) 544 (364–667)
Shi et al. 73 2020/5/14 China Diabetes Care – Death/no‐death 47 259 130.5 (92.0–369.8)/130.0 (103.0–277.0) 396.0 (293.0–599.0)/442.5 (264.5–676.0)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 184 (103–293) 645 (461–794)
Yang et al. 76 2020/4/29 China J Allergy Clin Immunol – Severe/no‐severe 36 14 377 (200.75–492.5)/246 (176–315.5) 561 (367–826)
Liu et al. 74 2020/5/13 China Clin Chim Acta Flow cytometry Severe/no‐severe 105 49 230.24 (40.13–760.24)/315.4 (54.96–1098.12) 311.34 (60.07–1134.24)
Yang et al. 77 2020/5/15 China J Med Virol – Severe/no‐severe 68 65 234.5 (155.5–353.5) 478 (326–571)
Xu et al. 52 2020/6/13 China Zhonghua Wei Zhong Bing Ji Jiu Yi Xue – Severe/no‐severe 30 125 330.43 ± 211.00 481.12 ± 243.60
Zheng et al. 78 2020/4/6 China J Clin Virol – Severe/no‐severe 26 63 273.92 ± 185.21 553.25 ± 377.81
Wang et al. 57 2020/3/15 China J Infect – Death/no‐death 65 274 191 (107–282) 349 (217–516)
Liu et al. 59 2020/7/31 China Ann Intensive Care – Death/no‐death 157 1033 211 (275–645) 388 (275–645)
Wei et al. 61 2020/4/16 China J Infect – Severe/no‐severe 30 137 282.00 (183.00–574.75) 490.40 ± 232.64)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 203.00 (126.50–284.25) 368.00 (246.00–549.00)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 299.00 (249.00–460.00) 573.50 (426.75–771.00)
168.50 (125.25–255.00)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 244.57 ± 135.87 342.39 ± 173.91
146.74 ± 125
CD8+T cells count (unit: cells/μL)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 128.0 (65.0–182.0) 217.0 (176.0–415.0)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 89.0 (61.5–130.3) 254.0 (183.3–312.8)
Diao et al. 70 2020/5/1 China Front Immunol – ICU/no‐ICU 43 212 64.3 (40.7–160) 208 (118–356)
Han et al. 67 2020/6/24 China Aging (Albany NY) – Severe/no‐severe 24 23 125.98 ± 84.71 345.00 ± 194.10
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 154.7 ± 116.5 201.9 ± 107.1
Shi et al. 17 2020/3/12 China medRxiv Flow cytometry Severe/no‐severe 25 19 311.33 ± 222.67 317.6 ± 150.67
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 117.0 (59.0–177.0) 234.0 (122.3–367.8)
Wan et al. 34 2020/2/10 China Br J Haematol – Severe/no‐severe 21 102 179 ± 23.87 288.6 ± 14.23
Wu et al. 9 2020/3/13 China JAMA Intern Med – ARDS/no‐ARDS 84 117 157.50 (76.00–289.50) 241.00 (159.0–323.00)
Xu et al. 41 2020/3/8 China medRxiv Flow cytometry Severe/no‐severe 25 44 88 (60–145) 266 (166–401)
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 139 (97–183) 453.5 (232.8–586)
Zeng et al. 71 2020/3/8 China medRxiv Flow cytometry ICU/no‐ICU 65 113 207 ± 142 455 ± 127
Zheng et al.(a) 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 109.694 ± 161.125 312.704 ± 432.54
Zhou et al. 75 2020/3/17 China Ann Palliat Med Aggravation/no‐aggravation 5 12 147 (116–446) 364 (111–799)
Zheng et al.(b) 11 2020/3/19 China Cell Mol Immunol – Severe/no‐severe 13 55 206.52 ± 117.72 336.96 ± 725.87
Liu et al. 27 2020/4/10 China Viral Immunol Severe/no‐severe 30 60 65 (33–112) 267 (210–405)
Fan et al. 45 2020/4/19 China Metabolism Death/no‐death 4 15 33 (23–135) 273 (122–377)
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 297.55 ± 223.32 301.03 ± 159.44
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 205.14 ± 153.09/202.22 ± 199.10 462.88 ± 154.43/355.33 ± 166.86
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 121 (54–197) 366 (274–482)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 134 (91–237) 417 (309–539)
Shi et al. 73 2020/5/14 China Diabetes Care – Death/no‐death 47 259 106.5 (42.0–212.5)/68.0 (52.0–156.0 268.0 (157.0–396.0)/221.0 (128.3–312.0)
Yang et al. 76 2020/4/29 China J Allergy Clin Immunol – Severe/no‐severe 36 14 146 (97–225.25) 139 (107–171.5) 453.5 (232.8–586)
Liu et al. 74 2020/5/13 China Clin Chim Acta Flow cytometry Severe/no‐severe 105 49 97.34 (21.82–733.95)/220.95 (49.45–833.76) 175.62 (40.73–865.47)
Xu et al. 52 2020/6/13 China Zhonghua Wei Zhong Bing Ji Jiu Yi Xue – Severe/no‐severe 30 125 233.50 ± 149.63 359.12 ± 191.26
Zheng et al. 78 2020/4/6 China J Clin Virol – Severe/no‐severe 26 63 202.31 ± 144.31 349.13 ± 256.5
Wang et al. 57 2020/3/15 China J Infect – Death/no‐death 65 274 73 (42–160) 204 (97–298)
Liu et al. 59 2020/7/31 China Ann Intensive Care – Death/no‐death 157 1033 129 (87–144) 242 (156–356)
Wei et al. 61 2020/4/16 China J Infect – Severe/no‐severe 30 137 191.00 (135.75–326.50) 316.00 (234.50–452.25)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 145.00 (70.00–213.00) 205.00 (111.00–303.00)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 188.00 (134.00–274.00) L 92.50 (70.75–141.50) 323.50 (232.75–448.75)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 156.52 ± 123.91 198.91 ± 120.65
110.87 ± 88.04
Treg cell count (unit: cells/μL)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 4.7 (2.6–5.4) 3.9 (3.6–4.3)
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 3. 7 ± 1.3 4.5 ± 0.9
Shi et al. 17 2020/3/12 China Immunology Flow cytometry Severe/no‐severe 25 19 7.13 ± 2.49 8.54 ± 2.09
Tan et al. 41 2020/5/27 China Immunology Severe/no‐severe 25 31 7.15 ± 3.84 8.58 ± 3.19
CD3+T cells ratio (unit: %)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 55.1 (52.2–60.5) 68.8 (64.7–75.2)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry Severe/no‐severe 69 11 65.85 ± 2.05 79.27 ± 1.94
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 60 (50–71) 72 (69–77)/73 (69–78)
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 60.0 ± 10.8 63.4 ± 8.5
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 29 31 64.75 (52.75–76.36) 66.85 (57.53–75.05)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 59.71 ± 15.21 65.58 ± 9.66
57.77 ± 11.95
Xie et al. 79 2020/4/24 China J Med Virol Severe/no‐severe 34 22 74.68 (70.81–78.92) 77.18 (68.35–82.03)
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 70.2 ± 13.41 70.21 ± 9.88
Zheng et al. 56 2020/3/27 China Int J Infect Dis – Severe/no‐severe 21 34 70.5 (39.5–86.8) 76.8 (62.9–89.6)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 60.49 (45.30–64.45) 69.00 (55.48–74.82)
CD4+T cells ratio (unit: %)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 36.7 (30.7–37.3) 36.4 (32.0–40.6)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry Severe/no‐severe 69 11 40.24 ± 1.46 45.61 ± 1.95
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 33 (25–42) 40 (33–43)/40 (37–46)
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 37.2 ± 8.4 39.8 ± 7.5
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 38.31 ± 7.31 42.82 ± 7.58
Xie et al. 79 2020/4/24 China J Med Virol Severe/no‐severe 34 22 44.92 (40.46–53.49) 46.29 (40.7–52.36)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 35.61 ± 8.93 38.47 ± 6.07
33.06 ± 14.05
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 20.0 (20.0–30.0) 50.0 (30.0–70.0)
Xie et al. 53 2020/6/13 China Circ J – Severe/no‐severe 24 38 36.7 (30.6–52.6) 41.4 (37.5–50.3)
42.2 (36.0–50.8)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 33.90 (27.09–39.58) 41.46 (32.95–46.58)
CD8+T cells ratio (unit: %)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 17.4 (14.7–23.4) 25.2 (22.8–34.2)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry Severe/no‐severe 69 11 23.29 ± 1.35 32.05 ± 2.53
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 20 (16–25) 26 (24–30)/26 (23–30)
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 19.7 ± 9.2 19.5 ± 6.2
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 30.92 ± 13.32 24.64 ± 10.68
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 10.0 (10.0–30.0) 30.0 (20.0–40.0)
Xie et al. 53 2020/6/13 China Circ J – Severe/no‐severe 24 38 17.3 (14.1–25.4)/22.8 (17.6–25.4) 27.6 (23.8–31.8)/23.5 (19.2–28.6)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 20.65 (13.36–32.06) 22.20 (16.52–29.90)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 21.76 ± 8.1 22.85 ± 9.5
25.76 ± 12.07
Xie et al. 79 2020/4/24 China J Med Virol Severe/no‐severe 34 22 23.52 (17.8–30.23) 25.16 (16.15–31.41)
CD4+CD8+ (ThTs) ratio (unit: %)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 173 1.78 (1.29–2.15) 1.68 (1.23–2.32)
Diao et al. 70 2020/5/1 China Front Immunol – ICU/no‐ICU 43 212 2.43 (1.5–4.25) 1.6 (1.17–2.28)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry Severe/no‐severe 69 11 2.32 ± 0.24 1.65 ± 0.19
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 2.2 ± 0.6 2.5 ± 1.5
Shi et al. 17 2020/3/12 China medRxiv Flow cytometry Severe/no‐severe 25 19 1.51 ± 0.71 2.01 ± 0.8
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 1.2 (1.1–1.7) 1.2 (0.9–1.6)
Wan et al. 34 2020/2/10 China Br J Haematol – Severe/no‐severe 21 102 1.509 ± 0.1701 1.671 ± 0.05941
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 2.26 (1.35–2.82) 1.71 (1.21–2.17)
Zheng et al.(a) 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 2.277 ± 3.164 0.965 ± 1.516
Fan et al. 45 2020/4/19 China Metabolism Death/no‐death 4 15 5.0 (2.0–6.2) 1.6 (1.3–2.4)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 29 31 1.99 (1.28–3.75) 1.46 (0.78–2.11)
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 1.52 ± 0.71 2.03 ± 0.81
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 1.28 ± 0.76/2.42 ± 1.56 1.53 ± 0.41/1.62 ± 1.86
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 135 1.57 (1.10–2.36) 1.66 (1.37–2.16)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 1.40 (0.79–2.08) 1.18 (0.96–1.58)
Yang et al. 77 2020/5/15 China J Med Virol – Severe/no‐severe 68 65 1.42 (1–2.02) 1.23 (0–1.68)
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 1.5 (0.9–2.4) 1.6 (1.1–2.4)
Xu et al. 52 2020/6/13 China Zhonghua Wei Zhong Bing Ji Jiu Yi Xue – Severe/no‐severe 30 125 1.80 ± 0.92 1.54 ± 0.67
Wei et al. 61 2020/4/16 China J Infect – Severe/no‐severe 30 137 1.51 ± 0.71 1.51 (1.11–1.91)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 1.59 (1.13–2.47) 1.93 (1.26–2.68)
Xie et al. 79 2020/4/24 China J Med Virol Severe/no‐severe 34 22 1.88 (1.39–2.85) 1.99 (1.52–3.19)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 2.17 ± 1.6 2.14 ± 1.17
1.66 ± 1.16
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 1.96 (1.02–2.70)/1.75 (1.06–2.28) 1.68 (0.96–2.18)
CD19+ B cells count (unit: cells/μL)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 184.0 (42.8–273.3) 115.5 (102.8–133.5)
Han et al. 67 2020/6/24 China Aging (Albany NY) – Severe/no‐severe 24 23 124.59 ± 62.64 167.03 ± 94.32
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 169 ± 140.9 196.1 ± 144.9
Shi et al. 17 2020/3/12 China medRxiv Flow cytometry Severe/no‐severe 25 19 131.3 ± 112.3 187.17 ± 133.69
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 82 (45.0–149.0) 115.5 (83.0–161.5)
Wan et al. 34 2020/2/10 China Br J Haematol MMFI Severe/no‐severe 21 102 125.3 ± 13.49 166 ± 11.98
Xu et al. 41 2020/3/8 China medRxiv Flow cytometry Severe/no‐severe 25 44 74 (45–196) 124 (72–240)
Zeng et al. 71 2020/3/8 China medRxiv Flow cytometry ICU/no‐ICU 65 113 126 ± 52 155 ± 51
Zheng et al. 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 109.5 ± 57.756 230.21 ± 217.257
Fu et al. 69 2020/4/22 China medRxiv Death/no‐death 14 71 106.00 (55.00–142.75) 128.00 (91.00–187.00)
He et al. 20 2020/4/14 China J Clin Virol Severe/no‐severe 69 135 91 (54–139) 190 (139–268)
Xu et al. 63 2020/4/18 China J Infect Flow cytometry Severe/no‐severe 107 80 97.00 (74.00–162.00)/73.00 (36.50–101.75) 213.50 (152.25–314.25)
Fan et al. 45 2020/4/19 China Metabolism Death/no‐death 4 15 84 (34–134) 104 (49–236)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 155.65 ± 98.21 174.86 ± 145.77
58.44 ± 37.21
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 128.83 ± 42.44/119.38 ± 59.07 330.71 ± 177.65/148.92 ± 89.33
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 92 (56–135) 163 (126–224)
Shi et al. 73 2020/5/14 China Diabetes Care – Death/no‐death 47 259 88.5 (54.8–175.0)/75.0 (45.0–163.0) 139.0 (91.5–221.5)/149.5 (111.3–237.0)
CD16+CD56+ NK cells count (unit: cells/μL)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 60.5 (27.5–109.0) 180.5 (115.0–228.0)
Han et al. 67 2020/3/24 China Aging (Albany NY) – Severe/no‐severe 24 23 115.65 ± 76.06 179.85 ± 80.27
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 113 ± 71.8 160.2 ± 90.8
Shi et al. 17 2020/3/12 China Immunology Flow cytometry Severe/no‐severe 25 19 90.32 ± 86.02 189.25 ± 75.27
Song et al. 18 2020/3/5 China medRxiv – Severe/no‐severe 42 31 100 (54.0–178.0) 232.5 (100.5–286.3)
Wan et al. 34 2020/2/10 China Br J Haematol Multiple microsphere flow immunofluorescence Severe/no‐severe 21 102 119.6 ± 16.5 147 ± 10.36
Zeng et al. 71 2020/3/8 China medRxiv Flow cytometry ICU/no‐ICU 65 113 239 ± 133 283 ± 131
Zheng et al.(a) 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 537.5 ± 674.557 250.706 ± 193.328
Zheng et al.(b) 11 2020/3/19 China Cell Mol Immunol – Severe/no‐severe 13 55 105.11 ± 79.05 188.32 ± 130
Xu et al. 63 2020/4/18 China J Infect Flow cytometry Severe/no‐severe 107 80 93 (60–161)/55.5 (32–91.25) 107.5 (82.75–149.75)
He et al. 20 2020/4/14 China J Clin Virol Severe/no‐severe 69 135 105 (66–168) 144 (93–231)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐sever 35 30 127.42 ± 107.41 133.92 ± 101.73
142.59 ± 96.63
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐sever 25 31 89.14 ± 86.21 192.01 ± 73.14
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 185.00 ± 180.11/102.88 ± 72.28 288 ± 175.93/203.63 ± 209.433
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 122 (51–162) 186 (122–302)
Shi et al. 73 2020/5/14 China Diabetes Care – Death/no‐death 47 259 51.0 (24.3–124.0)/100.0 (40.0–157.0) 132.5 (71.8–196.3)/137.5 (81.3–224.8)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 88.00 (39.5–176.25) 119.00 (74.00–171.00)
CD19+ B cells ratio (unit: %)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 20.2 (17.6–39.5) 10.8 (10.3–12.4)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry Severe/no‐severe 69 11 14.63 ± 1.83 14.63 ± 1.46
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 12 (9–22) 12 (10–16)/11 (9–15)
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 21.8 ± 12.2 18.5 ± 8.1
Zheng et al. 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 11.448 ± 5.666 12.537 ± 5.571
Fu et al. 69 2020/4/22 China medRxiv Death/no‐death 14 71 17.30 (10.33–40.30) 15.23 (11.55–21.22)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 29 31 21.59 (12.03–29.31) 14.88 (9.6023.87)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 22.38 ± 12.65/25.62 ± 12 18.49 ± 8.76
CD16+CD56+ NK cells ratio (unit: %)
Chen et al. 24 2020/3/27 China J Clin Invest Flow cytometry Severe/no‐severe 11 10 14.7 (7.5–21.0) 15.1 (11.6–22.8)
Liu et al. 15 2020/3/1 China medRxiv Flow cytometry Severe/no‐severe 69 11 13.87 ± 1.22 3.19 ± 0.82
Nie et al. 16 2020/3/24 China medRxiv – Severe/no‐severe 25 72 18 (12–31) 12 (8–19)/12 (9–19)
Qin et al. 10 2020/3/12 China Clin Infect Dis Flow cytometry Severe/no‐severe 27 17 16.9 ± 10.1 17.2 ± 10.1
Zheng et al. 72 2020/2/19 China medRxiv Flow cytometry Severe/no‐severe 8 95 38.2 ± 18.427 15.128 ± 10.337
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 29 31 7.71 (4.95–16.07) 11.77 (7.53–23.12)
Wang et al. 33 2020/4/23 China JCI Insight Severe/no‐severe 35 30 16.78 ± 10.48 15.03 ± 9.81
29.95 ± 12.11
Tan et al. 41 2020/5/27 China Immunology Flow cytometry Severe/no‐severe 25 31 14.99 ± 6.38 14.22 ± 9.77
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 17.32 (11.59–26.48) 13.24 (8.79–19.03)
Neutrophils count (unit: cells/μL)
Huang et al. 80 2020/5/8 China medRxiv – Severe/no‐severe 27 321 4.06 (3.26–6.42) 2.85 (2.28–3.79)
Huang et al. 81 2020/5/8 China PLoS Negl Trop Dis – Severe/no‐severe 23 179 4.5 (2.8–5.9) 2.8 (2.1–3.6)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 7.66 (6.16–11.6) 3.65 (2.58–5.80)
Wang et al. 33 2020/4/23 China JCI Insight – Severe/no‐severe 35 30 5.7 ± 3.7 3.8 ± 2.4
7.7 ± 3.9
Tan et al. 41 2020/5/27 China Immunology – Severe/no‐severe 25 31 7.21 ± 5.25 4.49 ± 3.64
Xie et al. 79 2020/4/24 China J Med Virol – Severe/no‐severe 34 22 4.31 (2.88–5.47) 2.78 (2.35–3.56)
Dong et al. 46 2020/5/29 China Transbound Emerg Dis – Severe/no‐severe 53 94 3.46 (2.42–5.40) 2.32 (1.75–3.51)
Zhang et al. 82 2020/5/30 China Eur Radiol – Death/no‐death 10 50 8.6 ± 5.1 5.2 ± 3.4
Li et al. 83 2020/5/15 China Theranostics – Death/no‐death 25 68 3.8 (2.7–5.2) 2.8 (2.2–3.6)
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 3.76 ± 1.85/5.54 ± 3.70 3.25 ± 0.82/2.70 ± 1.01
Sun et al. 84 2020/4/24 China Clin Chim Acta – Severe/no‐severe 27 89 6.07 (3.10–7.60) 2.90 (2.15–3.80)
Qi et al. 85 2020/5/20 China Gut – Death/no‐death 5 16 4.01 (1.54–7.45) 2.48 (1.64–4.22)
He et al. 20 2020/4/14 China J Clin Virol – Severe/no‐severe 69 136 3.87 (2.49–6.11) 2.69 (2.03–3.61)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 13 40 5.58 (1.76–5.87) 2.63 (1.98–4.19)
Shang et al. 86 2020/5/21 China J Med Virol – Severe/no‐severe 139 304 4.27 (2.65–6.24) 3.07 (2.35–4.15)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 4.65 (2.11–8.79) 2.83 (1.98–3.51)
Yip et al. 87 2020/5/18 Singapore Br J Haematol – Severe/no‐severe 20 56 4.56 (1.79–14.75) 3.15 (0.98–16.76)
Zhao et al. 88 2020/5/14 China EPMA J – Death/no‐death 29 503 6.3 ± 3.3 3.8 ± 2.9
Shi et al. 73 2020/5/14 China Diabetes Care – Death/no‐death 47 259 8.0 (5.1–11.7)/6.6 (4.2–12.4 3.3 (2.5–4.9)/8.0 (5.1–11.7)
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 4.06 (2.84–5.56) 2.99 (2.14–4.13)
5.79 (3.79–8.59)
Wang et al. 89 2020/4/30 China Crit Care – Death/no‐death 19 88 5.4 (3.2–8.5) 2.8 (2.0–3.9)
Yang et al. 76 2020/4/29 China J Allergy Clin Immunol – Severe/no‐severe 36 14 2.74 (1.81–3.13) 2.8 (2.17–4.43)
3.53 (2.29–5.56)
Hou et al. 30 2020/5/4 China Clin Exp Immunol – Severe/no‐severe 221 168 4.71 ± 2.66 3.43 ± 2.55
9.86 ± 5.97
Yu et al. 90 2020/4/27 China Clin Ther – ARDS/no‐ARDS 24 71 3.21 ± 1.34 3.36 ± 1.51
Hong et al. 35 2020/5/7 South Korea Yonsei Med J – ICU/no‐ICU 13 85 7.7 ± 3.3 4.1 ± 3.2
Wang et al. 91 2020/2/7 China JAMA – ICU/no‐ICU 36 102 4.6 (2.6–7.9) 2.7 (1.9–3.9)
Liu et al. 2 2020/2/12 China medRxiv – Severe/no‐severe 17 44 2.8 (2.3–4.4) 2.4 (1.9–3.4)
Liu et al. 68 2020/2/12 China medRxiv – Severe/no‐severe 13 27 4.7 (3.6–5.8) 2.0 (1.5–2.9)
Huang et al. 92 2020/5/14 China J Med Virol – Death/no‐death 16 283 5.6 ± 3.4 3.2 ± 2
Zheng et al.(a) 72 2020/2/19 China medRxiv – Severe/no‐severe 8 95 2.465 ± 0.91 2.98 ± 1.26
Fu et al. 93 2020/5/6 China Thromb Res – Severe/no‐severe 16 59 5.63 ± 3.50 2.92 ± 1.21
Lu et al. 94 2020/2/19 China medRxiv – Severe/no‐severe 22 243 3.3 (2.7–4.8) 2.8 (2.3–3.8)
Liu et al. 95 2020/2/23 China medRxiv – Severe/no‐severe 7 44 5.2 (3.2–9.9) 3.5 (2.4–5.6)
Feng et al. 3 2020/2/23 China medRxiv – Progressive/Stable 15 126 3.2 (2.6–5.2) 3.4 (2.2–4.3)
Mao et al. 96 2020/2/23 China medRxiv – Severe/no‐severe 88 126 3.8 (0.0–18.7) 2.6 (0.7–11.8)
Qian et al. 97 2020/2/25 China QJM – Severe/no‐severe 9 82 3.32 (3–5.82) 2.8 (2.18–3.49)
Wang et al. 98 2020/3/17 China medRxiv – Severe/no‐severe 38 72 4.26 (2.84–4.84) 3.38 (2.33–5.24)
Liang et al. 99 2020/5/12 China JAMA Intern Med – Severe/no‐severe 131 1459 6.4 (3.6) 3.9 (1.9)
Rica et al. 100 2020/6/24 Spain Microorganisms – ICU/no‐ICU 21 27 6.76 (3.58) 5.62 (3.12)
Xiong et al. 101 2020/5/8 China J Am Soc Nephrol – Severe/no‐severe 30 101 5.3 (3.4–6.6) 3.7 (2.6–5.6)
Huang et al. 102 2020/5/5 China J Med Virol – Progressive/stable 45 299 4.7 ± 3.3 3 ± 1.7
Giacomelli et al. 103 2020/5/6 Italy Pharmacol Res – Death/no‐death 48 185 5.7 (3.8−8.3) 3.9 (2.8−5.3)
Liu et al. 104 2020/2/29 China Chin Med J – Progression/stabilization 11 67 4.69 (2.96–7.06) 2.94 (2.20–4.60)
Li et al. 105 2020/5/5 China Invest Radiol – Severe/no‐severe 25 58 4.36 (2.87–6.48) 3.50 (2.64–4.46)
Ji et al. 106 2020/5/6 China Epidimiol Infect – Severe/no‐severe 69 88 3.3 (2.5–6.1) 3.2 (2.2–4.2)
8.5 (4.2–10.6)
Fan et al. 107 2020/2/29 Singapore Am J Hematol – ICU/no‐ICU 9 58 4.40 ± 4.14 2.8 ± 1.33
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 2.98 (2.12–3.7) 2.32 (1.75–4.28)
Luo et al. 108 2020/5/23 China Clin Infect Dis – Death/no‐death 84 214 6.92 (4.33–10.79) 3.20 (2.53–4.56)
Buckner et al. 109 2020/5/22 USA Clin Infect Dis – Severe/no‐severe 51 54 5.4 (3.3–8.4) 3.8 (2.8–5.1)
Wu et al. 110 2020/5/7 China Eur Respir J – Severe/no‐severe 82 217 24.1 (2.7–5.6) 2.9 (1.9–3.9)
Shi et al. 111 2020/6/3 China BMC Med – Progressive/Stable 16 69 3.5 ± 1.5 3.1 ± 1.6
Gayam et al. 50 2020/7/16 USA J Med Virol – Death/no‐death 132 276 7.2 (4.7–10.35) 5.6 (3.9–8.4)
Lee et al. 112 2020/7/21 South Korea Int J Infect Dis – Severe/no‐severe 137 557 4.57 (3.00) 2.93 (1.36)
Yu et al. 113 2020/7/17 China J Infect Public Health – Severe/no‐severe 864 799 3.9 (2.8−5.7) 3.6 (2.6−4.9)
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 4.7 (3.1–8.7) 3.3 (2.2–4.5)
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 10 40 5.58 (1.76–5.87) 2.63 (1.98–4.19)
Chen et al. 114 2020/5/29 China medRxiv – Severe/no‐severe 50 241 3.34 (2.17–4.18) 3.56 (2.55–4.62)/2.80 (2.14–3.56)
Cao et al. 66 2020/3/4 China medRxiv – ICU/no‐ICU 19 174 3.47 (2.97–4.74) 2.81 (2.33–3.81)
Xie et al. 53 2020/6/13 China Circ J – Severe/no‐severe 24 38 3.2 (3.0–3.8) 3.0 (2.1–4.0)
3.5 (3.0–4.5) 3.5 (2.5–4.6)
Cao et al. 115 2020/6/17 China PLoS One – Death/no‐death 27 53 3.3 (1.9–5.5) 2.2 (1.7–2.8)
Zhang et al. 116 2020/3/6 China J Clin Virol – Severe/no‐severe 55 166 5.4 (2.8–8.4) 2.6 (1.8–4.0)
Wang et al. 117 2020/5/19 China Open Forum Infect Dis – Severe/no‐severe 45 230 3.7 (2.7–5.2) 2.7 (2–3.5)
Liu et al. 118 2020/5/1 China Zhonghua Wei Zhong Bing Ji Jiu Yi Xue – Severe/no‐severe 42 236 4.4 ± 3.1 2.8 ± 1.2
4.9 ± 2.5 2.9 ± 1.3
Song et al. 18 2020/4/9 China medRxiv – Severe/no‐severe 42 31 5.8 (2.8–10.2) 2.8 (1.8–4.1)
Li et al. 119 2020/6/1 China Am J Med Sci – Death/no‐death 14 60 6.3 (2.8–10.0) 5.0 (2.9–7.1)
Xu et al. 41 2020/3/5 China medRxiv – Severe/no‐severe 25 44 2.9 (2.4–4.6) 2.3 (1.8–3.3)
Zhang et al. 120 2020/7/8 China Infect Dis Poverty – Severe/no‐severe 78 710 3.2 (2.6–5.0) 3.6 (2.0–5.0)
5.8 (2.8–8.0) 2.9 (2.2–3.8)
Zheng et al. 78 2020/4/6 China J Clin Virol – Severe/no‐severe 32 67 63.81 ± 16.51 42.51 ± 15.11
Zhang et al. 121 2020/7/23 China Int J Lab Hematol – Severe/no‐severe 162 251 6.35 ± 3.96 3.22 ± 1.67
8.39 ± 3.37 5.02 ± 3.27
Qin et al. 10 2020/3/8 China Clin Infect Dis – Severe/no‐severe 286 166 4.3 (2.9–7.0) 3.2 (2.1–4.4)
Levy et al. 122 2020/6/2 USA medRxiv – Death/no‐death 1185 4048 6.36 (4.37–9.13) 5.05 (3.59–7.09)
Myers et al. 123 2020/4/24 USA JAMA – ICU/no‐ICU 113 264 5.6 (3.9–7.4) 4.3 (3.1–5.9)
Hadjadj et al. 12 2020/4/23 France medRxiv – Severe/no‐severe 35 15 5.37 (3.23–6.38) 3.3 (2.76–4.0)
7.36 (4.54–9.18)
Ouyang et al. 124 2020/4/17 China Clin Infect Dis – Severe/no‐severe 6 5 6.135 (1.80–9.24) 2.34 (1.2–2.81)
Gao et al. 37 2020/4/10 China J Med Virol – Severe/no‐severe 15 28 2.65 ± 1.49 3.43 ± 1.63
Gong et al. 125 2020/4/16 China Clin Infect Dis – Severe/no‐severe 28 161 3.7 (2.8–5.2) 2.8 (2.0–3.6)
Lei et al. 126 2020/4/4 China EClinicalMedicine – ICU/no‐ICU 15 19 7.9 (4.1–10.7) 4.1 (3.1–5.8)
Wang et al. 55 2020/3/24 China Int J infect Dis – Severe/no‐severe 25 100 3.86 ± 2.18 3.49 ± 1.62
Wan et al. 127 2020/3/18 China J Med Virol – Severe/no‐severe 40 95 4.1 (3.1–5.7) 3.6 (3.0–3.9)
Feng et al. 128 2020/4/10 China Am J Respir Crit Care Med – Severe/no‐severe 124 352 3.6 (2.59–5.99) 3.39 (2.5–4.64)
5.99 (3.47–9.55)
Yang et al. 129 2020/6/26 China medRxiv – Death/no‐death 16 53 7.(50.6–8.4) 4 (4.0.0–5.9)
Bai et al. 130 2020/3/27 China medRxiv – Severe/no‐severe 54 79 4.15 ± 2.29 3.54 ± 1.9
Yan et al. 131 2020/3/23 China medRxiv – Severe/no‐severe 35 131 4.2 (3.0–7.7) 2.9 (2.2–3.9)
Han et al. 67 2020/6/24 China Aging (Albany NY) – Severe/no‐severe 24 23 7.34 ± 4.10 3.03 ± 1.53
Wang et al. 132 2020/3/27 China medRxiv – Death/no‐death 15 101 8.2 (6.2–10.0) 5.2 (2.8–5.7)
Li et al. 26 2020/3/23 China medRxiv – Severe/no‐severe 15 87 8.0 (3.5–10.6) 4.1 (2.8–6.2)
Chen et al. 24 2020/3/27 China J Clin Invest – Severe/no‐severe 11 10 6.9 (4.9–9.1) 2.7 (2.1–3.7)
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 9.0 (5.4–12.7) 3.2 (2.4–4.5)
Huang et al. 133 2020/3/30 China BMJ – Severe/no‐severe 32 93 3.50 ± 1.77 3.26 ± 1.28
Lo et al. 134 2020/3/15 China Int J Biol Sci – Severe/no‐severe 4 6 3.82 ± 1.81 2.49 ± 0.9
Zheng et al. 56 2020/3/27 China Int J Infect Dis – Severe/no‐severe 21 34 3.46 (0.56–9.29) 2.77 (0.93–5.93)
Wang et al. 57 2020/3/15 China J Infect – Death/no‐death 65 274 7.65 (4.35–11.74) 4.01 (2.63–5.97)
Cai et al. 36 2020/4/17 China Allergy – Severe/no‐severe 58 240 7.35 (5.4–9.6) 6.65 (5.3–8.7)
Xie et al. 135 2020/4/2 China Liver Int – Severe/no‐severe 28 51 3.8 (3.2–5.7) 3.7 (2.7–5.1)
Du et al. 136 2020/4/7 China Ann Am Thorac Soc ICU/no‐ICU 51 58 8.3 ± 5.2 6.9 ± 4.1
Wang et al. 32 2020/6/1 China Am J Respir Crit Care Med – Death/no‐death 133 211 8.0 (5.5–12.2) 3.7 (2.5–5.3)
Feng et al. 137 2020/4/10 China medRxiv – Severe/no‐severe 69 495 4.4 (2.7–6.8) 2.9 (2.2–3.9)
Du et al. 138 2020/5/7 China Eur Respir J – Death/no‐death 21 158 7.7 (3.0–11.5) 3.9 (2.6–6.1)
Zhang et al. 139 2020/4/11 China Eur Radiol – Severe/no‐severe 30 90 3.1 ± 2.6 1.6 ± 1.1
Jiang et al. 140 2020/4/14 China medRxiv – Severe/no‐severe 8 47 3.39 (1.82–9.52) 3.01 (2.34–3.51)
Wang et al. 141 2020/4/14 China medRxiv – Severe/no‐severe 30 131 10.51 ± 5.10 6.69 ± 3.83
Chen et al. 142 2020/4/14 China medRxiv – Severe/no‐severe 8 24
Xie et al. 143 2020/6/20 China Allergy – Severe/no‐severe 12 85 3.4 (2.2–4.1) 3.3 (2.3–3.8)
Liu et al. 59 2020/7/31 China Ann Intensive Care – Death/no‐death 157 1033 14.7 (9.9–20.3) 4.1 (2.8–6.2)
Chen et al. 58 2020/4/17 China Clin Infect Dis – Severe/no‐severe 27 21 2.9 (2.0–3.78)/7.1 (5.3–9.2) 3.4 (2.8–4.3)
Yang et al. 144 2020/4/13 China Int Immunopharmacol – Severe/no‐severe 24 69 7.73 ± 5.4 4.55 ± 0.21
Brill et al. 145 2020/6/25 UK BMC Med – Death/no‐death 173 237 6.6 (4.178–9.750) 5.32 (3.48–7.82)
Wei et al. 61 2020/4/16 China J Infect – Severe/no‐severe 30 137 3.93 (2.23) 3.43 (2.39–4.40)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 10.10 (6.58–13.49) 3.96 (2.85–5.72)
Zhu et al. 22 2020/4/22 China Int J Infect Dis – Severe/no‐severe 16 111 3.89 (2.25–6.57) 3.29 (2.54–4.40)
Shi et al. 62 2020/4/23 China medRxiv – Severe/no‐severe 46 88 3.0 (2.3–4.3) 2.9 (2.1–4.0)
Yao et al. 146 2020/4/24 China Pol Arch Intern Med – Death/no‐death 12 96 6.55 (3.39–9.66) 2.53 (1.89–3.78)/3.33 (1.99–5.07)
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 4.87 (3.43–7.64) 3.12 (2.18–4.20)
6.14 (3.33–10.15)
Pereira et al. 64 2020/4/24 USA Am J Transplant – Severe/no‐severe 27 41 3.64 (1.62–7.27) 4.1 (2.02–5.42)
Neutrophils ratio (unit:%)
Huang et al. 80 2020/5/8 China medRxiv – Severe/no‐severe 27 321 72.48 ± 13.70 63.29 ± 11.44
Zhang et al. 147 2020/5/9 China medRxiv – ICU/no‐ICU 30 105 83.9 (80.7–92.5) 70.0 (59.8–78.9)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 91.1 (82.9–93.8) 77.1 (69.1–82.8)
Li et al. 83 2020/5/15 China Theranostics – Death/no‐death 25 68 74.2 (12.0) 64.7 (11.6)
Yang et al. 76 2020/4/29 China J Allergy Clin Immunol – Severe/no‐severe 36 14 69.3 (57–75.3)/69.3 (66.65–82.1) 58.8 (52.75–71.4)
Sun et al. 148 2020/5/5 China J Med Virol – Severe/no‐severe 15 40 15 ± 100 29 ± 72.5
Liu et al. 105 2020/5/5 China Invest Radiol – Severe/no‐severe 5 58 80.08 ± 9.51 67.84 ± 10.00
Chen et al. 114 2020/5/29 China medRxiv – Severe/no‐severe 50 241 73.15 (63.45–82.85) 70.30 (59.80–78.40)/62.70 (56.10–70.45)
Shi et al. 149 2020/5/11 China Eur Heart J – Death/no‐death 62 609 91 (86–93) 68 (59–76)
Wu et al. 110 2020/5/7 China Eur Respir J – Severe/no‐severe 82 217 76.3 (66.1–84.9) 64.1 (56.6–73.6)
Yang et al. 150 2020/5/25 China J Clin Pharm Ther – Severe/no‐severe 33 103 77.8 (64.1–88.5) 65.9 (57.7–74.6)
Yang et al. 65 2020/3/2 China medRxiv – Severe/no‐severe 34 19 69.95 (61.35–79.93) 60.90 (52.95–69.30)
Yu et al. 113 2020/7/17 China J Infect Public Health – Severe/no‐severe 864 799 70.8 (60.8–79.7) 67.4 (59.0–75.9)
Liu et al. 118 2020/5/1 China Zhonghua Wei Zhong Bing Ji Jiu Yi Xue – Severe/no‐severe 42 236 0.72 ± 0.13/0.73 ± 0.14 0.51 ± 0.12/0.59 ± 0.11
Li et al. 119 2020/6/1 China Am J Med Sci – Death/no‐death 14 60 0.9 (0.8–0.9) 0.8 (0.7–0.9)
Zhang et al. 121 2020/7/23 China Int J Lab Hematol – Severe/no‐severe 162 251 78.01 ± 11.31 61.48 ± 6.65
86.79 ± 6.01 71.02 ± 12.64
Qin et al. 10 2020/3/8 China Clin Infect Dis – Severe/no‐severe 286 166 77.6 (68.9–86.5) 67.5 (57.8–75.8)
Levy et al. 122 2020/6/2 USA medRxiv – Death/no‐death 1185 4048 81.00 (73.47–86.50) 76.25 (68.38–82.30)
Bai et al. 130 2020/3/27 China medRxiv – Severe/no‐severe 54 79 74.60 ± 13.42 66.94 ± 12.16
Tao et al. 151 2020/3/23 medRxiv China – Severe/no‐severe 22 143 65.50 ± 16.15 61.64 ± 32.24
Yan et al. 131 2020/3/23 China medRxiv – Severe/no‐severe 35 132 74.8 (67.6–83.1) 62.1 (55.6–69.2)
Xie et al. 143 2020/6/20 China Allergy – Severe/no‐severe 12 85 71.9 (52.6–77.8) 71.3 (56.2–78.5)
Zhu et al. 22 2020/4/22 China Int J Infect Dis – Severe/no‐severe 16 111 75.70 (64.53–88.98) 66.50 (59.60–73.90)
Fu et al. 69 2020/4/22 China medRxiv – Death/no‐death 14 71 89.65 (85.63–92.28) 69.30 (62.10–79.10)
Yang et al. 77 2020/5/15 China J Med Virol – Severe/no‐severe 68 65 76.6 (45.3–97) 58.1 (18–83.2)
Monocytes count (unit: cells/μL)
Huang et al. 80 2020/5/8 China medRxiv – Severe/no‐severe 27 321 0.50 (0.24–1.07) 0.41 (0.35–0.58)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.33 (0.24–0.56) 0.41 (0.27–0.56)
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 0.33 ± 0.19/0.37 ± 0.19 0.46 ± 0.16/0.55 ± 0.99
Sun et al. 84 2020/4/24 China Clin Chim Acta – Severe/no‐severe 27 89 0.42 (0.31–0.76) 0.38 (0.29–0.48)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 13 40 0.51 (0.37–0.60) 0.39 (0.31–0.51)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 0.32 (0.14–0.42) 0.39 (0.30–0.50)
Yip et al. 87 2020/5/18 Singapore Br J Haematol – Severe/no‐severe 20 56 0.48 (0.17–1.36) 0.54 (0.19–1.35)
Wei et al. 21 2020/4/29 China J Med Virol Severe/no‐severe 121 131 0.6 ± 0.7 0.51 ± 0.25
0.6 ± 0.3
Chen et al. 152 2020/4/28 China Infection – Severe/no‐severe 43 102 0.4 (0.3–0.5) 0.4 (0.3–0.5)
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 0.36 (0.26–0.52) 0.41 (0.30–0.53)
0.38 (0.22–0.49)
Huang et al. 92 2020/5/14 China J Med Virol – Death/no‐death 16 283 0.5 ± 0.9 0.3 ± 0.2
Rica et al. 100 2020/6/24 Spain Microorganisms – ICU/no‐ICU 21 27 0.40 (0.20) 0.58 (0.33)
Huang et al. 102 2020/5/5 China J Med Virol – Progressive/stable 45 299 0.3 ± 0.1 0.3 ± 0.2
Ji et al. 106 2020/5/6 China Epidimiol Infect – Severe/no‐severe 69 88 0.4 (0.2–0.5) 0.5 (0.3–0.6)
0.3 (0.1–0.6)
Wu et al. 110 2020/5/7 China Eur Respir J – Severe/no‐severe 82 217 0.4 (0.2–0.5) 0.3 (0.2–0.4)
Lee et al. 112 2020/7/21 South Korea Int J Infect Dis – Severe/no‐severe 137 557 0.47 (0.24) 0.45 (0.16)
Yu et al. 113 2020/7/17 China J Infect Public Health – Severe/no‐severe 864 799 0.5 (0.4−0.6) 0.5 (0.4−0.6)
Huang et al. 31 2020/6/13 China J Med Virol – Death/no‐death 10 40 0.51 (0.37–0.60) 0.39 (0.31–0.51)
Wang et al. 117 2020/5/19 China Open Forum Infect Dis – Severe/no‐severe 45 230 0.3 (0.2–0.4) 0.4 (0.3–0.5)
Zhang et al. 121 2020/7/23 China Int J Lab Hematol – Severe/no‐severe 162 251 0.44 ± 0.23 0.35 ± 0.1
0.43 ± 0.18 0.42 ± 0.2
Levy et al. 122 2020/6/2 USA medRxiv – Death/no‐death 1185 4048 0.47 (0.30–0.68) 0.46 (0.32–0.65)
Hadjadj et al. 12 2020/4/23 France medRxiv – Severe/no‐severe 35 15 0.35 (0.30–0.43) 0.40 (0.28–0.52)
0.38 (0.20–0.77)
Gao et al. 37 2020/4/10 China J Med Virol – Severe/no‐severe 15 28 0.37 ± 0.16 0.43 ± 0.19
Lei et al. 126 2020/4/4 China EClinicalMedicine – ICU/no‐ICU 15 19 0.6 (0.3–1.1) 0.5 (0.4–0.70)
Gong et al. 125 2020/4/16 China Clin Infect Dis – Severe/no‐severe 28 161 0.3 (0.3–0.4) 0.4 (0.3–0.5)
Wang et al. 55 2020/3/24 China Int J Infect Dis – Severe/no‐severe 25 100 0.30 (0.235–0.52) 0.36 (0.26–0.51)
Yan et al. 131 2020/3/23 China medRxiv – Severe/no‐severe 35 130 0.4 (0.3–0.6) 0.4 (0.3–0.5)
Han et al. 67 2020/6/24 China Aging (Albany NY) – Severe/no‐severe 24 23 0.39 ± 0.20 0.61 ± 0.24
Wang et al. 132 2020/3/27 China medRxiv – Death/no‐death 15 101 0.5 (0.3–0.7) 0.5 (0.4–0.6)
Chen et al. 25 2020/3/26 China BMJ – Death/no‐death 113 161 0.4 (0.2–0.6) 0.4 (0.3–0.5)
Wang et al. 57 2020/3/15 China J Infect – Death/no‐death 65 274 0.32 (0.22–0.49) 0.43 (0.30–0.62)
Jiang et al. 140 2020/4/14 China medRxiv – Severe/no‐severe 8 47 0.28 (0.18–0.60) 0.49 (0.40–0.61)
Wang et al. 141 2020/4/14 China medRxiv – Severe/no‐severe 30 131 0.43 ± 0.27 0.50 ± 0.25
Xie et al. 143 2020/6/20 China Allergy – Severe/no‐severe 12 85 0.6 (0.2–0.7) 0.5 (0.3–0.6)
Yang et al. 144 2020/4/13 China Int Immunopharmacol – Severe/no‐severe 24 69 0.5 ± 0.84 0.41 ± 0.2
Xu et al. 63 2020/4/18 China J Infect – Severe/no‐severe 107 80 0.42 (0.29–0.61) 0.39 (0.31–0.52)
0.32 (0.18–0.44)
Monocytes ratio (unit: %)
Huang et al. 80 2020/5/8 China medRxiv – Severe/no‐severe 27 321 7.2 (4.0–13.6) 9.5 (7.3–11.3)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 3.9 (2.6–5.4) 8.8 (5.4–10.0)
Zheng et al.(a) 72 2020/2/19 China medRxiv – Severe/no‐severe 8 95 8.063 ± 3.478 8.12 ± 2.92
Liu et al. 105 2020/5/5 China Invest Radiol – Severe/no‐severe 25 58 6.16 ± 4.00 7.60 ± 2.23
Wu et al. 110 2020/5/7 China Eur Respir J – Severe/no‐severe 82 217 7.0 (4.5–8.8) 7.7 (5.7–9.8)
Yu et al. 113 2020/7/17 China J Infect Public Health – Severe/no‐severe 864 799 8.2 (6.3−10.6) 8.7 (6.9−10.9)
Li et al. 119 2020/6/1 China Am J Med Sci – Death/no‐death 14 60 0.01 (0.04–0.08) 0.01 (0.03–0.06)
Zhang et al. 121 2020/7/23 China Int J Lab Hematol – Severe/no‐severe 162 251 6.1 ± 2.62/4.7 ± 1.85 7.54 ± 2.63/6.94 ± 2.72
Qin et al. 10 2020/3/8 China Clin Infect Dis – Severe/no‐severe 286 166 6.6 (4.3–8.8) 8.4 (6.5–10.8)
Levy et al. 122 2020/6/2 USA medRxiv – Death/no‐death 1185 4048 12.70 (11.10–14.30) 13.40 (12.20–14.50)
Xie et al. 143 2020/6/20 China Allergy – Severe/no‐severe 12 85 8.3 (5.4–10.1) 7.9 (5.8–9.2)
Eosinophils count (unit: cells/μL)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.00 (0.00–0.00) 0.00 (0.00–0.38)
Cheng et al. 153 2020/4/27 China medRxiv Severe/no‐severe 8 51 0.01 (0.01–0.33) 0.02 0.01–026)
0.02 (0.00–0.05)
Sun et al. 47 2020/4/24 China J Autoimmun – Severe/no‐severe 19 44 0.01 ± 0.00/0.09 ± 0.14 0.14 ± 0.06/0.03 ± 0.04
Sun et al. 84 2020/4/24 China Clin Chim Acta – Severe/no‐severe 27 89 0.01 (0.00–0.02) 0.03 (0.01–0.05)
Zhang et al. 28 2020/5/21 China J Med Virol – Death/no‐death 13 40 0 0.01 (0–0.05)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 0.00 (0.00–0.01) 0.04 (0.01–0.11)
Yip et al. 87 2020/5/18 Singapore Br J Haematol – Severe/no‐severe 20 56 0.01 (0–0.24) 0.05 (0–0.42)
Pei et al. 29 2020/4/28 China J Am Soc Nephrol – Severe/no‐severe 189 144 0.00 (0.00–0.06) 0.00 (0.00–0.09)
0.00 (0.00–0.01)
Qian et al. 97 2020/2/25 China QJM – Severe/no‐severe 9 82 0.01 (0–0.01) 0.02 (0.01–0.06)
Wu et al. 110 2020/5/7 China Eur Respir J – Severe/no‐severe 82 217 0.00 (0.00–0.01) 0.01 (0.00–0.03)
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 0.00 (0.00–0.02) 0.01 (0.00–0.04)
Chen et al. 114 2020/5/29 China medRxiv – Severe/no‐severe 50 241 0.00 (0.00–0.01) 0.02 (0.00–0.06)/0.02 (0.00–0.05)
Wei et al. 154 2020/7/29 China BMC Infect Dis – Severe/no‐severe 14 262 0 (0–0.01) 0.01 (0–0.03)
Levy et al. 122 2020/6/2 USA medRxiv – Death/no‐death 1185 4048 0.00 (0.00–0.01) 0.00 (0.00–0.02)
Yan et al. 131 2020/3/23 China medRxiv – Severe/no‐severe 35 130 0 (0–0.02) 0.04 (0.01–0.1)
Wang et al. 132 2020/3/27 China medRxiv – Death/no‐death 15 101 0.0 (0.0–0.0) 0.1 (0.0–0.1)
Huang et al. 133 2020/3/30 China BMJ – Severe/no‐severe 32 93 0 (0–0) 0.04 (0.1–0.12)
Cai et al. 36 2020/4/17 China Allergy – Severe/no‐severe 58 240 0.01 (0–0.03) 0.02 (0–0.05)
Wang et al. 141 2020/4/14 China medRxiv – Severe/no‐severe 30 131 0.00 ± 0.01 0.04 ± 0.06
Basophils count (unit: cells/μL)
Wu et al. 19 2020/7/15 China mSphere – Severe/no‐severe 39 32 0.01 (0.01–0.02) 0.01 (0.00–0.02)
Li et al. 48 2020/5/19 China JCI Insight – Severe/no‐severe 26 43 0.01 (0.01–0.02) 0.01 (0.01–0.03)
Yip et al. 87 2020/5/18 Singapore Br J Haematol – Severe/no‐severe 20 56 0.01 (0–0.10) 0.02 (0–0.09)
Qian et al. 97 2020/2/25 China QJM – Severe/no‐severe 9 82 0 (0–0.01) 0.01 (0.01–0.02)
Wu et al. 110 2020/5/7 China Eur Respir J – Severe/no‐severe 82 217 0.01 (0.01–0.02) 0.01 (0.01–0.01)
Chen et al. 51 2020/6/4 China Clin Transl Med – Death/no‐death 82 578 0.01 (0.01–0.02) 0.01 (0.01–0.02)
Wang et al. 141 2020/4/14 China medRxiv – Severe/no‐severe 30 131 0.02 ± 0.02 0.02 ± 0.01
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Abbreviations: CLIA, chemiluminescence immunoassay; ELISA, enzyme‐linked immunosorbent assay; MMFI, multiple microsphere flow immunofluorescence.

2.5. Predictors and outcome

The included studies varied in their differentiation of patients' disease status, with classifications of ‘mild, moderate, severe and critical’, ‘ordinary and severe/critical’, ‘common and severe’, ‘acute respiratory distress syndrome (ARDS) and non‐ARDS’ and ‘non‐severe and severe’. To allow comparability between studies for meta‐analysis, these were grouped into a single disease severity, with the outcome measure used was severe (including both severe and critical cases, ICU admission, death, ARDS, etc.) versus non‐severe disease (including non‐severe, mild disease, ordinary disease, non‐ICU admission and non‐ARDS, etc.).

2.6. Statistical analysis

Quantitative syntheses and meta‐analyses were analysed using the meta package in the R statistical language (Version 3.6.3). First, we collected the mean and standard deviation (SD) from each value of immune mediators in severe and non‐severe groups of COVID‐19 patients. Where necessary, the mean and SD were converted from the median and interquartile range (IQR) using a previously standard approach. 155 For some articles, data regarding the immunological signature were extracted from the figures by measuring the pixel positions of the electronic figures and then computing the actual values. For box plots, medians and ranges were used to compute means and SDs, and for scatter plots, the individual values were used to compute means and SDs. Second, forest plots were conducted to illustrate the differences in the two groups. For fear of that the recruited studies used different experiment methods, for which means and differences cannot be pooled directly to estimate the effect, we calculated a dimensionless effect measure from each study for the pooling use. The standardized mean difference (SMD) was computed from means and SDs, and used as the effect size. 156 Finally, we undertook the meta‐analyses for each immune mediator. The heterogeneity of the studies was tested by the Cochran Chi‐square test and I 2 index, and the pooled SMD were calculated by using the random‐effects model. All results were pooled and presented in the forest plots. Leave‐one‐out sensitivity analysis was applied to detect the robustness of the results. Funnel plot method and Egger's regression were used to test the publication bias. If the funnel plot was asymmetric or p < 0.05, the trim‐and‐fill method was adopted to further test publication bias. The statistical testing with p < 0.05 was considered to be significant (two‐sided).

3. RESULTS

3.1. Review of the included studies

A detailed flow diagram of study selection and the selected number are shown in Figure 1. Our literature search identified 19,802 records through 15 August 2020. After removing duplicates, the title and abstract of the remaining 19,688 articles were screened, and 16,613 records were excluded. For 3075 potentially relevant studies, full‐text was retrieved and evaluated for eligibility, and then 2861 studies were excluded from the meta‐analysis: 1305 studies contained data from only case series, 1,312 studies were literature reviews, 52 studies provided no comparison data between disease severity, and 192 studies didn't provide enough data. As five studies were further excluded because the described immune mediators were investigated in <3 studies (Table S4), at last 214 studies were included in the qualitative synthesis. Those remained in the study were collated for the meta‐analysis consisted of 149 distinct studies that were performed in China (133), the United States (6), South Korea (2), Singapore (2), the United Kingdom (1), France (1), Germany (1), Italy (1), Spain (1), and both China and USA (1) (Table 1). All the included studies had reported patients with severe patients and non‐severe patients. These articles included data from 33,691 patients, 25.96% (n = 8746) with severe COVID‐19 disease and 74.04% (n = 24,945) with non‐severe disease. Of these studies, 55 studies had evaluated the data on 10 cytokines, including interleukins 2 (IL‐2), IL‐2R, IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, interferon γ (IFN‐γ), tumour necrosis factor α (TNF‐α) and IL‐1β,1, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 157 8 studies investigated the antibodies (IgA, IgG, IgM and IgE)10, 16, 20, 25, 66, 67, 68, 69 and 40 studies assessed the T cells [CD3+ T cells count, CD4+ T cells count, CD8+ T cells count, CD4+CD25+CD127−Treg cells count, CD3+ T cells ratio, CD4+ T cells ratio, CD8+ T cells ratio and CD4+/CD8+ (Th/Ts)],9, 10, 11, 15, 16, 17, 18, 19, 20, 24, 27, 33, 34, 41, 45, 47, 48, 51, 52, 53, 56, 57, 59, 61, 63, 65, 66, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 157 and 22 studies estimated the B cells and NK cells (CD16+CD56+ NK cells count, CD19+ B cells count,CD16+CD56+ NK cells ratio and CD19+ B cells ratio),10, 11, 15, 16, 17, 18, 19, 20, 24, 33, 34, 41, 45, 47, 48, 63, 67, 69, 71, 72, 73, 157 124 studies on the evaluation of neutrophils, eosinophils and basophils cells (comprised of neutrophils cells counts/cells ratio, monocytes cells counts/cells ratio, eosinophils cells counts and basophils cells counts).2, 3, 10, 12, 18, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31, 32, 33, 35, 36, 37, 41, 46, 47, 48, 50, 51, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 72, 73, 76, 77, 78, 79, 157 , 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 For each study, various details including the baseline information of study population, study design, the number of patients in each study group, the measured immunological indicators and their test methods, and the definitions used to measure outcome, were extracted into Table S5. For these studies, only the measurements acquired in the acute phase of infection were used for the analysis. Table 1 summarizes the detailed characteristics of the included studies for each immune mediator. The quality scores by NOQAS of the included studies ranged from 5 to 8, and 116 out of 149 was greater than or equal to six stars, indicating good quality (Table S6).

FIGURE 1.

FIGURE 1

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A flow diagram of the inclusion criteria for the study selection process

3.2. Cytokines and COVID‐19 severity

A total of 55 studies were evaluated 10 mediators of cytokines between the severe (n = 3038) and non‐severe groups of COVID‐19 patients (n = 5895), including IL‐2, IL‐2R, IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, IFN‐γ, TNF‐α and IL‐1β with three or more studies included (Figure S1).1, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 157 Compared with the non‐severe patients of COVID‐19, we found that serum levels of seven cytokines were significantly up‐regulated in severe patients, including IL‐2 (SMD, 0.40; 95% CI, 0.10–0.71; p < 0.01), IL‐2R (SMD, 1.12; 95% CI, 0.80–1.44; p < 0.01), IL‐4 (SMD, 0.71; 95% CI, 0.10–1.33; p = 0.02), IL‐6 (SMD, 1.16; 95% CI, 0.94–1.38; p < 0.01), IL‐8 (SMD, 0.75; 95% CI, 0.49–1.00; p < 0.01), IL‐10 (SMD, 1.26; 95% CI, 0.92–1.59; p < 0.01) and TNF‐α (SMD, 0.55; 95% CI, 0.32–0.78; p < 0.01), respectively (Figure S1a–g). In contrast, serum IL‐5, IL‐1β and IFN‐γ did not showed significant inter‐group differences with the SMDs of 0 (95% CI, −0.94 to 0.95, p = 0.99), 0.33 (95% CI, 0.00–0.67, p = 0.05), and 0.46 (95% CI, −0.25 to 1.17, p = 0.20), respectively (Figure S1h–j).

3.3. SARS‐CoV‐2‐specific antibodies and COVID‐19 severity

Four SARS‐CoV‐2‐specific antibody mediators were included in the meta‐analysis between severe and non‐severe COVID‐19 patients, immunoglobulin A (IgA), IgG, IgM and IgE.10, 16, 20, 25, 66, 67, 68, 69 A total of eight studies evaluated the levels of IgA, IgG and IgM involving 563 severe and 828 non‐severe cases, and the levels of IgE involving 131 severe and 257 non‐severe cases (Figure S2). Compared with the non‐severe patients, the severe patients had significantly higher levels of IgA and IgG with SMDs of 0.39 (95% CI, 0.10–0.68; p < 0.01; Figure S2a), and 0.22 (95% CI, 0.01–0.42; p = 0.04; Figure S2b), respectively. The level of IgM in the severe patients was slightly lower than those in the non‐severe patients of COVID‐19 (SMD, −0.18; 95% CI, −0.32 to −0.03, p = 0.02; Figure S2c). No significant differences were noted in the serum levels of IgE between two groups (SMD, 0.16; 95% CI, −0.16 to 0.43, p = 0.43; Figure S2d).

3.4. T cells and COVID‐19 severity

A total of 40 studies involving 1623 severe cases and 4342 non‐severe cases evaluated the T cells count or percent in relation to the COVID‐19 disease severity.9, 10, 11, 15, 16, 17, 18, 19, 20, 24, 27, 33, 34, 41, 45, 47, 48, 51, 52, 53, 56, 57, 59, 61, 63, 65, 66, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 157 Eight measurements of T cells were described in over three studies, including CD3+ T cells count, CD4+ T cells count, CD8+ T cells count, CD4+CD25+CD127− Treg cells count, CD3+ T cells ratio, CD4+ T cells ratio, CD8+ T cells ratio and CD4+/CD8+ (Th/Ts) in Figure S3. Compared with the non‐severe group, severe group had significantly lower CD3+ T cells count (SMD, −1.14; 95% CI, −1.41 to −0.88; p < 0.01; Figure S3a) as well as CD4+ T cells count (SMD, −116; 95% CI, −1.44 to −0.89; p < 0.01; Figure S3b), CD8+ T cells count (SMD, −1.03; 95% CI, −1.27 to −0.79; p < 0.01; Figure S3c), CD4+CD25+CD127‐ Treg cells count (SMD, −0.45; 95% CI, −0.76 to −0.13; p < 0.01; Figure S3d), CD3+ T cells ratio (SMD, −1.10; 95% CI, −1.77 to −0.42; p < 0.01; Figure S3e), and CD4+ T cells ratio (SMD, −0.61; 95% CI, −1.02 to −0.19; p < 0.01; Figure S3f). In contrast, no significant difference was attained for CD8+ T cells ratio (SMD, −0.61; 95% CI, −1.35 to 0.12; p = 0.10; Figure S3g), or CD4+/CD8+ (Th/Ts) (SMD, 0.16; 95% CI, −0.10 to 0.42; p = 0.23; Figure S3h).

3.5. The B cells, NK cells and COVID‐19 severity

A total of 22 studies on the evaluation of B cells and NK cells between severe and non‐severe COVID‐19 patients were included.10, 11, 15, 16, 17, 18, 19, 20, 24, 33, 34, 41, 45, 47, 48, 63, 67, 69, 71, 72, 73, 157 As shown in Figure S4, the CD19+ B cells count and CD16+CD56+ NK cells count in the severe group were significantly lower than those in the non‐severe group with SMDs of −0.74 (95% CI, −1.05 to −0.42; p < 0.01; Figure S4a), and −0.61 (95% CI, −0.84 to −0.38; p < 0.01; Figure S4b), respectively. In contrast, the CD19+ B cells ratio and CD16+CD56+ NK cells ratio were significantly higher in the severe patients than in the non‐severe patients with SMDs of 0.35 (95% CI, 0.15–0.55; p < 0.01; Figure S4c), and 1.19 (95% CI, 0.30–2.07; p < 0.01; Figure S4d), respectively.

3.6. The neutrophils, monocytes, eosinophils, basophils and COVID‐19 severity

About 124 studies on the evaluation of neutrophils, monocytes, eosinophils and basophils cells between severe and non‐severe COVID‐19 patients were included.2, 3, 10, 12, 18, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31, 32, 33, 35, 36, 37, 41, 46, 47, 48, 50, 51, 53, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 72, 73, 76, 77, 78, 79, 157 , 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 As shown in Figure S5, the neutrophils cells count and neutrophils cells ratio in the severe group were significantly higher than those in the non‐severe group with SMDs of 0.72 (95% CI, 0.61–0.82; p < 0.01; Figure S5a), and 0.62 (95% CI, 0.35–0.88; p < 0.01; Figure S5b), respectively. The monocytes cells ratio and eosinophils cells count were significantly lower in the severe patients than in the non‐severe patients of COVID‐19 with SMDs of −0.36 (95% CI, −0.51 to −0.21; p < 0.01; Figure S5c), and −0.45 (95% CI, −0.59 to −0.31; p < 0.01; Figure S5d), while the monocytes cells count and basophils cells count were comparable between the two groups with SMDs of −0.06 (95% CI, −0.15 to 0.04; p = 0.24; Figure S5e), and −0.14 (95% CI, −0.43 to 0.15; p = 0.34; Figure S5f), respectively.

3.7. Sub‐analysis of only peer reviewed studies

The sub‐analysis considering only peer‐reviewed studies for each immune mediator was performed, and the results were presented in Table 2, but without obvious difference with those of all the included literatures analysed.

TABLE 2.

The results of meta‐analyses for each immune indicator in the study

Variables Number of studies included Heterogeneity I 2 SMD (95% CI) p * Publication bias
T p #
Cytokines
IL‐2 9 77% 0.40 (0.10, 0.71) <0.01 0.721 0.495
IL‐2R 12 89% 1.12 (0.80, 1.44) <0.01 3.146 0.011
IL‐4 11 95% 0.71 (0.10, 1.33) 0.02 1.406 0.193
IL‐6 54 94% 1.16 (0.94, 1.38) <0.01 2.435 0.018
IL‐8 13 80% 0.75 (0.49, 1.00) <0.01 1.301 0.220
IL‐10 27 95% 1.26 (0.92, 1.59) <0.01 3.236 0.003
TNF‐α 26 88% 0.55 (0.32, 0.78) <0.01 0.856 0.400
IL‐5 3 92% 0.00 (−0.94, 0.95) 0.99 1.052 0.484
IL‐1β 13 79% 0.33 (0.00, 0.67) 0.05 0.841 0.425
IFN‐γ 12 96% 0.46 (−0.25, 1.17) 0.20 1.724 0.116
Specific antibodies
IgA 8 79% 0.39 (0.10, 0.68) <0.01 1.902 0.106
IgG 8 59% 0.22 (0.01, 0.42) 0.04 0.626 0.555
IgM 8 22% −0.18 (−0.32, −0.03) 0.02 0.376 0.719
IgE 4 26% 0.16 (−0.11, 0.43) 0.24 3.307 0.081
T cells
CD3+ T cells count 22 88% −1.14 (−1.41, −0.88) <0.01 −0.712 0.485
CD4+ T cells count 32 92% −1.16 (−1.44, −0.89) <0.01 −2.857 0.008
CD8+ T cells count 32 89% −1.03 (−1.27, −0.79) <0.01 −0.938 0.356
CD4+CD25+CD127− Treg cells count 4 0% −0.45 (−0.76, −0.13) <0.01 1.317 0.319
CD3+ T cells ratio 10 92% −1.10 (−1.77, −0.42) <0.01 −3.268 0.012
CD4+ T cells ratio 10 85% −0.61 (−1.02, −0.19) <0.01 −1.125 0.293
CD8+ T cells ratio 10 95% −0.61 (−1.35, 0.12) 0.10 −3.784 0.005
CD4+/CD8+ (Th/Ts) 23 87% 0.16 (−0.10, 0.42) 0.23 0.575 0.571
B cells, NK cells
CD19+B cells count 17 86% −0.74 (−1.05, −0.42) <0.01 0.798 0.437
CD16+CD56+NK cells count 17 74% −0.61 (−0.84, −0.38) <0.01 0.664 0.517
CD19+ B cells ratio 8 0% 0.35 (0.15, 0.55) <0.01 0.113 0.913
CD16+CD56+NK cells ratio 9 95% 0.19 (0.30, 2.07) <0.01 5.821 0.001
Neutrophils, monocytes, eosinophils and basophils
Neutrophils cells count 114 91% 0.72 (0.61, 0.82) <0.01 1.590 0.115
Neutrophils cells ratio 25 96% 0.62 (0.35, 0.88) <0.01 0.793 0.436
Monocytes cells count 36 70% −0.06 (−0.15, 0.04) 0.24 −1.148 0.259
Monocytes cells ratio 11 79% −0.36 (−0.51, −0.21) <0.01 −0.418 0.686
Eosinophils cells count 19 62% −0.45 (−0.59, −0.31) <0.01 0.079 0.937
Basophils cells count 7 62% −0.14 (−0.43, 0.15) 0.34 −1.332 0.254
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Note: p*, p value for the variable in the forest plot analysis; p #: p value for the variable in the publication bias analysis.

Abbreviations: IFN‐γ, interferon γ; IL, interleukin; SMD, standardized mean difference; TNF‐α, tumour necrosis factor α.

3.8. Sensitivity analysis

The results showed that none of the exclusions altered the results of the previous analysis for cytokines (except for IL‐4 and IL‐10), four specific antibodies, T cells, B cells, NK cells (except for CD16+CD56+ NK cells ratio), neutrophils, monocytes, eosinophils and basophils, indicating the good reliability and stability of the results of this meta‐analysis (Figure S6). For IL‐4, one study by Hong et al. 35 had a strong influence on the result of the meta‐analysis. For IL‐10, Wan et al. 37 study had a strong influence on the result of the meta‐analysis. For CD16+CD56+ NK cells ratio, one study by Liu et al. 15 had a strong influence on the result of the meta‐analysis. However, the results of meta‐analysis were not badly altered to be the opposite.

3.9. Publication bias

The p value from Egger's regression and funnel plots suggested that the publication bias presented in seven mediators including IL‐2R, IL‐6, IL‐10, CD4+ T cells count, CD3+ T cells ratio, CD8+ T cells ratio and CD16+CD56+ NK cells ratio (Table S5 and Figure S7). Therefore, we adopted the trim‐and‐fill method to further test publication bias. As shown in Table S6, the results showed that there was no significant change in the pooled value change before (p < 0.05) and after (p < 0.05) trim‐and‐fill, indicating that the original pooled SMD was relatively robust.

4. DISCUSSION

Inflammation is the body's first coordinated line of defense against tissue damage caused by either injury or infection, involving both the innate and adaptive immune responses. 57 However, exuberant immune responses following infection have been frequently associated with excessive levels of pro‐inflammatory cytokines and widespread tissue damage including ARDS.158, 159, 160

In most previous studies, patients with SARS‐CoV‐2 infection are associated with a cytokine storm, which is characterized by increased production of IL‐2, IL‐7 and IL‐10, granulocyte‐colony stimulating factor, interferon‐α‐inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha and TNF‐α.16, 18, 157 However, there had been conflicting opinion as to whether the cytokine storm was responsible for the severe outcome. One argument was that the pathological process of severe COVID‐19 disease was mainly due to the direct lung injury that induced the subsequent ARDS, and respiratory depression. In addition to the virus‐induced direct lung injury, it is also considered that COVID‐19 invasion triggers the immune responses that lead to the activation of immune cells to release many pro‐ and anti‐inflammatory cytokines including TNF‐α, IL‐1β, IL‐6 and so on. Overwhelming secretion of cytokines causes severe lung damage, which manifest as extensive damage of pulmonary vascular endothelial and alveolar epithelial cells as well as increased pulmonary vascular permeability, leading to the pulmonary oedema and hyaline membrane formation.15, 25, 36, 66

Multiple studies have been conducted to characterize the profiles of immune mediator during different phases of the COVID‐19 disease in different geographic locations.43, 161, 162, 163 However, results varied, which might be due to the difference in clinical sample preparations, assay platforms and recursion criteria of the patients among studies. Here by performing meta‐analysis on studies that explored the association between cytokine storm and disease severity, we have determined that several cytokines, including IL‐2, IL‐2R, IL‐4, IL‐6, IL‐8, IL‐10 and IFN‐γ, were induced to significantly higher levels in severe cases than in non‐severe cases, but not for IL‐1β or TNF‐α.

It is notable that IL‐6 and IL‐10 were two of the cytokines that were most consistently enhanced in severe patients, and with large intergroup differences. The direction of association remained consistent in 20 of the 22 studies for IL‐6, and in all 13 studies for IL‐10. Extensive studies have been conducted to characterize the profile of IL‐6 in patients with SARS‐CoV‐2 infection, as well as for their relation with the clinical outcome.9, 10, 15, 23, 24, 25, 36, 37, 38, 39, 66 For example, IL‐6 was reported to be elevated during the acute phase of SARS‐CoV‐2 infection,9, 25, 26 and also associated with high viremia in COVID‐19 patients. The plasma IL‐6 level was increased dramatically in SARS‐CoV‐2‐infected patients with cardiac injury, which was associated with fatal outcome induced by fulminant myocarditis. 164 Significantly elevated systemic level of IL‐6 have been reported in several COVID‐19 patient cohorts and shown to correlate with disease severity. 165 IL‐6 level diverges profoundly between non‐survivors and survivors in the third week after symptom onset and is a predictor of COVID‐19 severity and in‐hospital mortality,15, 58 which suggest that IL‐6 production might play a more important role than viral burden in the pathogenesis COVID‐19, since high viral loads were observed at the early clinical process.65, 166, 167, 168 In a consistent manner, a study performed on medical staff with COVID‐19 disease in Wuhan disclosed normal IL‐6 levels on admission were favourable for discharge after infection. 169 Until now, there had been only two studies that showed a reversed direction for the IL‐6‐severe disease association according to our meta‐analysis.18, 42 All these evidences had supported a critical role of IL‐6 in determining the outcome. Transcriptional profiling found that SARS‐CoV‐2 infection in addition to activating type‐I interferon and IL‐6‐dependent inflammatory responses, also results in robust engagement of the complement and coagulation pathway activation. 170 As a simple, fast and readily available screen, we propose it reasonable to take an immediate evaluation of IL‐6 and IL‐10 levels upon hospital admission of COVID‐19 patients, due to its potential benefits to assess worsening clinical features and disease progression in COVID‐19. For example, a notably elevated IL‐6 value over a certain level by using a predetermined detection kit and following a standard protocol should alert clinicians to adopt aggressive therapeutic approaches without delay.

Accompanying the inflammatory process is the lymphopenia depressed CD4+, CD8+ T cells, NK and B cells in COVID‐19 patients. Studies found that acute SARS‐CoV‐2 infection resulted in broad immune cell reduction including T, NK, monocyte, and dendritic cells (DCs). 171 In the meta‐analysed studies, lymphopenia was ubiquitous in severe COVID‐19 infection and was associated with adverse outcome. CD3+, CD4+ and CD8+ T cells counts were always below normal range, and CD19+ B cells and CD16+56+ NK cells counts were consistently depressed in the severe versus non‐severe cases. Recently studies have shown that the extent of lymphopenia seemingly correlates with COVID‐19‐associated disease severity and mortality.2, 4, 24, 68, 70, 71, 172, 173, 174, 175 Patients with mild symptoms, however, typically present with normal or slightly higher T cell counts.176, 177 The presence of lymphopenia and depressed T cell counts seems to correlate with serum IL‐6, IL‐10 and TNF‐α, which might also act as a signature of severe COVID‐19.34, 70 SARS‐CoV‐2‐specific antibodies production in COVID‐19 patients suggested the mounting of humoral responses, especially with a higher level of IgA antibody in the severe patients. However, insignificant difference of IgG, IgM or IgE antibody between severe and non‐severe patients was observed. The role of adaptive immunity in COVID‐19 patients cannot be deciphered according to the current analysis.

These findings have potential application in the effective therapy choice. Until recently, anti‐viral drugs with proven safety profiles are lacking, thus targeting the hyper‐inflammation might be promising and critical for reducing mortality. For example, Tocilizumab, a monoclonal antibody targeting the IL‐6 receptor, is currently being investigated for the treatment of patients with COVID‐19‐CSS. 159 The approved randomized controlled trial that evaluates the efficacy and safety of tocilizumab in the treatment of COVID‐19 might bring about potential benefit soon. The lymphopenia plays an important role in the pathogenesis of the disease, thus the drugs targeting lymphocyte proliferation or apoptosis (IL‐7 and PD1/PD‐L1 inhibitors) could help to restore lymphocyte counts in severe patients suffering COVID‐19.

The recruited studies evaluated by NOQAS in the meta‐analysis revealed good quality, which provided the strong evidence for the association between immune signatures and SARS‐CoV‐2 infection. However, our study was subject to limitations that were inherent to meta‐analysis. All types of severe diseases, such as ARDS development, ICU entrance, the critical ill patients, were pooled into one for comparison. This broad range of severe disease, although been defined according to standard criteria, might cause bias away from the actual estimation of the association. However, with all association with these complications undoubtedly toward the same direction, we would consider these results adaptable for the disease severity prediction. Age and comorbidities are important risk determinants of severity and mortality of COVID‐19 patients, which effects however was not measured, as there were only few literatures presenting the subgrouping data on the immune signatures and disease severity, based on age or comorbidities. We also failed to consider the effect of therapy on the disease outcome, because most of the therapy information was missing from the included studies, for which further investigation are warranted.

5. CONCLUSION

Our systematic review and meta‐analysis are the first to reveal that multiple immune mediators were significantly associated with clinical outcome in COVID‐19 patients in a comprehensive way. A dysregulated immunological response with hypercytokinemia and lymphopenia assembled among severe COVID‐19 disease was disclosed. The screening for the currently significant biomarkers, especially cytokine of IL‐6, IL‐10 and the T cells counts, have important implication in assisting prompt recognition of severe patients and guiding early treatment.

CONFLICT OF INTEREST

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

AUTHOR CONTRIBUTIONS

Wei Liu, Jing‐Yun Li and Qing‐Bin Lu conceived the idea. Tong Yang and Xue‐Fang Peng searched the studies. Kun Liu, Tong Yang, Xue‐Fang Peng, Shou‐Ming Lv, Tian‐Shuo Zhao, Xiao‐Lei Ye, Jia‐Chen Li and Zhong‐Jun Shao collected and analysed the data. Wei Liu and Kun Liu wrote the manuscript. All authors read and approved the final manuscript.

6.

Supporting information

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ACKNOWLEDGEMENTS

We thank all medical staff and health practitioners who have contributed to fight against the disease of COVID‐19. This work was supported by the China Mega‐Project on Infectious Disease Prevention (No. 2018ZX10713002, 2018ZX10101003 and 2017ZX10103004), and the National Natural Science Foundation of China (81803289, 81825019). The funding agencies had no role in the study design, data collection and analysis, or preparation of the manuscript.

Liu K, Yang T, Peng X‐F, et al. A systematic meta‐analysis of immune signatures in patients with COVID‐19. Rev Med Virol. 2021;31(4):e2195. 10.1002/rmv.2195

Kun Liu and Tong Yang contributed equally to this study.

Contributor Information

Qing‐Bin Lu, Email: lwbime@163.com.

Jing‐Yun Li, Email: lwbime@163.com.

Wei Liu, Email: lwbime@163.com.

DATA AVAILABILITY STATEMENT

All data used for analysis are available upon a proper request from the corresponding author Wei Liu at lwbime@163.com.

References

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Associated Data

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Supplementary Materials

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Data Availability Statement

All data used for analysis are available upon a proper request from the corresponding author Wei Liu at lwbime@163.com.

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