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Wen-Hua Kong, Rong Zhao, Jun-Bo Zhou, Fang Wang, De-Guang Kong, Jian-Bin Sun, Qiong-Fang Ruan and Man-Qing Liu. Serologic Response to SARS-CoV-2 in COVID-19 Patients with Different Severity[J]. Virologica Sinica, 2020, 35(6): 752-757. doi: 10.1007/s12250-020-00270-x
Citation: Wen-Hua Kong, Rong Zhao, Jun-Bo Zhou, Fang Wang, De-Guang Kong, Jian-Bin Sun, Qiong-Fang Ruan, Man-Qing Liu. Serologic Response to SARS-CoV-2 in COVID-19 Patients with Different Severity [J].VIROLOGICA SINICA, 2020, 35(6) : 752-757.  http://dx.doi.org/10.1007/s12250-020-00270-x

不同临床分型的新型冠状病毒病例中的新冠病毒血清学反应

  • 通讯作者: 刘满清, liumq33@hotmail.com, ORCID: 0000-0002-9754-3102
  • 收稿日期: 2020-05-31
    录用日期: 2020-07-07
    出版日期: 2020-07-23
  • 新冠肺炎(COVID-19)在全球的快速扩散和大流行,要求我们更加深入地认识该疾病的免疫学特征,包括基本免疫指标出现的时序。本研究纳入了88名来自武汉的新冠病例,其确诊时间为2020年一至二月,包括32名临床分型为重型/危重型的病例和56名轻型/普通型病例。病例平均年龄56.43岁、年龄范围17至83岁、男女性别比为43:45。我们使用商用试剂检测了病例呼吸道标本的新冠病毒核酸,使用磁微粒化学发光法检测了其血样中的新冠IgM和IgG抗体水平,并分析其与疾病严重程度的相关性。血清学与核酸联合检测在88名病例中确认了84名新冠感染阳性者,阳性率为95.45%,显著高于单纯核酸检测(73.86%)或单纯血清学检测(65.91%)(P < 0.001)。我们进一步分析了新冠抗体反应的时间顺序,结果显示血清抗体转换始于症状出现后的第五天,且IgG抗体出现早于IgM。对不同临床分型病例的比较显示较早的血清抗体转换和高抗体水平可能与较轻的临床症状有关。以上结果支持在常规新冠感染诊断中应用血清-核酸联合检测,同时也为理解不同临床分型病例间抗体反应的差别提供了证据。

Serologic Response to SARS-CoV-2 in COVID-19 Patients with Different Severity

  • Corresponding author: Man-Qing Liu, liumq33@hotmail.com
  • ORCID: 0000-0002-9754-3102
  • Received Date: 31 May 2020
    Accepted Date: 07 July 2020
    Published Date: 23 July 2020
  • The immense patient number caused by coronavirus disease 2019 (COVID-19) global pandemic brings the urge for more knowledge about its immunological features, including the profile of basic immune parameters. In this study, eighty-eight reported COVID-19 patients in Wuhan were recruited from January to February, 2020, including 32 severe/critical cases and 56 mild/moderate cases. Their mean age was 56.43 years (range 17-83) and gender ratio (male/female) was 43:45. We tested SARS-CoV-2 RNA with commercial kits, investigated the level of serologic IgM and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using magnetic particle chemiluminescence immunoassays, and compared the results of serologic tests and nucleic acid test (NAT). Among 88 patients, 95.45% were confirmed as positive by the combination of NAT and antibody test, which was significantly higher (P < 0.001) than by single nucleic acid test (73.86%) or serologic test (65.91%). Then the correlation between temporal profile and the level of antibody response was analyzed. It showed that seroconversion started on day 5 after disease onset and IgG level was rose earlier than IgM. Comparison between patients with different disease severity suggested early seroconversion and high antibody titer were linked with less severe clinical symptoms. These results supported the combination of serologic testing and NAT in routine COVID-19 diagnosis and provided evidence on the temporal profile of antibody response in patients with different disease severity.

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    Serologic Response to SARS-CoV-2 in COVID-19 Patients with Different Severity

      Corresponding author: Man-Qing Liu, liumq33@hotmail.com
    • 1. Wuhan Center for Disease Control and Prevention, Wuhan 430024, China
    • 2. Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430060, China

    Abstract: The immense patient number caused by coronavirus disease 2019 (COVID-19) global pandemic brings the urge for more knowledge about its immunological features, including the profile of basic immune parameters. In this study, eighty-eight reported COVID-19 patients in Wuhan were recruited from January to February, 2020, including 32 severe/critical cases and 56 mild/moderate cases. Their mean age was 56.43 years (range 17-83) and gender ratio (male/female) was 43:45. We tested SARS-CoV-2 RNA with commercial kits, investigated the level of serologic IgM and IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using magnetic particle chemiluminescence immunoassays, and compared the results of serologic tests and nucleic acid test (NAT). Among 88 patients, 95.45% were confirmed as positive by the combination of NAT and antibody test, which was significantly higher (P < 0.001) than by single nucleic acid test (73.86%) or serologic test (65.91%). Then the correlation between temporal profile and the level of antibody response was analyzed. It showed that seroconversion started on day 5 after disease onset and IgG level was rose earlier than IgM. Comparison between patients with different disease severity suggested early seroconversion and high antibody titer were linked with less severe clinical symptoms. These results supported the combination of serologic testing and NAT in routine COVID-19 diagnosis and provided evidence on the temporal profile of antibody response in patients with different disease severity.

    • In this study, we included confirmed patients with both throat swab and blood sample delivered to the Wuhan CDC laboratory before March 1st, 2020. Clinical samples of 88 COVID-19 patients were collected at eleven designated hospitals (People's Hospital of Dongxihu District, Wuhan Pulmonary Hospital, Wuhan Hankou Hospital, Wuhan Red Cross Hospital, Wuhan Jingyintan Hospital, Wuhan Third Hospital, Wuhan Sixth Hospital, Renmin Hospital of Wuhan University, Tongji Hospital, Wuhan Union Hospital, and General Hospital of the Yangtze River Shipping) and were delivered for laboratory diagnosis of SARS-CoV-2. With the verbal consent of patients, throat swabs were collected in 3.5 mL viral transport medium for NAT. Blood samples were collected in 5 mL non-additive tubes and serum remnants were separated and refrigerated at − 20 ℃ before antibody testing. The COVID-19 severity level of the participant was retrieved from the National Infectious Disease Information System (NIDIS). Every patient was characterized as one of the four severity levels (mild, moderate, severe and critical) by his/her physician (National Health Commission of the People's Republic of China 2020a, b; Epidemiology Working Group for NCIP Epidemic Response and Chinese Center for Disease Control and Prevention 2020; Pan et al. 2020) and the data were recorded in the NIDIS.

    • The nucleic acid was extracted from 200 μL of throat swab medium using a GeneRotex automated nucleic acid extraction system (Tianlong, Xi'an, China). Due to medical resource limitations, two commercial quantitative PCR (qPCR) kits were employed in the detection of SARS-CoV-2 RNA. One of the assays (Daan Gene, Guangzhou, China) was used from January to early February, targeting at SARS-CoV-2 ORF1ab and N gene, with a limit of detection (LoD) of 500 copies/mL. The other assay (BGI, Shenzhen, China) which was used after February 5th targeted at ORF1ab fragment only and its LoD was 100 copies/mL. The cutoff cycle-threshold (Ct) was 40 for both kits. Both assays were approved by the National Medical Products Administration (NMPA) of China and had been established in our laboratory.

    • The levels of SARS-CoV-2-binding IgM and IgG antibodies were assessed using semi-quantitative magnetic particle chemiluminescence immunoassays (M-CLIAs) on an Axceed 260 automated magnetic analyzer (Bioscience, Chongqing, China) (Loeffelholz and Tang 2020), as described by Long et al.(2020). Both IgM and IgG assays had received NMPA approvals with registration numbers of 20203400182 and 20203400183, respectively. The sensitivity and specificity of the IgM assay in pre-marketing clinical evaluation were 88.30% and 99.50%, while those of the IgG assay were 87.25% and 99.25%. Fifteen microliter of serum was diluted for 50 times before being used in each test. Procedures and cut-off value set-up were performed following the manufacturers' instructions. Antibody levels were presented as the measured chemiluminescence values divided by the cutoff (S/Co) (Long et al. 2020).

    • Statistical analyses were performed with Prism 8.0 (GraphPad, San Diego, USA). Categorical variables were compared using Chi square test. For continuous variables, t test or Mann–Whitney U test were employed after their normality determined by Kolmogorov–Smirnov test. A P-value of less than 0.05 was considered statistically significant.

    • A total of 88 COVID-19 patients from eleven designated hospitals were included in this study, of whom 43 were male and 45 were female. Their mean age was 56.43 years old (range 17–83) and the median interval between initial symptom onset and sample collection was 11 days (range 1–37). Thirty-two patients (36.4%) had severe/critical illnesses and required oxygen supplementation or higher life support, while the other 56 patients had mild or moderate symptoms (Table 1).

      Mild/moderate cases Severe/critical cases P
      Total 56 (63.64%) 32 (36.36%)
      Gender 0.136
        Male 24 (42.86%) 19 (59.38%)
        Female 32 (57.14%) 13 (40.62%)
      Age (mean ± SD, years) 57.05 ± 13.94 55.34 ± 12.89 0.571
      Sample collecting time (days)a 0.003
        Median 12 9
        Interquartile range 9–18 5–12
      Nucleic acid test 0.748
        Positive 42 (75.00%) 23 (71.88%)
        Negative 14 (25.00%) 9 (28.13%)
      Antibody tests
        IgM positive 24 (42.86%) 5 (15.63%) 0.009
        IgM negative 32 (57.14%) 27 (84.37%)
        IgG positive 44 (78.57%) 14 (43.75%) 0.001
        IgG negative 12 (21.43%) 18 (56.25%)
      aSampling time: the time interval between symptom onset and sample collection

      Table 1.  Demographic information and test results of the studied subjects.

      qPCR test confirmed 65 SARS-CoV-2 infected cases among 88 participants (73.86%). No significant difference was observed between the positive rates of two qPCR kits (37/53 versus 28/35, χ2 = 1.133, P = 0.287). On the other hand, the positive rates of serum IgM and IgG antibody against SARS-CoV-2 were 32.95% (29/88) and 65.91% (58/88), respectively (Table 2). Altogether, 84 COVID-19 cases (95.45%) were identified among all patients by the combination of NAT and antibody test, which was significantly more than single NAT (χ2 = 15.793, P < 0.001) or serologic test (χ2 = 24.643, P < 0.001). The consistency rate between results of antibody test and NAT was 48.86% [(39 + 4)/88].

      NAT resultsa Antibody test resultsa Total
      IgM IgG/IgM + IgG
      Positive Negative Positive Negative
      Positive 20 (22.73%) 45 (51.14%) 39 (44.32%) 26 (29.55%) 65 (73.86%)
      Negative 9 (16.98%) 14 (15.91%) 19 (21.59%) 4 (4.54%) 23 (26.14%)
      Total 29 (32.95%) 59 (67.05%) 58 (65.91%) 30 (34.09%) 88 (100%)
      aCombination of NAT and antibody test had significantly higher detection rate than single NAT (χ2 = 15.793, P < 0.001) or serologic test (χ2 = 24.643, P < 0.001).

      Table 2.  Comparison of results of serum SARS-CoV-2 antibody tests and nucleic acid test (NAT).

    • Notably, all the patients that were positive for SARS-CoV-2 IgM were also positive for SARS-CoV-2 IgG. The earliest seroconversion of IgG antibody was observed 5 days after the disease onset, and that time interval of IgM antibody was 8 days (Fig. 1). For 51 patients with sample collected at 10 days or later after symptom onset, the seroconversion rate was 47.06% for IgM (24/51) and 82.35% for IgG (42/51). Both antibodies were detectable in samples collected over 30 days after onset.

      Figure 1.  The correlation between sample collecting time of COVID-19 patients and different test results combination. Six categories of samples with different test results were characterized on the left side of the figure. Each colored dot represented one patient sample and its time interval between symptom onset and sample collection was scaled on the lateral axis. The median time interval and interquartile range were reported for each category. PCR+: positive for SARS-CoV-2 RNA in nucleic acid test; PCR−: negative for SARS-CoV-2 RNA in nucleic acid test; IgM+/IgG+: positive for SARS-CoV-2 IgM/IgG antibody in serologic test; IgM−/IgG−: negative for SARS-CoV-2 IgM/IgG antibody in serologic test.

      When comparing patients with mild/moderate symptoms and patients with severe/critical diseases, no obvious difference was found between their gender ratios (P = 0.136), age composition (P = 0.571) and NAT positive rates (P = 0.748), but the mild/moderate group had later sampling time and higher antibody positive rates than the severe/critical group (Table 1). When comparing to the severe/critical cases with the same sampling time, mild/moderate cases presented higher seroconversion rate and higher antibody titer for both IgM and IgG antibodies (Fig. 2). Similar analysis was performed on cases of different genders and in different age groups, but no significant difference was observed between their antibody levels and temporal profiles (Fig. 3).

      Figure 2.  Comparison of nucleic acid and serologic test results between COVID-19 patients with different disease severity. Study subjects were separated into mild/moderate cases (black dots) and severe/critical cases (red dots), and their nucleic acid and serologic test results were compared. The time interval between symptom onset and sample collection was scaled on the lateral axis in each panel. For nucleic acid test (left) and IgM (middle)/IgG (right) antibody tests, the vertical axes reported qPCR cycle thresholds (Ct) and S/Co values, respectively. The dash line represented the threshold of each test.

      Figure 3.  Comparison of serologic test results between COVID-19 patients of different genders and age groups. A The serologic test results of males (black dots) and females (grey dots) were compared. Every dot represented one patient and the vertical axis reported the S/Co values of SARS-CoV-2 IgM and IgG antibody tests. B The serologic test results of < 60 years group (black dots) and ≥ 60 years group (grey dots) were compared. Every dot represented one patient and the vertical axis reported the S/Co values of SARS-CoV-2 IgM and IgG antibody tests. The dash line represented the threshold of each test.

    • Although NAT has been regarded as the gold standard of COVID-19 laboratory diagnosis, it is not suitable for low viral load patients and its accuracy is largely depended on the sampling procedure (To et al. 2020). It makes serologic test a valuable compliment for clinical diagnosis as well as providing information about the disease dynamic. In this study, two NMPA approved M-CLIA kits were used to detect the level of SARS-CoV-2 IgM and IgG antibodies in the serum of COVID-19 patients. In addition to the 65 COVID-19 patients identified by NAT, the antibody tests identified another 19 SARS-CoV-2 infected patients among the 88-person cohort, which diminished the need of multiple sampling and significantly improved the diagnostic accuracy. Meanwhile, the relatively low consistency between NAT and antibody test results also indicated those results should not be interpreted independently. These data provided adequate evidence that serology is a particularly important supplementary tool for diagnosis of the novel and emerging SARS-CoV-2 (Loeffelholz and Tang 2020).

      Temporal profile of serum antibody is vital for the interpretation of serologic test result and evaluating the immune protection situation of subject. In this study, level of serum antibody against SARS-CoV-2 started to rise since day 5 after disease onset and remained high in samples collected 1 month after onset. IgG level was rose earlier than IgM, just like in several other studies (Thevarajan et al. 2020; To et al. 2020; Zhang et al. 2020), but it could be related to the unbalanced sensitivity of IgM and IgG assays, since earlier IgM seroconversion has also been reported (Xiang et al. 2020; Zhao et al. 2020a). The validation and standardization of SARS-CoV-2 serologic assays in large clinical cohort is crucial for enabling uniform assessment of immunogenicity and efficacy (Okba et al. 2020).

      We further looked into the possible correlates of serum antibody level with demographic features, including gender, age and disease severity. Our results suggested early seroconversion and high antibody titer were likely linked with less severe clinical symptoms. The finding is in consistent with earlier observations of recovered patients (Dong et al. 2020; Thevarajan et al. 2020) and the 'two-phase immune response' theory in which early adaptive immune response plays protective role in the course of COVID-19 (Shi et al. 2020), but opposite to a previous study which reported positive correlation between clinical severity and antibody titer (Zhao et al. 2020a). Such conflicted data warrant further study of the immunological characteristics of COVID-19 patients with different disease severity.

      There are several limitations in this study. First, only one blood sample was collected from each patient, causing a delay between the reported seroconversion time and the actual seroconversion time. Second, two different NAT assays were exploited in the detection of SARS-CoV-2 RNA due to the urgent procurement in the outbreak, which leaded to a potential difference in test sensitivity. Finally, participants' comorbid conditions were not included in the analysis, because we did not have access to the clinical information of participants.

      In summary, this study supported the combination of serologic testing and NAT in routine COVID-19 diagnosis and provided evidence on the temporal profile of antibody response against SARS-CoV-2 in patients with different disease severity. More insights about the immunological features of COVID-19 patients are important for disease prognosis prediction and vaccine development.

    • The work was supported by the Emergency Scientific Research Project for COVID-19 from Wuhan City (Grant No. 2020020101010008).

    • WHK and MQL designed the study. WHK, RZ, JBZ, DGK, JS, QR, and MQL collected samples and clinical information and analyzed data. WHK, RZ and MQL analyzed and interpreted the data. WHK and MQL wrote and revised the manuscript. MQL finalized the manuscript. All authors had full access to the final version of the report and agreed to the submission.

    • The authors declare that they have no conflict of interest.

    • All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with 1964 Helsinki declaration and later amendments or comparable ethical standards. This study was reviewed and approved by the Ethics Committee of Wuhan Centers for Disease Prevention and Control. Since samples were collected with medical necessity and in accordance to the government guidance, written informed consent was waived.

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