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Immune and inflammation features of severe and critical Omicron infected patients during Omicron wave in China

BMC Infectious Diseases volume 24, Article number: 809 (2024) Cite this article

Abstract

Objective

The current study aimed to investigate the baseline immune and inflammatory features and in-hospital outcomes of patients infected with the Omicron variant (PIWO) who presented with different disease severities during the first wave of mass Omicron infections in the Chinese population has occurred.

Method

A cross‐sectional study was conducted on 140 hospitalized PIWO between December 11, 2022, and February 16, 2023. The clinical features, antibodies against SARS-CoV-2, immune cells, and inflammatory cytokines among mildly, severely, and critically ill PIWO at baseline and during follow-up period were compared.

Result

Patients with severe (n = 49) and critical (n = 35) disease were primarily male, needed invasive mechanical ventilation treatment, and exhibited higher mortality than those with mild disease (n = 56). During acute infection, SARS-CoV-2-specific antibody levels fluctuated with disease severity, serum antibodies increased and the incidence of severe cases decreased in critically ill PIWO over time. Antibody titers in severe or critical PIWO with no antibody responses at baseline did not increase significantly over time. Meanwhile, CD4+T cell, CD8+T cell, and natural killer cell counts were negatively correlated with disease severity, whereas interleukin (IL)-6 and IL-10 levels were positively correlated. In addition, combined diabetes, immunosuppressive therapy before infection, serum amyloid A, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO. Among the 11 nonsurvivors, 8, 2, 1 died of respiratory failure, sudden cardiac death, and renal failure, respectively. Compared with survivors, nonsurvivors exhibited lower seropositivity of SARS-CoV-2-specific antibody, reduced CD3+T and CD4+T cell counts, and higher IL-2R, IL-6, IL-8, and IL-10 levels. Of note, lactate dehydrogenase was a significant risk factor of death in severe or critically ill PIWO.

Conclusion

This present study assessed the dynamic changes of SARS-CoV-2-specific antibodies, immune cells and inflammatory indexes between severely and critically ill PIWO. Critical and dead PIWO featured compromised humoral immune response and excessive inflammation, which broadened the understanding of the pathophysiology of Omicron infection and provides warning markers for severe disease and poor prognosis.

Highlights 

1. Specific anti-SARS-CoV-2 antibodies showed a trend of increasing first and then decreasing with the progression of disease severity.

2. The severity of infection decreased and the levels of the four antibodies against SARS-CoV-2 increased in critically ill PIWO over time.

3. Negative antibodies in severe/critical PIWO at baseline did not increase significantly with therapeutic intervention.

4. Dead PIWO exhibited disordered features of immunocompromised, hyperinflammatory, abnormal coagulation and myocardial injury.

5. Combined diabetes, immunosuppressive therapy before infection, high levels of SAA, IL-10 and neutrophil counts were the risk factors for severe/critical illness.

6. High LDH was related to death event in severely/critically ill PIWO.

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Introduction

Due to large number of mutations in the spike origin, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant not only reduced the neutralizing function of antibodies induced by prior infection or vaccination but also enhanced its infectivity, worsening the epidemiological situation worldwide [1]. In addition to immune evasion, mutations in the Omicron sublineage reduced the effectiveness of sotrovimab, the only approved monoclonal antibody against the Omicron variant [2, 3]. Although the clinical efficacy of other available small molecule antivirals (remdesivir, molnupiravir, and nirmatrelvir) had remained effective against Omicron, their efficacy was limited to patients with early and mild disease stages [4].

Compared with the other predecessors of SARS-CoV-2, Omicron showed decreased lung infectivity and became less pathogenic [5]. Of note, patients infected with the Omicron variant (PIWO) exhibited more severe extrapulmonary organ disruptions, including renal and hematological failures, along with more frequent comorbidities [6]. In addition, the Omicron variant has been associated with less severe disease, lower in-hospital mortality, and less frequent need for intensive care than the Delta variant [7,8,9,10], which can be attributed to the evolved immune recognition processes (such as adaptive T cell responses induced by vaccination or infection to cross-recognize the Omicron variant) [11, 12], slow spread of Omicron from the main bronchus to the distal portion of the bronchioles [5], and reduced production of proinflammatory cytokines [13]. However, recent observational and prospective studies have reported that the mortality and invasive mechanical ventilation (IMV) requirement in critically ill PIWO were not significantly different from that in patients infected with the previous variant Delta [6, 14]. During the acute infection period, PIWO with severe disease were characterized by elevated interleukin (IL)-6, C-reactive protein (CRP), ferritin, D-Dimer, and lactate dehydrogenase (LDH), which is also associated with oxygen therapy, ICU admission, disease progression, and deceased[15,16,17,18,19,20,21]. Compared with mild patients, severely ill PIWO exhibited higher levels of white blood cells and neutrophils, lower levels of lymphocytes and its subsets. Lower CD4+T cell counts reflected the longer time of viral shedding [15, 16, 19, 22,23,24]. In addition, neutralizing antibody against Omicron variants were higher in vaccinated PIWO with pneumonia or hypoxemic respiratory failure than in those without [24].

Above studies combined severely and critically ill PIWO in one group to analyze their inflammatory and immunological trajectory, and the number of critical patients was too small to show the differences between severe and critically ill PIWO. Therefore, in the present study, clinical features and outcomes, the expression pattern and kinetics of antibodies against SARS-CoV-2, immune cells, and inflammatory cytokine expression among mildly, severely, and critically ill PIWO were compared; the characteristics of nonsurviving patients were explored; and the potential risk factors associated with coronavirus disease 2019 (COVID-19) severity and mortality were identified among PIWO from the North China area from December, 11, 2022, to February, 16, 2023, during the first Omicron infection wave.

Methods

Patient enrollment and data collection

PIWO were recruited from Baoding First Central Hospital (designated hospital for patients with COVID-19) during the first Omicron pandemic wave in China. Inclusion criteria for participants were as follows: (1) age ≥ 18 years; (2) documented positive result for SARS-CoV-2 using real-time reverse transcriptase-polymerase chain reaction from nasopharyngeal and/or oropharyngeal swabs; (3) no previous infection with other SARS-CoV-2 strains from self-report and medical records; (4) acute illness that necessitated hospitalization for their symptoms; and (5) ability to provide informed consent. Based on the data published by the Chinese Center for Disease Control and Prevention, all the included patients were diagnosed as infected with the Omicron variant (https://www.chinacdc.cn/jkzt/crb/zl/szkb_11803/jszl_13141/202301/t20230125_263519.html). Finally, 140 patients who met the inclusion criteria were enrolled in this study between December, 11, 2022, and February, 16, 2023.

The baseline information of the included PIWO at the time of admission, including age, sex, clinical symptoms and vital signs, SARS-CoV-2 vaccination status, comorbidity, and laboratory parameter tests, was collected. In addition, the data on treatment drugs, disease progression, and outcome after Omicron infection, of the participants were also recorded during their hospitalization. The patients were classified as per latest recommendations on the diagnosis and clinical management of COVID-19 infection (2023) [25] for disease severity. PIWO with mild disease were defined as those with the symptoms of fever, sore throat, and headache, but not of severe or critical illness. Patients who met any of the following were classified as having severe disease: (1) respiratory distress with respiratory rate ≥ 30 times/min; (2) oxygen saturation ≤ 93% at rest; (3) partial pressure of oxygen in arterial blood/fraction of inspiration oxygen ≤ 300 mm Hg; and (4) imaging suggesting the extent of lung involvement was > 50%. PIWO with critical condition were those who developed respiratory failure requiring IMV, or whose blood pressure drop required vasopressor drugs, or who were diagnosed with acute respiratory distress syndrome or septic shock. A total of 140 PIWO were divided into mild (n = 56), severe (n = 49), and critical (n = 35) illness groups.

The data on routine laboratory indices that reflect inflammation, coagulation, myocardial injury, blood oxygen, blood cell parameters, liver and kidney function, and electrolytes were derived from the laboratory information system. The details of laboratory index and the SARS-CoV-2 vaccination program are listed in the Supplementary materials.

For all enrolled PIWO, blood samples were collected at the time of their first examination after hospitalization (baseline). For severe and critically ill PIWO, blood samples were collected at baseline and were followed up once a week during hospitalization for the dynamic monitoring of antibody levels and inflammatory cytokines in PIWO. According to the sampling time after symptom onset, the time points of dynamic monitoring classified as follows: within 10 days (time point 1, T1), 10–17 days (T2), 17–24 days (T3), and > 24 days (T4) after symptom onset. The study design is shown in Fig. 1. Whole peripheral blood was obtained for lymphocyte subset analysis, where the serum was separated for cytokine and antibody assessments. Serum samples were isolated, numbered, and stored at − 80℃ until use.

Fig. 1
figure 1

Study design

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The present study was approved by the Medical Ethics Committee of Baoding First Central Hospital ([2022]059), and informed consent was obtained from all enrolled patients.

SARS2-CoV-2-specific antibodies

Total antibodies against SARS-CoV-2 (including IgM, IgG, and IgA) targeting the receptor‐binding domain (RBD) region of the S1 subunit (Beijing Wantai Biological Pharmacy Enterprise, Beijing, China), neutralizing antibodies (NAbs) against SARS-CoV-2 wild type (WT) and Omicron BA.4/5 subvariant, which block the interaction between the RBD of the viral spike glycoprotein and human angiotensin-converting enzyme 2 (ACE2) (GenScript cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit, USA), along with IgG antibodies against SARS-CoV-2 spike RBD (Hangzhou Proprium Biotech Co, Ltd., China) were measured as previously described [26]. ELISA plates were scanned at the wavelengths of 450 nm and 620 nm. For interpretation, the OD value of total anti-SARS‐CoV‐2 antibodies ≥ 0.19, the inhibition rate of SARS‐CoV‐2-NAbs ≥ 30%, and the concentration of IgG anti-RBD antibody ≥ 11.6 BAU/mL were considered positive.

Lymphocyte subsets

Lymphocyte subsets were measured on a flow cytometer (BeamCyte1026M) using a fluorescence monoclonal antibody kit (Tianjin QuantoBio Biotechnology Co.Ltd). The antibody clones that were used for flow cytometric analysis were as follows: FITC anti-CD3, PE anti-CD16 + 56, PerCP-Cy5.5 anti-CD45, PC7 anti-CD4, APC anti-CD19, and APC-Cy7 anti-CD8. First, a total of 20 µL antibody reagent and 50 µL whole blood were added to a tube, and incubated at room temperature in the dark for 20 min. Then 450 µL hemolysin was added to the tube, and after incubation at room temperature in the dark for another 15 min, the percentages of lymphocyte subsets were detected on the flow cytometer. The cell populations were as follows: B lymphocytes (CD45+CD19+), CD3+T lymphocytes (CD45+CD3+), CD4+T lymphocytes (CD45+CD3+CD4+), CD8+T lymphocytes (CD45+CD3+CD8+), and natural killer (NK) cells (CD3−CD16+CD56+). The absolute values of total B cells, NK cells, T cells, and T cell subsets were calculated from the absolute values of lymphocytes enumerated using a hematology analyzer.

Cytokines

Six inflammatory cytokines including IL-1β, IL-2R, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α were detected using immunofluorescence luminescence (Tianjin QuantoBio Biotechnology Co.Ltd). First, 20 µL of capture microspheres coated with different specific antibodies against cytokines was mixed with 20 µL of serum and 20 µL of biotin-labeled detection antibodies. Then incubate the mixture at room temperature for 2 h in the dark with shaking (the shaking frequency was approximately 500 rpm) to form a complex of antibody capture microspheres-cytokine detection antibodies. Then, 20 μL of PE-labeled streptavidin was added to each tube, incubated at room temperature for 30 min with shaking in the dark, and analyzed on the flow cytometer. The flow cytometry data were processed using the FCAP software for obtaining cytokine concentration.

Statistical analysis

The primary outcome of the current study was severe/critical illness in PIWO and death in severe/critical PIWO. Ordinal logistic regression analyses were performed to investigate independent factors that influence COVID-19 severity in PIWO (from mild illness to severe to critical). Four characteristics of PIWO, including clinical parameters (time from symptom onset to hospitalization, sex, comorbidities, vaccination status, and previous immunosuppressive therapy), titers of the abovementioned four SARS-CoV-2-specific antibodies, count of immune subsets, and level of inflammatory factors (IL-1β, IL-2R, IL-6, IL-8, IL-10, TNF-α, CRP, serum amyloid A (SAA), and procalcitonin (PCT)), were included in the logistic regression models and analyzed using the step by step option. The models included the adjusted Model 1 (intaking clinical parameters, antibodies, or immune cells or inflammatory factors) and adjusted Model 2 (intaking all clinical parameters, antibodies, immune cells and inflammatory factors). Binary logistic regression was initially performed to define the clinical and laboratory risk factors associated with the mortality of PIWO. The statistically significant indicators identified between the survivors and nonsurvivors were included in univariate regression analyses. Next, statistically significant variables (p < 0.05) associated with deceased PIWO in the univariable analyses were analyzed using multivariable logistic regression analyses. Meanwhile, the variance inflation factor was < 3 and tolerance was > 0.3, indicating no multicollinearity.

The Shapiro–Wilk test was performed to assess the normality of distribution of the values. Independent sample t-test or one-way analysis of variance, respectively, was used to compare two groups or multiple groups for values with normal distribution. By contrast, the Wilcoxon rank-sum test or Kruskal–Wallis test was used for non-normally distributed data. The χ2 test was used to compare differences between categorical variables. Mean (standard deviation, SD) and median (interquartile range, IQR) are used to denote quantitative data that followed normal and non-normal distribution, respectively, whereas categorical variables are presented as numbers and percentages. The correlation analysis of the non-normally distributed data was performed using Spearman’s correlation coefficient. All statistical analyses were performed using R software (version 4.1.3), IBM SPSS Statistics (version 26.0), and or GraphPad Prism (version 8.0). P < 0.05 indicated statistical significance.

Results

Demographics and clinical characteristics of PIWO

The clinical and laboratory characteristics at baseline, along with the treatment and outcomes of PIWO during hospitalization are shown in Table 1–2 and Supplementary Table 1. Of all PIWO, 86% (120/140) had at least one underlying disease, with the most common comorbidities being hypertension (58%), heart disease (35%), diabetes (32%), and brain stroke (23%). No statistical difference was observed in the comorbidities, time from symptom onset to hospitalization, vaccination status, and second infection among the mildly, severely, and critically ill patients. A higher proportion of males, IMV treatment, and poor clinical outcome was observed in PIWO with severe and critical illness. The immunosuppressd medications before infection administered to severely ill (16%, 8/49) and critically ill patients (11%, 4/35) were similar (P = 0.753). In addition, the level of indicators that reflected inflammation, abnormal coagulation, and myocardial injury increased with disease severity.

Table 1 The baseline demographic and clinical characteristics of PIWO
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Table 2 The treatment and prognosis of PIWO during hospitalization
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Antibody signature of severely or critically ill PIWO

The level of total anti-SARS-CoV-2 antibodies, IgG anti-RBD antibodies, and NAbs against SARS-CoV-2 WT and Omicron BA.4/5 variant in PIWO at baseline showed a trend of an initial increase and subsequent decrease with disease severity (Fig. 2A-D). Severe patients had the highest total anti-SARS-CoV-2 antibodies titers, IgG anti-SARS-CoV-2 spike RBD antibody concentrations, the inhibition rates of NAb-WT and -BA.4/5 than mild or critical individuals. However, there was no significant difference in the titers of four specific antibodies against SARS-CoV-2 between the mild and critical patient group (Supplementary Table 1).

Fig. 2
figure 2

Comparison of SARS-CoV-2-specific antibody titers and seropositivity at hospitalization among PIWO with mild, severe, and critical disease in PIWO. A-D. Box plots show the level of total SARS-CoV-2-specific antibodies, anti-RBD IgG, and neutralizing antibodies against SARS-CoV-2 wild type and BA.4/5 in the mild, severe, and critical groups. E–H. Seropositivity of SARS-CoV-2-specific antibodies among different COVID-19 disease severity groups. The numbers on the orange columns represent the number of individuals with positive SARS-CoV-2-specific antibodies in different groups

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The seropositivity of the total antibodies against SARS‐CoV‐2 and anti-RBD IgG after the Omicron infection was comparable among the mild, severe and critical patient groups (Fig. 2E, F). While the positivity of NAb against WT and BA.4/5 were higher among severely ill patients than that among mildly or critically ill patients (Fig. 2G, H), exhibiting similar results to the inhibition rate.

The neutralizing effect of NAb-WT and NAb-BA.4/5 in blocking infection against SARS‐CoV‐2 WT and Omicron were similar in PIWO (Supplementary Fig. 1), indicating that the Omicron variant might harbor the same conserved sites as the WT strain, facilitating the development of therapeutically NAbs.

Additionally, we followed-up 12 critically ill PIWO and found that the incidence of severe cases decreased and serum levels of the four specific antibodies against SARS-CoV-2 increased over time (Fig. 3A-H. Supplementary Tables 2, 3). The enhancement of antibody titers and inhibition rate was more obvious in critical PIWO who had the good prognosis at the time of discharge (Fig. 3I-L). The kinetics of antibodies of the 13 severely ill PIWO were not consistent with those of critically ill. The inhibition rate of NAb-WT and -BA.4/5 remained high, while the anti-RBD IgG and total anti-SARS-CoV-2 antibodies fluctuated (Supplementary Fig. 2).

Fig. 3
figure 3

Dynamics of changing antibody levels in critically ill PIWO during hospitalization. A-D. The line chart shows the trend of the NAb-BA.4/5, NAb-WT, anti-RBD IgG, total anti-SARS-CoV-2 antibodies and the proportion of severe disease in critically ill patients over time. Red line represents the levels of anti-SARS-CoV-2 antibody, and blue line represents the percentage of severe cases. E–H. Kinetics of four SARS-CoV-2-specific antibodies levels of PIWO with critical disease. I-L. The dynamic changes of SARS-CoV-2-specific antibodies in each critically ill patient. Red lines represent critically ill PIWO become asymptomatic or mild during follow-up. M–N. Kinetics of SARS-CoV-2-specific antibodies levels in PIWO with negative antibody responses at admission in severe and critical group. Note: A-P: The x-axis represents sampling time after symptom, T1: within 10 days, T2: 10–17 days, T3: 10–24 days, T4: > 24 days. A-D: The right y-axis displays the antibody level, and the left y-axis shows the percentage of severe/critical cases. The dotted line represents the positive threshold. A-L: T1 (n = 11), T2 (n = 10), T3 (n = 12), T4: (n = 6)

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Nine of the 25 PIWO followed-up had negative antibody responses at baseline. Among these patients, the proportions of males and critical cases were 67% (6/9) and 67% (6/9), respectively. Four patients had not received any COVID-19 vaccine, four underwent IMV therapy, three experienced secondary infections, and two died (Supplementary Table 4). Except for the inhibition rate of NAb-WT, the levels of the other three antibodies did not increase with therapeutic intervention during hospitalization. Of note, the inhibition rate of NAb-WT remained below the positive threshold (30%) in the later stages of hospitalization (Fig. 3M-P, Supplementary Table 5). The levels of the four antibodies in PIWO with severe or critical disease did not enhance significantly over time, which may be related to the subsequent poor prognosis.

In the current study, 74% (104/140) PIWO received SARS-CoV-2 vaccination and the median sampling time after the last vaccine was 376 days (Table 1). The doses of SARS-CoV-2 vaccine were positively correlated to the levels of four antibodies (Supplementary Fig. 3). Given that vaccination rates and sampling times after the last vaccine dose were comparable across PIWO in the mild, severe and critical groups (Table 1, Supplementary Fig. 4), we think that the difference in SARS-CoV-2-specific antibody levels among the three groups may be due to the severity of the Omicron infection in this situation.

Immune cell profiling of severely and critically ill PIWO

PIWO in the severe and critical groups were characterized by high counts of neutrophil and monocyte counts (Fig. 4A, B) and low level of lymphocyte counts (Fig. 4C) compared with those in the mild group, indicating obvious active inflammatory response. However, CD3+T, CD4+T, and CD8+T lymphocytes that participate in cellular immunity (Fig. 4D-F), B lymphocytes that impart humoral immunity (Fig. 4G), and NK cells that kill targeted cells (Fig. 4H) were reduced to varying degrees in severe, particularly critical, PIWO.

Fig. 4
figure 4

Immune cell differences among PIWO with different disease severities at the first sampling. A-C. Violin plots show the comparison of the counts (left) and proportions (right) of neutrophils (A), monocytes (B), and lymphocytes (C). D-H. Count (left) and percentage (right) differences in CD3+T cells (D), CD4+T cells (E), CD8+T cells (F), B cells (G), and NK cells (H) among different disease severity groups. Note: n = 56, 47, and 33 for PIWO with mild, severe, and critical condition, respectively. Four patients with severe or critical disease who had hematological malignancies were excluded

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The Qin’s study observed the irreversible reduction of NK and CD8+T cells with over-expressed activation marker (CD38) and proliferation marker (Ki-67) in severe and critical PIWO. And overactivated NK cells and/or cytotoxic T-lymphocytes induced by the persistence of SARS-CoV-2 in patients with severe or critical illness could infiltrate lung tissue, leading to a worse clinical outcome [27]. In present study, CD4+T cells showed obviously increase in both critically and severely ill PIWO. PIWO with critical disease featured slight elevated CD8+T cells, significantly reduced B cells, and unchanged NK cell, which was inconsistent with the trend of cell changes in severe patients (Supplementary Figs. 5, 6).

Besides, preinfection immunosuppressive therapy including glucocorticoids and immunosuppressants such as prednisone, hydroxychloroquine sulfate had no effect on the count and percentage of neutrophils, monocytes, lymphocytes and lymphocyte subsets at baseline (Supplementary Fig. 7).

Inflammatory factors in PIWO of different severities

According to the heatmap of cytokines, critical PIWO presented with the characteristics of increased inflammation (Fig. 5A). Multivariable comparisons showed that IL-6, IL-10, SAA, and PCT levels were significantly different among the different groups (Fig. 5B-G and Supplementary Table 1). Besides, IL-1β, IL-6, SAA, PCT, and CRP were positively associated with disease severity (Fig. 5H, I), supplementary Fig. 8).

Fig. 5
figure 5

Cytokine characteristics of severely and critically ill PIWO at baseline A. Heatmap showing six inflammation-related cytokines in the mild (n = 56), severe (n = 49), and critical (n = 35) groups. Log10 (cytokine expression) was calculated for each row (each cytokine) and used for graphical visualization. B-G. Serum concentration of cytokines with different disease severities at baseline. H-I. Spearman rank correlation analysis was performed to evaluate the correlation of serum IL-6 (H) and IL-10 (I) with COVID-19 severity in PIWO

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The longitudinal changes of different inflammation markers in 13 severe and 12 critical PIWO showed that above six cytokines waned with the extension of hospital stay among the majority of patients in severe group, while critically ill PIWO demonstrated the stable and high levels of inflammatory cytokines, so is CRP and PCT (Supplementary Figs. 9, 10).

Spearman’s correlation analysis demonstrated that the inhibition rate of NAb against WT and BA.4/5, the concentrations of IgG anti-RBD antibodies, and the levels of total anti-SARS-CoV-2 antibodies were all negatively correlated with the expression of IL-1β, IL-10 and TNF-α, while the level of total anti-SARS-CoV-2 antibodies was positively correlated with the counts of B lymphocytes. In addition, IL-2R and IL-10 were also inversely associated with the level of T lymphocyte subsets such as CD3+T, CD4+T, CD8+T cells. Furthermore, the severity of infection had positively correlation with male gender, and previous immunosuppressive therapy, and the levels of IL-6 and IL-10. Poor prognosis at the time of discharge is associated with high inflammatory cytokines, low B lymphocyte and T-cell subsets (Supplementary Fig. 11).

Risk factors associated with the COVID-19 severity and PIWO death

According to the adjusted Model 1, we identified total anti-SARS-CoV-2 antibodies and CD4+T cell counts were associated with mild condition, whereas male, concomitant diabetes, neutrophil counts and SAA were significantly risk factors linked with severity. When all variables were included into the adjusted Model 2, immunosuppressive therapy before infection and IL-10 had also been proved as the independent risk factors (Table 3).

Table 3 Risk factors for severe and critical illness in PIWO
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Because no patient with mild disease were died of the disease progression, the characteristics of surviving and nonsurviving PIWO in severe and critical groups were compare. Compared with the survivors, nonsurvivors who were mainly in the critical condition (10/11, 90.91%) and had received IMV (8/22, 72.72%), exhibited immunosuppression, which manifested as the lower positive rates of total anti-SARS-CoV-2 antibodies, anti-RBD IgG, and NAbs against WT and BA.4/5 along with lower counts of CD3+T cells and CD4+T cells. In addition, the level of IL-6, IL-8, and IL-10 in nonsurviving PIWO were significantly higher than that in surviving PIWO. Furthermore, baseline D-Dimer, creatine kinase, myoglobin, LDH, and creatinine levels in PIWO who died were higher than those who survived, indicating abnormal coagulation, myocardial injury, or kidney damage. Among the 11 nonsurvivors, 8 died of respiratory failure, 2 of sudden cardiac death, and 1 of renal failure (Table 3 and Supplementary Fig. 12).

The statistically significant indicators in Table 4 were included in univariate regression analyses. Myoglobin, LDH, CD4+T cells, negative total anti-SARS-CoV-2 antibody, negative IgG anti-RBD antibody, negative NAb-BA.4/5, and negative NAb-WT were the independent factors associated with the death outcome in PIWO with severe or critical condition. Multivariate logistic regression analyses with the above risk and protective factors showed that LDH was a significant risk factors contributing to the death of PIWO (Table 5).

Table 4 The comparison between dead and surviving patients in severe and critical group
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Table 5 Identified risk factors for death in severe/critical PIWO
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Discussion

With the high incidence of Omicron infections but lower disease severity, Chinese authorities altered the epidemic prevention and control strategy, and changed the “dynamic zeroing policy” policy to the “reopening in an orderly and effective manner” policy on December, 7, 2022. However, owing to the high infectivity of Omicron, the strategy led to a huge health burden on the public, with the number of PIWO surging and reaching a peak of 6.94 million [28]. Moreover, severely ill and nonsurviving patients in the hospital reached a peak of 128,000 and daily peak of 4,273, respectively [28]. Therefore, the early identification and dynamic monitoring of the immune responses and inflammation characteristics of severe and critical PIWO can help to explore the potential pathological mechanism of disease progression. This present study accurately and extensively analyzes the anti-SARS-CoV-2 specific antibodies and lymphocyte subset alterations in addition to the expression pattern of inflammation factors among severely and critically ill PIWO as well as nonsurvivors during acute infection.

This retrospective study included 56 mild, 49 severe, and 35 critical PIWO during the loosen policy of China's epidemic control. Compared with previous studies (Supplementary Table 6), our research further demonstrates the levels of CD4+T cell, CD8+T cell, B cell, and NK cell were negatively correlated with COVID-19 severity, while pro-inflammation cytokines IL-6 and IL-10 positively. In addition, we found that (1) During acute infection, we showed an incremental trend of specific anti-SARS-CoV-2 antibodies first, which then decreased with disease severity; (2) The incidence of severe cases and the levels of the four specific antibodies against SARS-CoV-2 displayed the opposite trend in PIWO with critical illness over time; (3) Negative antibody responses in severe/critical PIWO at baseline did not increase with therapeutic intervention; (4) Nonsurvivors exhibited disordered features of immunocompromised, hyperinflammatory, abnormal coagulation and myocardial injury; (5) Combined diabetes, receiving immunosuppressive drugs, SAA, IL-10 and neutrophil counts were independently associated with severe and critical illness in PIWO, and high LDH was the significant risk factor for death in PIWO with severe or critical condition.

Several studies have reported that SARS-CoV-2-specific antibody titers were higher in patients with moderate/severe illness than in patients with asymptomatic/mild illness over the course of SARS-CoV-2 infection [29,30,31]. Moreover, males produced stronger SARS-CoV-2 -specific antibody responses than females [32] because of higher levels of ACE2 expression in men than in women [33]. Likewise, in the present study, anti-RBD IgG and NAbs against WT and BA.4/5 in PIWO with severe disease were higher than those with mild disease. The body's immune system generates immunoglobulin M (IgM) within 3–5 days of infection and produces IgG antibodies within 7 days to response the SARS-CoV-2 and exert protective functions[34]. NAbs prevent SARS-CoV-2 from binding to host cells, or prevent the conformational changes required to mediate fusion with host cell membranes, non-NAbs can activate immune effector cells through the interaction between Fc region and Fc receptor to clear viruses or infected cells [35]. However, antibody-dependent phagocytosis and antibody-dependent cellular cytotoxicity [36, 37], aberrant glycosylation patterns were observed in the anti-SARS-CoV-2 IgG antibodies among patients with severe disease but not in the those with mild illness, which induced high cytokine production, immune cell infiltration into the lungs, or platelet-mediated thrombosis, aggravating pathological damage in severe patients [38]. Thus, additional studies are required to interpret this dual role of antibodies in COVID-19, particular with regard to their pathological functions.

PIWO with non-mild (severe plus critical) disease had higher inhibition rates of NAb against WT and BA.4/5 and concentrations of anti-RBD IgG compared to those with mild disease (Supplementary Fig. 13), which is similar to patients infected with other SARS-CoV-2 strains [39, 40]. Of note, critically ill PIWO had the lower titers of total antibodies against SARS-CoV-2, IgG anti-RBD, and NAb against WT inhibition rates than severely. This characteristic was also observed in previous studies. Due to the decreased B cells and impaired immune response, patients admitted to ICU had lower anti-SARS-CoV-2 IgG than those not admitted to ICU [41], as did critically ill patients compared to severely ill patients [42]. Non-survivors also exhibited the deficient anti-RBD or/and anti-S IgG expression [43, 44]. The reasons for this impaired humoral immunity signature are as follows: (1) Patients with fatal outcomes showed the slower NAbs dynamics, even though they reached higher levels later in the disease trajectory, which is consistent with our current research. The delayed and incomplete antibody responses prolonged viral shedding. Elicited NAb responses within 14 day of symptom onset contributed to good recovery, whereas those induced at later time points lose protective effect [44] Anna et.al detected the anti-RBD IgG titers 34 days after onset of symptoms and found critical patients had higher antibodies, but the time of antibody production and the quality of antibodies are not enough to effectively control viral load [45]. (2) Critically ill COVID-19 patients exhibited functionally compromised antiviral T-cell response, whose SARS-CoV-2-specific CD4+ T cell inhibited IFN-γ, IL4, and IL-21 production [45]. IFN-γ could recruit other immune cells and dampens viral replication [46]; IL-4 induced suppressive functions of regulatory T cells through antagonizing Th1 and Th17 responses [47]; and IFN-γ and IL-4 inhibited the expression of ACE2 on cell surface and hinder SARS-CoV replication [48]. Furthermore, IL-21 can act directly on B cells and regulate the germinal center response [49]. Meanwhile, PIWO receiving immunosuppressive drug before infection was the risk factors for disease severity, suggesting the impaired B- and T-cell responses cannot withhold SARS-CoV-2 infection. (3) Moreover, in critically ill patients, vascular leakage enhanced circulating antigen-inexperienced naïve T cells infiltration to lungs and subsequent pulmonary edema. In view of the defects in germinal center induction (such as inefficient generation of T follicular helper cell (Tfh)) in the pathological tissues of deceased patients [50] and circulating Tfh dysfunction in critically ill patients [45]. Future studies should focus on the exact mechanism of late antibody response failure and the role of Tfh in COVID-19 immunity.

The expression of IL-6 and IL-10 gradually increases with disease severity in PIWO, this phenomenon was also seen in patients infected with other SARS-CoV-2 strains [51,52,53,54]. Previous studies have shown that IL-6 was the key molecule related to cytokine storm [55], and that it is extremely elevated in acute SARS-CoV-2 infection [56, 57]. Elevated serum IL-6 levels causing immune defects such as lymphopenia, impaired lymphocyte cytotoxicity, and endothelial activation could be partially restored by IL-6 blockade treatment with tocilizumab [55]. Additionally, IL-10 had dual role of anti-inflammatory and immune stimulation during the progression of COVID-19. It could inhibit Th1 cell activity and enhance ACE2 expression against increased pro-inflammatory mediators after infection [58,59,60]. However, elevated IL-10 leading to overstimulation of CD8+ T cells (potentially pro-inflammatory function) and IL-10 “resistance” (impaired anti-inflammatory function) amplify systemic inflammation [61]. Although IL-6 and IL-10 showed a consistent rise in levels independently of the genetic variant of the virus (ancestral Wuhan strain, Alpha, Delta and Omicron) compared with healthy donors, the level of these cytokines reduced with virus mutation [62, 63]. The current study yielded similar results. Severely ill, critically ill, and nonsurviving PIWO with higher IL-1β, IL-2R, IL-6, IL-8, or IL-10 levels did not develop cytokine storm syndrome. Upon infection, endothelial cells, epithelial cells, neutrophils, and monocytes cells release inflammatory mediators that activate immune cells, which collectively trigger a release of multiple proinflammatory cytokines and chemokines to eliminate SARS-CoV-2 virions [64]. However, a hyperactive cytokine response could increase the frequency of CD3+CD4+CD28−CD57+ T cells with the expression of programmed death 1, thereby contributing to T cell exhaustion or senescence and subsequent acute immunodeficiency [65]. This suggests that the unregulated activation of the immune system can easily cause severe and critical illness, leading to poor outcomes. In addition the levels of the aforementioned cytokines vary depending on the variant of the virus, indicating that mutations in viral proteins may be associated with the pathogenesis of the infection and mechanisms of immune responses. Debmalya et al. have found that mutations in structural S and N proteins and the pathogenicity-associated accessory protein ORF3a in the Omicron variant produced less pro-inflammatory epitopes and more anti-inflammatory epitopes compared with the Delta and other variants, which hampered proinflammatory IL-6 stimulation and upgraded IFN-γ and IL-4 induction efficacy [66].

As a proinflammation cytokine, IL-2R is a risk factor of severe disease and death prognosis [67, 68]. The present study revealed that IL-2R level increased with disease severity and was higher in nonsurvivors than in survivors. In addition, IL-2R was associated with decreased T lymphocyte subset counts [69, 70]. IL-2 is essential for the proliferation, differentiation, and function of Tregs, CD4, and CD8 cells [71, 72]. Thus, the increase in circulating IL-2R level reflects a decrease in cell response to IL-2 [73], indicating that IL-2R may act as a T cell negative regulatory factor contributing to lymphopenia. On the one hand, high CD25 (IL-2R ɑ chain) level inhibited Ki67 expression among CD3/CD4/CD8 T cells through IL-2 signaling inhibition [74], and on the other hand, overactivated inflammatory response promoted T cell apoptosis [75]. However, the situation of patients with COVID-19 is more complicated, and future research should focus on whether IL-2R is a decisive factor for lymphopenia in COVID-19.

In the current study, the total mortality rate of PIWO was 8% (11/140). Of note, 0%, 2%, and 29% deaths were observed in mild, severe, and critical groups, respectively, which was lower than the 35% or 37.8% mortality rate observed in critically ill French or American PIWO [6, 76].The deceased PIWO exhibited immunosuppressed features on hospitalization, which was demonstrated by low SARS-CoV-2 specific antibody seroconversion rates, lymphopenia, active proinflammatory cytokine production, and heart and kidney damage, which is similar to the dead patients infected with other strains who were characterized by lymphopenia, high inflammation status (like neutrophils to lymphocytes ratio, platelet to lymphocytes ratio, and systematic immune-inflammation index), and increased serum BUN and creatinine at admission [77]. Meanwhile, certain risk factors in PIWO with severe and critical illness also influenced the clinical prognosis. Indeed, myoglobin and LDH, which reflect myocardial injury, were independently risk factors associated with PIWO death. It has been shown that SARS-CoV-2 infection causes severe cardiovascular complications such as acute myocardial infarction and heart failure [78]. Cardiac myocytes specifically express ACE2 to which the SARS-CoV-2 spike protein RBD binds with high affinity, which explains cardiac involvement in COVID-19 [79]. Two patients in this study died of cardiac involvement, both had a history of coronary atherosclerotic heart disease. This is consistent with the findings of Loba et al. [80]. Meanwhile, compared with surviving PIWO, the nonsurvivor group had a far lower positive rate of the four SARS-CoV-2 antibodies, negative specific antibodies against SARS-CoV-2 increased the risk of death by five to nine times. Several studies have reported that B-cell deficient patients had prolonged in-hospital stay and higher mortality [81,82,83,84], and that convalescent plasma therapy relieved their clinical symptoms [85]. Because the included PIWO had no previous infection with other variants, vaccination might have produced a neutralizing effect to SARS-CoV-2 WT. Indeed, SARS-CoV-2-specific T cell responses with cross-reactivity can recognize multiple epitopes across the SARS-CoV-2 proteome, thereby providing protection against other variants [12, 86]. In addition, different vaccine platforms exhibited > 80% preservation of memory T cell responses, and CD4 and CD8 cell responses after vaccination were shown to be active against other variants (including Omicron) [87]. Therefore, it is necessary to vaccinate different target groups to resolve the gap in immunity and reduce the risk of severe illness and death.

This study has some limitations. As the monitoring of viral variants was based on data from the Chinese Center for Disease Control and Prevention, we did not perform for all included patients with COVID-19. The relatively small number of longitudinally followed-up hospitalized patients have yielded statistically insignificant results. Third, due to the complexity of treatment protocols and clinical complications such as secondary infections, we were unable to quantify their effects on immune and inflammatory parameters. Finally, because of sample restrictions, differences in SARS‐CoV‐2-specific CD4 cells, and activated/functional T cells among PIWO groups with different severity could not be analyzed.

Conclusion

Taking together, the trajectory of the peripheral antibodies, immune cells and inflammatory features were different between severely and critically ill PIWO. Impaired SARS-CoV-2-specific antibody responses were observed in PIWO with critical illness and adverse outcomes. Combined diabetes, immunosuppressive therapy before infection, SAA, IL-10 and neutrophil counts were the risk factors of severe/critical illness, and high LDH was correlated with death in PIWO. The current research and results are valuable to save lives, especially PIWO with elderly age, comorbidities and inadequate antibody responses.

Availability of data and materials

The data will be available upon requested. Professor Yongzhe Li (yongzhelipumch@126.com) and Shuqin Guo (baoding8888@126.com) are responsible for data

provision.

Abbreviations

ACE2:

Angiotensin-converting enzyme 2

COVID-19:

Coronavirus disease 2019

CRP:

C-reactive protein

IL:

Interleukin

IQR:

Interquartile range

IMV:

Invasive mechanical ventilation

LDH:

Lactate dehydrogenase

NAb:

Neutralizing antibodies

NK cells:

Natural killer cells

PIWO:

Patients infected with Omicron

PCT:

Procalcitonin

RBD:

Receptor‐binding domain

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

SAA:

Serum amyloid A

SD:

Standard deviation

TNF-α:

Tumor necrosis factor α

WT:

Wild type

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Acknowledgements

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Funding

This work was supported by the Beijing Municipal Natural Science Foundation (M23008, 7234383), National Key Research and Development Program of China (2018YFE0207300), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-124), China Postdoctoral Science Foundation (2023T160060), and the Baoding Key Laboratory of research on the pathogenicity and predictive value of autoantibodies (2163P045).

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Author notes

  1. Yongmei Liu, Yaping Guo, Haoting Zhan and Xin Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory, State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 No. 1, Shuaifuyuan, Dongcheng District, Beijing, 100010, China

    Yongmei Liu, Haoting Zhan, Xiaomeng Li, Haolong Li, Linlin Cheng & Yongzhe Li

  2. Department of Clinical Laboratory, Baoding First Central HospitalBaoding NO.1 Central Hospital, No. 320, Great Wall North Street, Baoding, Hebei, 071000, China

    Yaping Guo, Xin Liu, Jingjing Cui, Sha Feng & Xiaoyan Li

  3. Department of Endocrinology, Baoding NO.1 Central Hospital, No. 320, Great Wall North Street, Baoding, Hebei, 071000, China

    Shuqin Guo

  4. Department of Clinical Laboratory, Peking University People’s Hospital, NO.11, Xizhimen South Street, Beijing, 100035, China

    Xiaomeng Li

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Contributions

YML and HTZ designed the research, analyzed the data, drafted the first manuscript, and constructed the figures. YPG was responsible for managing the operation of experiments. XL was responsible for the selection of participants, the collection of patient data, and the quality control of experimental operations. JJC undertook the work of reviewing medical records. SF and XYL performed experiment operations. XML, HLL, and LLC organized data and searched literature. YZL, YPG and LLC were responsible for the support of experimental funds. YML, HTZ, YZL, and SYG provided direction and guidance throughout the preparation of this manuscript. YZL and SYG designed the research, supervised the work, and reviewed the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Shuqin Guo or Yongzhe Li.

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Ethics approval and consent to participate

This study was approved by Medical Ethics Committee of Baoding First Central Hospital ([2022]059). Informed consents were obtained from all enrolled patients.

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The authors declare no competing interests.

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Liu, Y., Guo, Y., Zhan, H. et al. Immune and inflammation features of severe and critical Omicron infected patients during Omicron wave in China. BMC Infect Dis 24, 809 (2024). https://doi.org/10.1186/s12879-024-09652-y

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BMC Infectious Diseases

ISSN: 1471-2334

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