Omicron infection alters the profile of organ failure in severe COVID-19: a multicenter study comparing Omicron and the wild-type strain

Abstract

Introduction

The Omicron variant of SARS-CoV-2 has exhibited altered transmissibility and virulence compared with the Wild-type strain. Currently, no research has focused on the differences in organ failure caused by the two strains. Understanding the clinical characteristics and organ failure patterns of Omicron infection is essential to improve management strategies for severe cases.

Methods

This multicenter retrospective observational study included two cohorts: the Omicron cohort, consisting of 7,000 COVID-19 patients admitted to 10 national research centers in China from December 2022 to January 2023, and the Wild-type cohort, consisting of 733 patients from designated hospitals during the early outbreak in 2020. Demographic, clinical, laboratory, and treatment data were collected and analyzed. We compared the differences in patient characteristics, developments of organ dysfunction and outcomes between the two cohorts. Multivariate logistic regression models were employed to identify risk factors for severe COVID-19 and death.

Results

The Omicron cohort included 7000 patients, 1551 (22.2%) of whom had severe cases. The median age of the patients was 73.0 [60.0, 84.0] years, with 4319 male patients (61.7%). Regarding underlying comorbidities, 5305 patients (75.7%) presented with at least one chronic condition, most frequently hypertension (46.0%) and diabetes mellitus (26.3%). The overall in-hospital mortality rate was 15.5%, and 5666 patients (80.9%) experienced at least one organ dysfunction, with respiratory failure being the most prevalent (72.6%). Compared with the Wild-type cohort, severe Omicron patients were older, had a greater proportion of males, and more comorbidities. Severe Omicron cases showed a distinct pattern characterized by a higher prevalence of extrapulmonary organ dysfunction, particularly kidney failure. Multivariate analysis identified older age, male sex, lack of vaccination, preadmission corticosteroid use, and comorbidities as independent predictors of severe disease. Among severe patients, older age, malignancy, hypoxemia, thrombocytopenia, and elevated troponin were independent predictors of mortality.

Conclusion

After the widespread emergence of Omicron, severe COVID-19 predominantly affected older patients with multiple comorbidities and showed a different organ failure spectrum, with greater extrapulmonary involvement, particularly kidney failure, in the early phase of hospitalization. These findings highlight the evolving clinical and pathophysiological features of COVID-19 in the Omicron era.

Clinical trial number

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-026-12997-1.

Introduction

Since the onset of the Coronavirus Disease 2019 (COVID-19) pandemic, over 700 million people have been infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), resulting in more than 6.9 million deaths worldwide. The Omicron variant was first identified in Africa in November 2021 and became the dominant global strain by January 2022 [1]. Although previous studies suggested that the Omicron variant has reduced virulence, primarily causing upper respiratory tract infections, it remains highly transmissible [2]. In China, after the large-scale spread of the Omicron variant, an outbreak of the Omicron variant occurred in December 2022. The number of severe COVID-19 cases subsequently increased sharply. By late December to early January, the daily increase in severe cases had approached 10,000, placing an immense burden on health care resources in a short period [3, 4].

The characteristics of patients infected with different SARS-CoV-2 genotypes vary significantly. A large multicenter retrospective study conducted in South Africa demonstrated notable differences in demographic characteristics, hospitalization rates and mortality rates during outbreaks caused by the wild-type strain, Beta variant, Delta variant, and Omicron variant [5]. Compared with previous variants, the Omicron variant was associated with significantly lower hospitalization and mortality [6]. However, since the implementation of the epidemic prevention policy, the number of infected patients in China has increased rapidly. The peak number of hospitalized COVID-19 patients was 1.625 million, with a daily increase of nearly 10,000 severe cases [2, 5]. This finding indicates that the population characteristics may have changed.

Organ failure is a key determinant of poor prognosis in COVID-19. Recent studies have suggested that organ dysfunction may vary across different SARS-CoV-2 variants [7, 8]. However, there is limited research on the differences in organ failure between the Omicron and Wild-type strains. Although risk factors for patients infected with different variants have been identified, large multicenter studies are still lacking to elucidate the clinical characteristics and risk factors associated with severe COVID-19 and mortality during the nationwide spread of the Omicron variant [9, 10].

Therefore, the aim of this study was to describe the clinical characteristics of patients infected with the Omicron variant of COVID-19, especially in terms of organ dysfunction, compared with patients infected with the Wild-type strain, and to identify the risk factors for severe cases and death in patients infected with the Omicron variant.

Methods

This analysis was reported in light of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement [see STROBE Checklist]. This study was a multicenter retrospective observational study that included two cohorts. The Omicron cohort included patients with SARS-CoV-2 who were admitted to 10 national research centers between December 1, 2022 and January 31, 2023 [see Additional file, Table S1]. According to Chinese Center for Disease Control and Prevention (China CDC) surveillance data, all valid SARS-CoV-2 genome sequences reported nationwide during this period were identified as the Omicron variant [3]. This study was approved by the Clinical Research Ethics Committee of the Affiliated Zhongda Hospital, Southeast University (2023ZDKYSB003). The Wild-type cohort consisted of patients with SARS-CoV-2 who were admitted to designated hospitals between January 1 and February 29, 2020 [see Additional file, Table S1]. This period predated the emergence of variants of concern; thus, the circulating virus was exclusively the ancestral strain. The study was approved by the ethics committee of Jin Yin-tan Hospital (KY-2020-10.02). The informed consent was waived due to the retrospective and observational nature of the study.

Inclusion criteria

The Omicron cohort included adult patients who met at least one of the following criteria: (1) had clinical symptoms consistent with COVID-19 infection; (2) had a positive COVID-19 nucleic acid test; (3) had a positive COVID-19 antigen test; or (4) had a COVID-19-specific IgG (Immunoglobulin G) antibody level in the recovery phase that was at least four times higher than that in the acute phase. During the nationwide surge, case identification was primarily symptom-driven. Unlike in 2020, widespread community screening had ceased.

The Wild-type cohort included COVID-19 patients from a previous study completed by our team [11]. All adult patients with COVID-19 who were admitted to ICUs were included in this study, if they met the following inclusion criteria: (1) laboratory-confirmed diagnosis of COVID-19; (2) severe respiratory failure requiring advanced respiratory support [i.e. high flow nasal oxygen (HFNO), noninvasive mechanical ventilation (NIV), and invasive mechanical ventilation (IMV)], circulatory shock, or multiorgan failure. Patients were identified through a strategy of universal screening and active surveillance. “Confirmed cases” were defined strictly by positive RT-PCR results from pharyngeal swabs.

Data collection

The day of hospital admission was defined as hospital day1. Clinical characteristics, including sex, age, height, weight, body mass index (BMI), comorbidities, vaccination status, and preadmission treatment, were recorded. Additionally, laboratory data collected included complete blood count, electrolytes, hepatic and renal function tests, coagulation tests, arterial blood gas, C-reactive protein (CRP), creatine kinase isoenzyme (CK-MB) and hypersensitive cardiac troponin I (TnI) levels on day1, 3, and 7. Treatment included respiratory support and the main therapeutic medications. Sequential organ failure assessment (SOFA) scores were calculated according to standard criteria. SOFA scores were calculated using laboratory and physiological measurements obtained on day1, day3, and day7 after ICU admission. Testing frequency was determined by routine clinical practice. If no data were available within this time window, the corresponding SOFA component was treated as missing.

Outcome

The primary outcomes were incidence of severe COVID-19 and in-hospital mortality. Patients who required high-flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation to maintain respiratory function were defined as having severe COVID-19. Patients who died without receiving respiratory support were also defined as having severe COVID-19 [11].

The secondary outcome measures included the length of hospital stay and organ dysfunction during hospitalization. Organ dysfunction was defined as a SOFA score of ≥ 2 in any individual organ system. To ensure comparability, comparisons of characteristics, developments of organ dysfunction and outcomes were performed exclusively between the severe strata of both cohorts.

Statistical analysis

Continuous variables that followed a normal distribution are expressed as the mean ± standard deviation. Otherwise, the data are expressed as the median and interquartile range for continuous variables. Categorical variables are described as frequencies and percentages. Continuous variables were compared via Student’s t test or nonparametric tests, depending on the distribution. Comparisons of categorical variables were conducted via the chi-square test or Fisher’s exact test, as appropriate. A two-sided P < 0.05 was considered statistically significant.

First, missing data for baseline characteristics and daily organ function parameters were handled using Multiple Imputation by Chained Equations (MICE) based on the Random Forest (RF) algorithm [see Additional file, Table S1, Table S2, Table S3]. We generated five imputed datasets. The Random Forest method was employed to accommodate potential non-linear relationships and interactions between variables.

Second, to determine the association between waves and organ failure, univariate logistic regression analysis was performed. Variables with P < 0.05 in univariate analysis were entered into multivariable logistic regression models. Additionally, propensity score matching (PSM) was used to minimize baseline imbalances.

Third, to clarify the risk factors for severe and death cases, we performed univariate logistic regression analysis. Variables with P < 0.05 in univariate analysis were entered into multivariable logistic regression models. We used Generalized Linear Mixed Models (GLMM) to account for center-level heterogeneity. We treated the study center as a random effect to account for unmeasured center-level heterogeneity, while patient outcomes remained fixed effects. All the statistical analyses were performed via IBM SPSS Statistics Version 26.0.0 and R Version 4.3.3.

Results

Patient enrollment

A cohort of 7,000 patients admitted to 10 centers across China was included in the Omicron cohort, of whom 1,551 (22.2%) had severe disease. The Wild-type cohort comprised 733 COVID-19 patients in Wuhan, all with severe illness [see Additional file, Table S4, Table S5, Figure S1].

Baseline demographic and clinical characteristics

In the comparison between the severe Omicron cohort (n = 1551) and the Wild-type cohort (n = 733), significant differences in clinical characteristics were observed. Compared with that of the Wild-type cohort, the median age of the Omicron cohort was notably greater (78.00 [69.00, 85.00] vs. 65.00 [56.00, 73.00], P < 0.001). There was a greater proportion of male patients in the severe Omicron cohort (70.0% vs. 65.2%, P = 0.024). Comorbidities, including hypertension (53.9% vs. 42.0%, P < 0.001), diabetes (32.1% vs. 18.8%, P < 0.001), coronary heart disease (20.3% vs. 12.7%, P < 0.001), chronic obstructive pulmonary disease (7.7% vs. 5.0%, P = 0.020), chronic heart failure (14.2% vs. 2.2%, P < 0.001), chronic kidney disease (15.0% vs. 1.8%, P < 0.001), rheumatic diseases (4.2% vs. 0.7%, P < 0.001), immunosuppression (3.6% vs. 0.8%, P < 0.001), and malignant tumors (12.2% vs. 3.3%, P < 0.001), were more prevalent in the severe Omicron cohort (Table 1).

Table 1.

Demographic and clinical characteristics of severe cases in different cohorts

	Omicron Cohort (n = 1551)	Wild-type Cohort (n = 733)	P
Age, median [IQR], years	78.00 [69.00, 85.00]	65.00 [56.00, 73.00]	<0.001
Sex, n(%)			0.024
Female	465 (30.0)	255 (34.8)
Male	1086 (70.0)	478 (65.2)
Comorbidities, n(%)
Hypertension	838 (53.9)	308 (42.0)	<0.001
Diabetes	499 (32.1)	138 (18.8)	<0.001
Coronary heart disease	316 (20.3)	93 (12.7)	<0.001
COPD	119 (7.7)	37 (5.0)	0.020
Chronic heart failure	220 (14.2)	16 (2.2)	<0.001
CKD	233 (15.0)	13 (1.8)	<0.001
Liver cirrhosis	33 (2.1)	11 (1.5)	0.309
Rheumatic diseases	66 (4.2)	5 (0.7)	<0.001
Immunosuppression	56 (3.6)	6 (0.8)	<0.001
Malignant tumors	190 (12.2)	24 (3.3)	<0.001
Prognosis
Number of deaths, n (%)	1085 (70.0)	475 (64.8)	< 0.001
Length of hospital stay, median [IQR], day	10.8 [5.0, 19.5]	16.0 [9.0, 25.0]	< 0.001
Organ dysfunction, n (%)
Respiratory failure	1380 (89.0)	682 (93.0)	0.002
Coagulation dysfunction	772 (50.0)	339 (46.2)	0.116
Liver dysfunction	119 (7.7)	100 (13.6)	0.005
Kidney dysfunction	366 (23.6)	87 (11.9)	< 0.001

COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease

Comparison of outcomes and organ failure between cohorts

Compared with that in the Wild-type cohort, mortality was slightly greater in the severe Omicron cohort (70.0% vs. 64.8%, P < 0.001), with shorter hospital stays (10.8 [5.0, 19.5] vs. 16.0 [9.0, 25.0] days, P < 0.001). Throughout the hospitalization period, respiratory failure was slightly less common in the severe Omicron cohort (89.0% vs. 93.0%, P = 0.002), whereas kidney dysfunction was significantly more prevalent (23.6% vs. 11.9%, P < 0.001). Other organ dysfunctions, such as coagulation and liver dysfunction, were not significantly different between the two cohorts (Table 1).

For the analysis of organ failure during the first day of hospitalization in patients, the proportion of organ failure varied by organ type. In Wild-type cohort, respiratory failure was more prevalent, with 82.3% of patients experiencing lung dysfunction. This was significantly higher than the 75.4% observed in the Omicron cohort (P < 0.001). Conversely, compared with Wild-type cohort, Omicron cohort exhibited a notably higher prevalence of extra-lung organ dysfunction (35.5% vs. 24.8%, P < 0.001). Particularly, kidney failure was more prominent in the Omicron cohort (19.5% vs. 6.0%, P < 0.001). Liver failure was observed in a slightly lower proportion of Omicron cohort (5.6% vs. 7.5%, P = 0.097), though this difference was less pronounced. As for coagulation dysfunction, there was no significant difference between1the two cohorts (16.7% vs. 16.8%, P = 0.999) (Fig. 1).

Fig. 1.

Proportion of severe patients with different variants developed organ dysfunction on day 1

Organ-specific patterns and temporal changes

To clarify the development of disease, the incidence of extra-lung organ failure and hospital mortality were compared between two cohorts. Although there were significant differences in extrapulmonary organ failure on the first day of hospitalization, at Day 3, the difference between the two variants became not statistically significant, with Omicron cohort showing 30.4% and Wild-type cohort showing 31.7% of patients with extra-lung organ failure (P = 0.568). Moreover, by Day 7, Omicron patients exhibited a significantly lower proportion of extra-lung organ failure compared to Wild-type patients (23.7% vs. 31.1%, P < 0.001). The hospital mortality of the two cohorts of patients also differed obviously. At Day 3, compared to Wild-type cohort, the hospital mortality of Omicron cohort was notably higher (28.5% vs. 4.65%, P < 0.001). At Day 7, the hospital mortality of Omicron cohort was higher as well (28.5% vs. 12.8%, P < 0.001) (Fig. 2).

Fig. 2.

Number of severe patients with different variants developed organ dysfunction and mortality of severe patients with different variants

The Sankey diagram shows the dynamic changes in organ failure among the two cohorts of severe patients within 7 days of hospitalization. On the first day, patients presented similarly, with varying levels of organ dysfunction. However, a greater number of patients infected with Omicron died within this 7-day period (Fig. 3).

Fig. 3.

Temporal changes in organ dysfunction in severe patients with different variants

When analyzing individual organ systems (Fig. 4), Omicron patients demonstrated a higher incidence and persistence of renal and coagulation failure, while hepatic failure occurred less frequently than in the Wild-type strain cohort. Respiratory failure dominated in both groups, and most patients with respiratory failure had poor prognosis. These findings suggest that although Omicron infection is associated with milder respiratory involvement, extrapulmonary organ dysfunction—particularly renal and coagulation failure—may play a prominent role in progression.

Fig. 4.

Temporal changes in different organ dysfunction in severe patients with different variants

Association between waves and organ failure

In multivariable logistic regression analyses adjusting for age, sex, and comorbidities, the Omicron wave remained independently associated with an increased risk of kidney failure on day 1 (OR 2.43, 95% CI 1.72–3.44, P < 0.001) and within 7 days (OR 1.57, 95% CI 1.20–2.07, P < 0.001) [see Additional file, Table S6, Table S7.]. In contrast, Omicron wave was associated with a lower risk of respiratory failure on day 1 (OR 0.64, 95% CI 0.51–0.80, P < 0.001) and within 7 days (OR 0.42, 95% CI 0.31–0.57, P < 0.001) [see Additional file, Table S8, Table S9].

After PSM (1:1), 532 patients were included in each cohort. Baseline characteristics were well balanced, with all standardized mean differences below 0.1. Despite matching for comorbidities, kidney dysfunction on day 1 remained more frequent in the Omicron cohort compared to the Wild-type cohort (15.6% vs. 7.5%, P < 0.001). Similarly, kidney dysfunction within 7 days occurred more often in the Omicron cohort (19.0% vs. 13.5%, P = 0.02). In contrast, respiratory, coagulation, and liver dysfunction were more common in the Wild-type cohort [see Additional file, Table S14].

Risk factors for severe disease in the omicron cohort

A comparison between non-severe patients and severe patients in the Omicron cohort is shown in the supplementary material [see Additional file, Table S15]. A comparison between survival and death in the severe Omicron cohort is shown in the supplementary material [see Additional file, Table S16].

After multivariate logistic regression analysis, male sex, older age, lower BMI, lack of vaccination, the use of corticosteroids before admission, the presence of underlying comorbidities, lower oxygenation, a strong inflammatory response, myocardial injury, liver injury, renal injury, and coagulation dysfunction were associated with an increased risk for severe cases [see Additional file, Table S17]. Twenty-two independent risk factors associated with the risk of severe disease were included in the forest plot (Fig. 5). In the GLMM accounting for center-level heterogeneity, the association between male sex, older age, lack of vaccination, the use of corticosteroids before admission, the presence of underlying comorbidities, lower oxygenation, a strong inflammatory response, myocardial injury, liver injury, renal injury and severe cases remained statistically significant [see Additional file, Table S18].

Fig. 5.

Risk of severe disease for patients with COVID-19 and risk of death for patients with severe COVID-19

Risk factors for mortality among severe cases

After multivariate logistic regression analysis, older age, the presence of malignant tumors, lower oxygenation, decreased platelet count, and elevated troponin levels were associated with an increased risk for death in severe patients [see Additional file, Table S19]. Five independent risk factors associated with the risk of death were included in the forest plot (Fig. 5). In GLMM accounting for center-level heterogeneity, the association between older age, the presence of malignant tumors, lower oxygenation, decreased platelet count, elevated troponin levels and death remained statistically significant [see Additional file, Table S20].

Discussion

In this large-scale, multicenter, retrospective study of 7,000 patients with COVID-19 caused by the Omicron variant, we reported an in-hospital mortality of 70.0% among severe patients, which exceeds the 64.8% mortality observed among severe patients infected with the wild-type strain. The organ failure profile in patients with severe Omicron variant infection differed from wild-type strain. The Wild-type strain was associated with more severe pulmonary damage, while the Omicron strain resulted in a higher prevalence of extra-lung organ failure, particularly affecting the kidneys. Additionally, we explored independent risk factors that contributed to progression to severe disease and death. Notably, the use of corticosteroids before admission served as an independent risk factor for severe COVID-19. We selected these two cohorts as they represent the significant pandemic surges in China. The ‘Dynamic Zero-COVID’ policy during the Delta wave resulted in limited and geographically dispersed severe cases, making the construction of a comparable large-scale multicenter cohort unfeasible.

During the epidemic of Omicron, severe COVID-19 was characterized by older age, a greater proportion of males, and a greater prevalence of comorbidities. During the initial 3 years of the COVID-19 pandemic, China maintained a low level of COVID-19-related excess mortality by enforcing strict mitigation measures [2]. Stringent control measures limit population movement, providing significant protection to vulnerable populations, such as elderly individuals living at home [12]. However, after the changes in mitigation measures, these previously protected populations became exposed to the pandemic of COVID-19, leading to infection and adverse outcomes; this may explain the characteristics of the severe Omicron cohort in our study [13]. During the widespread Omicron outbreak in Hong Kong, China, the population also exhibited an increased mortality rate, which was driven primarily by elderly individuals who were unvaccinated [14]. This is consistent with the characteristics of the population in our study. While we analyzed the number of vaccine doses, we lacked granular data on the interval between the last dose and infection and the specific vaccine manufacturer. Given that most vaccinations in China were administered months prior to the Omicron surge, the protective effect observed in our study might be attenuated by waning immunity. The in-hospital mortality rate of 70.0% observed in our severe Omicron cohort is notably higher than that reported in many international studies regarding the Omicron era. This discrepancy must be interpreted within the specific context of the study.

It is crucial to acknowledge that the two cohorts represent distinct eras with fundamentally different medical contexts. The Wild-type cohort (early 2020) was managed without specific antiviral therapies or vaccination. In contrast, the Omicron cohort (late 2022) had access to evolved standard of care, including vaccines and small-molecule antivirals. The fact that high severity and mortality persisted despite these medical advancements underscores the frailty of the older patients in the Omicron surge. Second, the study coincided with a massive surge in infections that challenged the surge capacity of the healthcare system. The shortage of ICU beds and ventilators likely contributed to the high mortality, as optimal respiratory support could not always be guaranteed for every patient. Therefore, this mortality should not be viewed as a measure of the intrinsic virulence of the Omicron variant, but rather as a reflection of the outcomes for the most vulnerable patients during a period of healthcare resource strain.

Our finding of risk factors for severe and death cases is consistent with the majority of previous studies on risk factors for severe COVID-19 [9, 15]. Notably, preadmission corticosteroid use was identified as an independent risk factor for severe cases in our study. The risk of developing severe disease was 1.96 times greater in patients who had used corticosteroids before admission than in those who had not. In the early stages of COVID-19 treatment, the use of glucocorticoid therapy was highly controversial. A randomized controlled trial by Angus et al. revealed that methylprednisolone did not reduce mortality in hospitalized COVID-19 patients [16]. The controversy was largely settled by the RECOVERY trial, a large-scale randomized controlled study, which demonstrated that dexamethasone reduced 28-day mortality in patients requiring invasive mechanical ventilation or supplemental oxygen but did not contribute to reducing mortality in patients without supplemental oxygen [17]. As a result of these findings, glucocorticoid therapy has since become a standard treatment for patients hospitalized with Covid-19. Additionally, the evidence on glucocorticoid therapy is limited by variations in doses, patient conditions, and disease severity. The effectiveness of glucocorticoids in severe viral respiratory infections likely depends on selecting the right dose, timing, and patient. High doses may be more harmful than beneficial, especially when viral replication is still active and inflammation is minimal. This may relate to slower viral RNA clearance has been observed in patients treated with glucocorticoids during SARS (severe acute respiratory syndrome), MERS (Middle East respiratory syndrome), and influenza [18–20]. Unfortunately, due to the retrospective nature of the data collection, we could not reliably distinguish the specific indications for preadmission steroids, strictly causal inferences cannot be drawn. The association between preadmission corticosteroid use and severe outcomes likely reflects indication bias, where patients with more severe initial symptoms were more likely to receive steroids prior to hospital admission.

Moreover, the organ failure profile in patients with severe Omicron variant infection differs from wild-type strain. Our study indicated that patients with Omicron exhibited more severe extrapulmonary organ damage upon hospitalization. Although the proportion of patients with extrapulmonary organ damage gradually decreased over time, there was a corresponding increase in mortality, which may have explained the higher in-hospital mortality rate observed in Omicron patients. Additionally, the observed reduction in extrapulmonary organ failure at later time points in the Omicron cohort may partly reflect survival bias. Patients presenting with more advanced organ dysfunction may have been at increased risk of hospital mortality, thereby influencing the composition of the population assessed at later time points. This dynamic may contribute to the temporal differences observed between cohorts. Existing studies have shown that certain mutations in the Omicron spike protein enhance its binding affinity to ACE2 (angiotensin-converting enzyme 2), while reducing its dependence on TMPRSS2 and favoring cell entry through the endocytic pathway [21, 22]. These changes may alter its entry efficiency in different epithelial and tissue types, thereby potentially influencing the viral tissue tropism across various organs and cells [23]. However, direct in vivo evidence confirming this mechanism’s role in multi-organ injury is still lacking. Viral-mediated imbalance of the endothelial dysfunction and cytokine storm are also important causes of organ damage [24, 25]. Although Omicron tends to cause milder pulmonary pathology, its systemic inflammatory and vascular disturbances may still contribute to multi-organ injury [26]. In elderly patients or those with pre-existing organ dysfunction, even mild inflammatory stimulation can further exacerbate organ failure [27, 28]. These factors may underlie the altered pattern of organ injury observed in patients infected with the Omicron variant.

This study has several limitations. First, as a retrospective study conducted during a period of high-intensity transmission, although missing data for the major variables were minimal, we used imputation models to account for this. Second, as a retrospective observational study, some findings can only demonstrate associations rather than causal relationships, and further research is needed. Third, the study population in this research was collected over a relatively short period and therefore did not encompass all subvariants of the Omicron lineage, nor could it differentiate between the various Omicron subtypes. Fourth, during periods of intense transmission, medical resources may be relatively scarce, and variations in health care resources across different regions in China may influence patient outcomes, leading to different clinical results. Fifth, variant assignment based on temporal dominance poses a theoretical risk of misclassification. However, this bias is minimal, as the historical cohort predated variants, and surveillance data confirmed that Omicron accounted for effectively 100% of circulating strains during the study period.

Conclusions

After the large-scale spread of the Omicron variant, severe population was characterized by older age, male gender, and more comorbidities. The organ failure profile in patients with severe Omicron variant infection differs from wild-type strain by increased extrapulmonary involvement during the early phase of hospitalization, likely driven by the interaction between the virus and a highly vulnerable elderly population under resource-constrained conditions. Older age, comorbidities, and organ failure were key determinants of disease severity and mortality.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

SARS‑CoV‑2

Severe acute respiratory syndrome coronavirus 2

COVID-19

Coronavirus disease 2019

STROBE

Strengthening the reporting of observational studies in epidemiology

MICE

Multiple Imputation by Chained Equations

RF

Random Forest

PSM

Propensity Score Matching

GLMM

Generalized Linear Mixed Models

IgG

Immunoglobulin G

BMI

Body mass index

CRP

C-reactive protein

CK-MB

Creatine kinase isoenzyme

TnI

Hypersensitive cardiac troponin I

SOFA

Sequential organ failure assessment

COPD

Chronic obstructive pulmonary disease

CKD

Chronic kidney disease

SARS

Severe acute respiratory syndrome

MERS

Middle East respiratory syndrome

ACE2

Angiotensin-converting enzyme 2

Author contributions

RY, RZ, and XC contributed equally to this work and share joint first authorship. RY and NS had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the analyses. Concept and study design: HC and JX . Data acquisition, analysis, and interpretation: RY, RZ, XC, NS, and JX . Statistical analysis: NS, and RY . Drafting of the manuscript: NS, RY, and RZ . Critical revision of the manuscript for important intellectual content: HQ, HZ, JJ, CW, and SX . Funding acquisition: HQ, YY and JX . Administrative, technical, or material support: MH, HZ, YW, and YY . Supervision: HQ, JX, and YY . All authors have read and approved the final manuscript.

Funding

The research was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0506500, 2023ZD0506506); the National Natural Science Foundation of China (82341032, 81930058, 82402565); National Key Research and Development Program of China (2022YFC2504405); Jiangsu Provincial Key Research and Development Program (BE2023602).

Data availability

The datasets used during the current study are not publicly available. However, de-identified data of this study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Clinical Research Ethics Committee of the Affiliated Zhongda Hospital, Southeast University (2023ZDKYSB003) and the Ethics Committee of Jin Yin-tan Hospital (KY-2020-10.02). Given its observational design, the study did not involve any medical, pharmacological, or behavioral interventions in addition to standard protocols used in physicians practice, regardless of the registry. Due to the retrospective nature of the study and the use of anonymized patient data, the requirement for written informed consent was waived. Research has been carried out and data concerning patient consent were handled in agreement with the principles laid out in the original Declaration of Helsinki and its later amendments.

Consent to participate

Not applicable.

Consent for publication

All authors have read the manuscript and consented for publication.

Competing interests

The authors declare no competing interests.