Impact of the first wave of COVID-19 on Crohn’s disease after the end of “zero-COVID” policy in China

Background The incidence and severity of coronavirus disease 2019 (COVID-19) among Crohn’s disease (CD) patients are unknown in China. This study aimed to clarify the clinical courses and outcomes of CD patients in the first COVID-19 wave after the end of “zero-COVID” policy in China. Methods Clinical characteristics, including vaccination doses and medications of 880 CD patients from a prospective cohort were collected for analysis. Results Of the enrolled patients (n = 880) who underwent nucleic acid or antigen testing for COVID-19 from Dec 7, 2022, to Jan 7, 2023, 779 (88.5%) were infected with COVID-19. Among the infected patients, 755 (96.9%) were mild, 14 (1.8%) were moderate, one patient with leukemia died of cerebral hemorrhage (mortality, 0.1%) and only 9 (1.2%) were asymptomatic. Fever, cough, headache and appetite loss were the most frequently observed symptoms in general, respiratory, neurological and gastrointestinal manifestations, respectively. The age and disease duration were significantly higher (40/32, 5.6/3.6, all p < 0.05) in moderate patients than those in mild patients. All other clinical characteristics, including CD activity and medication exposure, showed no significant differences between the above two groups. Furthermore, no significant difference in vaccination or comorbidities was observed between the two groups. Conclusion Most CD patients contracted the Omicron infection and experienced mild disease courses in the first COVID-19 wave attack after China ended the “zero-COVID” policy irrespective of vaccination dose or comorbidities.


Introduction
Crohn's disease (CD), one main type of inflammatory bowel disease (IBD), is a chronic inflammatory condition of the gastrointestinal tract with a relapsing-remitting and progressively disabling pattern (1). The management of CD during the coronavirus disease 2019 (COVID-19) pandemic has been a research priority for the IBD community worldwide over the last 3 years (2). Patients with CD, especially in the presence of immunosuppressive medications, are supposed to be at high risk of serious viral and bacterial infections (3). Evidence from studies in the phases of earlier variants (alpha, beta, gamma, and delta) revealed no differences in COVID-19 hospitalization or mortality between patients with IBD or without IBD (4), while advanced age and the presence of comorbid conditions were found to be key risk factors for severe infection (5). Very few data concerning the impact of the new Omicron strain with high transmissibility on CD patients have been reported (6)(7)(8).  vaccines are believed to play a protective role against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, concerns about vaccination efficacy are one reason for hesitancy (9). Along with the adjustment of the "zero-COVID" strategy in China on 7 December 2022, the first nationwide Omicron-based outbreak started shortly after the relaxation of nonpharmaceutical public health intervention measures (including social distancing, mass testing, quarantine and travel restrictions), and passed the peak rapidly within 1 month (Dec 8, 2022 to Jan 7, 2023) with more than 50,000 deaths. 1 The impact of this on CD patients who were naïve to COVID with different vaccination backgrounds should be clarified to promote our understanding of COVID-19 and CD management. This study aimed to clarify the clinical courses and outcomes of CD patients in the first COVID-19 wave after the end of "zero-COVID" policy in China.  Jan 7, 2023) were enrolled in this study ( Figure 1). Clinical data, including comorbidities, medications and vaccinations, were collected from the cohort database and follow-up information. The incidence and severity of COVID-19 among CD patients were analyzed. This study was approved by the Institutional Review Board of the Ethics Committee of the Second Affiliated Hospital, School of Medicine, Zhejiang University in China (approved No. 2023-0134). In all cases, informed written consent was obtained from participants or their legal surrogates before enrollment. The study followed the STROBE reporting guideline.

Patients
CD was diagnosed based on a combination of clinical, laboratory, endoscopic, cross-sectional imaging, and histological assessments. The exclusion criteria were as follows: (1) patients who were living abroad during the first wave; or (2) patients who did not undergo any nucleic acid or rapid antigen tests for COVID-19. All patients in the cohort were followed up in a short time to reduce recall bias and underreported bias.

Criteria for COVID-19 diagnosis and severity
COVID-19 diagnosis was based on viral tests (by nucleic acid or rapid antigen tests, irrespective of symptoms) and disease severity was classified according to the ninth edition of the COVID-19 diagnosis and treatment protocol (10). Symptomatic COVID-19 infections were

Data collection and procedure
Demographic (including sex and age) and diagnostic profiles (diagnosis, disease duration and chronic illness history) were extracted from the cohort database. The following information was collected during follow-ups: COVID-19 diagnosis status, COVID-19 symptoms, body mass index (BMI), COVID-19 vaccination doses, disease activity prior to COVID-19 infection [as defined by the Harvey-Bradshaw Index, HBI (12)], medication exposure at time of COVID-19 diagnosis and whether medications were discontinued, chest imaging and COVID-19 treatments. Patients with COVID-19 diagnosed less than 7 days prior were followed up again to confirm any progression on Jan 20th, 2023.

Statistical analysis
For continuous variables, the means (standard deviations, SDs) and medians (interquartile ranges, IQRs) were used for normally and nonnormally distributed data, followed by unpaired t tests and Mann-Whitney U tests when appropriate. Categorical variables were expressed as numbers (%) and compared using Fisher's exact test. p < 0.05 was considered statistically significant and SPSS (V.26.0) was used for all analyses.

Results
A total of 1,226 CD patients were extracted from the cohort database and 880 patients were enrolled for the final analysis. Of the enrolled patients, 779 (88.5%) were diagnosed with COVID-19 infection, of whom, 9 (1.2%) were asymptomatic, 755 (96.9%) were mild, 14 (1.8%) were moderate, and one patient with leukemia died of cerebral hemorrhage after COVID-19 infection ( Figure 1 and Table 1).
Fifteen percent of patients had at least one comorbidity in addition to CD, the most common being chronic hepatitis B virus infection (5.6%) and hypertension (3.1%). Comparative analysis between the infection and non-infection groups showed no difference in sex, age, disease duration, vaccination doses or comorbidities.
The vaccination doses and comorbidities of symptomatic patients are summarized in Table 3

Discussion
We used cohort-based clinical data and follow-up COVID-19 information to clarify the impact of Omicron on the infection-naïve CD population during the China's first wave after the end of "zero-COVID" policy. The results showed that most CD patients experienced symptomatic infections and mild clinical courses. The first nationwide COVID-19 wave in China started shortly after the implementation of measures, peaked in late December, then declined continuously and ended in late January 2 . From Dec 8th, 2022, to Jan 7th, 2023, the first wave of COVID-19 in China claimed more than 50,000 lives (see footnote 1). Although the dominant strains that drove the wave were Omicron BF.7 and BA.5.2, which were regarded as highly transmissible but low-virulence subvariants, COVID-19 still triggered great anxiety and stress among CD patients who had never been exposed to COVID. During the observation time, the incidence rate of COVID-19 among CD patients was 88.5%, which was approximately equal to that in the general population reported in Henan province in early January (urban 89.1%, rural 88.9%) (13). Among the infected patients, the majority of them experienced mild (96.9%) or moderate (1.8%) courses. Lu et al. recently reported that 96.97% of the general population infected with COVID-19 experienced mild or moderate symptoms during the same time of our study (14). This similar outcome may be associated with the younger age structure and use of biologics and immunosuppressants in our CD population (15). The lack of biosamples for further genetic analysis is our limitation, as CD patients were encouraged to follow home treatment during the pandemic. No severe/critical cases were observed in our study, and the only death case was caused by complications of leukemia, exacerbated by COVID-19. Given that hematological malignancies have a high mortality rate (29.3-40%) during COVID-19 (16,17), these groups of patients should be a priority for protection in future outbreaks.
Age and comorbidities are the most important prognostic factors for more severe COVID-19 among IBD patients according to previous studies of earlier variants (18,19). In the analysis of IBD medications, systemic corticosteroids, the combination of TNF antagonists with azathioprine and active IBD were associated with poor outcomes of COVID-19 (20). Older age and longer CD disease duration were found to be associated with moderate COVID-19, indicating that age and accumulated damage may influence the viral-induced immune response. All other clinical characteristics, including CD activity, medication exposure and comorbidities, showed no significant differences between the above two groups. Given the low rates of moderate/severe cases in our study, our findings need validation in large external cohorts.
The symptom profile reflects the potential of COVID-19 to damage multiple systems through immune responses (21), and changes with the evolution of variants (11). Consistent with the findings that influenza-like symptoms were more frequently reported in Omicron (11), this study demonstrated the highest prevalence of general symptoms among symptomatic patients. Fluctuation of CD-related symptoms was another concern for most patients and physicians during the infection. Over 40% of patients in our study reported fluctuations in CD-related symptoms, including common GI symptoms and CD-specific manifestations. In contrast to the data from Surveillance Epidemiology of Coronavirus Under Research Exclusion (22), patients in our cohort presented a higher rate of common GI symptoms (diarrhea 20.9% vs. 30.0%, abdominal pain 8.9% vs.10.9%); this needs further validation in external cohorts. It is necessary to prolong the observation time for activity patterns and outcomes among these patients.
Although vaccination against SARS-CoV-2 has been recommended to IBD patients since the beginning of the pandemic (23), the rate of uptake among our CD patients was approximately 75% which was lower than that in the general population, reflecting the phenomenon of vaccine hesitancy in this immunosuppressed population (24). Categorization and ranking of symptom profiles.
Frontiers in Public Health 06 frontiersin.org Vaccine effectiveness against viral acquisition and severe outcomes was assessed in recent population-based studies during Omicron outbreaks, suggesting that a booster dose of COVID-19 vaccine is needed for older patients and high-risk populations against severe or fatal outcomes (25). Bivalent booster vaccines are now encouraged among IBD patients taking TNF antagonists and tofacitinib based on emerging evidence regarding the effectiveness of COVID-19 vaccines (8,26). No significant difference in vaccination doses was observed between the infection and non-infection group or between the mild and moderate groups in this study despite the same infection-naïve background. It is worth noting that the vaccine effectiveness in IBD patients is influenced by many factors, such as vaccine type, doses, and waning antibodies Frontiers in Public Health 07 frontiersin.org with time. This study was limited by its retrospective design and inadequate sample size; therefore, future prospective studies with large cohorts are needed to evaluate the effectiveness and adjust the vaccination protocol for this special population.
In summary, our study reported the impact of COVID-19 on CD patients from a prospective cohort in the first countrywide wave after the end of "zero-COVID" policy in China. Most CD patients contracted the Omicron infection and experienced mild disease courses irrespective of vaccination dose or comorbidities. Our study presents clinicians with first-hand data on COVID-19 in CD patients during the first wave attack and may help ease the health anxiety of patients in the next wave of the pandemic.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement
The studies involving human participants were reviewed and approved by the Institutional Review Board of the Ethics Committee of the Second Affiliated Hospital, School of Medicine, Zhejiang University in China (approved No. 2023-0134). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

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