Since the beginning of December 2022, following a relevant policy change in China, there has been a large outbreak of SARS-CoV-2 infection, predominantly with the Omicron strain [10]. The COVID-19 epidemic has significantly influenced patients with rheumatic diseases, and patients with AOSD are no exception. The present study analyzed the clinical characteristics of patients with AOSD and COVID-19 and the impact of various factors on the prognosis of the infectious process.

The infection rate of SARS-CoV-2 in patients with AOSD was 75.5%, including patients with confirmed and highly suspected COVID-19, consistent with the general population (63.52% confirmed rate up to 25 December 2022) [9]. Of note, the infection rate might be underestimated, because some patients might be asymptomatic. Among all patients with AOSD with confirmed or suspected COVID-19, the COVID-19-related hospitalization rate was 4.9% (7 out of 142) and the mortality rate was 0.7% (1 out of 142). Given the low hospitalization rate in our study, extrapolation to the general population is challenging, although previous data showed similar critical or mortality rates (533 of 48,234 [1.1%]) [11]. Remarkably, the shortage of medical resources due to this large outbreak in a short period may have prevented the hospitalization of some patients with COVID-19, resulting in a lower hospitalization rate. The cause of death in one patient was considered to be severe HLH, one of the most serious complications of AOSD. However, it is challenging to determine whether the cause of her death was the onset of COVID-19, the flare of AOSD, or a combination of both. Additionally, the COVID-19 probably worsened her pulmonary hypertension. Similarly, patients with severe COVID-19 may also develop secondary HLH, which usually occurs in patients presenting with acute respiratory distress syndrome (ARDS) [12]. The HLH of this patient might be secondary to AOSD because the pneumonia was not severe.

The patients with AOSD in this study received mainly inactivated SARS-CoV-2 vaccines, and our previous study has shown that inactivated vaccines did not cause disease relapse in clinically inactive patients with AOSD and that adverse effects were mild and self-limiting [13]; however, the efficacy of inactivated vaccines is unclear. Following logistic regression analysis of risk factors for COVID-19 severity, although no statistical difference was reached, it was found that vaccination may result in a superior outcome for patients, consistent with the findings in the general population [11] and other populations with rheumatic diseases [14], but our conclusion requires further validation. Possible reasons include the long interval between vaccination and infection, and the suppression of the immunogenicity of the vaccine due to the use of immunosuppressive drugs or glucocorticoids, which requires further validation. In addition, not surprisingly, age and the presence of comorbidities (COPD or asthma and possible hypertension) increase the risk of deterioration of COVID-19 in patients with AOSD, which is consistent with the previous studies.

In terms of medication use, medium or high-dose oral glucocorticoids (> 7.5 mg/day) were associated with more severe COVID-19, which is concordant with data from patients with other rheumatic diseases [15,16,17]. The mechanisms involved have not been fully elucidated, but this is not surprising since glucocorticoids are comprehensive inhibitors of the host inflammatory response to defend against the virus. Moreover, patients on medium or high-dose glucocorticoids may still have immune dysregulation which contributes to the worse outcome of COVID-19. Although hydroxychloroquine was originally proposed as a therapeutic agent for COVID-19, it was not shown to be protective in preventing adverse patient outcomes in our cohort, in line with previous reports on patients with rheumatic diseases [17], including systemic lupus erythematosus (SLE) [18]. The use of JAK inhibitors is strongly associated with an adverse prognosis of COVID-19 in patients with rheumatic diseases [15, 19], and similar to previous studies, we found that patients receiving JAK inhibitors had a worse outcome. While caution is needed in drawing this conclusion since the number of patients using JAK inhibitors in our study was so small. However, one study found that baricitinib reduced mortality in patients hospitalized for COVID-19 [20]. This may be related to the timing of drug use, where baseline use of JAK inhibitor at the initial phase of SARS-CoV-2 infection may suppress the immune response against the virus, whereas initiation of JAK inhibitor at the time of clinical deterioration may attenuate the abnormal systemic inflammatory response.

Our study identified six patients with AOSD suffering from AOSD flares within 3 months of SARS-CoV-2 infection, four of whom were hospitalized and one died, suggesting that SARS-CoV-2 might cause flares of AOSD. During the follow-up period, no disease flares were reported in patients with AOSD without COVID-19, and there was no statistical difference compared to patients with COVID-19 (p = 0.339). A case of AOSD onset after COVID-19 has been reported previously [5]. The potential pathogenic role of various pathogens in AOSD, particularly viruses, has attracted extensive attention. The formation of a cytokine storm is the key to the pathogenesis of AOSD. The starting point of the cytokine storm may arise from specific viral danger signals. Both severe COVID-19 and AOSD can be grouped as hyperferritinemia syndrome, share the same clinical features of high inflammation and cytokine storm, and possibly have the same molecular mechanisms [21]. Studies have shown that ferritin induces NETs (neutrophil extracellular traps) release and promotes systemic inflammation in AOSD [22], and a ferritin–NETs–cytokine storm loop may also be present in COVID-19 due to the formation of NETs and hyperferritinemia syndrome which are characteristic of patients with severe COVID-19. A potentially faulty immune response against SARS-CoV-2 may have triggered AOSD in patients.

This is the first study to evaluate the impact of COVID-19 in patients with AOSD and, as a result of a short-term outbreak of COVID-19, participants were infected with a similar strain of SARS-CoV-2. However, there are limitations. First, because of the rareness of the disease, the sample size was limited. In addition, owing to the retrospective observational study setting, unmeasured confounding factors may affect the results.