Association of chronic spontaneous urticaria with the first exposure to general anaesthesia

To the Editor, Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by recurrent wheals and pruritus lasting more than 6 weeks; its prevalence tends to increase every year.1 Moreover, CSU can be a considerable social burden for patients and can substantially impair the quality of life, because of its longterm nature and unpredictable symptoms.1 Although various factors are associated with CSU occurrence, idiopathic cases account for approximately 80% of all CSU cases.2 General anaesthesia (GA) is associated with nonallergic disorders as well as various allergic disorders3; previous mastocytosis or chronic urticaria is a known risk factor for severe complications of GA.4 However, the longterm effects of GA exposure on these allergic disorders have not been evaluated, and the relationship between GA and CSU remains unclear. Thus, we conducted a retrospective cohort study to determine whether the risk of CSU increases after exposure to GA using Korean National Health Insurance Service national sample cohort data from 2002 to 2015.5 We included individuals exposed (n = 145,903) and unexposed (n = 291,806; control participants) to GA (1:2 ratio). Diagnosis of the sample cohort was based on the International Classification of Diseases, Tenth Revision (ICD10). We divided GA exposure into intravenous injection, endotracheal tube, and mask anaesthesia, and the total duration of GA was calculated. To reduce selection bias, we set the first 2 years (2002– 2003) as the washout period, and those with diagnostic codes of CSU (L501, L508, and L509) before the first recorded exposure to GA in the study period were excluded. For the GA participants, the observation began on the day of the first exposure (cohort entry date). In order to obtain a nonGA cohort, age group(within 5 years), sex, and income, cohort entry datematched controls that were unexposed to GA were randomly selected in a 1:2 ratio. We followed up both cohorts for 2 years from the cohort entry dates to the day when the diagnostic code of urticaria was first assigned during CSU treatment, or to death, emigration, or December 2015 (the date of the last followup of the sample cohort), whichever came first. Participants with subsequent CSU were defined as those who had (1) more than two ICD10 diagnostic codes of CSU, (2) more than 6 weeks of medical claims records for CSU, and (3) more than 6 weeks of a history of antihistamine prescription for treating CSU. Moreover, the CSUrelated treatment record of each patient was collected even after the end of the followup to investigate the differences in the clinical features of CSU such as disease duration and frequency of systemic treatment in both groups. The Kaplan– Meier method and a Cox proportionalhazard regression model were used to obtain survival curves and hazard ratios (HRs). The Cox proportionalhazards assumption of proportionality was also checked using Schoenfeld residuals. The results were considered statistically significant when the twotailed pvalue was <0.05. Statistical analyses were performed using SAS Enterprise Guide 7.1 (SAS Institute Inc., Cary, NC, USA). All characteristics, except for the CharlsonDeyo score, were not significantly different between the groups. The GA group had a higher proportion of those who had been exposed to regional anaesthesia and had a medical history of common systemic, allergic, and dermatological comorbidities compared to the nonGA group. The mean followup time in both groups was 1.83 years. The 2year cumulative incidence of CSU in the GA and nonGA participants was 0.54% (270/100,000 personyears) and 0.37% (184/100,000 personyears) respectively. The Kaplan– Meier curve showed a significant difference in the cumulative incidence of CSU between the groups (logrank p < 0.001) (Figure 1). The HRs for CSU in the cohort are summarized in Table 1. In the univariate analysis, the risk of CSU was significantly higher in the GA group than in the nonGA group (HR 1.47; 95% CI 1.34– 1.62). In the multivariate analysis, after adjusting for all covariates, the statistical significance of the HR was still maintained, although the HR showed a slight decrease (adjusted HR 1.33; 95% CI 1.20– 1.47). In the GA group, participants with longer exposure to GA were more likely to develop CSU, while the types of GA and the type of surgery (cancer vs noncancer surgery) were not associated with the occurrence of CSU. The risk of CSU also differed according to the types of anaesthetic used in the GA group. The use of enflurane increased the risk of CSU (adjusted HR 1.28; 95% CI 1.05– 1.58) compared to nonexposure to enflurane. However, the use of thiopental decreased the risk of CSU compared to nonexposure to thiopental (adjusted HR 0.68; 95% CI 0.52– 0.90). Subgroup analysis according to different age groups showed that only in older age groups (≥20 years old), the cumulative incidence of CSU was significantly higher in the GA cohort than that in the nonGA cohort. Likewise, multivariate Cox regression analysis stratified according to age showed that GA exposure significantly increased the risk of CSU in the older age groups.