Study Population

A total of 1,527,072 patients with IC/AID aged ≥ 18 years in ROK were considered eligible for inclusion in the study between 2016 and 2020.

Of these patients, 557,243 were later excluded from the study cohort on the basis of the exclusion criteria: 20,316 aged below 18 years during the study period; 7 with missing age; 98,827 diagnosed with HZ before CED; 176,642 without continuous enrolment during the baseline period of at least 1 year before cohort entry; 1322 diagnosed with solely documented cases of liver cirrhosis and without decompensated events; 108,357 diagnosed with two or more IC/AID conditions on CED and 151,772 with less than 1 year of follow-up. Eligible patients for the study cohort consisted of 969,819 patients aged ≥ 18 years with IC/AID between 2016 and 2020 (Supplementary Fig. S2).

Baseline Characteristics of Immunocompromised Patients

Prior to matching, the mean age (standard deviation [SD]) of the “IC/AID with HZ” group (57.40 [14.14]) was higher than that of the “IC/AID without HZ” group (53.60 [16.47]). Among IC/AID with HZ and IC/AID without HZ groups, 64.92% and 55.61% of patients were female, respectively. The mean (SD) value of CCI was 1.16 (1.44) for the IC/AID with HZ group, and 0.92 (1.39) for the IC/AID without HZ group (p < 0.0001; Table 1).

Table 1 Baseline characteristics of patients with IC/AID with or without HZ before and after matching

Rheumatoid arthritis was the most common IC/AID condition in both IC/AID with HZ and without HZ groups. Individuals with IC/AID and HZ (n = 65,976) were matched 1:3 to patients with IC/AID without HZ (n = 197,062) (Supplementary Fig. S2). After matching, the cohorts were well balanced with regard to age, sex, medical institution, CCI, and IC/AID conditions (Table 1).

HZ Incidence and RecurrenceMain Analysis

From 2016 to 2020, the total number of patients with IC/AID more than doubled from 557,521 to 1,229,948 (Table 2). Accordingly, the number of patients with HZ and IC/AID also more than doubled from 11,838 in 2016 to 28,129 in 2020. The annual IR (95% CI) per 1000 persons fluctuated from 2016 to 2020; it was at its lowest in 2016 (21.23 [20.86–21.62]) and peaked in 2018 (24.52 [24.21–24.84]), averaging at 23.41 (22.21–24.62) throughout the study period.

Table 2 Trend of HZ incidence rates per 1000 persons among patients with IC/AID in the Republic of Korea from 2016 to 2020, stratified by year, age, sex, IC/AIDs, and HZ-related complications

HZ was more common in female patients with IC/AID (IR [95% CI] 26.85 [25.40–28.31]) than in male patients with IC/AID (18.96 [18.03–19.89]). In addition, the IR of HZ among patients with IC/AID remained high across all age strata, ranging from 10.43 (9.88–10.97) among individuals aged 18–29 years to 30.43 (29.17–31.69) among individuals aged 65–69 years. Overall, incidence was highest in patients above 50 years of age. When stratified by etiology of IC/AID, the IR (95% CI) of HZ per 1000 persons was highest in patients with transplants (including both solid organ and hematopoietic stem cell transplants) (37.12 [35.45–38.79]), followed by patients with hemato-oncology conditions (35.47 [31.62–39.32]; Table 2).

Forty-eight percent of the patients with HZ (14,683/30,562) did not experience HZ complications (15.84 [14.95–16.72]). Among the cases where complications occurred, “other complications”-related cases (3.84 [1.95–5.73]) were the most common, followed by PHN (1.87 [1.42–2.31]; Table 2). The category “other complications” (ICD-10 code B02.8) includes zoster which has spread to other organs and does not fall under ICD-10 codes B02.0–B02.7 or B02.9 (zoster without complications).

The trend of HZ recurrence was generally homogenous to that of HZ incidence. The average recurrence rate per 1000 persons across the study period was 1.71 (0.30–3.11). The recurrence rate was highest among women (2.20 [1.09–3.31]), individuals aged 60–64 years (2.51 [1.26–3.76]), and individuals with transplants (3.35 [2.54–4.17]; Table 3).

Table 3 Trend of HZ recurrence rates per 1000 persons among patients with IC/AID in the Republic of Korea from 2017 to 2020, stratified by year, age, sex, and IC/AIDSensitivity Analysis

Patients with incident and recurrent HZ were identified in the sensitivity analysis by the HZ diagnosis code only and need not have received antiviral medication within 1 week of HZ diagnosis. Hence, the number of cases, IRs, and recurrence rates were relatively higher in the sensitivity analysis compared with the main analysis. However, the trends of HZ incidence and recurrence rates among patients with IC/AID in both analyses were largely consistent (Tables 2 and 3; Supplementary Tables S2 and S3).

HCRU and All-Cause Medical Cost AssessmentHZ Healthcare Burden

Compared to patients with IC/AID without HZ, patients with IC/AID and HZ had higher HCRU during the 12-month observation period in all HCRU categories (number of outpatient visits, emergency room visits, inpatient visits, and length of hospitalizations; Table 4). The ratio of healthcare utilization (95% CI) for all patients with HZ was 1.28 (1.28–1.29) in outpatient visits, 1.32 (1.31–1.33) in emergency room visits, 1.31 (1.30–1.32) in inpatient visits, and 1.14 (1.14–1.15) in the length of hospitalizations. The incremental HCRU attributable to HZ in each resource category increased for patients with HZ-related complications, and substantially increased for patients with HZ and PHN complications (Table 4). The ratio of outpatient visits (95% CI) was significantly higher in patients with HZ and PHN, with a mean of 25.43 additional claims for services compared with patients without HZ (1.61 [1.60–1.62]) through the 12 months following diagnosis.

Table 4 Healthcare resource utilization associated with HZ in patients with IC/AID during the 12-month follow-up periodAll-Cause Total, Direct, and Indirect Medical Costs

Compared with the IC/AID without HZ group, the IC/AID with HZ group had significantly higher all-cause total medical cost (cost ratio 1.19 [1.18–1.20]), and an additional 1,338,475 Korean Republic won (KRW; 1138 United States dollar [USD] according to the 2020 conversion rate from UNCTAD [19]; 1 KRW = 0.00085 USD) was incurred per patient during the 12-month observation period. Among patients with HZ and complications, patients with PHN were the primary cost drivers with incremental all-cause total medical costs over 40% of that of patients without HZ during the 12-month observation period (1.42 [1.37–1.47]), incurring an additional burden of 3,090,973 KRW (2627 USD) per patient (Table 5).

Table 5 All-cause total medical costs associated with HZ among patients with IC/AID during the 12-month follow-up period

During the 12-month observation period, patients in the IC/AID with HZ group incurred significantly higher direct medical costs (1.18 [1.17–1.19]), resulting in the additional cost of 973,013 KRW (827 USD) per patient (Supplementary Table S4). Whereas in the inpatient setting, adjusted cost ratios of direct medical costs for patients in the IC/AID with HZ group were slightly lower than that of the IC/AID without HZ group (0.95 [0.93–0.97]). Significant incremental direct medical costs were incurred in patients with HZ and PHN compared to matched patients in the IC/AID without HZ group. Differences in mean direct medical costs were 2,343,338 KRW (1992 USD) per patient and the cost ratio of direct medical costs was 1.40 (1.35–1.45).

During the 12-month observation period, patients in the IC/AID with HZ group incurred significantly higher indirect medical costs (cost ratio 1.25 [1.24–1.26]), resulting in the additional cost of 365,462 KRW (311 USD) per patient (Supplementary Table S5). In the inpatient setting, however, there was no significant difference in indirect medical cost between IC/AID with HZ and IC/AID without HZ groups. The indirect medical cost for patients with HZ and PHN was approximately 1.65 times that of patients in the IC/AID without HZ group (1.65 [1.60–1.70]), incurring an additional burden of 747,635 KRW (635 USD) per patient.