Risk Factors for Herpes Zoster Infection in Patients With Chronic Kidney Disease: A Case-control Study

Background: Chronic kidney disease (CKD) increases the susceptibility to the infection of herpes zoster (HZ). Less is known about the risk factors of HZ in CKD patients. Methods and Participants: This is a case-control study. CKD patients diagnosed with HZ infection between January 2015 and October 2020 in a tertiary hospital were identied. One age- and gender-matched control was paired for each case, matched to the date of initial HZ diagnose. The uni- and multivariate analysis were used to evaluate the risk factors for development of HZ in CKD patients. Results: Forty-six HZ patients and controls were identied. In general, about 80% (72 out of 92) patients were classied at end-stage renal disease (ESRD, CKD (cid:0) to (cid:0)). Multivariate analyses revealed that immunosuppressive agents (odds ratio: 12.50, 95% CI: 1.53-102.26, P=0.021) and dialysis (odds ratio: 3.33, 95% CI: 1.13-9.78, P=0.029) were independent risk factors of HZ in patient with CKD. Conclusion: Immunosuppressive medication and dialysis were associated with HZ infection in CKD. Further guideline may highlight the necessity of zoster vaccine for patients with CKD, who undertake immunosuppressive or dialysis treatment.


Introduction
The burden of chronic kidney disease (CKD) has become a great challenge of global healthcare system, affected almost 15% of adults in the United States. 1 As progression of CKD, costly therapy such as dialysis or kidney transplant may be required to maintain the function of kidney. Moreover, patients with CKD exhibit great risk to develop cardiovascular disease, in both dialysis-and non-dialysis dependent population. 2 Infectious disease is the second most common cause of morbidity and mortality in CKD, accounting for 30-36% of death. 3,4 The mechanism underlying the immune dysfunction of CKD includes poor nutritional condition, immunosuppressive medication and uremic toxins. 5 Consequently, infectiousrelated mortality increased signi cantly in patients with CKD, especially for those have progressed to endstage renal disease (ESRD). 6 Herpes zoster (HZ), also known as shingles, is a common viral infection that occurs with reactivation of the varicella-zoster virus. Accumulating evidence has suggested that CKD as an important risk factor for HZ. [7][8][9][10][11][12] Incidence of postherpetic neuralgia (PHN), the most common complication of HZ, also increases signi cantly among CKD cohort. 13 PHN patients often present physical, occupational, social, and psychosocial disabilities as a result of the unremitting pain. 14 Furthermore, the overall risk for developing cardiovascular event also increased after zoster attack. 15,16 One effective approach to reduce the morbidity of HZ and postherpetic neuralgia is to apply zoster vaccine. 17 Recent study has demonstrated that zoster vaccine was effective against incident zoster for the elderly with CKD. 18 In addition to advancing ages, less is known about the other risk factors for HZ lesion in CKD population. To achieve better clinical outcome of CKD, early recognition of potential HZ infection and subsequent protective vaccine therapy is urgently needed. In current study, we aim to examine the potential risk factors to develop HZ in CKD patients.

Study Population
The study was approved by the ethics committee of the Third Xiangya Hospital, Central South University (NO.2050-s388), and informed consent was waived due to the observational design in this study.

Cases
Ninety-two CKD patients diagnosed with HZ (ICD-10-CM codes: B02) between January 2015 and October 2020 at the Third Xiangya Hospital of Central South University were identi ed. Forty-six cases who underwent transplant were not included in this study.
Controls. The controls were randomly retried from the remaining CKD patients, age-and sex-matched with the HZ cases. One control was identi ed for each case and matched to the date of initial herpetic diagnose.

Data Collection
Two colleagues (Q. W and ZX. L) independently reviewed the medical record of all cases and controls.
One standard data collection form was applied to record the general characteristics and clinical information. The age of patient was identi ed as the onset of herpes rash. The rst data available follow admission was recorded and applied for further analysis.

Statistical Analysis
Chi-squared test or Fisher exact test were conducted to compare categorical data. The Student t test or Mann-Whitney U test was used when appropriate to analyze continuous data. Uni-and multivariate logistics analysis was performed to evaluate the independent risk factors associated with HZ infection in CKD patient. Only variables with a p value < 0.05 between cases and controls were included for multivariate logistics analysis. All continuous data are presented as mean ± standard deviation.
Estimation of risk was presented as odds ratios (ORs) with 95% CIs, and two-tailed p value < 0.05 was considered statistically signi cant. All data analysis was processed with SPSS (version 16.0, Chicago, IL).

General Characteristics
The research of medical database initially identi ed a total of 46 CKD cases with a diagnose of HZ. Next, forty-six age-and sex-matched controls were selected randomly from the remaining CKD cohort. The mean duration of CKD was approximately 45 months in HZ group, almost 2 times longer compared with control group (P = 0.07). Only one out of 46 patients (2.1%) took regular immunosuppressive agents in the control group, and 22.7% (n = 10/44) for HZ group respectively (P = 0.004). Compared with control group, more patients required the renal replacement therapy of dialysis (71.7% versus. 45.7%, P = 0.003). The majority of patients (80.4%) in this study were identi ed as ESRD (CKD to ). However, no signi cant difference of disease severity was found between groups (P = 0.46). The general information of enrolled participants is given in Table.1.

Laboratory Result
The diagnostic detail of laboratory test is shown as Table.2. In general, the HZ patients presented a signi cant dysfunction of immune system, characterized by reduced total lymphocyte account (P = 0.003) and neutrophil-to-lymphocyte ratio (P = 0.04). Meanwhile, the concentration of albumin was 31.65 ± 6.05 g/L in HZ cohort, signi cantly lower than control group (P = 0.004). No obvious difference of renal function was found between groups according to current data.

Discussion
In this case-control study, we investigated 92 patients with CKD at a tertiary hospital and aimed to evaluate the potential risk factors for development of HZ infection. To our knowledge, it is the rst time we identi ed immunosuppressive agents and dialysis treatment as independent risk factors for development of HZ in CKD population.
Kidney disease severity is classi ed into ve stages according to the level of glomerular ltration rate. 19 Previous study has demonstrated that ESRD as a risk factor for development of HZ infection. 10 Similarly, we found that most of HZ cases (74%, n = 34/46) were identi ed at the ESRD in this study. The overall incidence of ESRD increases with age and the majority of patients who reach ESRD are 65 years or older. 20 Despite disease severity, herpes zoster is also of particular concern in the elderly. 21,22 The mean age of subjects in this study was around 60 years old. Given the advancing age, we did NOT nd signi cantly increased disease severity in HZ patients compared with control group.
Consistent with previous reports, our data indicated an increased risk of HZ in patients who regularly take immunosuppressive medication. 23,24 In our study, we found that patients who took immunosuppressive drugs were at almost fourteen-fold increased risk of HZ compared with control group. The common comorbidity of CKD patients who use immunosuppressive therapy, includes rheumatoid arthritis and systemic lupus erythematosus. Despite immunosuppressive treatment, we found that dialysis was associated with greater risk of zoster. There were 33 out of 46 cases (71.7%) treated with dialysis, and 45.7% for control group respectively. The large cohort study conducted by Lin et al. showed similar results, that both peritoneal dialysis and hemodialysis patients presented higher incidence of HZ compared with control. 25 The highest risk of HZ infection was reported in patients underwent renal transplant. 25 Although we identi ed 46 HZ cases after renal transplant in the initial research. We did not enroll these patients due to the complex factors in the status of renal transplant.
There are some correlations between the immune de ciency and the incidence of infectious complications in CKD patient, characterized by a signi cant lymphopenia. 26 Similarly, we found that the total lymphocyte account was signi cantly lower in HZ patient compared with control group. The mechanism underlying the lymphopenia in CKD is that lower T cell homeostatic proliferation. 27 It is not surprising that total leukocyte counts showed no signi cant difference between groups, mainly due to routine medication to prevent leukopenia. Thus, combination of mild neutrophilia and signi cant lymphopenia potentially caused an increased neutrophil-to-lymphocyte ratio. 26 A plethora of corroborative evidence in CKD population has suggested inverse relationship between serum albumin and poor prognosis. 28,29 However, the context in herpetic infection remains unclear. In our study, we found signi cant reduction of serum albumin in CKD patient with HZ, compared with control group. Although the prognostic value of serum albumin was not statistically signi cant in the logistic regression analysis. The allocation of CKD patient based on serum albumin levels is helpful in prediction of infection-related death, but not available in this study due to limited number of subjects. 29 Our study has some limitations beyond the limited sample size. First, the retrospective nature of this study design is likely to omit the feature data. The data we collected were derived from general characteristics and routine laboratory test. Speci c examination of immune function such as lymphocyte subset analysis and interleukin 2. 26,30 Second, information regarding the patient`s course after discharge was not available for control group. This supports the need for future research to conduct long-term follow-up.
In conclusion, immunosuppressive and dialysis therapy are independent risk factors for the development of HZ infection in patients with CKD. Further guideline may highlight the necessity of zoster vaccine for patients with CKD, who undertake immunosuppressive or dialysis treatment.