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 first time we identified immunosuppressive agents and dialysis treatment as independent risk factors for development of HZ in CKD population.
Kidney disease severity is classified into five stages according to the level of glomerular filtration 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 identified 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 find significantly 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 co-morbidity 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 identified 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 deficiency and the incidence of infectious complications in CKD patient, characterized by a significant lymphopenia.26 Similarly, we found that the total lymphocyte account was significantly 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 significant difference between groups, mainly due to routine medication to prevent leukopenia. Thus, combination of mild neutrophilia and significant 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 significant reduction of serum albumin in CKD patient with HZ, compared with control group. Although the prognostic value of serum albumin was not statistically significant 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. Specific 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.
Table 1
General characteristics of herpetic and non-herpetic patients with CKD.
Variables | HZ | Non-HZ | P value |
N | 46 | 46 | |
Age (years) | 58.89 ± 13.85 | 56.15 ± 13.37 | 0.340 |
Sex (female, %) | 21 (45.6) | 21 (45.6) | 1.000 |
Body Mass Index (kg/m2) | 21.97 ± 3.20 | 22.94 ± 30.41 | 0.540 |
Known CKD duration (months) | 44.64 ± 48.7 | 22.94 ± 30.41 | 0.070 |
Intervention (n, %) | | | |
Immunosuppressive agents | 10/44, (22.7) | 1/46, (2.1) | 0.004 |
Dialysis therapy | 33/46, (71.7) | 21/46, (45.7) | 0.003 |
CKD stage (n, %) | | | 0.460 |
Ⅰ | 0 (0) | 0 (0) | |
Ⅱ | 6 (13) | 2 (4) | |
Ⅲ | 6 (13) | 4 (9) | |
Ⅳ | 5 (11) | 14 (30) | |
Ⅴ | 29 (63) | 26 (57) | |
CKD: Chronic Kidney Disease; HZ: Herpes Zoster. |
Table 2
Laboratory findings of CKD patients.
laboratory indicators | HZ | Non-HZ | P value |
White blood cell count, 109/L | 6.42 ± 2.41 | 7.00 ± 2.29 | 0.240 |
Neutrophil count, 109/L | 4.88 ± 2.20 | 5.10 ± 2.27 | 0.640 |
Lymphocyte count, 109/L | 0.93 ± 0.50 | 1.24 ± 0.46 | 0.003 |
Eosnophils count,109/L | 0.14 ± 0.15 | 0.20 ± 0.49 | 0.379 |
Basophil count, 109/L | 0.02 ± 0.02 | 0.03 ± 0.03 | 0.103 |
Platelet count, 109/L | 173.33 ± 86.17 | 174.98 ± 72.38 | 0.921 |
Red blood cell count, 109/L | 3.08 ± 0.77 | 3.00 ± 0.85 | 0.649 |
Hb (g/L) | 93.43 ± 22.93 | 89.89 ± 25.21 | 0.482 |
Hematocrit(%) | 28.80 ± 6.77 | 27.82 ± 7.35 | 0.508 |
Neutrophils-lymphocytes ratio(%) | 7.01 ± 5.44 | 4.97 ± 5.32 | 0.040 |
C-reactive protein (mg/L) | 23.43 ± 47.60 | 15.91 ± 36.85 | 0.580 |
Erythrocyte sedimentation rate(mm/hr) | 40.25 ± 27.29 | 45.06 ± 32.36 | 0.500 |
Glucose(mmol/L) | 5.39 ± 2.07 | 5.23 ± 1.66 | 0.680 |
Procalcitonin(ng/ml) | 1.0 ± 0.97 | 0.86 ± 1.77 | 0.800 |
Serum albumin(g/L) | 31.65 ± 6.05 | 35.17 ± 5.18 | 0.004 |
Serum globulin(g/L) | 25.14 ± 6.09 | 24.91 ± 4.16 | 0.830 |
Ratio of albumin to globulin | 1.32 ± 0.38 | 1.46 ± 0.33 | 0.070 |
Alanine aminotransferase(U/L) | 18.62 ± 13.65 | 17.18 ± 13.31 | 0.616 |
Aspartate aminotransferase(U/L) | 20.22 ± 15.52 | 20.54 ± 10.43 | 0.912 |
Total bilirubin(umol/L) | 7.65 ± 5.25 | 8.29 ± 5.56 | 0.572 |
Direct bilirubin(umol/L) | 2.40 ± 3.31 | 2.29 ± 2.18 | 0.854 |
Total bile acid(umol/L) | 5.02 ± 5.69 | 3.56 ± 2.58 | 0.126 |
Low-density lipoprotein(mmol/L) | 2.09 ± 0.72 | 2.06 ± 0.78 | 0.857 |
High-density lipoprotein(mmol/L) | 1.17 ± 0.41 | 1.13 ± 0.36 | 0.697 |
Total cholesterol(mmol/L) | 4.46 ± 1.21 | 4.11 ± 1.28 | 0.196 |
Triglyceride(mmol/L) | 2.17 ± 1.85 | 1.71 ± 1.89 | 0.248 |
Urea(mmol/L) | 33.04 ± 77.24 | 21.22 ± 10.03 | 0.310 |
Creatinine(umol/L) | 623.78 ± 432.07 | 620.87 ± 345.28 | 0.970 |
Table 3
Uni- and multivariate analysis of risk factors for herpes zoster in patients with chronic kidney disease.
Covariates | Univariate | P | Multivariate | P |
| OR (95% CI) | value | OR (95% CI) | value |
Total lymphocyte count | 0.26(0.10–0.66) | 0.005 | 0.43(0.11–1.64) | 0.216 |
Neutrophils-lymphocytes ratio | 1.11(1.00-1.24) | 0.046 | 0.99(0.86–1.13) | 0.828 |
Serum albumin | 0.90(0.83–0.97) | 0.006 | 0.96(0.87–1.05) | 0.356 |
Immunosuppressive agents | 12.50(1.53-102.26) | 0.019 | 13.90(1.48-130.75) | 0.021 |
Dialysis therapy | 3.79(1.52–9.24) | 0.003 | 3.33(1.13–9.78) | 0.029 |