Dan Yu · Ying Liu · Mu-Tong Zhao · Kai-Hu Yao · Mao-Quan Qin · Lin Ma

Herpes zoster (HZ) also known as shingles is caused by the reactivation of latent varicella zoster virus (VZV) from the dorsal root ganglia following primary infection [1,2]and is associated with severe disease in immunocompromised pediatric patients [3–6].Immunosuppression has been demonstrated to be related to a higher incidence of HZ [4].The prevalence and clinical features of HZ in the hospitalization of patients who have a history of other medical conditions has been studied [7].Few studies have shown HZ incidence and characteristics in HZ pediatric patients,while there have been several studies focused on exploring the risk of HZ occurrence in immunocompromised pediatric patients [6].Recently,the epidemiology of HZ in a population of aged ≥ 50 years from China between 2015 and 2017 was reported [8].A systematic literature review was also reported assessing the burden of HZ disease in patients 18 years of age and older in China [9].In short,the clinical characteristics of HZ have been well studied in a range of adult ages;however,the same studies in pediatric HZ patients from China are largely absent.In this study,we summarized the clinical characteristics of pediatric HZ patients in our hospital and found that hospital-attended HZ was not rare in immunocompetent pediatrics.Hospitalized HZ cases were treated in a more comprehensive way,including extensive anti-infection and topical antivirals,compared to HZ patients treated in an outpatient environment.HZ was diagnosed during hospitalization of these patients who had received hematopoietic stem cell transplant (HSCT),despite being treated prophylactically with antivirals.

Our analysis was based on the medical record database from January 2007 to August 2020 in National Center for Children’s Health,Beijing,China.In our study,a case of HZ was defined as any case in which the patient has been diagnosed of a definite HZ by a physician according to the typical clinical characteristics of HZ.We reviewed the complete medical records of the hospitalizations and outpatients aged <18 years to verify the diagnosis of HZ and collect additional data.We excluded any case with coexistent varicella in the list of diagnoses.Cases that were diagnosed as questionable or possible HZ were excluded.There was a total of 106 HZ cases in hospitalization,of whom 4 were excluded due to the uncertainty of HZ diagnosis.There was a total of 707 HZ outpatients,of whom 27 were excluded due to uncertainty of HZ diagnosis or missing of clinical information.Immunocompromised condition was defined as listed in Supplementary Table 1.

Table 1 Clinical characteristics of the study population

Values are presented as (%). a Patients treated with chronic immunosuppressive medications,which was listed in Supplementary Table 1; b patients with malignancy medical conditions,which was listed in Supplementary Table 1; c infection included tuberculosis,central nervous system infection,chronic active Epstein-Barr virus infection,cryptococcal meningitis,viral encephalitis,pneumonia; d others included abdominal closure injury,unknown

Treatment with antiviral agents were determined based on whether the patients were administrated intravenous or oral antiviral agents for VZV (acyclovir,valaciclovir,ribavirin,ganciclovir,penciclovir and vidarabine) within ± 7 days of a HZ diagnosis.External antiviral agents were determined based on whether the patients were treated with external antiviral agents (acyclovir,valaciclovir,ganciclovir,penciclovir).The information that whether patients were treated with antibiotics,gamma globulin and vitamin B1 or B12 was also evaluated.Data manipulation and statistical analyses were performed with SPSS software.Continuous variables were presented as median (interquartile range).Categorical variables were presented as

n

(%).

Clinical characteristics of the study population are presented in Table 1.HZ occurred in a total of 782 cases,with a median age of 9 years (range 0.3–17.3 years),with 102 of these cases requiring hospitalization at a median age at 10.1 years (range 1.1–16.1 years),and 680 of the cases needing only outpatient treatment,at a median age at 7.9 years (range 0.3–17.3 years).In our center.HZ occurrence was gradually elevated as the increase of age peaked at 6 to <13 years of age.The group consisted of 418(53.5%) boys and 364 (46.5%) girls.A total of 547 (69.9%)cases were first diagnosed with HZ,of whom 542 cases were treated in an outpatient setting,accounting for 79.7%(542/680) of total HZ outpatients,and 5 cases required hospitalization,accounting for 4.9% (5/102) of total HZ hospitalizations.An underlying malignancy or immunosuppressant treatment could be found for 129 (16.5%) cases,of whom HZ were diagnosed in 86 cases during hospitalization,accounting for 84.3% (86/102) of total HZ hospitalizations,and 42 cases were treated in an outpatient setting for 6.2% (42/680) of total outpatients with HZ.There were 73 (9.3%) patients who experienced coinfection of HZ and another pathogen and seven patients required hospitalization,accounting for 6.9% (7/102) of total HZ hospitalizations,and 66 of the coinfection patients were treated in an outpatient setting,accounting for 9.7% (66/680) of total HZ outpatients.There were 34 (4.3%) cases diagnosed with other underlying diseases and four required hospitalization,accounting for 3.9% (4/102) of total HZ hospitalizations,and 30 of these patients were treated in an outpatient setting,accounting for 4.4% (30/680) of total HZ outpatients.

Among 782 HZ cases,672 (85.9%) were treated with antiviral drugs,including those who were medicated in an outpatient setting,accounting for 85.7% (583/680) of total HZ outpatients,and patients who were medicated in a hospital setting,accounting for 87.3% (89/102) of total hospitalized HZ patients.There were 64 patients (8.2%) that were given antibiotics,including 27 patients (4% of total HZ outpatient patients) treated in an outpatient setting and 37 patients (36.3% of total HZ hospitalization patients).22.3%(174/782) of HZ patients received vitamin supplementation,22.9% (156/680 of total HZ outpatient patients) of which were treated in an outpatient setting and 17.6% (18/102 of total HZ hospitalization patients) of HZ patient treated in a hospital setting.10.4% (81/782) of patients were treated with topical antiviral drug,with 8.4% (57/680 of total HZ outpatient patients) of patients treated in an outpatient setting,and 23.5% (24/102 of total HZ hospitalization patients)of patients treated in a hospital setting.Among the 102 hospitalized HZ cases,33.3% (34/102) were given immunoglobulin treatment.The medications of 10.9% (85/782) cases were unspecified.

There were five (4.9%) cases hospitalized due to HZ,of whom three were boys and two were girls aged 5–14 years.All of the five were medicated with acyclovir (4 intravenously,1 orally) three were also given antibiotics,and all were given topical treatment.One of the five cases reported neuralgia and ophthalmalgia,which was significantly improved by the second day of treatment with adenosine cobalt amine.Two of the five cases received anti-inf lammatory dexamethasone treatment,one of which was diagnosed with juvenile rheumatoid arthritis and had a history of longterm use of dexamethasone,another one was reported to have virus encephalitis.

Clinical features were reviewed for 102 hospitalizations as presented in Table 2.There were only six of the 100 patients that reported a history of chickenpox.There were 11 patients that reported a history of VZV vaccination record.Of 102 HZ patients that were hospitalized,there were 86 (84.3%) HZ patients who were defined as immunocompromised (Supplementary Table 1).Among these,two(2.3%) were diagnosed with known primary immunodeficiency,21 (24.4%) were under immunosuppressants therapy conditions,and 63 (73.3%) were diagnosed with malignancy.Specifically,47 (54.7%) of patients with malignancies were diagnosed with leukemia and 20 (23.3%) had suffered bone marrow immunosuppression associated with previously receiving a bone marrow transplant.

HZ was diagnosed in 21 cases during hospitalization,at a median of 119 days (24–240 days) after HSCT.Moreover,only one patient had two episodes of HZ,with the first being at 24 days post-HSCT and the second being at 115 days post-HSCT,and this patient also had the earliest HZ occurrence.As specified in the medical records,this patient had fever in both HZ episodes.For the first episode of HZ,the patient had the localization of rash around the eyes,indicating cranial nerve involvement.For the second episode of HZ,the localization of the rash also involved the cranial nerve region around the scalp.During the second episode of HZ,the patient also suffered graft-versus-host disease (GVHD).The proportions of immune status,underlying diseases,co-infection,and the occurrence of GVHD of HSCT patients are shown in Table 3.Allogeneic-HSCT was occurred prior to HZ in 20 cases,while autotransplantwas proceeded in one case.Leukemia was diagnosed in 15 cases,non-Hodgkin’s lymphoma was diagnosed in four cases,and aplastic anemia or non-Hodgkin’s lymphoma primary immunodeficiency was found in one case.Co-infection was also analyzed in these patients.Cytomegalovirus viremia was found in one case.Pneumonia was diagnosed in three cases,of whom one was found to have chronic activation of Epstein-Barr virus.GVHD was found in 11 (52.4%)cases.

Table 2 Clinical features of herpes zoster cases during hospitalization(=102)

Table 3 Characteristics of herpes zoster patients after HSCT (=21)

hematopoietic stem cell transplant, cytomegalovirus, graft-versus-host disease

Systematic surveillance of HZ has not been performed in China 10].We investigated the clinical features of pediatric HZ patients,including the largest number of cases up until now in a Chinese single-hospital system.We’ve made two important observations in our study.A total of 129 (16.5%)immunocompromised HZ patients were identified in this study,among which 86 cases were diagnosed during hospitalization,accounting for 84.3% of the total hospitalizations with HZ,which was higher than the 51.6% that had been reported previously.Of these 86 cases,73.6% were diagnosed with a malignancy,which has been documented in previous reports as an important risk factor for HZ occurrence [11].

Recombinant zoster vaccine or inactivated varicella vaccine was found to benefit adult immunocompromised populations [12,13].In addition,the immunogenicity and safety of recombinant zoster vaccine in adults with hematological malignancies and the transplant recipients has also been discussed [14].In immunocompromised pediatrics,early initial prevention and therapy is necessary due to the fact that severe complications,such as facial paralysis,meningitis,uveitis,keratitis,and acute retinal necrosis may occur.Therefore,clinical evaluation of an HZ immunization strategy,especially the recombinant zoster vaccine,needs to be considered for this population.

Low-dose acyclovir has been demonstrated to effective in preventing HZ in immunocompromised patients that cannot receive a vaccine against VZV,such as HSCT patients[15].Another observation here was that,even though antiviral prophylaxis was used 6 months,all 21 HZ cases was diagnosed of HZ within 8 months after HSCT,which was much earlier than what is reported in adult studies [16],and has been consistently documented in the previous studies [17].Consistent with this,a high incidence of HZ after cord blood hematopoietic cell transplant was reported in the adults,despite using a longer duration of antiviral prophylaxis [18].These results remind us that a longer duration of antiviral prophylaxis for these immunocompromised pediatric patients may be needed and a long-term follow-up cohort study to confirm this.

There are several limitations to this study.The limitations associated with using data from one single center is described elsewhere and it could restrict the number and types of patients ultimately visiting our center and getting included in our study,although most of the patients in this study came from cities all over China,as listed in Supplementary Table 2.Therefore,our study may underestimate the HZ incidence of patients needing only outpatient treatment,as a large proportion of patients in our center were patients who had other severe diseases and came to us after they could not be treated at local hospitals,whereas HZ is typically a relatively mild disease that could normally be treated at a local hospital.Although this study is limited to making comparisons with other studies,it highlights the need for preventive efforts in this high-risk group.

The vaccination information on the patients in this study was limited due to the absence of VZV in the inquiry form for vaccination information in our center,because VZV vaccination has not been required in China.The effect of childhood vaccination against varicella on HZ incidence has been shown to be complex,as some studies found that HZ incidence was not much affected or even increased following introduction of varicella vaccination programs,while others showed that the vaccination of VZV was likely to decrease HZ incidence or prevalence[19,20].Another limitation in this study is that HZ diagnosis was only based on the typical clinical characteristics without laboratory testing,which may lead to misclassification.In summary,this study provides an investigation on the clinical characteristics of HZ in Chinese children based on the electronic medical records kept in our hospital.A better understanding of HZ incidence in Chinese pediatrics warrants further population-based study.

Supplementary Information

The online version contains supplementary material available at https:// doi.org/ 10.1007/ s12519-022-00525-5.

Acknowledgements

We thank Dr.Jie Zheng for discussion of the work.

Author contributions

YD and LY contributed equally to the work.YD and LY contributed to data curation,formal analysis,funding acquisition,investigation,methodology,and writing of original draft,resources,investigation,methodology,reviewing and editing.ZMT contributed to formal analysis,methodology,reviewing and editing.YKH contributed to project administration,supervision,validation,reviewing and editing.QMQ contributed to conceptualization,resources,reviewing and editing.ML contributed to conceptualization,funding acquisition,project administration,resources,reviewing and editing.All the authors approved the final version of the manuscript.

Funding

This work is supported by The National Natural Science Foundation of China (No.31900132),The Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority (No.XTZD20180502) and The Beijing Hospitals Authority(No.QM20191202).

Data availability

The data in this study are available from the authors on reasonable request.

Declarations

Ethical approval

Ethical approval was obtained from the Ethics Committee of Beijing Children’s Hospital,Capital Medical University(approval number: [2021]-E-106-R).

Conflict of interest

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.The authors have no conf lict of interest to declare.