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Higher Prevalence and Distinct Features of Herpes Zoster Infection in Children than Adults with Systemic Lupus Erythematosus

Gormezano, Natali W.S. MD*†; Silva, Clovis A. MD, PhD*†; Otsuzi, Carini I. MD*; Barros, Diego L. MD*; da Silva, Mariana A. MD*; Sallum, Adriana M.E. MD, PhD; Pasoto, Sandra MD, PhD*; Pereira, Rosa M.R. MD, PhD*; Bonfá, Eloisa MD, PhD*

The Pediatric Infectious Disease Journal: August 2015 - Volume 34 - Issue 8 - p 905–907
doi: 10.1097/INF.0000000000000756
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Herpes zoster infection was significantly more often observed in children (10%, N = 362) than in adults (4%, N = 1830). At herpes zoster infection diagnosis, disease activity score (8 vs. 3, P = 0.002) was higher in children, and fever (43% vs. 12%, P < 0.0001), nephritis (45% vs. 25%, P = 0.038), anti-double-stranded DNA autoantibodies (76% vs. 15%, P < 0.0001) and low C4 (48% vs. 22%, P = 0.017) were more often observed in children versus adults. Post herpetic neuralgia was less common in children than adults (3% vs. 24%, P =0.005).

Supplemental Digital Content is available in the text.

From the *Division of Rheumatology, and Pediatric Rheumatology Unit, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Accepted for publication February 9, 2015.

C.A.S. and E.B. have contributed equally to this paper.

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 302724/2011–7 to CAS), Federico Foundation (to C.A.S.) and Núcleo de Apoio à Pesquisa “Saúde da Criança e do Adolescente” da USP (NAP-CriAd) to C.A.S. The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Clovis A Silva, MD, PhD, Faculdade de Medicina da Universidade de São Paulo, Disciplina de Reumatologia, Av. Dr. Arnaldo, no. 455, 3° andar, sala 3190—Cerqueira César São Paulo, SP 05403-010, Brazil. E-mail: clovisaasilva@gmail.com

Herpes zoster infection (HZI) has been the most common viral infection reported in childhood1 and adult systemic lupus erythematosus (SLE) patients.2

It is unknown whether this infection has distinct characteristic and/or outcome in childhood and adult SLE patients, with a possible association with active disease1 in the former group and with immunosuppressive therapy in adults.2

The aim of this study was to assess the HZI prevalence, demographic data, clinical manifestations, laboratory findings, treatment and outcome in large pediatric and adult lupus populations.

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PATIENTS AND METHODS

This retrospective study evaluated 362 childhood SLE and 1830 adult SLE patients followed at pediatric and adult lupus clinics of the same tertiary hospital. All patients fulfilled the American College of Rheumatology criteria for SLE.3

HZI was defined according to the presence of acute vesicular-bullous lesions on erythematous/edematous base, in a dermatomal distribution.4 Postherpetic neuralgia was defined as persistent pain after 1 month of resolution of lesions in the same dermatome.5 Data concerning the HZI onset, dermatomal involvement and location, treatment, recurrence and complication associated with HZI were also determined.

Medical charts were assessed regarding demographic data (age at HZI diagnosis, disease duration until HZI diagnosis, duration of HZI and gender). Clinical manifestations of SLE included fever (38°C), hepatomegaly (>3 cm below the costal arch), splenomegaly (>3 cm below the costal margin), cutaneous lesions (malar or discoid rash, photosensitivity, mucosal ulcers, alopecia or cutaneous vasculitis), articular involvement (arthritis or myositis), serositis (pericarditis or pleuritis), neuropsychiatry involvement (central nervous system and peripheral nervous system), nephritis (proteinuria ≥0.5 g/24 hours, presence of cellular casts, hematuria, leukocyturia excluding infection and acute and chronic renal failure), arterial hypertension (≥140 × 90 mm Hg) and hematologic complications (hemolytic anemia, leukopenia with a white blood cell count <4000/mm3 or lymphopenia <1500/mm3 on 2 or more occasions and thrombocytopenia with platelet count <100,000/mm3 in the absence of drugs).

SLE disease activity index and cumulative damage were measured in all patients, using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)6 and the Systemic Lupus International Collaborating Clinics/ACR—Damage Index.7

Erythrocyte sedimentation rate was performed by Westergren method and C-reactive protein by nephelometry. Anti- double-stranded DNA was detected by indirect immunofluorescence using Crithidia luciliae as substrate. Presence of anticardiolipin antibodies IgG and IgM was analyzed by enzyme-linked immunosorbent assay, and lupus anticoagulant was detected according to the guidelines of the International Society on Thrombosis and Hemostasis.

Data concerning the use and current dosage of prednisone, intravenous methylprednisolone pulse, intravenous cyclophosphamide, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, intravenous immunoglobulin and treatment for HZI were also assessed.

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Statistical Analysis

Results are presented as the mean ± standard deviation or median (range) for continuous variables and as the number (%) for categorical variables. Data were compared by the Student t-test or by the Mann–Whitney test for continuous variables to evaluate differences between HZI in childhood and adult SLE patients. For categorical variables, differences were assessed by Fisher’s exact test and Pearson χ2. P values less than 0.05 were considered significant.

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RESULTS

HZI was more frequently observed in childhood SLE patients than in adult SLE [38 of 362 (10%) vs. 70 of 1830 (4%), P = 0.0001]. The dermatomes were described in 86 of 108 events, and the locations of dermatome in children and adult populations were thoracic (48% vs. 43%), lumbar (20% vs. 21%), cervical (20% vs. 4%), facial (3% vs. 20%) and sacral (8% vs. 12%), respectively. Disseminated zoster was not observed in children and in only 1 adult patient. In 1 adult patient, an ophthalmic complication was present, and there were no deaths in both groups.

Table (Supplemental Digital Content 1, http://links.lww.com/INF/C144) includes demographic data, clinical manifestations, disease activity/damage scores and outcomes of HZI in childhood SLE and adult SLE patients. Disease duration until HZI diagnosis was significantly lower in children compared with adults [21 (1–117) vs. 62 (2–408) months, P = 0.001], with a trend of lower duration of HZI in the former group [8 (5–23) vs. 10 (5–30) days, P = 0.057]. At HZI diagnosis, current fever (43% vs. 12%, P < 0.0001), nephritis (45% vs. 25%, P = 0.038) and arterial hypertension (40% vs. 18%, P = 0017) were significantly higher in children, as well as the median of SLEDAI-2K at HZI diagnosis [8 (0–20) vs. 3 (0–18), P = 0.002].

Laboratory data and treatment of HZI in childhood SLE and adult SLE patients are show in Table (Supplemental Digital Content 2, http://links.lww.com/INF/C145). At HZI diagnosis, the median of erythrocyte sedimentation rate [28 (4–62) vs. 17(2–96) mm/1st hour, P = 0.012] and C-reactive protein [9.2 (3–103) vs. 4.5 (3–42.9) mg/dL, P = 0.021] were significantly higher in children versus adults. The frequencies of hematuria (32% vs. 13%, P = 0.018), leukocyturia (45% vs. 16%, P = 0.002), anti-double-stranded DNA autoantibodies (76% vs. 15%, P < 0.0001) and low C4 (48% vs. 22%, P = 0.017) were higher in childhood SLE patients at HZI diagnosis.

The median prednisone dosage was comparable in children and adults (20 vs. 20 mg/day, P = 0.784). Immunosuppressive use was similar in childhood SLE and adult SLE patients, with exception of lower frequency of mycophenolate mofetil in children group (8% vs. 34%, P = 0.004). Intravenous acyclovir use (78% vs. 29%, P < 0.0001) and hospitalizations because of HZI (78% vs. 29%, P < 0.0001) were more often observed in children than in adults. With regard to outcome, postherpetic neuralgia was less common in children than adults (3% vs. 24%, P = 0.005; see Table, Supplemental Digital Content 2, http://links.lww.com/INF/C145).

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DISCUSSION

This is the first report identifying a higher prevalence of HZI in children than in adults with SLE.

The major strength of our study is the large cohort of patients from adult and pediatric units at the same tertiary and university hospital. The main limitation is the retrospective analysis with possible missing data and the absence of viral culture or polymerase chain reaction for HZI confirmation. However, the typical presentation of lesions along dermatomal distribution strongly supports the HZI diagnosis, as in other studies.1,4

Herpes zoster is not common in healthy subjects. The annual incidence is reported in less than 0.5% for general population.1 It rises after 50 years of age and in immunocompromised patients.1,4,8,9 The prevalence of HZI, however, varies widely in adult10 and in pediatric SLE patients,1,11 with a possible higher frequency in Asian patients.1 Assessment of patients from the same institution and the large sample size evaluated herein allowed a more precise definition of higher HZI prevalence in pediatric than adult lupus.

Of note, almost 50% of our childhood SLE patients had moderate disease activity (SLEDAI-2K > 6) reinforcing previous observation that infection can exacerbate or induce flare in pediatric lupus population.1,11 In contrast, only approximately one fourth of adult patients had active disease at HZI onset. Nephritis was the main involvement associated with this infection in pediatric patients, as also reported previously.1

Impairment of cell-mediated immunity induced by the disease itself is the possible underlying mechanism for the higher frequency of HZI in lupus patients,9 with some evidence that varicella-zoster virus-specific CD4 T-cell responses, varicella-zoster virus-specific interferon-γ-positive and tumor necrosis factors-α-positive CD4 T-cell were significantly lower in patients with disease activity.9

Current therapy is another issue that should be considered as a potential HZI risk factor.1,2,10 In fact, most patients in both groups were receiving 20 mg/day of glucocorticoid therapy. Mycophenolate mofetil use was previously associated with this infection in adult SLE patients.10 One third of our patients were receiving this therapy at HZI onset, a frequency lower than the 8% observed in pediatric lupus.

With regard to HZI clinical aspects, we observed a predominance of thoracic dermatomal involvement in pediatric and adult SLE patients, which is the most common site for all age groups in the general population.4,5,10 Importantly, postherpetic neuralgia was less frequently observed in pediatric than adult lupus patients.5

Cutaneous dissemination or ophthalmic complications were uncommon, and there were no deaths, supporting the notion of a mild disease. Hospitalization and intravenous acyclovir comprise the established protocol for HZI treatment in our pediatric unit to optimized adherence to acyclovir and may account for the higher frequency of these procedures in this group of patients.

The most effective management strategy for viral infections is prevention through vaccines, as reported in a pilot study of herpes zoster vaccination in 10 adult SLE patients older than 50 years of age,12 but the efficacy and safety of this live-attenuated virus vaccine in a large SLE population is unknown.

In conclusion, lupus in children has a higher susceptibility to HZI and is characterized by a shorter disease duration, disease activity and lower frequency of postherpetic neuralgia than in adults with SLE. Both groups have a comparable and good overall outcome.

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ACKNOWLEDGMENT

Our gratitude to Ulysses Doria-Filho for the statistical analysis.

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REFERENCES

1. Lee PP, Lee TL, Ho MH, et al. Herpes zoster in juvenile-onset systemic lupus erythematosus: incidence, clinical characteristics and risk factors. Pediatr Infect Dis J. 2006;25:728–732
2. Chakravarty EF, Michaud K, Katz R, et al. Increased incidence of herpes zoster among patients with systemic lupus erythematosus. Lupus. 2013;22:238–244
3. Hochberg MC.. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725
4. Kawai K, Gebremeskel BG, Acosta CJ.. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open. 2014;4:e004833
5. Kost RG, Straus SE.. Postherpetic neuralgia–pathogenesis, treatment, and prevention. N Engl J Med. 1996;335:32–42
6. Gladman DD, Goldsmith CH, Urowitz MB, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol. 2000;27:373–376
7. Gladman DD, Ibañez D, Urowitz MB.. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29:288–291
8. Barbosa CM, Terreri MT, Rosário PO, et al. Immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus. Clin Exp Rheumatol. 2012;30:791–798
9. Park HB, Kim KC, Park JH, et al. Association of reduced CD4 T cell responses specific to varicella zoster virus with high incidence of herpes zoster in patients with systemic lupus erythematosus. J Rheumatol. 2004;31:2151–2155
10. Borba EF, Ribeiro AC, Martin P, et al. Incidence, risk factors, and outcome of herpes zoster in systemic lupus erythematosus. J Clin Rheumatol. 2010;16:119–122
11. Faco MM, Leone C, Campos LM, et al. Factors associated to death in patients hospitalized with juvenile systemic lupus erythematosus. Braz J Med Biol Res. 2007;40:993–1002
12. Guthridge JM, Cogman A, Merrill JT, et al. Herpes zoster vaccination in SLE: a pilot study of immunogenicity. J Rheumatol. 2013;40:1875–1880
Keywords:

herpes zoster; postherpetic neuralgia; childhood systemic lupus erythematosus; adult systemic lupus erythematosus

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