Liora Harel

Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy

BACKGROUND Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study

Abstract Objectives: To examine the efficacy of aciclovir suspension for treating herpetic gingivostomatitis in young children. Design: Randomised double blind placebo controlled study. Setting: Day care unit of a tertiary paediatric hospital. Subjects: 72 children aged 1-6 years with clinical manifestations of gingivostomatitis lasting less than 72 hours; 61 children with cultures positive for herpes simplex virus finished the study. Main outcome measures: Duration of oral lesions, fever, eating and drinking difficulties, and viral shedding. Intervention: Aciclovir suspension 15 mg/kg five times a day for seven days, or placebo. Results: Children receiving aciclovir had oral lesions for a shorter period than children receiving placebo (median 4v 10 days (difference 6 days, 95% confidence interval 4.0 to 8.0)) and earlier disappearance of the following signs and symptoms: fever (1 v 3 days (2 days, 0.8 to 3.2)); extraoral lesions (lesions around the mouth but outside the oral cavity) (0 v 5.5 days (5.5 days, 1.3 to 4.7)); eating difficulties (4 v 7 days (3 days, 1.31 to 4.69)); and drinking difficulties (3 v 6 days (3 days, 1.1 to 4.9)). Viral shedding was significantly shorter in the group treated with aciclovir (1 v 5 days (4 days, 2.9 to 5.1)). Conclusions: Oral aciclovir treatment for herpetic gingivostomatitis, started within the first three days of onset, shortens the duration of all clinical manifestations and the infectivity of affected children. Further studies are needed to evaluate the ideal dose and length of treatment. Key messages Herpetic gingivostomatitis is the most common clinical manifestation of primary herpes simplex virus infection in young children The efficacy of oral aciclovir suspension was studied in a double blind placebo controlled study All clinical symptoms and viral shedding were shorter in children receiving aciclovir than in those receiving placebo Aciclovir was highly effective in treating children with herpetic gingivostomatitis

Dexamethasone therapy for septic arthritis in children: results of a randomized double-blind placebo-controlled study.

Background We evaluated the effect of adding dexamethasone to antibiotic therapy in the clinical course of septic arthritis in children. Methods A randomized double-blind placebo-controlled trial was performed. The study group included 49 children with septicarthritis. In addition to antibiotic therapy given, patients were randomly assigned to receive intravenous dexamethasone 0.15 mg/kg every 6 hours for 4 days or placebo. The groups were compared for clinical and laboratory parameters, length of hospital stay, and late sequelae. Results Mean age was 33±42 months (range: 6 to 161 mo). There was no significant difference between the dexamethasone and placebo groups in age, duration of symptoms, joint affected, or levels of acute phase reactants. Bacteria were isolated from joint fluid in 17 patients (35%) and from blood in 4 patients. Compared with the placebo group, patients treated with dexamethasone had a significantly shorter duration of fever (P=0.021; mean first day without fever 1.68 vs 2.83) and local inflammatory signs (P=0.021; mean first day without pain 7.18 vs 10.76), lower levels of acute phase reactants (P=0.003; mean last day of erythrocyte sedimentation rate>25 mm/h 3.76 vs 8.40), shorter duration of parenteral antibiotic treatment (P=0.007; mean of 9.91 d vs 12.60 d), and shorter hospital stay. No side effects of treatment were recorded in either group. Conclusions A 4-day course of dexamethasone given at the start of antibiotic treatment in children with septic arthritis, is safe, and leads to a significantly more rapid clinical improvement, shortening duration of hospitalization compared with those treated with antibiotics alone. Level of Evidence I.

The natural history of primary herpes simplex type 1 gingivostomatitis in children.

Abstract: Herpetic gingivostomatitis is the most common specific clinical manifestation of primary herpes simplex infection in childhood. The aim of the present study was to describe the clinical signs, symptoms, viral shedding, serologic findings, and complications in communityacquired gingivostomatitis. We prospectively followed children with herpes simplex type 1 gingivostomatitis lasting less than 72 hours. Clinical examination and viral culture were repeated every 2 to 3 days as long as symptoms or signs persisted. Thirty‐six children (ages 12–77 months) were included in the study. Mean duration of oral lesions was 12.0 ± 3.4 days; extraoral lesions (in 26 children), 12.0 ± 3.9 days; fever, 4.4 ± 2.4 days; and eating/drinking difficulties, 9.1 ± 3.0 and 7.1 ± 3.1 days, respectively. In all children, viral cultures of the oral lesions were positive for herpes simplex virus (HSV) type 1; viral shedding persisted for a mean of 7.1 ± 2.5 days (range 2–12 days). The main complications were dehydration, with three children hospitalized for intravenous rehydration, and one case of secondary bacteremia. Herpetic gingivostomatitis is a relatively severe manifestation of primary HSV type 1 infection in young children.

Parental Presence During Lumbar Puncture Anxiety and Attitude Toward the Procedure

We evaluated the anxiety state of 57 parents whose children required lumbar puncture (LP) as part of a diagnostic workup. We also examined parental attitude about their presence during the procedure. The parents were randomly divided into two groups: 29 (51%) were present during the LP (group A) and 28 (49%) remained outside (group B). There were no differences in the anxiety scores between the two groups. All parents in group A and seven in group B (25%) reported a preference for staying with the child should he/she need LP in the future. The results also showed that allowing the parents to be present during LP does not aggravate their anxiety compared with controls.

Presence of Viremia in Patients with Primary Herpetic Gingivostomatitis

BACKGROUND Presence of viremia during primary herpes simplex virus (HSV) infections has been previously investigated, but the findings for immunocompetent individuals have only rarely been reported. METHODS With use of polymerase chain reaction (PCR), we evaluated blood samples obtained from children with primary herpes simplex virus (HSV) gingivostomatitis for viremia. RESULTS There were 16 girls and 16 boys, aged 9-44 months (median age, 19 months). Serological test results for HSV type 1 were positive for 3 subjects (10.3%), borderline for 7 (24.1%), and negative for 19 (65.5%). Results of PCR of peripheral blood samples were positive for 11 subjects (34.4%). Time from disease onset to specimen collection was 24-216 h (median, 72 h) and was longer for subjects with positive results of serological tests (P =.014) and shorter for subjects with positive PCR results (P=.42). No cases with positive results of both PCR and serological tests were found. CONCLUSION PCR detected viremia in 34% of patients with primary herpetic gingivostomatitis. Presence of viremia may play a potential role in viral dissemination, providing a better understanding of the pathogenesis of HSV infections, especially of the central nervous system.

The Ped-APS Registry: the antiphospholipid syndrome in childhood

In recent years, antiphospholipid syndrome (APS) has been increasingly recognised in various paediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way. The project of an international registry of paediatric patients with APS (the Ped-APS Registry) was initiated in 2004 to foster and conduct multicentre, controlled studies with large number of paediatric APS patients. The Ped-APS Registry is organised as a collaborative project of the European Forum on Antiphospholipid Antibodies and Juvenile Systemic Lupus Erythematosus Working Group of the Paediatric Rheumatology European Society. Currently, it documents a standardised clinical, laboratory and therapeutic data of 133 children with antiphospholipid antibodies (aPL)-related thrombosis from 14 countries. The priority projects for future research of the Ped-APS Registry include prospective enrolment of new patients with aPL-related thrombosis, assessment of differences between the paediatric and adult APS, evaluation of proinflammatory genotype as a risk factor for APS manifestations in childhood and evaluation of patients with isolated nonthrombotic aPL-related manifestations.

Differentation of Post-Streptococcal Reactive Arthritis from Acute Rheumatic Fever

OBJECTIVE To perform a retrospective study comparing clinical and laboratory aspects of patients with acute rheumatic fever (ARF) and patients with post-streptococcal reactive arthritis (PSRA), to discern whether these are 2 separate entities or varying clinical manifestations of the same disease. STUDY DESIGN We located the records of 68 patients with ARF and 159 patients with PSRA, whose diseases were diagnosed with standardized criteria and treated by 8 pediatric rheumatologists in 7 medical centers, using the Israeli internet-based pediatric rheumatology registry. The medical records of these patients were reviewed for demographic, clinical, and laboratory variables, and the data were compared and analyzed with univariate, multivariate, and discriminatory analysis. RESULTS Four variables were found to differ significantly between ARF and PSRA and serve also as predictors: sedimentation rate, C-reactive protein, duration of joint symptoms after starting anti-inflammatory treatment, and relapse of joint symptoms after cessation of treatment. A discriminative equation was derived that enabled us to correctly classify >80% of the patients. CONCLUSION On the basis of simple clinical and laboratory variables, we were able to differentiate ARF from PSRA and correctly classify >80% of the patients. It appears that ARF and PSRA are distinct entities.

Improvement of atypical acute disseminated encephalomyelitis with steroids and intravenous immunoglobulins

Acute disseminated encephalomyelitis is a demyelinating syndrome that occurs infrequently in children. Various treatment modalities, such as plasmapheresis or steroids or intravenous immunoglobulins (IVIG), have been prescribed. The article describes the results of combined IVIG and high-dose steroids given for 3 days in the treatment of a patient with atypical encephalomyelitis. The results suggest that this approach may be more beneficial than the application of either drug alone.

Effectiveness of Inhaled Corticosteroids in Controlling Acute Asthma Exacerbations in Children at Home

Many clinicians advise their patients to increase the dose of inhaled corticosteroids during acute asthma exacerbations, without strong clinical evidence supporting this treatment. This study investigates the effectiveness of inhaled corticosteroids in controlling acute asthma exacerbations in children at home. The study population consisted of children with mild intermittent, mild and moderate persistent asthma aged 1 to 14 years who were treated in our outpatient clinic with inhaled budesonide for 1 year. After participating in an asthma education session, the parents were instructed to initiate treatment with inhaled budesonide at the first signs of asthma exacerbation, starting with 200 to 400 pg budesonide, in combination with beta-2 agonists 4 times a day and followed by a decrease in the dose in 4 to 8 days. Asthma status and peak expiratory flow rates were measured in the 3 monthly follow-up visits. Only children who complied with the treatment regimen and came for follow-up visits regularly were included in the final analysis. One hundred fifty children used our treatment protocol with inhaled budesonide to control their asthma attacks. Clinical improvement of asthma symptoms was achieved after a mean of 1.8 +0.7 days from the beginning of treatment. The parents were able to control 94% of the 1,061 episodes of asthma exacerbation occurring during a cumulative follow-up period of 239 years. In the 3-month period before enrollment, 101 children (67%) had used oral corticosteroids to control their asthma attacks and 50 (33%) were hospitalized. During the entire follow-up period, only 11 children (7%) used oral corticosteroids, and none of the children were hospitalized. The present study demonstrates that children with asthma can control their exacerbations at home using inhaled corticosteroids (budesonide). Treatment, starting with relatively high doses followed by a rapid reduction in dose over 4-8 days, resulted in a decrease in the use of oral steroids and in hospitalization. To achieve good results, patient compliance is essential.