[show abstract][hide abstract] ABSTRACT: 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.).
New England Journal of Medicine 02/2014; · 51.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Catastrophic antiphospholipid syndrome (APS) in pediatric medicine is rare. We report 3 adolescents who presented with acute onset of severe abdominal pain as the first manifestation of probable catastrophic APS. The 3 patients, 2 male patients and 1 female patient were 14 to 18 years old. One had been diagnosed with systemic lupus erythematosus in the past, but the other 2 had no previous relevant medical history. All presented with excruciating abdominal pain without additional symptoms. Physical examination was noncontributory. Laboratory results were remarkable for high inflammatory markers. Abdominal ultrasonography was normal, and abdominal computed tomography scan showed nonspecific findings of liver infiltration. Only computed tomography angiography revealed evidence of extensive multiorgan thrombosis. All patients had elevated titers of antiphospholipid antibodies. The patients were treated with full heparinization, high-dose steroids, and intravenous immunoglobulin with a resolution of symptoms. One patient was resistant to the treatment and was treated with rituximab. In conclusion, severe acute abdominal pain can be the first manifestation of a thromboembolic event owing to catastrophic APS even in previously healthy adolescents. Diagnosis requires a high index of suspicion with prompt evaluation and treatment to prevent severe morbidity and mortality.
[show abstract][hide abstract] ABSTRACT: We evaluated the effect of adding dexamethasone to antibiotic therapy in the clinical course of septic arthritis in children.
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.
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.
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.
Journal of pediatric orthopedics 03/2011; 31(2):211-5. · 1.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
The Journal of pediatrics 11/2008; 153(5):696-9. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the level of antibiotic resistance of viridans streptococci in the oral flora of children with a history of rheumatic fever, receiving long-term monthly intramuscular benzathine penicillin G prophylaxis.
Oral swabs from patients receiving monthly penicillin G prophylaxis for rheumatic fever were cultured and tested for viridans streptococci. The E-test was used to test susceptibility to penicillin G, clindamycin, clarithromycin and rifampin. Findings were compared with samples from healthy children who had not been exposed to antibiotic treatment for at least 2 months.
Twenty-six patients and 20 control children were included in the study. Duration of intramuscular antibiotic treatment ranged from 5 months to 13.5 years. Sixty isolates of viridans streptococci species were obtained, with a similar distribution in the two groups. Intermediate resistance to penicillin (MIC 0.25-2 mg/L) was documented in 10 of the 32 isolates (31.2%) in the study group, and high resistance in none, compared to seven of 28 isolates (25%) with intermediate or high resistance in the control group (p=NS). All isolates in the study group and all but one in the control group were susceptible to clindamycin, and all isolates from both groups were susceptible to rifampin. One isolate (3.1%) in the study group and two (7.1%) in the control group were resistant to clarithromycin.
Monthly Intramuscular penicillin prophylaxis has no effect on the antibiotic susceptibility of viridans streptococci in oral flora in children with a history of rheumatic fever, receiving secondary prophylaxis after rheumatic fever, regardless of the duration of treatment.
The Journal of infection 05/2008; 56(4):244-8. · 4.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypoalbuminemia is a common finding in children with massive parapneumonic pleural effusion; however, its incidence and pathogenesis are unclear. The objective of this study was to assess the presence and severity of hypoalbuminemia in children with parapneumonic pleural effusion and to propose a possible pathophysiologic mechanism.
The clinical charts of patients who were hospitalized in a tertiary pediatric center with bacterial pneumonia complicated by pleural effusion were reviewed. The volume of pleural fluid was assessed semiquantitatively and categorized as small, moderate, or large. The lowest serum albumin level was recorded, and caloric intake and protein loss were evaluated. Findings were compared with age- and gender-matched children who had bacterial pneumonia without pleural effusion and with children who had acute illnesses other than pneumonia.
Of the 50 patients in the study group, 15 (30%) had small effusions, 16 (32%) had moderate effusions, and 19 (38%) had large effusions. Moderate-to-severe hypoalbuminemia was found in 52% of the study group, 6% of the patients with pneumonia without pleural effusion, and none of the patients with other illnesses. Mean serum albumin level was lower in patients with large pleural effusions than in patients with small effusions (2.66 +/- 0.37 vs 3.66 +/- 0.47 g/dL). There was no evidence of albumin loss or significant malnutrition. Estimation of the amount of albumin in the drained pleural fluid suggested an albumin shift from blood to pleural fluid.
Significant hypoalbuminemia is common in children with parapneumonic pleural effusion. Large effusions are associated with low serum albumin levels, which might be explained in part by a shift from blood to pleural fluid.
[show abstract][hide abstract] ABSTRACT: Acne can be associated with severe musculoskeletal and constitutional symptoms. This is a case history of a 15 year-old boy with severe acne, treated with isotretinoin, who was admitted because of high fever and weight loss of 3 weeks duration. His complaints were of severe chest and back pain, and inability to walk. His laboratory results revealed elevated erythrocyte sedimentation rate and C-reactive protein. On a pelvic radiograph bilateral sacroiliitis was noticed. Radionuclide bone scan revealed increased uptake in the right sacroiliac joint, in small vertebral bodies and sternum. A diagnosis of acne-associated musculoskeletal syndrome was made and the patient was treated with high dose steroids. His symptoms resolved and his acne improved. This case report sheds light on the relationship between acne and associated musculoskeletal syndromes. Physicians should be aware of this association in order to provide prompt and efficient treatment.
[show abstract][hide abstract] ABSTRACT: The incidence of Haemophilus influenzae type B (HIB) infection, once the most common cause of periorbital cellulitis, declined dramatically after the introduction of HIB vaccine in 1990. The aim of the current study was to determine the predisposing factors and agents in the pathogenesis of periorbital cellulitis in hospitalized children in the post-HIB vaccination era.
Children with clinical findings of periorbital inflammation who were hospitalized in a tertiary pediatric hospital in Israel in 2000-2001 were observed prospectively. Special attention was directed to the predisposing medical condition in each case.
One hundred sixty-three patients had a final discharge diagnosis of periorbital cellulitis. Mean age was 34 months (median = 24 months). The predisposing conditions were conjunctivitis (42.9%), infected wound or trauma (20.9%), insect bites (9.8%), sinusitis (8%), dacryostenosis (4.9%), and Streptococcus pneumoniae bacteremia (0.6%). Children with conjunctivitis and sinusitis had the most severe inflammatory signs. None of the cultures was positive for HIB, although only 71% of the children had complete immunization.
The epidemiology of periorbital cellulitis in children has changed in the post-HIB vaccine era. The most common predisposing medical conditions are conjunctivitis or an infected wound in the vicinity of the eye. Bacteremia is rarely a source of the disease. These findings have important clinical implications in terms of choice of treatment.
[show abstract][hide abstract] ABSTRACT: Intra-articular corticosteroid injection in juvenile idiopathic arthritis (JIA) is often associated with anxiety and pain. Recent reports advocate the use of nitrous oxide (NO), a volatile gas with analgesic, anxiolytic and sedative properties.
To prospectively evaluate the effectiveness and safety of NO analgesia for intra-articular corticosteroid injection in JIA, and to assess patients and staff satisfaction with the treatment.
NO was administered to JIA patients scheduled for joint injection. The patient, parent, physician and nurse completed visual-analog scores (VAS) (0-10) for pain, and a 5-point satisfaction scale. Change in heart rate (HR) during the procedure was recorded in order to examine physiologic response to pain and stress. Patient's behavior and adverse reactions were recorded.
54 procedures (72 joints) were performed, 41 females, 13 males; 39 Jewish, 13 Arab; mean age was 12.2 +/- 4.7 year. The median VAS pain score for patients, parents, physicians and nurses was 3. The HR increased >/= 15% in 10 patients. They had higher VAS scores as evaluated by the staff. The median satisfaction level of the parents and staff was 3.0 and 5.0 respectively. Adverse reactions were mild.
NO provides effective and safe sedation for JIA children undergoing intra-articular injections.
[show abstract][hide abstract] ABSTRACT: An elevated expression of the alloantigen D8/17 on B lymphocytes has been previously proposed as a susceptibility marker in rheumatic fever. The aim of the study was to investigate the presence of the D8/17 marker on B lymphocytes in poststreptococcal reactive arthritis (PSRA). The study sample included 19 patients (15 boys, 4 girls; mean age 11.7 +/- 5.4 years) who were diagnosed with PSRA (mean age at diagnosis, 9.4 +/- 5.6 years) and 18 healthy controls (10 boys and 8 girls) matched for ethnic background. B-cell D8/17 expression was tested by flow cytometry assay using monoclonal antibodies. Laboratory results showed a higher expression of D8/17 in the patient group (23.1 +/- 10.4%, range 11.6-51.9%) than in the control group (17.1 +/- 8.2%, range 7.1-35.7) in controls; this difference was statistically significant after log transformation of the data (P = 0.035). The high rate of expression of the D8/17 marker in patients with PSRA suggests that RF and PSRA share the same genetic susceptibility.
Rheumatology International 07/2007; 27(8):695-8. · 2.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Folate is essential for normal brain development. This report describes a 15-month-old boy who presented with generalized and focal seizures and a decline in mental status. Laboratory tests revealed low folate levels in blood (1.13 nmol/L) and cerebrospinal fluid, accompanied by pancytopenia. Bone marrow aspiration confirmed the presence of megaloblastic anemia. Treatment with high-dose intravenous folinic acid led to normalization of cerebrospinal folate levels. These findings apparently indicate a defect in folic acid transport to the central nervous system. A clinical picture of developmental arrest, seizures, somnolence, and megaloblastic anemia should alert physicians to the possibility of folate deficiency.
Journal of Child Neurology 07/2007; 22(6):783-6. · 1.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Few studies have addressed antiphospholipid syndrome (APS) among children. Our aims were to analyze the clinical and laboratory manifestations in a pediatric APS cohort and to assess the influence of inherited thrombophilia factors on the outcome of children with APS.
This was a multicenter study of children with APS who had no previous systemic autoimmune disease. We retrospectively reviewed their clinical and laboratory data, including hereditary thrombophilic deficits and outcomes.
The cohort comprised 28 patients (17 females, mean +/- SD age at onset 10.6 +/- 6.1 years). The most common initial manifestations of APS were venous thrombosis, stroke, and thrombocytopenia. Lupus anticoagulant was detected in 96% of those tested. After a mean +/- SD followup of 5.7 +/- 4.8 years, 16 children (57.1%) had central nervous system disease, 9 exhibited hematologic involvement, and 5 (all females) had systemic lupus erythematosus (SLE). None had renal, heart, or new skin disease. Seven of 24 patients exhibiting vascular thrombotic events had recurrences. Infants with perinatal stroke had monophasic disease, and other manifestations of APS did not develop later. Hereditary thrombophilia was more common in children who experienced a single episode of APS (8 [53.3%] of 15 patients) than in those who experienced recurrences (2 [28.6%] of 7 patients). However, only 2 patients in the latter group (28.6%) received anticoagulants after the first manifestation, compared with 12 (70.6%) of the 17 patients without recurrences.
APS in children has unique features. SLE may develop in a significant percentage of girls presenting with APS. Hereditary thrombophilia did not predict recurrent thrombosis, whereas the preventive impact of anticoagulant treatment following the first thrombotic event was noteworthy.
[show abstract][hide abstract] ABSTRACT: Calcinosis is a devastating complication of juvenile dermatomyositis and a challenging therapeutic problem. We report the use of an external Ilizarov fixator for the treatment of Achilles tendon calcinosis causing severe disability in a young girl with juvenile dermatomyositis.
Clinical and experimental rheumatology 01/2007; 25(5):763-5. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to describe the clinical manifestations and outcomes of a national cohort of childhood systemic lupus erythematosus (cSLE). All cases of cSLE registered in the Israeli national registry of children with rheumatic diseases between 1987-2003 were examined for disease activity and damage by the SLE disease activity index (SLEDAI) and SLE collaborating clinics/American College of Rheumatology (SLICC/ACR) damage index. Demographic, clinical, laboratory and treatment factors were analysed for their effect on the outcome. One-hundred and two patients were identified, 81% females, with a mean age at diagnosis of 13.3 +/- 2.6 years. The mean SLEDAI score was 17.2 +/- 9.0 (range 2-60). Fifty four patients were followed for at least five years. The mean SLEDAI decreased to 7.6 +/- 6.3 (0-29) and the mean SLICC/ACR damage index was 0.7 +/- 1.6 (0-8). Five patients developed chronic renal failure. No patients died. No factors were found to be significantly associated with the outcome except the initial SLEDAI score. The five-year outcome of our national cSLE cohort was good; with relatively low activity and minimal damage in most patients. The initial SLEDAI predicted the development of late damage.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to describe the clinical manifestations and outcomes of a national cohort of childhood systemic lupus erythematosus (cSLE). All cases of cSLE registered in the Israeli national registry of children with rheumatic diseases between 1987–2003 were examined for disease activity and damage by the SLE disease activity index (SLEDAI) and SLE collaborating clinics/American College of Rheumatology (SLICC/ACR) damage index. Demographic, clinical, laboratory and treatment factors were analysed for their effect on the outcome. One-hundred and two patients were identified, 81% females, with a mean age at diagnosis of 13.3 ± 2.6 years. The mean SLEDAI score was 17.2 ± 9.0 (range 2–60). Fifty four patients were followed for at least five years. The mean SLEDAI decreased to 7.6 ± 6.3 (0–29) and the mean SLICC/ACR damage index was 0.7 ± 1.6 (0–8). Five patients developed chronic renal failure. No patients died. No factors were found to be significantly associated with the outcome except the initial SLEDAI score. The five-year outcome of our national cSLE cohort was good; with relatively low activity and minimal damage in most patients. The initial SLEDAI predicted the development of late damage.
[show abstract][hide abstract] ABSTRACT: To present an analysis of patients with protracted febrile myalgia (PFM), a rarely reported manifestation of familial Mediterranean fever (FMF), and propose clinical criteria for working diagnosis.
A multicenter retrospective cohort study of children with PFM was performed. Clinical and laboratory data were obtained by medical record review.
The study group included 15 patients with PFM. PFM occurred as the presenting sign of FMF in 33%. FMF was diagnosed clinically in all and by genetic analysis in 93%. M694V allelic involvement was noted in 93% of the patients. PFM occurred at a mean age of 9 +/- 3.4 years and was characterized by severe generalized muscle pain in all patients and fever in 71%. Mean duration up to diagnosis was 15.5 +/- 6 days. Mean erythrocyte sedimentation rate was 104 +/- 26 mm/h; mean C-reactive protein was 15.4 +/- 6.3 mg%. Creatine kinase was normal. Treatment included corticosteroids (4 patients) and nonsteroidal anti-inflammatory drugs (NSAIDs) (9 patients) with a symptomatic relief achieved at a mean of 7.7 +/- 4.3 days and 5 +/- 3.8 days, respectively (p = 0.14) (mean severity score 3 and 2.2, respectively, p = 0.075). Symptomatic relief in 2 untreated patients was achieved at a mean of 45.5 days.
Based on our data, we propose criteria for working diagnosis including: severe disabling myalgia of at least 5 days in a young patient with FMF, associated with fever, elevated levels of inflammatory markers and presence of at least one M694V mutation.
[show abstract][hide abstract] ABSTRACT: Anticonvulsant hypersensitivity syndrome is a specific severe idiosyncratic reaction to the aromatic antiepileptic drugs. The most frequent presenting symptoms are fever and rash, lymphadenopathy owing to lymphoid hyperplasia, hepatitis, and interstitial nephritis. Severe skin reactions (Stevens-Johnson syndrome or toxic epidermal necrolysis) have also been reported. Early detection is crucial owing to the high mortality rate. Although withdrawal of the offending drug is critical, the optimal treatment approach remains controversial. Previous studies report a severe course and prolonged hospital stay for cutaneous drug-related reactions, including referral to a burn center, skin débridement, and allograft skin coverage. The aim of the present report is to describe four adolescents with antiepileptic drug hypersensitivity syndrome who were treated with intravenous immunoglobulin and systemic corticosteroids. All recovered completely following an uncomplicated and relatively short course and hospitalization. Findings indicate that this regimen might be a promising treatment option in this patient population. Larger, controlled trials are needed to reach a definitive conclusion.
Journal of Child Neurology 06/2006; 21(5):380-4. · 1.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: To estimate the occurrence of antithyroid antibodies (ATA) and hypothyroidism in children with juvenile idiopathic arthritis (JIA) compared to matched healthy controls.
The occurrence of ATA, including antithyroglobulin (anti-TG) and antithyroid peroxidase (anti-TPO) antibodies, was evaluated by quantitative immunometric ELISA in children with JIA and in a healthy matched control group. Thyroid function was assessed in both groups.
The study group included 66 patients with JIA (50 girls, 16 boys) of mean age 11.7 +/- 4.4 years (range 2-23). The control group included 89 children (71 girls, 18 boys) of mean age 10.8 +/- 4.2 years (range 2-18). Mean age at onset of joint disease was 7.3 +/- 3.6 years (range 1-15). Anti-TG antibodies were found in 7 of 62 patients (11.3%) in the JIA group and 2 of 89 controls (2.2%) (p = 0.03); anti-TPO antibodies were found in 5 of 65 patients (7.9%) and one of 89 controls (1.1%) (p = 0.08). All patients with ATA had oligoarticular type JIA (p = 0.01). Mean thyroid stimulating hormone (TSH) levels were higher in the study group than in controls (2.6 +/- 2.3 vs 1.9 +/- 1.0 mIU/l; p = 0.01); levels were above normal range (0.4-4 mIU/l) in 8 study patients (12%) and 3 controls (3.4%) (p = 0.055). Overall, ATA were found in 9 of the 150 study participants, 4 (44%) of whom had TSH levels above 4 mIU/l (p = 0.001).
Children with JIA have a higher than normal incidence of ATA and subclinical hypothyroidism and should be routinely screened for these variables.
The Journal of Rheumatology 02/2006; 33(1):164-6. · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of the present study was to examine the efficacy of postexposure vaccination with Varilrix in the household setting. A randomized, double-blind, placebo-controlled design was used. Twenty-two children received the varicella vaccine and 20, a placebo. The relative risk of developing varicella with a placebo compared with the vaccine was 1.1 (95% confidence interval 0.55-2.21). The risk of developing moderate to severe disease was eight times greater in the placebo group (RR=8), indicating an 80% protective effect against moderate/severe disease. The varicella vaccine Varilrix may not be effective in preventing varicella when administered after household exposure, although it is highly effective in ameliorating the disease in those who acquire it under these circumstances.