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.).

Reduced bone density in patients with autosomal dominant hyper-IgE syndrome.

BACKGROUND AND PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency disorder . It has been recognized as a multisystem disorder and is characterized by both immunologic and non-immunologic manifestations. Possible bone involvement in autosomal dominant HIES include fractures, scoliosis, cystic bone changes, and osteopenia. We sought to evaluate the changes in bone density in adolescents and young adults with AD-HIES, mostly with proven STAT3 mutation, followed in our institute. METHODS: We studied eight patients with AD-HIES who attended our immunology clinic. All patients underwent at least one bone mass dual-energy x-ray absorptiometry assessment (dual-energy x-ray absorptiometry scan).These findings were evaluated. RESULTS: The age of the patients at the time of their first bone density scan ranged between 10 and 24 years (mean 16.1 ± 4.0 years); the duration of follow-up was 4-11 years (mean 5.8 ± 3.5 years). Four patients had a history of fractures. Mean Z score in these patients was -1.8 ± 0.7. For three patients, Z score was below -1. The other four patients had no history of fractures. Mean Z score in these patients was -0.9 ± 0.5. Only one patient in this group had a Z score below -1. Bone density was below average in all patients; mean spinal Z score was -1.6 ± 0.4. Four patients were followed through the second decade, and all showed progressive deterioration in bone density. Three were treated with alendronate sodium, with improvement in the bone scan results. CONCLUSIONS: Bone density decreases considerably over time in adolescents and young adults suffering from AD- HIES. Treatment with alendronate sodium may be effective in alleviating osteopenia.

Effect of instruction on the ability to use a self-administered epinephrine injector.

BACKGROUND: Patients with allergy as well as their parents frequently fail to use the self-administered epinephrine injection (EpiPen) properly in cases of allergic emergencies. OBJECTIVES: To determine the benefit of an instruction session with follow-up instruction. METHODS: We evaluated 141 patients aged 1.9-23.4 years (median 5.8 years, 83% with food allergy) or their parents (for those aged < 12 years) who were trained in the use of the EpiPen during the first diagnostic visit to the allergy clinic during 2006-2009. At the next follow-up visit, the patients or their parents were asked to list the indications for epinephrine administration and to demonstrate the five steps involved in using the EpiPen. Each step was scored on a scale of 0-2. RESULTS: Fourteen participants (9.9%) had used self-injectable epinephrine in the past. Only 65 (46%) brought the device with them to the follow-up visit. The mean total score for the whole sample was 4.03 +/- 3. Fifty-three participants (38%) failed to remove the cap before trying to apply the device. Only 8 (5.6%) had a maximum score. The patients and their parents were reinstructed in the use of the device: 41 participants were reexamined at a subsequent follow-up visit after 1.02 +/- 0.56 years; their mean score improved from 4.71 +/- 3.04 to 6.73 +/- 3.18 (P < 0.001). CONCLUSIONS: Patients with severe allergic reactions, as well as their parents, are not sufficiently skilled in the use of the EpiPen after only one instruction session with a specialist. Repeated instruction may improve the results and we therefore recommend that the instructions be repeated at every follow-up visit.

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.

SARS-CoV-2 Infection Among Health Care Workers Despite the Use of Surgical Masks and Physical Distancing-the Role of Airborne Transmission.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted mainly via respiratory droplets. A key question in the coronavirus disease 2019 pandemic is whether SARS-CoV-2 could be transmitted via the airborne route as well. We report for the first time SARS-CoV-2 nosocomial infections despite using surgical masks and physical distancing. This report may provide possible evidence for airborne transmission of SARS-CoV-2.

Selective IgA deficiency in children in Israel.

IgA deficiency is the most common human primary immune-deficiency. We evaluated the clinical and immunological characteristics of selective IgA deficiency in children in Israel. The study group included 63 children diagnosed with IgA deficiency from 1987 to 2005. Mean follow-up time per child was 10.6 years. Average age at diagnosis was 10.5 years. In one child, the IgA deficiency was transient. Infectious diseases, mainly recurrent pneumonia and ear infection, were common and occurred in 25 patients (39.7%). Allergic diseases were documented in 20 (31.7%) of our patients. Thirteen children (20.6%) had autoimmune diseases. Malignancies were diagnosed in three children (4.8%), an association that has not been reported in previous series. IgA deficiency appears to be a risk factor for infections, allergic diseases, autoimmune conditions, and malignancy.

Respiratory alkalosis and metabolic acidosis in a child treated with sulthiame.

OBJECTIVES: To report on severe acid-base disturbance in a child with symptomatic epilepsy treated with sulthiame. RESULTS: A 9.5-year-old boy with chronic generalized tonic-clonic seizures was treated with carbamazepine and valproic acid. Because of poor seizure control, sulthiame was added to the treatment. Two months later, he presented at the emergency department with severe weakness, headache, dizziness, dyspnea, anorexia, and confusional state. Arterial blood gas analysis showed mixed respiratory alkalosis with high anion gap metabolic acidosis. Sulthiame-induced acid-base disturbance was suspected. The drug was withheld for the first 24 hours and then restarted at a reduced dosage. The arterial blood gases gradually normalized, the confusion disappeared, and the patient was discharged home.Three months later, 4 weeks after an increase in sulthiame dosage, the patient was once again admitted with the same clinical picture. Improvement was noted after the drug dosage was reduced. CONCLUSIONS: This is the first report of mixed respiratory alkalosis and metabolic acidosis in a child treated with sulthiame. Monitoring of the acid-base status should be considered in patients treated with sulthiame.

The September epidemic of asthma in Israel.

BACKGROUND: The seasonality of asthma morbidity is well recognized. A peak in asthma exacerbations in September has been noted for years at our center. OBJECTIVE: To examine the hypothesis that the increment in asthma exacerbations in September is influenced by the beginning of the kindergarten and school year. METHODS: The monthly admission rate for asthma in patients of different ages was retrospectively evaluated in seven hospitals from various areas in Israel from January 2003 to December 2005. RESULTS: Of the 408,242 hospital admissions during the study period, 8,011 were for asthma exacerbations: 4,091 in adults (1.3% of adult admissions) and 3,920 in children (3.8% of pediatric admissions). The asthma admission rates varied considerably throughout the year, with a peak of 4% of total admissions in the winter months and a nadir of 2% in the summer months. September was unique for its particularly high rate of admissions for asthma attacks in children (6% of total admissions), especially toddlers and the school-age group. In adults there was a progressive increase in asthma admissions from September through December without a unique peak in September. CONCLUSIONS: There is a characteristic increase in asthma exacerbations and admissions in September in the pediatric age group. This phenomenon might be explained by the increased exposure to respiratory viruses, to new allergen exposure in school or kindergarten, increased emotional stress due to start of the new school year, or poor compliance and withdrawal of treatment during the summer. Clinicians should consider administering prophylactic treatment for asthma in children before onset of the school year.

Asplenia and functional hyposplenism in autoimmune polyglandular syndrome type 1.

Asplenia was diagnosed in four patients with autoimmune polyendocrine syndrome type-I (APS-I): two children, aged 2-4 years, from the same family and two adults, the father of the two children and his cousin. We have observed a worsening in splenic function in the children during a follow-up of a few years. Patients with APS-I should be evaluated for splenic function, since splenic dysfunction has important therapeutic implications, especially in children.

Periorbital cellulitis in the era of Haemophilus influenzae type B vaccine: predisposing factors and etiologic agents in hospitalized children.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Acute intermittent porphyria, Rasmussen encephalitis, or both?

A case of a young woman who suffers from refractory epilepsy in the form of Rasmussen encephalitis and acute intermittent porphyria is presented. The patient developed refractory partial seizures with progressive hemispheric atrophy in the first decade. Both her serum and cerebrospinal fluid contained significantly elevated levels of anti-GluR3B antibodies. Her serum also contained anti-NR2A antibodies (directed against the N-methyl-D-aspartate receptor). Seven years later, acute intermittent porphyria was diagnosed as she developed an acute episode of abdominal pain, dark urine, and hyponatremia. For several years, all attempts to discontinue porphyrinogenic antiepileptic drugs such as phenobarbital and valproate resulted in seizure worsening. During a major acute intermittent porphyria crisis, brain edema and coma developed, allowing the discontinuation of phenobarbital. On recovery, atrophy of the right hemisphere ensued. Several etiologic hypotheses are presented. Double insults, porphyria, and an autoimmune process are suggested for the development of Rasmussen encephalitis in this patient. The authors recommend testing for porphyria in cases of Rasmussen encephalitis and other intractable seizures.

Facial paralysis as a presenting symptom of leukemia.

Facial paralysis may occur as a complication of central nervous system leukemias in children, but it is rarely a presenting symptom. This report describes an 8-month-old child who presented with peripheral facial palsy, failure to thrive, anemia, and otitis media. Antibiotic and steroid treatment led to an improvement in the clinical condition, but not the paralysis. At readmission 3 weeks later, physical examination revealed bluish, firm, palpable masses on the scalp and facial areas, and laboratory and imaging studies confirmed the diagnosis of acute myeloid leukemia. This case should alert physicians to consider hematologic malignancies in children with facial paralysis.

Cervical Discitis in Children.

Cervical discitis, though rare, should be included in the differential diagnosis of torticollis, neck pain and neurodevelopmental regression in motor skills in children and infants. Magnetic resonance imaging is the diagnostic method of choice. Treatment should be conservative with antibiotics only. The aim of this study was to describe the 10-year experience of a tertiary pediatric medical center with cervical discitis.

Survey of tuberculin skin test positivity among Israeli pediatric hospital workers.

Tuberculin skin test (TST) was performed in 374 healthcare workers. TST results of induration of 10 mm or more and 20 mm or more were noted in 44.9% and 10.4%, respectively. Positive TST (> 10 mm) was found to be significantly associated with age, country of origin, and duration of employment.

Heat stroke in familial dysautonomia.

A 14-month-old female with familial dysautonomia was referred to the pediatric department with high fever (41.6 degrees C), watery diarrhea, and vomiting. A few hours later, signs of encephalopathy appeared. Laboratory tests revealed elevated levels of lactate dehydrogenase (3500 U/L), aspartate aminotransferase (640 U/L), alanine aminotransferase (320 U/L), and creatine kinase (28,420 U/L). The diagnosis was heat stroke. Impaired autonomic nervous system function may be another risk factor for the development of heat stroke in young children.

Adenovirus infection in hospitalized immunocompetent children.

This study investigated the clinical features of immunocompetent children with adenovirus infection requiring hospitalization. The files of 78 children (mean age 17 +/- 10 months) with community-acquired adenovirus infection admitted over a 2-year period were reviewed. The children were referred after 5.7 +/- 3.4 days of illness, all with fever (mean peak 39.8 +/- 0.8 degrees C). Temperature normalized after 3.5 +/- 2 days. Duration of hospitalization (mean, 7.0 +/- 3.9 days) correlated with lethargy, lung crackles, cracked lips, hypoxia, impaired liver tests, and high serum lactic dehydrogenase (LDH) concentration at admission. Serum LDH concentrations and hypoxemia predicted 70% of the variance in hospital stay. All patients recovered. Adenovirus infection may cause considerable morbidity, even in immunocompetent children. Disease severity, defined by duration of hospitalization, correlates with serum LDH concentrations and oxygen saturation at admission.