Asher Tal

Association between Common Toll-Like Receptor 4 Mutations and Severe Respiratory Syncytial Virus Disease

BACKGROUND The clinical spectrum of respiratory syncytial virus (RSV) bronchiolitis in previously healthy infants is extremely variable. Thus, it is likely that factors such as genetic heterogeneity contribute to disease severity. Toll-like receptor 4 (TLR4) and CD14 are part of a receptor complex involved in the innate immune response to RSV. METHODS The association of the TLR4 mutations (Asp299Gly and Thr399Ile) and the CD14/-159 polymorphism were analyzed in 99 infants hospitalized with severe RSV bronchiolitis (group I). Eighty-two ambulatory infants with mild RSV bronchiolitis (group II) and 90 healthy adults (group III) composed the 2 control groups. The TLR4 mutations and the CD14/-159 polymorphism were genotyped by use of reverse-transcriptase polymerase chain reaction and restriction fragment-length polymorphism analysis, respectively. RESULTS Each of the TLR4 mutations, either alone or in cosegregation, were associated with severe RSV bronchiolitis: the Asp299Gly and Thr399Ile mutations were significantly overrepresented in group I, compared with groups II and III. No association between the CD14/-159 polymorphism and RSV bronchiolitis was found. CONCLUSIONS These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.

The effect of adenotonsillectomy on serum insulin-like growth factor-I and growth in children with obstructive sleep apnea syndrome

OBJECTIVE Obstructive sleep apnea syndrome (OSAS) in children is frequently associated with growth interruption. The objective of this study was to evaluate the effect of OSAS and adenotonsillectomy on the insulin-like growth factor-I (IGF-I) axis in children. STUDY DESIGN Thirteen prepubertal children (mean age, 6.0 +/- 2.8 years) were studied before and after adenotonsillectomy (T&A). Weight, height, overnight polysomnography, and IGF-I and IGF-binding protein-3 levels were evaluated before and 3 to 12 months after T&A. The childrens weights and heights were monitored for 18 months. RESULTS The respiratory disturbance index improved from 7.8 +/- 9.1 events/h to 1.0 +/- 2.1 events/h after T&A (P <.02). Slow-wave sleep increased from 29.1% +/- 7.2% to 34.6% +/- 9.8% after T&A (P <.02). The weight standard deviation score increased from 0.86 +/- 1 to 1. 24 +/- 0.9, 18 months after T&A (P <.01). Serum IGF-I levels increased from 146.3 +/- 76.2 ng/mL before T&A to 210.3 +/- 112.5 ng/mL after surgery (P <.01), but IGF-binding protein-3 levels did not change significantly. CONCLUSION The respiratory improvement after T&A in children with OSAS is associated with a significant increase in serum IGF-I levels and weight. We conclude that the IGF-I axis is affected in children with OSAS.

Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction

BACKGROUND The exact amount of drug deposited in the respiratory and gastrointestinal tract in children with airway obstruction, when delivered from a metered-dose inhaler (MDI) via a spacer with mask, and its distribution in children with airway obstruction, are unknown. METHODS We studied 15 children, using salbutamol labeled with technetium 99m. Each patient was imaged with a gamma-camera immediately after one puff of labeled salbutamol was administered via a spacer with mask. Drug deposition was then analyzed to measure the distribution of the labeled spray in the oropharynx, the lungs, the stomach, and the spacer with mask (Aerochamber) itself. RESULTS Fifteen infants and children (mean age, 21 months (range, 3 months to 5 years); mean weight, 9.3 kg (range, 3.2 to 15 kg)) were studied. Mean aerosol deposition was 1.97% +/- 1.4% in the lungs, 1.28% +/- 0.77% in the oropharynx, and 1.11% +/- 2.4% in the stomach. The remainder was trapped in the spacer. Lung imaging after inhalation from an MDI via a spacer showed widespread deposition of the drug in central and peripheral intrapulmonary airways. In two adult volunteers the deposition after one puff of the same radiolabeled drug, inhaled from an MDI via a spacer with a mouthpiece, was 19% in the lungs and 2% in the stomach. CONCLUSIONS Infants and toddlers with obstructive lung disease can be reliably and safely treated with inhaled medication administered with an MDI via a spacer with mask. The doses of a drug given from an MDI to infants and toddlers when a spacer with mask is used are not yet well defined but should be higher than the currently recommended doses, perhaps as much as an adult dose.

Montelukast for Children With Obstructive Sleep Apnea: A Double-blind, Placebo-Controlled Study

OBJECTIVES: Children with nonsevere obstructive sleep apnea (OSA) benefit from alternative therapeutic interventions such as leukotriene modifiers. We hypothesized that montelukast might improve OSA in children. We tested this hypothesis in a double-blind, randomized, placebo-controlled fashion. METHODS: Of 50 possible candidates, we recruited 46 children with polysomnographically diagnosed OSA. In this prospective, double-blind, randomized trial, children received daily oral montelukast at 4 or 5 mg (<6 or >6 years of age, respectively) or placebo for 12 weeks. Polysomnographic assessments, parent questionnaires, and radiographs to assess adenoid size were performed before and after therapy. RESULTS: Compared with the 23 children that received placebo, the 23 children that received montelukast showed significant improvements in polysomnographic measures of respiratory disturbance (obstructive apnea index), childrens symptoms, and adenoid size. The obstructive apnea index decreased by >50% in 65.2% of treated children. No attrition or side effects occurred. CONCLUSIONS: A 12-week treatment with daily, oral montelukast effectively reduced the severity of OSA and the magnitude of the underlying adenoidal hypertrophy in children with nonsevere OSA.

B-Type Natriuretic Peptide and Cardiovascular Function in Young Children With Obstructive Sleep Apnea

OBJECTIVE N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of ventricular strain, and C-reactive protein (CRP), a marker of inflammation, are reportedly elevated in school-aged children with obstructive sleep apnea (OSA). We hypothesized that cardiovascular morbidity affects circulating markers and their echocardiographic and polysomnographic (PSG) correlates in young children with OSA. METHODS We assessed young children undergoing adenotonsillectomy (TA) for OSA by polysomnography, echocardiography, and serum CRP and NT-proBNP levels. RESULTS A total of 90 children with OSA (mean age 19 +/- 7 months; 71.2% male; BMI, z = 0.62 +/- 1.04) and 45 age- and sex-matched controls were included. Three months following TA, 72 children were reassessed for NT-proBNP and CRP. NT-proBNP level (pg/mL) was higher in subjects with OSA (189.1 +/- 112.7) vs control subjects (104.8 +/- 49.5; P = .006). Both NT-proBNP (187.8 +/- 114 vs 86 +/- 32.6; P = .002) and CRP levels (mg %) (0.49 +/- 0.41 vs 0.1 +/- 0.17; P < .05) decreased following TA. Doppler pulse wave measuring tricuspid regurgitation (TR), a reflection of pulmonary hypertension, correlated with CRP (r = 0.61, P < .01) but not NT-proBNP (r = -0.14, P = .53) levels. Left ventricle end-diastolic diameter (LVEDD) was at the maximal normal range (0.91 +/- 0.11), but did not correlate with CRP or NT-proBNP levels. Both CRP level and TR correlated with PSG variables reflecting nocturnal hypoxemia, whereas NT-proBNP level and LVEDD did not. Echocardiography in 40 children (out of 90) showed a decline in TR that was abnormal before TA and correlated with the decrease in CRP following TA. CONCLUSIONS NT-proBNP levels are increased in children with OSA and decrease following TA. Echocardiographic parameters suggesting increased pulmonary pressure in young children with OSA are related to nocturnal hypoxemia and systemic inflammation, which also decrease following therapy.

Hospitalization of Jewish and Bedouin infants in Southern Israel for bronchiolitis caused by respiratory syncytial virus

We conducted a prospective study to determine the clinical picture and impact of respiratory syncytial virus (RSV) on hospitalization for acute bronchiolitis of pediatric patients less than 2 years of age belonging to two different ethnic groups in Southern Israel: Jews and Bedouins. All patients younger than 2 years of age hospitalized for bronchiolitis during a typical RSV season were enrolled. During the study period 120 patients with bronchiolitis were hospitalized, and 83 (69%) were RSV-positive. Their age ranged from 20 days to 9 months. Fifty-five percent of all patients with RSV bronchiolitis were < or = 3 months old and 92% were < or = 6 months old. Patients with RSV bronchiolitis represented 18% of all hospitalized infants < or = 9 months old and 35% of all hospitalizations for respiratory problems of infants < or = 9 months old. The yearly incidence of hospitalization for RSV bronchiolitis was 5.4/1000 live births for Jews and 18/1000 live births for Bedouins. The total number of hospitalization days calculated for 1000 births was 32.1 for the Jews and 86.7 for the Bedouins. RSV has a serious impact on infant morbidity in Southern Israel.

Inflammation and sleep disordered breathing in children: a state-of-the-art review.

Sleep disordered breathing (SDB) represents a spectrum of breathing disorders, ranging from snoring to obstructive sleep apnea syndrome (OSAS), that disrupt nocturnal respiration and sleep architecture. OSAS is a common disorder in children, with a prevalence of 2–3%. It is associated with neurobehavioral, cognitive, and cardiovascular morbidities. In children, adenotonsillectomy is the first choice for treatment and is reserved for moderate to severe OSAS, as defined by an overnight polysomnography. In adults, OSAS is the result of mechanical dysfunction of the upper airway, manifesting as severity‐dependent nasal, oropharyngeal, and systemic inflammation that decrease after continuous positive airway pressure therapy. Inflammatory changes have been reported in upper airway samples from children with OSAS, and systemic inflammation, as indicated by high‐sensitivity C‐reactive protein (hsCRP) levels, has been shown to decrease in children with OSAS after adenotonsillectomy. Anti‐inflammatory treatments for children with mild OSAS are associated with major improvements in symptoms, polysomnographic respiratory values, and radiologic measures of adenoid size. Inflammation is correlated to some extent with OSAS‐related neurocognitive morbidity, but the role of inflammatory markers in the diagnosis and management of OSAS, and the role of anti‐inflammatory treatments, remains to be clarified. This review examines the role of inflammation in the pathophysiology of sleep‐disordered breathing in pediatric patients and the potential therapeutic implications. Pediatr. Pulmonol. 2008; 43:1151–1160.

Salmonella diskitis in a 2-year old immunocompetent child.

Spine infections are uncommon in paediatrics and are generally caused by Staphylococcus aureus. Salmonella spp. are a rare cause of spine infections, usually affecting children with sickle-cell anaemia. We present a case of group C1 Salmonella diskitis in a previously healthy 2-y-old child, and review the relevant literature.

Carbamate and organophosphate poisoning in early childhood

Twenty-five infants and young children intoxicated by carbamate and organophosphorus compounds are described. Presenting signs and symptoms in children differed from those described in adults and were mainly related to severe CNS depression, coma and stupor, dyspnea, and flaccidity. Other clinical signs such as miosis, excessive salivation and tearing, sweaty, cold skin, and gastrointestinal symptoms were less frequent, while fasciculations and bradycardia were quite uncommon on arrival. Only two patients presented with all typical signs of organophosphate poisoning as described in adults. Signs of carbamate poisoning were indistinguishable from those of organophosphate poisoning and included signs of myoneural and CNS cholinergic receptor involvement, in addition to parasympathetic muscarinic dysfunction. Atropine sulfate was found to have a clear beneficial CNS effect in addition to its known peripheral antimuscarinic effect. Our data suggest that the clinical presentation of carbamate and organophosphate poisoning in early childhood and its response to therapy are quite different from those of adults and older children.

Impaired behavioral and neurocognitive function in preschool children with obstructive sleep apnea.

We aimed to examine the hypothesis that behavioral and neurocognitive functions of preschool children with Obstructive Sleep Apnea Syndrome (OSAS) are impaired compared to healthy children, and improve after adenotonsillectomy (TA).