Benjamin Volovitz

The Release of Leukotrienes in the Respiratory Tract during Infection with Respiratory Syncytial Virus: Role in Obstructive Airway Disease

ABSTRACT: Samples of nasopharyngeal secretions from a group of 73 infants with bronchiolitis or upper respiratory illness alone during infection with respiratory syncytial virus were analyzed for leukotriene C4 (LTC4) content using a reverse-phase high-pressure liquid chromatography assay with confirmation by radioimmunoassay. Titers of respiratory syncytial virus (RSV)-specific IgE in nasopharyngeal secretion (NPS) specimens were determined using an enzyme-linked immunosorbent assay. The highest concentrations of LTC4 were found in the first 3 to 8 days after the onset of illness, and LTC4 was detectable in progressively lower concentrations in samples obtained up to 28 days after the onset of illness. LTC4 was detected in samples of NPS obtained in the acute phase of illness from 67% of infants with bronchiolitis due to RSV and in 33% of samples of NPS obtained during the same interval from infants with upper respiratory illness alone (p < 0.025). Concentrations of LTC4 in children with bronchiolitis were 5-fold higher (1271 pg/ml) then the mean concentration of LTC4 in children with upper respiratory illness (224 pg/ml, p < 0.02). LTC4 was detected in 83% of the children developing an RSV-IgE response and in 24% of subjects not developing an RSV-IgE response (p < 0.001). Quantities of LTC4 measured in NPS were directly correlated with the magnitude of the RSV-IgE response in secretions (r = 0.33, p < 0.02). These studies lend support to previous investigations suggesting that severe bronchiolitis due to RSV results from IgE-mediated hypersensitivity reactions to viral antigens, with release of chemical mediators of airway obstruction. Their implications should be considered in new approaches to therapy of RSV bronchiolitis.

Growth and pituitary-adrenal function in children with severe asthma treated with inhaled budesonide

BACKGROUND The increased use of inhaled corticosteroids in the management of asthma raises concern about the safety of these drugs in children. We sought to determine the safety of long-term administration of inhaled budesonide in young children with asthma. METHODS We studied 15 children 2 to 7 years old who had severe perennial asthma. They inhaled 100 micrograms of budesonide twice daily for three to five years. Efficacy was assessed by serial evaluation of respiratory symptoms and the need for other medications, and safety by serial evaluation of height, height velocity, weight, bone age, and pituitary-adrenal function. RESULTS The severity of asthma decreased within the first month after the initiation of therapy, as demonstrated by a 58 percent reduction in the number of days with symptoms of asthma and a 75 percent decrease in the use of bronchodilators. This improvement was maintained thereafter. The growth pattern of all patients, including their height, weight, and bone age, was normal (as compared with standard normal values) throughout the treatment period. Pituitary-adrenal function was not adversely affected by the treatment, as demonstrated by normal serum cortisol concentrations in the morning and 60 minutes after stimulation with corticotropin, normal 24-hour serum cortisol concentrations (mean [+/- SD] of samples collected at 30-minute intervals for 24 hours, 8.4 +/- 4.2 micrograms per deciliter [232 +/- 116 nmol per liter]), and normal urinary cortisol excretion (34 +/- 9 micrograms [95 +/- 25 nmol] per day). CONCLUSIONS Prolonged administration of 200 micrograms of inhaled budesonide daily to young children with severe asthma does not impair growth or pituitary-adrenal function.

Effectiveness and safety of inhaled corticosteroids in controlling acute asthma attacks in children who were treated in the emergency department: A controlled comparative study with oral prednisolone

BACKGROUND Inhaled corticosteroids have a greater antiinflammatory potency and fewer systemic effects than intravenous, intramuscular, or oral corticosteroids. However, their role in acute asthma has not been established. We prospectively investigated the efficacy and safety of inhaled corticosteroids in controlling moderately severe acute asthma attacks in children who were treated in the emergency department. METHODS Children who were treated in the emergency department with moderately severe asthma attacks after receiving treatment with inhaled terbutaline were allocated by double-blind design to receive 1 dose of either 1600 micro(g) budesonide turbohaler or 2 mg/kg prednisolone. The pulmonary index score and peak expiratory flow rate were measured hourly for the first 4 hours. After discharge the children were treated with the same initial doses given 4 times daily, followed by a 25% reduction in dose every second day for 1 week. Parents recorded asthma symptoms and use of beta-2 agonists on a daily diary card. Serum cortisol concentration was measured at the end of weeks 1 and 3. RESULTS Twenty-two children (11 in each group) with similar baseline parameters completed the study. There was a similar improvement in pulmonary index score and peak expiratory flow rate in the 2 groups. Children treated with budesonide showed an earlier clinical response than those given prednisolone, who also showed a decrease in serum cortisol concentration. CONCLUSION In children with moderately severe asthma attacks who were treated in the emergency department, a short-term dose schedule of inhaled budesonide turbohaler, starting with a high dose and followed by a decrease over 1 week, is at least as effective as oral prednisolone, without suppressing serum cortisol concentration.

Absence of Tooth Staining With Doxycycline Treatment in Young Children

The aim of the study was to determine if doxycycline causes tooth staining in young children. A dentist examined 31 randomized children who had been treated with doxycycline and 30 children who had not received doxycycline. Mean age of the children was 10.4 ∓ 2.1 years. Mean age at receipt of the first doxycycline treatment was 4.1 ∓ 1.6 years, and mean number of doxycycline courses was 2.0 ∓ 1.3. No tooth staining was detected by the dentist in any of the children in either group. These findings indicate that treatment with doxycycline in children aged 2 to 8 years is not associated with tooth staining.

Safety of 1 year of treatment with budesonide in young children with asthma

Inhaled budesonide has been demonstrated to be effective and safe when it is used in the prophylaxis of severe asthma in adults and school-age children but has not been studied in younger patients with asthma. Sixteen children, aged 3 1/2 to 7 years, with severe asthma, were treated with budesonide aerosol, 200 micrograms daily, via a spacer for 1 year in an open study. One month after starting budesonide therapy, a significant decrease in the number of days with asthmatic symptomatology, mean symptom scores, use of concomitant antiasthmatic medications, and increase in the peak expiratory flow rates were observed compared with the 1 month run-in period. This improvement was maintained throughout the year with budesonide therapy. During the study period, the height and weight of the children were not significantly deviated from the expected, and their bone age advanced normally. Adrenal function, as evaluated by fasting 8 AM blood cortisol levels and after adrenocorticotropic hormone stimulation, demonstrated no adverse effects with budesonide therapy. The suspectibility to severe infections was low, as evidenced by infrequent use of antibiotics. We conclude that a 12-month administration of inhaled budesonide to preschool-age children is safe and efficient and can be useful in the management of severe asthma in this young age group.

Leukotriene C4 release in upper respiratory mucosa during natural exposure to ragweed in ragweed-sensitive children

With high-pressure liquid chromatography and specific radioimmunoassay, the concentration of leukotriene C4 (LTC4) was measured in nasopharyngeal secretions (NPS) of groups of children with allergic rhinitis before, during, and after the ragweed-pollen season. Increase LTC4 concentrations in NPS were noted in all the children during the pollen season; the concentration of LTC4 increased from a preseasoned mean of 1.87 +/- 0.43 ng/ml to 5.52 +/- 0.7 ng/ml at the peak of the ragweed season (p less than 0.001). The mean LTC4 concentration 2 weeks after the end of the ragweed season declined only to about 4.45 +/- 1.04 ng/ml. The seasonal variation of LTC4 concentrations and symptom scores of the children paralleled the pattern of the ragweed-pollen count. All children studied were ragweed sensitive, and six children were additionally sensitive to Alternaria (mold). The mold-sensitive children demonstrated higher concentrations of LTC4 in their NPS before and continued to have high LTC4 levels after the peak ragweed season, coinciding with peaks of mold-spore counts. Data presented in this study suggest that mast cells and other target cells in the nasal mucosa of children with allergic rhinitis produce pharmacologically active mediators, such as LTC4, during natural exposure to ragweed or Alternaria.

Montelukast, a leukotriene receptor antagonist, reduces the concentration of leukotrienes in the respiratory tract of children with persistent asthma.

BACKGROUND Leukotrienes are bronchoactive mediators secreted by inflammatory cells in the respiratory mucosa on exposure to asthma triggers. OBJECTIVE We investigated the effect of montelukast, a leukotriene receptor antagonist, on the release of leukotrienes in the respiratory mucosa of children with persistent asthma. METHOD Twenty-three children aged 6 to 11 years with moderately severe asthma were treated in a cross-over design starting, after a 2-week run in period, with either montelukast (n = 12) or cromolyn (n = 11) for 4 weeks with a 2-week washout period between treatments. Twelve of them were then treated with either montelukast or beclomethasone for 6 months. The use of beta(2)-agonists was recorded on a diary card. The concentration of leukotriene C(4) (LTC(4)) was measured by HPLC in nasal washes obtained before and at the end of each treatment period. Eosinophilic cationic protein (ECP) was measured in the nasal washes by RIA. RESULTS The LTC(4) concentration significantly decreased in the children treated for the first 4 weeks with montelukast, from 5.03 +/- 1.17 to 1.42 +/- 0.33 ng/mL (P <.005), and a nonsignificant increase was noted in children treated with cromolyn, from 3.37 +/- 1.11 to 5.88 +/- 2.17 ng/mL (P =.17). ECP concentration also decreased in the children receiving montelukast (P =.12). The concentration of LTC(4) remained low after 3 and 6 months of treatment with montelukast (0.8 +/- 0.7 and 1.0 +/- 0.3 microg/mL) and was lower than with beclomethasone. Children treated with montelukast required significantly fewer beta(2)-agonists (P <.04), CONCLUSION Montelukast reduces the concentration of leukotrienes in the respiratory tract of children with persistent asthma parallel to reduction in ECP and clinical improvement. This effect was not observed when the same children were treated with cromolyn.

Rapid induction of clinical response with a short-term high-dose starting schedule of budesonide nebulizing suspension in young children with recurrent wheezing episodes

BACKGROUND There are no data currently available on the correct schedule for the initiation of treatment with nebulized suspension of budesonide in children with recurrent wheezing episodes. We compared the efficacy and safety of starting with a high dose followed by a stepwise decrease to a continuous low dose. METHODS In a double-blind design, 42 children aged 6 months to 3 years were randomly allocated to receive either a high starting dose of 1 mg budesonide twice daily followed by a stepwise decrease of 25% every second day for 1 week (group A) or a low dose of 0.25 mg twice daily for 1 week (group B). Efficacy was assessed with daily symptom scores and the systemic effect of the corticosteroids with the adrenocorticotropic hormone test. RESULTS The two groups were comparable for all parameters evaluated. During the first week of treatment, there was a significant decrease in asthmatic symptomatology only in group A: a 59% decrease for wheezing (p = 0.0001), 39% for diurnal cough (p = 0.036), and 39% for nocturnal cough (p = 0.04). Mean time to clinical response was 3.0 days in group A and 5.7 days in group B (p = 0.02). This early improvement was sustained for the rest of the follow-up period. The high dose starting schedule was not associated with any change in serum cortisol level. CONCLUSIONS The administration of nebulized suspension of budesonide at a high starting dose schedule followed by a rapid (1 week) stepwise decrease yields a significant early improvement in asthma symptoms and causes no change in serum cortisol levels.

Post-Infectious Acute Cerebellar Ataxia in Children

Acute cerebellar ataxia is a relatively common neurologic disorder among children. Our aim was to characterize the clinical picture, etiology, and prognosis of acute cerebellar ataxia. The medical records of all children with a diagnosis of acute cerebellar ataxia hospitalized in our center and Hasharon Medical Center from 1990 to 2001 were reviewed. The diagnosis of acute cerebellar ataxia was based on the following criteria: acute onset of ataxia with or without nystagmus; absence of known genetic predisposing factors, such as familial degenerative disorders; and absence of drug intoxication, bacterial meningitis, and metabolic disorders. Thirty-nine children were identified; 54% were male; mean age at presentation was 4.8±3.8 years. All patients were observed for at least 1 year. A prodromal febrile illness was noted in 74.4%: varicella, 31%; mumps, 20%; nonspecific viral infection, 15.4%; mycoplasma, 5%; Epstein Barr virus, 3%. Latency from the prodromal illness to the onset of ataxia was 8.8±7.4 days. The most common associated neurologic findings were nystagmus and dysmetria. Full gait recovery took less than 2 weeks on average, and the longest duration of neurologic signs was 24 days (mumps-related). Acute cerebellar ataxia in childhood is a self-limited disease. The recovery was faster than that reported in previous publications and was complete in all children without any neurologic sequelae. Imaging studies are needed only in atypical presentation or if there is no spontaneous improvement after 1 to 2 weeks.

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.