Impact of Mycobacterium vaccae immunization on lung histopathology in a murine model of chronic asthma.

BACKGROUND: Therapeutic modalities of asthma have not been proved to be successful in reversing the already established chronic changes of airways. OBJECTIVE: We aimed to determine the impact of heat-killed Mycobacterium vaccae immunization, a potent Th1 stimulant, on chronic changes of asthma. METHODS: Newborn BALB/c mice were divided into three groups; mice in M. vaccae group received 107 colony-forming units (CFU)/50 micro L of heat-killed M. vaccae subcutaneously on days 3, 14 and 42 before the development of chronic asthma model, whereas mice in control and chronic asthma groups received saline. Subsequently, mice in M. vaccae and chronic asthma groups were administered 10 micro g/100 micro L of ovalbumin (OVA) on days 43, 45, 47, 49, 51, 53 and 55 intraperitoneally, and 20 micro g/10 micro L of OVA on days 83, 86 and 89 intratracheally. Mice in control group received saline on the same days. RESULTS: Comparison of M. vaccae and chronic asthma groups showed statistically significant differences in goblet cell numbers, thickness of basement membrane and subepithelial smooth muscle of small, medium and large airways and epithelial thickness of medium airways. There was no significant difference between the control and M. vaccae groups except for goblet cell numbers of medium and large airways, and epithelial thickness of medium airways. CONCLUSION: Results of our study suggested that immunization by M. vaccae of newborn mice would prevent some of the chronic changes of airways due to asthma.

Acute effect of inhaled budesonide on bronchial inflammation in asthmatic rats.

Although anti-inflammatory potency of inhaled corticosteroids is well established, little is known about their role in the acute phase. The aim of this study was to compare the acute anti-inflammatory effect of inhaled budesonide with systemic dexamethasone on allergen-induced inflammatory changes in asthmatic rats. Eighty-four Sprague Dawley rats were divided into four groups; group I (control, n = 24), group II (ovalbumin sensitized, n = 24), group III (systemic dexamethasone, n = 24), and group IV (budesonide, n = 12). All groups except group I were given ovalbumin aerosol challenges 14 days after sensitization with ovalbumin. The same procedure was applied to the control group using 0.9% saline. Group III received dexamethasone 0.3 mg/kg intraperitoneally and group IV received inhaled budesonide 10mL (0.5mg/mL) twice before the challenge. Eight hours after the challenge, bronchi of all the rats were evaluated for the degree of peribronchial inflammation. The most severe inflammation was seen in 8 of 24 rats (33%) in the second group, in 1 of 24 rats (4%) in the third group, and in 1 of 24 rats (4%) in the control group. None of the rats in group IV showed severe inflammation. No statistically significant difference was detected with respect to the presence of 3+ inflammation between the control vs. dexamethasone-, control vs. budesonide-, and dexamethasone vs. budesonide-receiving groups. Budesonide administration via nebulizer prior to exposure to an allergen may attenuate bronchial inflammation as effectively as systemic dexamethasone in rats.

Efficacy of sublingual immunotherapy in children with asthma and rhinitis: a double-blind, placebo-controlled study.

To evaluate the efficacy of specific sublingual immunotherapy (SLIT), we enrolled 15 children with asthma and rhinitis (7 girls, 8 boys, mean +/- SD age of 11.7 +/- 3.3) allergic to house dust mite (HDM) into a double-blind, placebo-controlled study. After a run-in period, patients were randomized to receive either placebo (n = 7) or SLIT (n = 8) with a standardized Dermatophagoides pteronyssinus (D. pteronyssinus) + Dermatophagoides farinea (D. farinea) 50/50 extract. They received increasing doses up to 100 index units of reactivity (IR) every day for 4 weeks, then 100 IR/day for another 4 weeks, followed by maintenance therapy consisting of 20 drops 2 times a week for 4 months. Efficacy was assessed at the end of 6 months of therapy according to symptom and medication scores, serum total IgE levels, results of lung function tests, methacholine provocation tests, and skin prick tests. Daily means for the asthma score and use of inhaled beta-2-mimetics decreased significantly in the SLIT group (P = 0.05, P = 0.028, respectively), whereas no such difference was observed in the placebo group. At the end of follow-up, mean daily doses of intranasal steroids needed for control of rhinitis symptoms decreased significantly in the SLIT group (P = 0.04). Baseline skin sensitivity to D. pteronyssinus and D. farinea was not significantly different between in the two groups, whereas end-point wheal diameter obtained with D. pteronyssinus extract was significantly less in the SLIT vs. the placebo group (P = 0.026). At the end of 6 months, peak expiratory flow (PEF) values in the placebo group was significantly lower than in the SLIT group (P = 0.049). Throughout the treatment period, the SLIT group was found to have less asthma exacerbations than the placebo group (P = 0.007). The provocation concentration causing a 20% drop in forced expired volume in 1 sec did not change throughout the treatment period in either groups. None of the patients reported local or systemic side effects from SLIT. Results of this study suggests that SLIT may be a useful alternative or additional therapy in the treatment of children with asthma/rhinitis due to HDM.

Risk factors for the persistence of respiratory symptoms in childhood asthma.

OBJECTIVE: To evaluate the parameters which could predict the persistence of respiratory symptoms in asthmatic children who have been treated with a considerably uniform therapy. METHODS: A retrospective review was performed on the records of 279 children with asthma. An end of study visit, results of spirometry and prick tests completed the data. The mean age at referral and at final visit was 6.2 +/- 3.7 years and 8.9 +/- 4.1 years, respectively; and the children were followed up for a mean of 3 +/- 1.2 years. RESULTS: Eighty-five of the 279 patients (30%) experienced no respiratory symptoms in the previous 12 months. There was no significant difference between those with and without current respiratory symptoms with respect to age, sex, age at onset of symptoms, duration of followup, age at referral, therapeutic choice, severity of asthma and duration of symptoms at referral. For subjects with current respiratory symptoms the initial serum total IgE level, and the percentage of RAST/prick test positivity was significantly higher than those without current respiratory symptoms (P = 0.0027, P = 0.011, respectively). Although the initial FEF 25%-75%, FEV1, and FEV1/FVC was significantly lower in those with current respiratory symptoms (P = 0.003; P = 0.005; and P = 0.04, respectively), there was no statistically significant difference between lung functions of the two groups at the end of followup. The persistence of respiratory symptoms was significantly predicted by initial FEF25%-75% and sensitivity to allergens (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: We concluded that the risk factors for the persistence of respiratory symptoms in our patient population have been low FEF25%-75% value and sensitivity to allergens at referral.

Heat-killed Mycobacterium bovis-bacillus Calmette Guerin-suppressed total serum IgE response in ovalbumin-sensitized newborn mice.

To determine the impact of bacillus Calmette Guerin (BCG) vaccination on IgE production in ovalbumin (OVA)-sensitized newborn mice, four groups (I, II, III, IV) of BALB/c mice were immunized on the first day of life with live BCG, killed BCG, BCG diluent, and saline, respectively. No injection was applied to mice in group V (control). All mice except group V were sensitized and challenged with OVA in the fourth and sixth weeks, respectively, and serum total IgE levels were determined at 8 weeks, 2 weeks after the second OVA challenge. IgE levels of all groups were significantly higher than the control group except for group II (p = 0.95). Mice in group II showed significantly lower IgE values than group IV and I (p = 0.007 and p = 0.003, respectively). We concluded that heat-killed BCG may downregulate IgE response to OVA in newborn mice.

Inhaled corticosteroid therapy is safe in tuberculin-positive asthmatic children.

BACKGROUND: Although treatment with oral corticosteroids can cause reactivation of latent Mycobacterium tuberculosis (TB) infection in purified protein derivative (PPD)-positive individuals with no evidence of clinical disease, little is known about the effects of inhaled corticosteroids in this respect. OBJECTIVE: This study was undertaken to assess whether inhaled corticosteroid (CS) therapy reactivates latent TB infection in PPD-positive asthmatic children. METHOD: We studied 32 PPD skin test-positive (> or =10 mm) children [age (mean +/- SD), 7.9 +/- 4.1 years] with no family history and no evidence of TB infection on chest radiograms who were receiving inhaled budesonide for the treatment of asthma. They were further evaluated with thorax computed tomography (CT) and erythrocyte sedimentation rate and closely observed for an additional 9 months. RESULTS: At enrollment the mean diameter of PPD reaction was 12.8 +/- 2.7 mm. The mean duration of inhaled CS treatment and the mean cumulative CS dose were 9.8 +/- 7.6 months and 275 +/-199 mg, respectively. Thorax CT studies revealed mediastinal lymph nodes in 7 of the 32 patients. There was no significant difference between children with and without mediastinal lymph nodes according to age, gender, size of PPD skin testing, erythrocyte sedimentation rate and duration and cumulative CS dose of inhaled budesonide therapy before study. A second thorax CT was obtained 9 months later in those 7 patients with lymphadenopathy (additional mean cumulative CS dose, 222.57 mg). There was no change in the size of their lymph nodes. CONCLUSION: Long term inhaled budesonide therapy appears to be safe in PPD-positive asthmatic children.

Is serum ECP level helpful in determining discontinuation of inhaled corticosteroid therapy in asthmatic children?

BACKGROUND: Serum eosinophil cationic protein (ECP) has been promoted as a direct marker of eosinophilic inflammation of the airways in patients with asthma. However, its role in monitoring disease activity and management of inhaled corticosteroid (ICS) therapy is not well defined. METHODS: We determined serum ECP (s-ECP) levels in 95 children (mean +/- SD age, 6.2 +/- 3.9 years) with asthma. At the time of measurements, 34 out of 95 children were symptomatic whereas 61 were in stable condition; and 56 of 95 patients were on maintenance ICS therapy. ICS prophylaxis was withdrawn in 16 of those 56 patients who remained asymptomatic with a dose of 100 micrograms/day of budesonide for 8 weeks. Eight out of these 16 children had to restart ICS therapy within the following 12 weeks, while the remaining 8 children continued to be asymptomatic within the same period. RESULTS: ECP values and number of patients with a high ECP level (> or = 15 micrograms/L) were significantly higher in the symptomatic group (p = 0.01 and p = 0.006, respectively). Also, ECP levels were significantly lower in the group who achieved clinical remission (n = 16) in which ICS therapy was withdrawn when compared with those who needed to continue ICS prophylaxis. On the other hand, no difference was observed in the comparison of the ECP levels of children who had to restart ICS therapy and those who did not. CONCLUSION: Our results suggest that, although the determination of s-ECP levels are in accordance with clinical evaluation of disease activity, it is not useful in determining discontinuation of ICS therapy.

Effect of pre-immunization by killed Mycobacterium bovis and vaccae on immunoglobulin E response in ovalbumin-sensitized newborn mice.

A recently advanced hypothesis suggests that decreased exposure to T-helper (Th) 1-inducing agents causes Th2-biased differentiation in response to concomitant allergens. We therefore examined the effect of pre-immunization with killed Mycobacterium bovis and killed M. vaccae which are known to be very potent inducers of Thl immune response, on serum IgE response in ovalbumin (OVA)-sensitized newborn mice. Eighty-four newborn Balb/c mice were divided into four groups and were immunized intraperitoneally 24 h after birth with 50 microl of 5 x 10(4) colony-forming units (c.f.u.) of killed M. bovis in group I (M. bovis group, n = 19), with 25 microl of 2.5 x 10(8) c.f.u. of killed M. vaccae plus 25 microl of 5 x 10(4) c.f.u. of killed M. bovis in group II (M. vaccae + M. bovis group, n = 28) and with 50 microl of only phosphate-buffered saline (PBS) in group III (no mycobacterial immunization, n = 18). No injection was applied to mice in group IV (control group, n = 19). Starting from 8 weeks of age, all mice except the control group were sensitized with 0.5 ml of 20 mg/ml OVA administered intraperitoneally 7 times every other day. Thirty days after the final injection, all animals except those in the control group were challenged with an aerosol of 2 mg/ml OVA. Forty-eight hours later, blood was collected from all mice for determination of serum IgE levels. A statistically significant difference was observed in the serum total IgE levels between groups III and IV (p = 0.0099), indicating that the mice were successfully sensitized with OVA. Serum total IgE values of the female mice in M. bovis group were found to be significantly lower than group III (p = 0.009), while no difference was observed in males. Serum total IgE levels of the M. vaccae + M. bovis group were found to be significantly lower than group III both in male and female mice (p < 0.0001 and p = 0.0001, respectively). Female values were even lower than controls (p = 0.0092). Pre-immunization in the newborn period with killed M. bovis alone or in addition to M. vaccae may potentially be helpful in down-regulating an IgE response.

Parental smoking behavior and the urinary cotinine levels of asthmatic children.

To determine whether parental reports of smoking habits and modifications in smoking behavior are associated with urinary cotinine levels (UCLs), UCLs were measured in 77 asthmatic children. Parental reports and UCLs agreed for 58 of the 77 children (75%). Although UCLs of children whose parents smoked indoors and outdoors were significantly higher than UCLs of children whose parents did not smoke (p<0.0001, p<0.002, respectively), there was no statistically significant difference between the UCLs of children whose parents smoked indoors and outdoors (p = 0.286). We concluded that encouraging smoking parents of asthmatic children to smoke outdoors may not be an effective way to lessen exposure.

Thorax high resolution computerized tomography findings in asthmatic children with unusual clinical manifestations.

BACKGROUND: It has been consistently observed in high resolution computerized tomography (HRCT) scans that asthmatic patients manifest more abnormalities related to airways remodeling than do normal subjects. OBJECTIVE: To find the underlying abnormalities in the lungs of asthmatic children with unusual manifestations. METHOD: Asthmatic children not responding as expected to inhaled steroid therapy with or without localized permanent or temporary recurrent auscultation findings (rales) were evaluated with chest radiographs and HRCT scans. Bronchoscopy was performed on the ones with localized rales. RESULTS: The sample consisted of 16 asthmatic children (6 girls and 10 boys, mean age = 7.75+/-4.43 years). Chest radiograph abnormality rate was 44% and the thorax HRCT scan abnormality rate was 75% (56% fibrotic retractions, 38% atelectasis, 19% bronchiectasis, and 19% bronchial wall thickening). Two patients with localized permanent rales and with right middle lobe (RML) atelectasis in HRCT scan underwent bronchoscopy which revealed RML syndrome due to mucus plugging in one and lymph node pressure in the other. In one patient with localized temporary recurrent rales and major bronchiectasis in HRCT scan, bronchoscopy revealed bronchitis. The patient with RML syndrome due to mucus plugging required lobectomy. CONCLUSION: We conclude with this experience that thorax HRCT scanning may be a helpful adjunct in the evaluation of an asthmatic children with atypical clinical findings.

Efficacy of aminophylline in the treatment of acute asthma exacerbation in children.

BACKGROUND: The role of aminophylline (ethylene diamine salt of theophylline) in the treatment of acute exacerbation of asthma has not been well established in children. OBJECTIVE: The aim of the study was to determine the additional therapeutic benefit of intravenous aminophylline in the treatment of children hospitalized for acute asthmatic exacerbation and treated with inhaled bronchodilators and glucocorticoid therapy. METHODS: Thirty-eight children aged from 2 to 16 years (mean age 5.64 +/- 3.31), admitted for acute exacerbation of asthma, participated in a prospective, randomized, double-blind, placebo-controlled study. All the subjects received methylprednisolone, administered intravenously, and nebulized salbutamol. The treatment group received intravenous aminophylline therapy and the placebo group received 0.9% saline solution for 24 hours. RESULTS: The number of salbutamol nebulizations needed and the clinical asthma scoring were recorded both at onset and at the end of 24 hours. There was no significant difference in either the mean number of nebulizations or the clinical asthma scores between the two groups (P = .7843, P = .8452). CONCLUSION: Intravenous aminophylline (ethylene diamine salt of theophylline) demonstrated no additional beneficial effect to the combination of beta adrenergic agonists and glucocorticoid treatment in acute asthma attack in children.

Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children.

BACKGROUND: The role of topical corticosteroids in the treatment of acute sinusitis has not been established in children. OBJECTIVE: An attempt was made to determine the impact of topical corticosteroids as an adjunct to antibiotic treatment in the management of childhood sinusitis. METHODS: In a double-blind, placebo-controlled study, 151 children with sinusitis were recruited from a general pediatric outpatient clinic and 89 completed a 3-week trial. Treatment consisted of amoxicillin-clavulanate potassium, 40 mg/kg/d tid, combined with bid nasal spray of either budesonide, 50 micrograms, to each nostril (n = 43) or placebo )n = 46_ for 3 weeks. Patients maintained daily symptom cards throughout the study and were examined by the same physician each week. RESULTS: Clinical symptoms and signs decreased significantly in both treatment groups in comparison to baseline (P < .01). We detected a significant improvement in the scores of the cough and nasal discharge at the end of second week in the budesonide group when compared with placebo (P < .05). Friedman nonparametric repeated measures ANOVA test revealed a significant decrease in the total weekly scores of cough during the second week of budesonide treatment (P < .001) in contrast to continuous decline during the second and third weeks in the placebo group (P < .001 and P < .05, respectively). While the nasal discharge score decreased significantly during the second week in the budesonide group (P < .01), no significant effect on the nasal discharge score was observed in the placebo group. CONCLUSION: These data suggest that topical corticosteroids may be a useful ancillary treatment to antibiotics in childhood sinusitis and effective in reducing the cough and nasal discharge earlier in the course of acute sinusitis.

Serum TNF-alpha, sCD8 and sIL-2R levels in childhood tuberculosis.

In this study we have determined the serum tumor necrosis factor-alpha (TNF-alpha), soluble CD8 (sCD8) and soluble interleukin-2 receptor (sIL-2R) levels in children with active pulmonary tuberculosis (n = 66) and healthy controls (n = 20). Measurable serum TNF-alpha levels were detected in nine of 86 children (10.5%), all of whom belonged to the group with active disease. Serum sCD8 and sIL-2R determinations revealed a significant difference between the group with active pulmonary tuberculosis and the controls (p < 0.05). Deeper insight into the involvement of cytokines and T cells will provide a better understanding

Effect of interferon-alpha therapy on serum IgE, IL-4, and sCD23 levels in childhood asthma.

Seven children with asthma were included in a trial of recombinant interferon-alpha 2a (rIFN-alpha 2a). Patients received either 2 million U/m2 rIFN-alpha 2a (n = 4) or placebo (n = 3) three times a week for 4 weeks. Pulmonary function test, peak expiratory flow rates (PEFR), and clinical symptom scores were monitored throughout the trial. Serum interleukin-4, soluble low-affinity receptor for IgE Fc epsilon RII/CD23 (sCD23), and immunoglobulin E (IgE) levels were measured at the beginning of the trial, and at the second week, fourth week, and sixth week. Compared with placebo, rIFN-alpha 2a therapy did not result in a significant change in the above-mentioned parameters. Further studies with a larger number of patients are needed to draw firmer conclusions in regard to efficacy of rIFN-alpha 2a therapy in childhood asthma.

The importance of early erythematous reaction in purified protein derivative skin testing.

We attempted to assess the diagnostic value of the early erythematous reaction observed at the sixth hour after the application of purified protein derivative (PPD) skin testing. For this purpose, 64 children with pulmonary tuberculosis and 49 healthy age-matched controls were PPD skin tested. Our results showed that the erythematous reaction of 5 mm or greater at the sixth hour was able to detect patients with active tuberculosis with 76% sensitivity, 85% specificity, 87% positive predictivity and 73% negative predictivity. Among 113 subjects, 6 h erythematous reaction of 5 mm or greater in size had 83% sensitivity to detect the ones who subsequently developed 10 mm or greater induration reaction at 48 h. We concluded that the sixth hour early erythematous reaction is just as helpful as the 48 h induration of 10 mm or greater in detecting patients with pulmonary tuberculosis.

Serum tumor necrosis factor levels in acute myocardial infarction and unstable angina pectoris.

Tumor necrosis factor (TNF) enhances leukocyte adherence to vascular endothelium and increases procoagulant activity in the endothelial cells. Thus it may be implicated in the pathogenesis of acute vascular occlusions. To study the role of TNF in the early stages of acute myocardial infarction (MI), the authors measured circulating TNF levels in the sera of patients with acute MI and unstable angina pectoris. Blood samples were obtained within six hours after onset of chest pain and stored at -70 degrees until tested. A sensitive sandwich enzyme-linked immunosorbent assay (ELISA) test was used for TNF measurement. C-reactive protein (CRP) levels were determined semiquantitatively. Immediate complications such as heart failure, arrhythmia, and shock were also noted. Twenty-four patients with electrocardiographically and biochemically confirmed acute MI and 14 patients with unstable angina pectoris were included in the study. TNF levels were serially assessed at the time of admission and at hours 6, 24, 48, 72, and 96 after onset of chest pain in 2 patients with acute MI. Detectable TNF was found in 13 sera of the acute MI group (range; 10-1510 pg/mL) and 4 sera of the angina pectoris group (range; 15-240 pg/mL). There was no correlation between the serum TNF levels and the occurrence of complications and the extent of myocardial damage. CRP response was unrelated to TNF levels. Contrary to previous reports, serial measurement of TNF revealed that peak values were reached within six hours and disappeared after twenty-four hours.(ABSTRACT TRUNCATED AT 250 WORDS)