Diagnosis and therapy of nocturnal asthma

The bronchial tonus depends on circadian oscillations like all other organ functions. The tendency to increased nocturnal bronchoconstriction in some asthmatic subjects is well known. The reasons of such individual variations are different concentrations of cortisol, adrenaline, histamine, cAMP in serum as well as imbalance between vagal and sympathetic interactions. In practice, the early diagnosis of severe nocturnal bronchial constriction is important for prevention of asthma attacks and status asthmaticus. We report on our circadian measurements of airway resistance (Ros) or peak-flow. By adequate therapy an improvement of the individual bronchial tolerance could be achieved, however the biorhythm remained unchanged. Measurements of airway resistance at 2 a.m. were significantly improved by therapy, as was the mean level measurements during 4-hourly readings. High dose bedtime or slow release theophylline decreased the number of nocturnal asthma attacks.     

Serum interleukin-5 measurements for monitoring acute asthma in children.

Cytokine-mediated interactions among the inflammatory cells may play a role in the pathogenesis of bronchial asthma. Interleukin-5 (IL-5) is a major cytokine in the recruitment of neutrophils to the area of inflammation. Serum IL-5 is a marker of disease activity and treatment efficacy in bronchial asthma. To understand the role of IL-5 in disease activity in acute asthma, changes in serum concentrations of IL-5 elaborated by activated eosinophil before and after prednisolone therapy with clinical improvement were determined in the present study. Circulating levels of IL-5 in 16 normal control subjects and in sera from 22 allergic asthmatic children with acute exacerbation and in stable condition were determined by using commercially available assay kits. The mean concentration of serum IL-5 was higher in patients with acute exacerbation (6.30 +/- 2.21 pg/mL) and in stable asthmatics (5.55 +/- 2.23 pg/mL) compared to control group subjects (4.81 +/- 0.54 pg/mL; p > 0.05). However, the difference was not statistically significant between the acute exacerbation and stable asthmatics groups (p > 0.05). Serum IL-5 is a poor indicator of disease activity in acute asthma; therefore, monitoring serum IL-5 concentration is of limited value. The clinical value of serum IL-5 as a marker of disease activity remains to be established.     

Airway resistance variability and response to bronchodilator in children with asthma.

Variability of airway function is a feature of asthma, spanning timescales from months to seconds. Short-term variation in airway resistance (R(rs)) is elevated in asthma and is thought to be due to increased variation in the contractile activation of airway smooth muscle. If true, then variation in R(rs) should decrease in response to bronchodilators, but this has not been investigated. Using the forced oscillation technique, R(rs) and the variation in R(rs) from 4-34 Hz were measured in 39 children with well-controlled mild-to-moderate asthma and 31 healthy controls (7-13 yrs) before and after an inhaled bronchodilator (200 microg salbutamol) or placebo. In agreement with other findings, baseline R(rs) at all frequencies and the sd of R(rs) (R(rs) sd) below 14 Hz were found to be elevated in asthma while neither forced expiratory volume in one second nor the mean forced expiratory flow between 25 and 75% of forced vital capacity were different compared with controls. The present authors found that R(rs) sd changed the most of any measurement in asthma, and this was the only measurement that changed significantly more in children with asthma following bronchodilator administration. The present results show that like airway narrowing, short-term airway variability of resistance may be a characteristic feature of asthma that may be useful for monitoring response to therapy.     

Two aminophylline preparations in nocturnal asthma.

In a double-blind trial the effects of aminophylline suppositories and slow-release aminophylline tablets were compared with similar placebo preparations in nine patients whose complaint was asthma which woke them from sleep at night. Forced expired volume in one second (FEV1) was measured in each patient at three-hourly intervals from 1900 hours to 0700 hours on four separate nights, the preparation being administered immediately after the 2200 hour measurement. On the nights when a placebo was administered the FEV1 showed a statistically significant fall between 1900 and 0400 hours. Aminophylline had a statistically highly significant effect in reducing or preventing this fall, suppositories and tablets being equally effective in this single-dose study.     

Spectrum of corticosteroid sensitivity in nocturnal asthma.

The nocturnal worsening of asthma is a common problem, and the contribution of inflammation to its pathogenesis remains unclear. We investigated the responses of 11 asthmatic subjects to overnight intravenous infusion of hydrocortisone. Prior to the study, all the subjects demonstrated clinically stable daytime asthma but persistent nocturnal worsening of spirometry. As a group, their overnight decrement in FEV1 improved from 46 +/- 4% at baseline to 12 +/- 3% (p less than 0.001) after steroid infusion. Nine of the 11 subjects demonstrated individual improvement in their overnight decrements in FEV1 of greater than 40%. The mean improvement between baseline and steroid infusion nights was 67 +/- 11%. A spectrum of response was evident, and only four of the subjects reached the normal circadian variability in overnight FEV1 measurements of less than 8%. We conclude that the nocturnal worsening of asthma often has a significant corticosteroid-sensitive component that may be both dose- and time-dependent.     

Neuroendocrine response to supine posture in healthy children and patients with nocturnal enuresis

Objective To elucidate the background behind the attenuated circadian rhythm of vasoactive hormones in patients with nocturnal enuresis, we tested the hypothesis that enuretic children exhibit an abnormal neuroendocrine response to a baroreflex stimulus during daytime. Design and patients In fifteen children and adolescents (aged 13·4 ± 0·9 years) with severe nocturnal enuresis and 10 age‐ and sex‐matched healthy controls, we performed a ‘daytime supine posture’ (DSP) study at 10:00 h. Measurements Blood was sampled for measurements of plasma vasopressin (P_AVP), angiotensin II (P_ANGII), atrial natriuretic peptide (P_ANP) and serum aldosterone (S_ALDO), and mean arterial blood pressure (MAP) and heart rate (HR) were measured during the study. Results In both controls and patients with enuresis, DSP at 10:00 h resulted in a marked fall in MAP and HR, a rise in pulse pressure (PP) and estimated plasma volume (PV) and a significant suppression of P_AVP, P_ANGII and S_ALDO, whereas P_ANP increased. There were no significant differences between groups in haemodynamic or neuroendocrine responses to DSP. Conclusions The study showed that children with nocturnal enuresis exhibit a normal neuroendocrine response to supine posture during daytime indicating that baroregulatory mechanisms per se are not playing a significant pathogenic role. Interestingly, the normal neuroendocrine response to supine posture seems to undergo marked circadian changes, as supine posture at night‐time is associated with increased levels of vasoactive hormones.     

Wheeze phenotypes and lung function in preschool children

Distinct phenotypes can be identified in childhood wheezing illness. Within the context of a birth cohort study, we investigated the association between preschool lung function and phenotypes of wheeze. From parentally reported history of wheeze (interviewer-administered questionnaire, age 3 and 5 years), children were classified as never wheezers, transient early wheezers, late-onset wheezers, or persistent wheezers. Lung function (specific airway resistance [sRaw]; kPa/second) was assessed at age 3 (n = 463) and 5 years (n = 690). Persistent wheezers had markedly poorer lung function compared with other groups. In children who had wheezed by age 3, the risk of persistent wheeze increased with increased sRaw (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.3-22.0; p = 0.02). In a multivariate model, increasing sRaw (OR 5.5, 95% CI 1.2-25.9; p = 0.03) and the child's sensitization (OR 2.8, 95% CI 1.3-5.8; p = 0.008) were significant independent predictors of persistent wheezing. We found no association between lung function at age 3 and late-onset wheeze in children who had not wheezed previously (OR 0.6, 95% CI 0.07-5.3; p = 0.64). In conclusion, poor lung function at age 3 predicted the subsequent persistence of symptoms in children who had wheezed within the first 3 years, but was not associated with the onset of wheeze after age 3 in children who had not wheezed previously.     

Snoring in preschool children: prevalence and association with nocturnal cough and asthma

INTRODUCTION: The association between snoring, nocturnal cough, and allergic symptoms in young children is not known. OBJECTIVE: To measure the prevalence of habitual snoring and its association with nocturnal cough, asthma, and hay fever in preschool children. SETTING: A cross-sectional study. SUBJECTS: Preschool children aged 2 to 5 years. METHOD: The data were collected in a cross-sectional study. A total of 974 children were randomly selected from two areas of Lismore and Wagga Wagga in New South Wales, Australia. RESULTS: The prevalence of snoring was 10.5%, with no gender difference (p = 0.99) or trend association with age (p = 0.58). The association between snoring and nocturnal cough was highly significant (odds ratio [OR], 3.68; 95% confidence interval [CI], 2.41 to 5.63; p = 0.001). This association was significant in both the nonasthmatic and asthmatic groups when examined separately. Snoring was also significantly associated with asthma (OR, 2.03; 95% CI, 1.34 to 3.10; p = 0.001). In subjects without hay fever, the association between snoring and asthma was also highly significant (41.2% vs 24.8%; OR, 2.12; 95% CI, 1.34 to 3.37; p = 0.001). CONCLUSION: The prevalence of snoring in preschool children was 10.5% for both genders. Snoring was significantly associated with both nocturnal cough and asthma. Because snoring, asthma, and nocturnal cough may have a common etiology, it is possible that effective treatment of one symptom may lead to reductions in the presence or severity of the other symptoms.     

Cardiorespiratory response to physical conditioning in children with bronchial asthma

The relationship of physical conditioning to changes in static lung volumes (hyperinflation) and airway dynamics (bronchoconstriction) as well as to ventilatory gas exchange, heart rate reserve, breathing reserves, and working capacity at a heart rate of 170/min (WC 170) was evaluated in 23 children (16 girls, 7 boys) between 6 and 15 years of age who had perennial asthma. Lung function tests including incremental cycle ergooxymetry were performed before and after a 15-week period of regular physical training (RPT). Lung function data obtained after RPT showed a significant improvement (P less than 0.05) in both hyperinflation and specific airway conductance, whereas oxygen consumption only increased related to lean body mass and heart rate. However, WC 170 and work tolerance during the endurance phase of the exercise test were significantly increased (P less than 0.05 and less than 0.01, respectively). In view of the relationship that has recently been found between exercise tolerance and lung mechanics in adults, the decreased hyperinflation and bronchoconstriction observed in our population after RPT is striking. This finding was presumably a consequence of the effect of RPT on breathing technique and chest wall mechanics. Ventilation of the lungs may improve because of mobilization of the costovertebral articulations, inspiratory muscle relaxation, an optimized force-length relationship of the respiratory muscles, and closer linkage between the diaphragm and intercostal muscles. Therefore, RPT might be an effective addition to standard drug regimens in the management of childhood asthma.     

Enhanced production of oxygen radicals in nocturnal asthma.

Although the mechanisms of nocturnal worsening of pulmonary function in asthmatics have not been entirely established, airway inflammation is felt to be a major factor in disease severity. Consequently, to determine whether changes in bronchoalveolar lavage (BAL) fluid cellular components and their functions are related to nocturnal airway obstruction, we performed BAL at 4:00 A.M. and at 4:00 P.M. in asthma subjects with (n = 5) and without (n = 10) nocturnal asthma. No significant changes were observed from 4:00 P.M. to 4:00 A.M. in the concentration of total cells or the percentage or concentration of eosinophils or neutrophils in BAL fluid from subjects with or without nocturnal asthma. However, superoxide anion generation by air-space cells from subjects with nocturnal asthma was significantly greater at 4:00 A.M. than at 4:00 P.M. (6.9 +/- 1.7 versus 1.8 +/- 0.5 nmol/500K cells/h, p less than 0.05). Moreover, superoxide production at 4:00 A.M. was greater in subjects with than in those without nocturnal asthma (6.9 +/- 1.7 versus 2.2 +/- 0.6, p less than 0.02). Furthermore, in our group of asthmatics, the change in generation of superoxide anion from 4:00 P.M. to 4:00 A.M. was significantly correlated with the change in FEV1 (r = -0.71, p less than 0.01). We conclude that the development of nocturnal airway obstruction in asthma is associated with enhanced production of oxygen radicals by air-space cells. Because oxygen radicals can cause airway injury and thus enhance bronchial obstruction, it is possible that the release of these reactive compounds is causally associated with nocturnal asthma.     

Lymphadenitis due to nontuberculous mycobacteria in children: presentation and response to therapy.

The most common manifestation of infection due to nontuberculous mycobacteria (NTM) in children is cervical lymphadenitis in an otherwise healthy patient. We identified and reviewed 19 cases of proven or presumptive lymphadenitis due to NTM seen at our hospital over the course of 13 months. Nine patients underwent initial surgical excision of involved lymph nodes. Ten children did not have involved lymph nodes excised initially and were treated with macrolide-containing antibiotic regimens. Of these patients, five required subsequent surgical excision and five were cured with combination chemotherapy. Six patients underwent radiographic imaging of the head and neck that revealed asymmetrical adenopathy with ring-enhancing masses but minimal inflammatory stranding of the subcutaneous fat, a finding that may distinguish adenitis caused by NTM from staphylococcal and streptococcal adenitis. Our data suggest that if surgical excision is not considered feasible, antimicrobial therapy for adenitis due to NTM may be beneficial for some patients.     

Quantitative assessment of the response to therapy in achalasia of the cardia.

Radionuclide oesophageal transit studies and manometry have been carried out in 15 patients with achalasia of the cardia, before treatment, after a course of nifedipine and after pneumatic bag dilatation. Transit studies were also done in 10 patients after cardiomyotomy and in 10 normal subjects. Images were recorded with the subjects seated in front of a gamma camera while swallowing a 10 ml bolus of 99Tcm-tin colloid and then after a further drink of 50 ml water. There was marked retention of tracer in the oesophagus in patients with achalasia compared with rapid clearance in control subjects. Bag dilatation significantly reduced lower oesophageal sphincter pressure but there was no significant difference in the 50% clearance time or percentage dose retained at 100s before and after the treatments. Oesophageal clearance of tracer after the additional drink of water, was improved by bag dilatation. Oesophageal transit in the patients after cardiomyotomy was similar to that in patients who had undergone bag dilatation. There was considerable retention of the tracer in the oesophagus overnight, but this did not result in pulmonary aspiration. Radionuclide oesophageal transit studies provided a quantitative assessment of therapy in achalasia and the proportion of tracer retained after the additional drink proved to be a sensitive measure of response to treatment. Nifedipine proved ineffective as a treatment for achalasia. Bag dilatation and cardiomyotomy were of similar value.     

SPECT scans for monitoring response to pleconaril therapy in chronic enteroviral meningoencephalitis

Chronic enteroviral meningoencephalitis (CEMA) is a rare complication of immunodeficient individuals and may present as insidious intellectual deterioration. Diagnosis requires isolation or PCR identification of enterovirus from the CSF. Pleconaril, a novel anti-picornaviral compound is available on a compassionate release basis to treat patients with potentially life threatening enteroviral infection. Non-invasive neuroimaging is an important new technique for both the diagnosis of encephalitis and as an objective assessment of response to treatment. We report two immunodeficient patients, one with common variable immunodeficiency and one with HIV, with an insidious presentation of CEMA. In both patients, perfusion single photon emission tomography scans were effective in monitoring treatment, correlating with clinical and virological response to pleconaril.     

Physiological assessment of severe chronic asthma in children

Measurements of maximum expiratory flows and lung volumes were made on 6 occasions at weekly intervals in 14 children who were known over several years to have severe chronic asthma. 11 of the 14 had persistent lung hyperinflation and marked reduction in maximum expiratory flow rates although there was considerable variability in individual measurements. The other 3 usually had hyperinflation and reduced expiratory flow rates. 3 times daily measurements at home of peak expiratory flow rate did not contribute further to assessment. The results of the study indicated that one or two measurements of maximum expiratory flow calculated from a maximum expiratory flow volume curve and of lung volumes recorded in a body plethysmograph are of value in identifying the child with severe chronic asthma.     

Treatment of nocturnal asthma with pulsed-release albuterol.

The treatment of nocturnal asthma remains a challenge. We investigated the use of a pulsed-released albuterol in ten patients with nocturnal symptoms of asthma. In a randomized, double-blind, placebo-controlled, crossover designed study, we tested the use of 8 mg of pulsed-release albuterol sulfate (Proventil Repetabs) vs placebo. The pulsed-release albuterol significantly blunted the overnight drop in FEV1, improved peak flow readings in the morning, and decreased subjective awakenings from sleep. We conclude that pulsed-released albuterol is an effective therapeutic option in patients with nocturnal asthma.