Management of children with chronic wet cough and protracted bacterial bronchitis: CHEST guideline and expert panel report

BACKGROUND: Wet or productive cough is common in children with chronic cough. We formulated recommendations based on systematic reviews related to the management of chronic wet cough in children (aged ≤ 14 years) based on two key questions: (1) how effective are antibiotics in improving the resolution of cough? If so, what antibiotic should be used and for how long? and (2) when should children be referred for further investigations? METHODS: We used the CHEST expert cough panel's protocol for systematic reviews and the American College of Chest Physicians (CHEST) methodologic guidelines and GRADE framework (the Grading of Recommendations Assessment, Development and Evaluation). Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus for the recommendations/suggestions made. RESULTS: Combining data from the systematic reviews, we found high-quality evidence in children aged ≤ 14 years with chronic (> 4 weeks' duration) wet/productive cough that using appropriate antibiotics improves cough resolution, and further investigations (eg, flexible bronchoscopy, chest CT scans, immunity tests) should be undertaken when specific cough pointers (eg, digital clubbing) are present. When the wet cough does not improve following 4 weeks of antibiotic treatment, there is moderate-quality evidence that further investigations should be considered to look for an underlying disease. New recommendations include the recognition of the clinical diagnostic entity of protracted bacterial bronchitis. CONCLUSIONS: Compared with the 2006 Cough Guidelines, there is now high-quality evidence for some, but not all, aspects of the management of chronic wet cough in specialist settings. However, further studies particularly in primary health) are required.

Exercise-induced hyperventilation: a pseudoasthma syndrome.

BACKGROUND: Exercise-induced asthma is common and generally responds well to an inhaled beta2 agonist. OBJECTIVE: We examined the physiologic changes in airflow and gas exchange that occurred during standardized treadmill exercise in patients previously diagnosed with exercise-induced asthma whose histories appeared atypical or where conventional treatment, including an inhaled beta2 agonist, was ineffective. METHODS: During a 1-year period 32 patients, aged 8 to 18, met these criteria. All had been previously diagnosed as having exercise-induced asthma. Exercise consisted of treadmill running at a time when the patients had received no inhaled beta2 agonist, cromolyn, or nedocromil for at least 4 hours. Spirometry was done before and at 2, 5, 10, and 15 minutes after exercise; oxygen saturation was monitored by pulse oximetry; and end-tidal CO2 was monitored with nasal cannula. RESULTS: Despite their previous diagnoses of exercise-induced asthma, 11 patients who described chest tightness during exercise had decreases in FEV1 less than 15% with all but one of those less than 10% (mean decrease 5.6%) but demonstrated decreases in end-tidal CO2 greater than in all of the other 21 patients (mean 23.2 versus 9.8%, P < .01). Only 4 patients had unequivocal evidence for bronchospasm with cough and wheezing accompanying chest tightness in association with decreases in FEV1 from 18 to 22%. Seventeen patients had neither their symptoms reproduced nor physiologic abnormalities. CONCLUSIONS: These data show that chest discomfort perceived as dyspnea during vigorous exercise may be associated with hypocapnia from hyperventilation without bronchospasm in children and adolescents previously misdiagnosed and treated as having exercise-induced asthma.

Evaluation of a noninstrumented disposable method for quantifying serum theophylline concentrations.

STUDY OBJECTIVE: To compare the performance of a new point-of-care theophylline assay (AccuMeter) with that of a standard laboratory assay (TDx), and another point-of-care method (AccuLevel). DESIGN: Prospective evaluation of consecutive patients receiving theophylline. SETTING: University-based, ambulatory, allergy-pulmonary clinic. PATIENTS: Forty subjects receiving maintenance theophylline therapy for asthma. INTERVENTIONS: Theophylline concentrations obtained from AccuMeter, TDx, and AccuLevel were compared. MEASUREMENTS AND MAIN RESULTS: The error, or difference, between TDx and AccuMeter results in 40 subjects on maintenance theophylline described accuracy. Mean error, an estimate of bias, was 1.1 (95% CI 0.72-1.5), 0.67 (0.34-1.0), and 0.98 (0.79-1.2) microg/ml for AccuMeter capillary, serum, and heparinized blood samples. Square root of the mean squared error, an estimate of precision, was 1.6 (1.2-2.0), 1.22 (0.90-1.5), and 1.14 (0.96-1.3) microg/ml for AccuMeter capillary, serum, and heparinized samples. Difference between AccuMeter and AccuLevel ME, an estimate of relative bias, was 0.59 (0.04-1.1) microg/ml. The difference in mean squared errors, an estimate of relative precision, was 0.86 (-0.54-2.3) microg/ml. CONCLUSIONS: AccuMeter demonstrated good precision and minimal bias compared with TDx and AccuLevel . Method of sample collection had no effect on its accuracy.

Apparent decrease in population clearance of theophylline: implications for dosage.

BACKGROUND: Having observed in recent years that the theophylline dose requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml infrequently reached previously described mean values, we hypothesized that a downward shift in the range of dose requirements had occurred among patients with asthma. STUDY DESIGN: We examined dosage requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml in all patients with chronic asthma treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared these doses to previous dose requirements from 1978 to 1983 determined in the same manner. RESULTS: Despite similar mean peak serum concentrations during both time periods (14 micrograms/ml), mean theophylline dosage requirements during the period of this study were approximately 25% lower among all age groups than those previously observed (p < 0.001). There were no significant differences in mean dosage requirements between the Iowa and Florida patients in any age group examined. CONCLUSIONS: Theophylline dose requirements needed to attain serum concentrations of 10 to 20 micrograms/ml have decreased significantly from those on which current dosing recommendations are based. This suggests a decrease in mean clearance of the population.

Chronic cough in childhood: approach to diagnosis and treatment.

Chronic cough in childhood has many possible causes. The two most common are asthma and viral upper respiratory infection. Although usually associated with wheezing, dyspnea, or both, cough may be the sole manifestation of asthma ("cough-variant asthma"). Most important to initial evaluation are physical examination, patient history, and chest radiograph. Bronchial provocation testing may also prove helpful but is usually unnecessary. A trial of antiasthma therapy is appropriate when the pattern of symptoms is typical of asthma (excepting the lack of wheezing) and when nothing incompatible with asthma is present in the clinical picture. Drug therapy for cough-variant asthma is the same as that for more typical asthma. A vigorous trial of antiasthma therapy should not be considered complete unless a short course of high oral doses of corticosteroids has been included. The presence of clinical signs or symptoms atypical or incompatible with asthma and the failure of symptoms to respond to aggressive antiasthma therapy both warrant a more aggressive and complete diagnostic study.

Comparative efficiency of a laboratory and examining room assay for therapeutic drug monitoring of theophylline in ambulatory patients.

The total clinical personnel time for therapeutic drug monitoring of theophylline with a non-instrumented disposable examining room assay was 446 seconds. For a traditional assay, 1115 seconds of clinical personnel time was required to obtain the sample, send it to the laboratory, and subsequently act on the results. The corresponding costs for time, materials, and laboratory charges were +18.02 and +37.25, respectively.

Influence of endotoxin-induced fever on the pharmacokinetics of theophylline in the rabbit model.

To assess fever-induced changes in theophylline pharmacokinetics in the rabbit model, six healthy, male, New Zealand white rabbits were studied using a randomized, matched-pair design. In treatment 1, 15 mg/kg of theophylline was infused into the left marginal ear vein, and several blood samples were collected from the opposite ear for 10 hours. Treatment 2 was conducted in an identical manner, except 20 to 40 micrograms/kg of Escherichia coli endotoxin was injected into the left marginal ear vein to induce fever. The majority of the rabbits had slight decreases in the slowest disposition rate constant and increases in the volume of distribution at steady state; however, total body clearance was only minimally (5%) changed. No statistically significant differences were noted between these values (Hotelling T2 = 0.32). Given the sample and methods, fever apparently does not affect theophylline pharmacokinetics.

Evaluation of passively absorbed saliva for determination of oral slow-release theophylline bioavailability in children.

Assessment in young children of the bioavailability of slow-release theophylline formulations is hampered by the requirement for frequent blood sampling. Calculations of bioavailability from serial serum and passively absorbed saliva samples were therefore compared in six 9- to 12-year-old asthmatic children receiving multiple doses of Theo-Dur Sprinkle every 12 hours, using Theo-Dur tablets, a previously characterized formulation, as a reference. Results indicated 85 +/- 5 percent and 82 +/- 8 percent (mean +/- SEM) relative bioavailability based on serum and salivary measurements, respectively. Correlation coefficient for serum and passively absorbed saliva bioavailabilities was 0.90. Passively absorbed saliva provides an acceptably accurate, noninvasive method for theophylline bioavailability assessment and may be a useful alternative for bioavailability studies in young children.

Oral bioavailability of slow-release theophylline from unencapsulated beads in preschool children with chronic asthma.

The relative bioavailability of two slow-release theophylline formulations using bead-filled capsules. Slo-bid and Theo-Dur Sprinkle, was examined in randomized crossover multiple-dose trials using collected saliva. Two groups of seven preschool-age asthmatic children received one of these and Slo-Phyllin Gyrocaps as a reference. Dose-normalized areas under the saliva concentration-time curves were significantly less than the reference for Theo-Dur Sprinkle (p = .02) but not for Slo-bid with the relative bioavailability determinations of 66 +/- 8% (mean +/- SEM) and 109 +/- 5% for Theo-Dur Sprinkle and Slo-bid, respectively. The less complete absorption of Theo-Dur Sprinkle during clinical use in preschool-age children is consistent with the malabsorptive effects of food previously reported for the former but not the latter formulation.

Relationship between rate and extent of absorption of oral theophylline from Uniphyl brand of slow-release theophylline and resulting serum concentrations during multiple dosing.

The relationship between a standardized assessment of rate and extent of absorption of slow-release theophylline and serum concentrations during multiple dosing was examined in eight healthy adult volunteers. Each subject received single doses of a reference theophylline solution in addition to single and multiple doses of Uniphyl, a "once-a-day" theophylline formulation, administered after an overnight fast and after a large breakfast. Extent of absorption was similar during single and multiple dosing but was significantly greater when dose was taken after breakfast; 68 +/- 7% (mean +/- SEM) and 61 +/- 4% of administered doses were absorbed during single and multiple dosing, respectively, when breakfast was withheld, whereas 83 +/- 4% and 86 +/- 4% of administered doses were absorbed when single and multiple doses, respectively, followed breakfast. Observed mean serum concentrations during multiple dosing approximated values predicted from the single-dose study; mean peak serum concentrations averaged more than twice the tough for both predicted and observed values after both fasting and postprandial administration. These data demonstrate incomplete absorption of theophylline from Uniphyl with greater extent of absorption when Uniphyl is taken after food. The study also provides further documentation that characterization of rate and extent of absorption from single doses permit prediction of the mean serum concentration-time profile during multiple dosing at defined rates of theophylline elimination. This provides the potential to anticipate fluctuations in serum concentrations at clinically relevant elimination rates that deviate from the mean of samples typically used for study.

Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators.

The effect of high orally administered doses of prednisone for 1 week early in the course of an acute exacerbation of asthma incompletely responsive to bronchodilators was examined in 41 patients randomly assigned to receive either prednisone or an identical appearing placebo. All 22 of the patients who received prednisone improved during the week of treatment, although one had a subsequent exacerbation 5 days after discontinuing the study medication. Of the 19 who received placebo, eight required rescue intervention (P = less than 0.004) in association with continued symptoms, increased frequency of metered-dose inhaler use, and decreased pulmonary function; the other 11 improved at about the same rate as those who received prednisone. Although the mean initial FEV1 was suggestively lower among those who did not improve and required intervention, there was considerable overlap with those who improved spontaneously, and no reliable distinguishing characteristics were found at entry into the study that could serve as predictors of those who would or would not improve spontaneously. There were no clinically important adverse effects from the prednisone. Because continued symptoms of asthma often result in emergency care or hospitalization, these data support early intervention with orally administered prednisone for acute exacerbations that do not respond fully to bronchodilators, at least in those patients with a prior history of a protracted course or emergency care.

Stability of theophylline elimination rate.

The elimination rate for theophylline varies greatly among patients, but recommendations for maintenance dosing schedules have assumed relatively little intrapatient variability even over extended time periods. Reports of large intrapatient variability of theophylline elimination rate and consequent clearance raise concerns regarding this assumption and also challenge the practice of assuming relative constancy of elimination rate in the performance of bioavailability studies of slow-release formulations. We therefore systematically studied under controlled conditions the elimination rate of theophylline in 10 patients over an extended time interval. The initial elimination rate constants ranged from 0.062 to 0.136 hours-1. The changes ranged from -5.9% to 9.4% of the initial value during intervals of 2 to 11 months. Correlation of the first and second values was 0.96. Thus the elimination rate of theophylline generally appears to vary little within individuals over time when studied under controlled conditions.

Relative efficacy of maintenance therapy with theophylline, inhaled albuterol, and the combination for chronic asthma.

The relative benefit of maintenance therapy with theophylline, inhaled albuterol, and the combination was examined in 18 adolescents and adults with chronic asthma during a 3-month, randomized, double-blind, crossover trial. Theophylline and combination regimens were associated with significantly fewer days with symptoms (52% and 55%) than albuterol (72%). The greater frequency of symptoms during the albuterol regimen was increasingly apparent more than 4 hours after albuterol doses and was greatest between 4 and 8 A.M. Albuterol transiently inhibited histamine-induced bronchospasm to a much greater degree than did theophylline, and combining the drugs produced at least an additive effect. The effect of albuterol was completely absent by 4 hours, however, whereas that of theophylline persisted. Thus, in spite of greater acute effects on the airways, the transient duration of effect from inhaled albuterol appears to limit its usefulness as maintenance therapy, especially for patients with nocturnal symptoms.

Extrapulmonary effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma.

The extrapulmonary effects of slow-release theophylline and an inhaled beta 2-agonist (albuterol) were examined separately and in combination among 18 adults and adolescents with asthma during a 3-month randomized, double-blind, crossover trial. Although neither global impressions nor daily diaries revealed differences in adverse effects, a structured questionnaire completed at the end of each regimen suggested a small but statistically significant increase in nausea and depressive and caffeine-like symptoms during the theophylline-containing regimens. Theophylline was also associated with improved verbal learning but decreased motor steadiness. Metabolic effects associated with theophylline included lower serum bicarbonate, greater urinary calcium excretion, and higher serum calcium, uric acid, and creatinine. Albuterol was associated with lower neutrophil counts and lower serum theophylline concentrations. There were no drug-induced effects on cardiac rhythm.