Biomedical subjects
Ronina Covar
Publications and source records attributed to Ronina Covar.
Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999-2002.
Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4-18 years of age. Retrospective cross-sectional analysis was performed on all spirometries done in children at the National Jewish Medical and Research Center from 1999-2002. In total, 2,728 children performed 24,388 measures. The mean +/- SD values for forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1)), FEV(1)/FVC ratio, and forced expiratory flow (FEF)(25-75) were 92.7 +/- 16.2, 92.2 +/- 18.0, 85.3 +/- 9.3, and 78.0 +/- 36.5 percent predicted, respectively. Seventy-seven percent of FEV(1) values were >/= 80%, 18.6% were between 60-80%, and 3.1% were <60% of predicted. FEV(1) was highest in 5-year-old children; it declined thereafter, reaching a nadir at 11 years, followed by a partial recovery from 12-18 years. Expressed in liters, FEV(1) values were lower than expected at every age, with the greatest difference at 18 years. FEV(1)/FVC ratios declined through childhood, suggesting impaired airway but not lung growth in children with asthma. In conclusion, the majority of asthmatic children attending a tertiary care facility had FEV(1) values within normal range. With increasing age, the increase in FEV(1) lags behind that of nonasthmatics, so that by 18 years, maximum FEV(1) is impaired. The NHLBI FEV(1) cutoff values do not appear to accurately stratify pediatric asthma, and no useful FEV(1) cutoff could be generated.
Histopathology of severe childhood asthma: a case series.
BACKGROUND: To date, little has been published describing the pathology of severe childhood asthma. The currently accepted model of asthma holds that persistent airway inflammation leads to various symptoms of asthma, airway hyperresponsiveness, and airway remodeling that ultimately results in permanent loss of lung function. METHODS: Evaluation of six children referred to the National Jewish Medical and Research Center with difficult-to-control asthma, despite aggressive anti-inflammatory therapy, who underwent bronchoscopy with endobronchial biopsy to better characterize their disease. RESULTS: In every case, endobronchial biopsies revealed changes consistent with airway remodeling characterized by thickening of the basement membrane, smooth-muscle hypertrophy, with varying degrees of goblet-cell and submucous gland hyperplasia. The degree of subbasement membrane thickening did not appear to correlate with baseline FEV(1), ultimate FEV(1) following aggressive therapy, or lability in lung function. In five of six cases, there was minimal to no histologic evidence for airway inflammation with mild and patchy submucosal lymphocytic infiltration noted; eosinophils and neutrophils were not present. Further, the majority of the patients achieved normal FEV(1) values despite significant subbasement membrane thickening, counter to the current beliefs regarding airway remodeling and irreversible loss of lung function. CONCLUSIONS: This case report highlights some of the shortcomings of the current inflammatory paradigm for severe asthma. Despite little evidence of ongoing airway inflammation, many of the subjects displayed significant lung function lability. The lack of inflammation argues against steroid resistance at a cellular level, although it could be argued that inflammation may have been distal to the site sampled. Additionally, normal to nearly normal lung function was achieved despite the presence of significant remodeling. These findings suggest the need to look beyond inflammation to fully treat severe asthma and ultimately alter its progression.
A comparison of the clinical characteristics of children and adults with severe asthma.
OBJECTIVES: This study sought to better define the clinical characteristics of severe asthma in both children and adults, and to evaluate the effect of asthma duration on multiple parameters of disease severity. DESIGN: Retrospective analysis of prospectively collected data on 275 patients (125 children) with severe asthma who were admitted to a tertiary asthma referral center. METHODS: Demographics, lung function (ie, spirometry and body box plethysmography), glucocorticoid (GC) pharmacokinetic studies, and lymphocyte stimulation assays were performed on all patients. RESULTS: Children were as likely to require therapy with high-dose inhaled GCs and long-term therapy with oral GCs, and to have had a prior intubation, yet they had significantly less airflow limitation (mean [+/- SEM] FEV(1), 74.0 +/- 2.1% predicted vs 57.1 +/- 1.8% predicted, respectively; p < 0.0001), less resistance to airflow (mean airway resistance, 140.3 +/- 8.5% predicted vs 311 +/- 18% predicted, respectively; p < 0.0001), and larger lung volumes (mean total lung capacity, 116.4 +/- 1.6% predicted vs 105.3 +/- 1.8% predicted, respectively; p < 0.0001) compared to adults. Children were more likely to be male and to display greater responsiveness to GCs in vitro. Lung function impairment was associated with asthma duration in children and in adults with onset of asthma in childhood, while there was no relationship between disease severity and asthma duration among those with adult-onset asthma. Despite significant differences in disease duration, patients with adult-onset asthma had equally compromised lung function compared to adults with long-standing asthma. CONCLUSIONS: Children with severe asthma tended to be male, to have less severe airflow obstruction, and to display greater responsiveness to GCs in vitro compared to adults. Symptoms and episodic acute declines in lung function may precede chronic airflow limitation in this group of children. As such, it may be more relevant to follow the deterioration in lung function over time in children. Finally, disease severity in children and adults whose onset of asthma occurred in childhood was related to disease duration, but not in patients with onset of asthma in adulthood.
Asthma: addressing consistency in results from basic science, clinical trials, and observational experience.
The basic science understanding of the pathophysiology of a disease often serves as the basis for clinical investigations. This knowledge is used to propose new directions in care and confirm initial concepts. The basic science of asthma demonstrates that the most comprehensive management of inflammation appears to be associated with the use of inhaled corticosteroids and proposes a mechanism for combination therapy with the addition of salmeterol. Randomized clinical trials are performed to confirm these initial observations and demonstrate both the safety and efficacy of therapeutic agents. These investigations are either placebo-controlled or direct comparisons of 2 medications. For the treatment of asthma, these studies have all consistently demonstrated that inhaled corticosteroids are the most effective primary controller therapy. Greater improvement in both lung function and patient-oriented symptom control is observed with the use of inhaled corticosteroids. For patients whose symptoms are not controlled with single-drug therapy, the addition of a long-acting bronchodilator appears to be the most effective add-on treatment with the greatest improvement in lung function and symptom control. Clinical trials have been used for the purposes of cost modeling. Therapies that produce the greatest effect size at the lowest incremental costs produce the greatest improvement in cost-effectiveness. Retrospective claims analysis, more recently, have been used to validate these observations from clinical trials. These studies measure both resource use and costs or charges. These analyses have confirmed that initial treatment with inhaled corticosteroids and combined treatment with inhaled corticosteroids and long-acting bronchodilators are the most effective stepwise approaches to the treatment of asthma.