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R M Cherniack

Publications and source records attributed to R M Cherniack.

At least 19 recordsLinked to original sources
PubMed2001

Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.

Our purpose was to identify clinical, radiological and physiological (CRP) determinants of survival and to develop a CRP scoring system that predicts survival in newly diagnosed cases of idiopathic pulmonary fibrosis (IPF). The study population consisted of 238 patients with biopsy confirmed usual interstitial pneumonia. For each patient, clinical manifestations, chest radiographs, and pulmonary physiology were prospectively assessed. We used Cox proportional-hazards models to assess the effect of these parameters on survival. The effects of age and smoking were included in the analysis. Survival was related to age, smoking status (longer in current smokers), clubbing, the extent of interstitial opacities and presence of pulmonary hypertension on the chest radiograph, reduced lung volume, and abnormal gas exchange during maximal exercise. A mathematical CRP score for predicting survival was derived from these parameters. We showed that this CRP score correlated with the extent and severity of the important histopathologic features of IPF, i.e., fibrosis, cellularity, the granulation/connective tissue deposition, and the total pathologic derangement. Using these models, clinicians are in a better position to provide prognostic information to patients with IPF and to improve the selection of the most appropriate patients for lung transplantation or other standard or novel therapeutic interventions.

Adult↗
PubMed2001

Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.

It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Adult↗
PubMed2001

The organization of the Asthma Clinical Research Network: a multicenter, multiprotocol clinical trials team.

Asthma is an increasingly serious cause of morbidity and mortality in the United States, affecting approximately 12 million people, including men and women, children and adults, and all racial and ethnic groups. It is now recognized that asthma is a complex disease of varied etiology triggered by a number of factors such as allergens, drugs, chemicals, exercise, cold dry air, infections, and emotions. Asthma is a chronic disease requiring multiple medications to treat and control symptoms as well as medications thought to control the underlying inflammation. Despite major advances in understanding the etiology and pathophysiology of asthma and the development of new therapeutic modalities, the prevalence, severity, and mortality from asthma have all increased over the past decades in all age groups. Hospitalizations for asthma have doubled in adults and increased fivefold for children over the past 20 years. Mortality appears to be particularly high in urban and rural minority populations. Asthma continues to place a heavy burden on patients and their families as well as the health-care system. In an attempt to respond to the need for well-designed clinical trials to allow rapid evaluation of new and existing therapeutic approaches for asthma and for dissemination of laboratory and clinical findings to the health-care community, the Division of Lung Diseases, National Heart, Lung, and Blood Institute, established the Asthma Clinical Research Network.

Adult↗
PubMed2001

Modem remote support of pulmonary-function testing and quality control systems.

The data coordinating center (DCC) of the Asthma Clinical Research Network (ACRN) is responsible for the support of 11 pulmonary-function testing systems and two quality control systems. Pulmonary-function data from these systems are used as outcome indicators in studies conducted by the ACRN. Each of these systems is composed of a spirometer, a personal computer for data acquisition from the spirometer, a modem, and a printer. These systems are located at six clinical centers nationwide. An analysis conducted at the beginning of the first ACRN protocol identified the following requirements: (1) standard pulmonary-function testing, (2) standard methacholine-challenge testing, (3) the ability to handle simultaneous multiple protocols as well as have data from non-ACRN subjects, (4) the ability to separate data from different protocols as well as separate ACRN and non-ACRN data, (5) the ability to transmit data from the remote clinical centers to the DCC, (6) the ability to ensure quality data and to report on those results, and (7) the ability to provide remote support.

Asthma↗
PubMed2001

Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.

The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV(1) 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV(1) and the methacholine PC(20). The FEV(1) decreased > or = 20% from the postbronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC(20) were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC(20) and should prove useful in the assessment of airway inflammation in multicenter clinical trials.

Aged↗
PubMed2001

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Adolescent↗
PubMed2000

Acute interstitial pneumonitis. Case series and review of the literature.

Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characterized by rapidly progressive diffuse pulmonary infiltrates and hypoxemia requiring hospitalization. The case-fatality ratio is high. Previous reports suggested that survivors of the acute event have a favorable outcome. We undertook this study to examine the natural history of survivors. We had observed several patients who experienced recurrent episodes of AIP and chronic progressive interstitial lung disease. We sought to determine longitudinal survival in these patients and to compare our experience with that in the medical literature. Overall, we identified 13 biopsy-proven cases of AIP. The mean patient age was 54 years in our review, which is identical to previous reports. Twelve patients were hospitalized and all 12 required mechanical ventilation. Overall hospital survival was 67%. All patients demonstrated abnormalities in gas exchange at presentation. Radiographs typically demonstrated bilateral patchy densities that progressed to a diffuse alveolar filling pattern in nearly all cases. All biopsy specimens showed organizing diffuse alveolar damage. Longitudinal data were available for 7 patients. Two died of AIP recurrences. A third died of complications of heart failure shortly after hospital discharge. One patient progressed to end-stage lung disease and required lung transplantation. Two patients experienced persistent pulmonary symptoms, accompanied in 1 by progressive lung fibrosis. One patient had nearly complete recovery of lung function 2 years following AIP. (Follow-up information was unavailable for 2 survivors.) In our literature review, 5 of 7 patients reported experienced some recovery of lung function. One case of progressive interstitial lung disease requiring lung transplantation was reported. The reported mortality was much higher than in our experience (74% versus 33%). The mean time from symptom onset to death was 26 days, compared with 34 days in our experience. The use of corticosteroids did not appear to influence survival, although this has not been tested in a rigorous manner. The better survival in our series may be related in part to a survivor selection bias. In contrast to previous reports, we found that survivors of AIP may experience recurrences and chronic, progressive interstitial lung disease. We did not identify any clinical or pathologic features that predict mortality in these patients. Likewise, there were no features that predicted the longitudinal course in survivors. Further study to identify causal factors is required in the hope of preventing morbidity and mortality related to this disease.

Acute Disease↗
PubMed2000

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Adolescent↗
PubMed1997

Bleomycin-induced lung disease in an animal model: correlation between computed tomography-determined abnormalities and lung function.

RATIONALE AND OBJECTIVES: The authors evaluated whether specific types of computed tomographic (CT) abnormalities could be correlated with physiologic impairment in animals with bleomycin-induced lung injury. METHODS: Lung injury was induced in 20 rabbits by means of intratracheal administration of bleomycin (3 U per kilogram of body weight), followed by 100% oxygen for 2 minutes. The animals underwent high-resolution CT scanning at 14 (n = 4), 28 (n = 6), or 56 (n = 10) days after injury. CT morphometry was used to determine the extent of abnormal lung. Physiologic evaluation was performed before injury and before scanning. RESULTS: The overall extent of abnormal lung and of parenchymal opacification on CT scans did not correlate with any physiologic variable. The extent of interstitial thickening correlated significantly with total lung capacity (r = -.783, P = .0005), airway pressure at maximal lung volume (r = .836, P = .0001), and alveolar-arterial oxygen gradient (r = .613, P = .004). CONCLUSION: CT findings of interstitial thickening are associated with impaired gas exchange and lung stiffness in rabbits.

Animals↗
PubMed1997

Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis.

Diffuse alveolar hemorrhage (DAH) resulting from pulmonary capillaritis typically accompanies the systemic vasculitides and collagen vascular diseases. Isolated pulmonary capillaritis and DAH without systemic disease occurs in patients with antineutrophil cytoplasmic antibodies. However, isolated pulmonary capillaritis and DAH is not described for patients without clinical or serologic evidence for an underlying systemic disease. To describe such patients, we undertook a retrospective chart review of 29 patients with DAH and biopsy-proven pulmonary capillaritis from seven Denver hospitals. Eight (28%) were diagnosed with isolated pulmonary capillaritis without clinical, serologic, or histologic evidence of an associated illness. Their median age was 30 yr. No association with occupational or drug exposures was identified. All had lower respiratory tract symptoms; seven had upper respiratory tract symptoms. None demonstrated systemic disease or evidence of glomerulonephritis. All were antineutrophil cytoplasmic antibody negative. Other serologies were not significant where measured. Direct immunofluorescence studies of lung tissue were negative in five. Six presented with acute respiratory failure, four requiring mechanical ventilation. One died during initial hospitalization; seven survived. Median follow-up is 43 mo (7 to 73 mo). Five remain in remission. Two experienced multiple recurrences of DAH but without development of systemic disease while on therapy. Herein we characterize DAH and isolated pulmonary capillaritis in the absence of clinical, serologic, or histologic evidence indicating an accompanying systemic illness. The prognosis for this group appears favorable.

Adult↗
PubMed1997

Quality control of peak flow meters for multicenter clinical trials. The Asthma Clinical Research Network (ACRN).

Although peak expiratory flow (PEF) measurements are recommended for monitoring and assessing treatment of asthmatic patients, and widely employed to assess outcome in clinical trials and epidemiologic studies, information about performance of peak flow meters (PFM) under field conditions is lacking. We describe a simple testing system consisting of a testing chamber, a spirometer, and a calibration syringe to evaluate the relative accuracy or median relative bias (MRB), precision, or inter-quartile range (IQR) of the mini-Wright PFM. The relative accuracy ranged from -4.4 to 13.2% (mean, 4.1%) and the precision from 0.06 to 11.5% (mean, 1.2%). Durability of this PFM was assessed during a 26-wk clinical trial in 255 asthmatic subjects at five centers. Seventy-one PFM (19.9%) were identified as having failed to meet acceptance criteria, predominantly because of loss of relative accuracy, by the clinics at follow-up visits (n = 36), and by the Data Coordinating Center on retrospective review of quality control measurements submitted by the clinics (n = 35). This study indicates that a simple device can be used to evaluate the relative accuracy and precision of a given PFM and to ensure the quality of PEF measurements during a clinical trial. To the extent that one can extrapolate these data to other devices, our findings indicate that the failure rate of PFM over time can be high, indicating that quality control of a PFM over time is absolutely essential in clinical trials as well as in routine clinical care.

Asthma↗
PubMed1997

An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.

Colchicine demonstrates an array of anti-inflammatory properties of potential relevance to asthma. However, the efficacy of colchicine as an alternative to inhaled corticosteroid therapy for asthma is unknown. Five centers participated in a controlled trial testing the hypothesis that in patients with moderate asthma needing inhaled corticosteroids for control, colchicine provides therapeutic benefit as measured by maintenance of control when inhaled steroids are discontinued. Subjects were stabilized on triamcinolane acetonide (800 microg daily) and then enrolled in a 2-wk run-in during which all subjects took both colchicine (0.6 mg/twice a day) and triamcinolone. At the end of the run-in, all subjects discontinued triamcinolone and were randomized to continued colchicine (n = 35) or placebo (n = 36) for a 6-wk double-blind treatment period. The treatment groups were similar in terms of disease severity. After corticosteroid withdrawal, 60% of colchicine-treated and 56% of placebo-treated subjects were considered treatment failures as defined by preset criteria. No significant difference in survival curves was found between treatment groups (log rank = 0.38). Other measures, including changes in FEV1, peak expiratory flow, symptoms, rescue albuterol use, and quality of life scores, also did not differ between groups. Of note, subjects failing treatment had significantly greater methacholine responsiveness at baseline than did survivors (PC20, 0.81+/-1.38 versus 2.11+/-2.74 mg/ml; p = 0.01). An analysis of treatment failures suggested that the criteria selected for failure reflected a clinically meaningful but safe level of deterioration. We conclude that colchicine is no better than placebo as an alternative to inhaled corticosteroids in patients with moderate asthma. Additionally, we conclude that the use of treatment failure as the primary outcome variable in an asthma clinical trial where treatment is withdrawn is feasible and safe under carefully monitored conditions.

Administration, Inhalation↗
PubMed1997

Methacholine challenge testing: safety of low starting FEV1. Asthma Clinical Research Network (ACRN).

STUDY OBJECTIVE: The lower limit for the baseline value to initiate methacholine bronchial hyperresponsiveness testing has not been well established. Recommendations have varied from > 1 L to above 80% of predicted. The objective was to determine if an FEV1 < 60% predicted was acceptable. DESIGN: Retrospective analysis of challenges in 88 patients with a baseline FEV1 of < 60% predicted (mean=45.8%; range, 22 to 59%. SETTING: Academic institutions. RESULTS: There were only four individuals whose FEV1 did not return to > 90% of baseline following one poststudy beta2-agonist treatment. All four responded to a second treatment. There were no adverse sequelae following challenge in any individual. Neither age (up to 79 years) nor gender influenced outcome. CONCLUSIONS: In chronic moderate to severe asthma, it appears that bronchial hyperresponsiveness testing can be safely performed even in those patients with a low baseline FEV1.

Adrenergic beta-Agonists↗
PubMed1996

The effect of inspiratory maneuvers on expiratory flow rates in health and asthma: influence of lung elastic recoil.

We studied the effect of breath holding and inspiratory speed on airflow during the FVC maneuver in seven healthy subjects and eight patients with asthma. The purpose of the study was to determine whether the effects of inspiratory speed and breath holding on expiratory flow were greater in patients with asthma than in healthy individuals; whether these effects were lessened by inhalation of aerosolized bronchodilator in the patients with asthma; and whether were was a relationship between the lung elastic recoil pressure and the expiratory flow achieved during four different maneuvers. We found that peak expiratory flow rate (PEFR) was significantly lower after both a slow inspiration and a breath hold than after a fast inspiration without a breath hold. In addition, a breath hold was associated with a significantly lower FEV1. The effects of inspiratory speed and breath holding in the patients with asthma were not significantly different from those observed in the healthy subjects. There was a significant relationship between lung elastic recoil pressure at the point of onset of the FVC maneuvers (Pel Blow) and expiratory flow in both healthy and asthmatic subjects. Also, the decrease in Pel Blow with equivalent breath-hold time was greater in asthmatic subjects, which is consistent with an increase in viscoelastic elements in the lung. These findings corroborate previous suggestions that inspiratory speed and the duration of breath holding have significant implications in the performance of spirometry and peak flow measurements, and indicate the importance of standardization of the preceding inspiration when determining FEV1 and PEFR.

Adult↗
PubMed1996

Increased surface tension of the lung and surfactant in bleomycin-induced pulmonary fibrosis in rats.

The increased elastic recoil of the lung in bleomycin-induced pulmonary fibrosis in the rat is due in part to increased surface forces. This study was designed to determine the role of surface tension in situ and in vitro 21 d after instillation of bleomycin. Using sequentially measured pressure-volume curves generated with air, saline, air after lavage with Tween 20, and saline, surface tension was significantly higher in bleomycin-treated lungs than in untreated lungs (4.7 +/- 1.1 versus 1.8 +/- 0.2 dyne/cm, p < 0.01). Surface tension was determined in vitro with a Wilhelmy balance using bronchoalveolar lavage fluid, surfactant, and organic solvent lipid extracts of surfactant. Bleomycin treatment resulted in elevated minimal surface tensions: BALF (20.7 +/- 0.6 versus 13.6 +/- 3.8 dyne/cm, p < 0.02), isolated surfactant (12.0 +/- 1.3 versus 3.0 +/- 0.5 dyne/cm, p < 0.02), and the organic solvent lipid extracted surfactant (11.0 versus 3.2 dyne/cm). These results indicate that the physical properties of surfactant in lungs of rats treated with bleomycin are abnormal and contribute to the increased elastic recoil in this model of pulmonary fibrosis.

Animals↗
PubMed1995

Correlation of structure and function in idiopathic pulmonary fibrosis.

The early stage of idiopathic pulmonary fibrosis (IPF) is thought to involve a smaller number of alveoli and to be characterized predominantly by cellularity and minimal fibrosis, whereas advanced disease involves a large number of alveoli and is characterized predominantly by fibrosis with minimal cellularity. In addition, correlative studies have indicated that prognosis and response to therapy is determined in part by the extent of fibrosis and cellularity. This study was undertaken to determine whether pulmonary function assessment would help distinguish between the cellular and fibrotic phases of this disorder, as determined by a semiquantitative pathology scoring system that comprised four factor scores: fibrosis, cellularity, granulation/connective tissue, and desquamation. Ninety-six untreated patients with biopsy-confirmed IPF (27 never smokers, 32 current smokers, and 37 ex-smokers) were evaluated. In the group as a whole, there was no significant relationship between the fibrosis or the connective/granulation tissue factor scores and any of the physiologic parameters. The DLCO correlated with the "desquamation" and the total pathology scores, whereas the TLC and FVC correlated with the cellularity factor score. In the current smokers, the coefficient of elastic retraction, DLCO/VA, and FEV1/FVC ratio were significantly lower than in never smokers and ex-smokers, and TLC and FVC were higher than in never smokers. Also, the mean cellularity and granulation/connective tissue factor scores were significantly lower, and the desquamation factor score was significantly higher than those in never smokers and ex-smokers. Both age and smoking status were significant for the cellularity factor score, whereas for the connective/granulation tissue factor score, age was not significant but smoking status was.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Physiologic diagnosis and function in asthma.

Asthma is a condition in which there is airway hyperresponsiveness, with the propensity for widespread, reversible airways narrowing on exposure to diverse inciting factors (triggers). Inhalation of nonspecific agents such as methacholine or histamine leads to bronchoconstriction in most cases, and in some, the bronchoconstriction follows exposure to specific agents such as antigen or occupational irritants. Chest tightness and cough, which are the most common symptoms of asthma, are probably the result of inflammation mucus plugs, edema, or smooth muscle constriction in the small peripheral airways. Because major obstruction of the peripheral airways can occur without recognizable increases of airway resistance or FEV1, the physiologic alterations in acute exacerbations are generally subtle in the early stages. Poorly ventilated alveoli subtending obstructed bronchioles continue to be perfused, and as a consequence, the P(A-a)O2 increases and the PaO2 decreases. At this stage, ventilation is generally increased, with excessive elimination of carbon dioxide and respiratory alkalemia. In the more severe exacerbation, lung volume is increased and the static volume-pressure curve is shifted up (lung volume is greater) and to the left (pressure is lower) while the shape of the curve is unaltered. The airway obstruction is reversible and there is generally improvement in air flow rates following administration of beta-agonists and anti-inflammatory agents. The changes in mechanical properties are also reversible, and therapeutic intervention usually results in a shift of the PV curve downward toward the normal position, for example, a decrease in TLC and an increase in the elastic recoil pressure at any particular lung volume. Failure to take these changes into account may underestimate the impact of therapy. The PaO2 decreases (and the P(A-a)O2 increases) as the work of breathing increases, and when it becomes excessive (and/or the FEV1 falls below 20% to 25%), the PaCO2 begins to increase. Therefore, in any patient with asthma, a decreasing PaO2 and an increasing PaCO2, even into the normal range, indicates severe airway obstruction that is leading to respiratory muscle fatigue and patient exhaustion.

Airway Resistance↗