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1.  Limited Impact of a Multicenter Intervention To Improve the Quality and Efficiency of Pneumonia Care*  
Chest  2004;126(1):100-107.
Study objectives
To evaluate the impact of a multifactorial intervention to improve the quality, efficiency, and patient understanding of care for community-acquired pneumonia.
Times series cohort study.
Four academic health centers in the New York City metropolitan area.
Patients or participants
All consecutive adults hospitalized for pneumonia during a 5-month period before (n = 1,013) and after (n = 1,081) implementation of an inpatient quality improvement (QI) initiative.
A multidisciplinary team of opinion leaders developed evidence-based treatment guidelines and critical pathways, conducted educational sessions with physicians, distributed pocket reminder cards, promoted standardized orders, and developed bilingual patient education materials.
Measurements and results
The average age was 71.4 years, and 44.1% of cases were low risk, 36.8% were moderate risk, and 19.2% were high risk. The preintervention and postintervention groups were well matched on age, sex, race, nursing home residence, pneumonia severity, initial presentation, and most major comorbidities. The intervention increased the use of guideline-recommended antimicrobial therapy from 78.1 to 83.4% (p = 0.003). There was also a borderline decrease in the proportion of patients being discharged prior to becoming clinically stable, from 27.0 to 23.5% (p = 0.06). However, there were no improvements in the other targeted indicators, including time to first dose of antibiotics, proportion receiving antibiotics within 8 h, timely switch to oral antibiotics, timely discharge, length of stay, or patient education outcomes.
This real-world QI program was able to improve modestly on some quality indicators, but not effect resource use or patient knowledge of their disease. Changing physician and organizational behavior in academic health centers will require the development and implementation of more intensive, system-oriented strategies.
PMCID: PMC4301308  PMID: 15249449
antibiotic therapy; guidelines; outcomes; pneumonia; quality improvement
2.  Trends in End-of-Life ICU Use Among Older Adults With Advanced Lung Cancer* 
Chest  2007;133(1):72-78.
There is increasing concern about the appropriateness of intensive medical care near the end of life in ICUs throughout the United States. As a result of hospice expansion in the 1990s, we hypothesized that ICU use decreased over time in older adults with advanced lung cancer.
Retrospective analysis using the linked Surveillance, Epidemiology and End Results Medicare database. There were 45,627 Medicare beneficiaries > 66 years of age with confirmed stage IIIB or IV lung cancer between January 1, 1992, and December 31, 2002, who died within a year of their cancer diagnosis from 1993 through 2002.
ICU use in the last 6 months of life increased from 17.5% in 1993 to 24.7% in 2002 (p < 0.001). After adjusting for patient characteristics, there was a 6.6% annual increase in ICU use from 1993 to 2002. During the same period, hospice use had risen from 28.8 to 49.9% (p < 0.001). A total of 6.2% of patients received both end-of-life ICU care and hospice care, a percentage that increased over time. The total health-care cost for Medicare fee-for-service patients during last 6 months was $40,929 for ICU users and $27,160 for non-ICU users (p < 0.001).
Despite increasing hospice use, ICU utilization among older adults dying with advanced lung cancer continued to rise in the United States during the 1990s.
PMCID: PMC4034445  PMID: 17989164
end-of-life care; hospice use; ICU care; lung cancer; older adults; utilization
3.  Ventilator settings and outcome of respiratory failure in chronic interstitial lung disease 
Chest  2007;133(5):1113-1119.
While patients with interstitial lung disease may be particularly susceptible to ventilator-induced lung injury, ventilator strategies have not been studied in this group of patients.
To describe the clinical course and outcome of patients with interstitial lung disease and acute respiratory failure in relation to ventilatory parameters.
We retrospectively identified a cohort of ventilated patients with interstitial lung disease admitted to five ICUs at a single institution. We analyzed demographic data, pulmonary function tests, severity of illness, and initial 24 hours of continuous ventilator parameters. Primary outcomes were survival to hospital discharge and one-year survival.
Main results
Of 94 patients with interstitial lung disease, 44(47%) survived to hospital discharge and 39(41%) were alive at one-year. Non-survivors were less likely to be postoperative, had higher severity of illness and were ventilated at higher airway pressures and lower tidal volumes. Step changes in positive end-expiratory pressure >10 cmH2O were attempted in 20 patients and resulted in an increase in plateau pressure (median difference +16; IQR, 9 to 24 cm H2O) and a decrease in respiratory system compliance (median difference -0.28: IQR, -0.43 to -0.13 mL/kg/cm H2O). Cox model revealed high positive end-expiratory pressure (hazard ratio 4.72; 95% CI, 2.06, 11.15), APACHE III predicted mortality (hazard ratio 1.33; 95% CI, 1.18,1.50), age (hazard ratio 1.03; 95% CI, 1,1.05) and low PaO2/FiO2(hazard ratio 0.96;95% CI, 0.92,0.99) to be independent determinants of survival.
Both severity of illness and high PEEP predict the outcome of interstitial lung disease patients receiving mechanical ventilation.
PMCID: PMC4003484  PMID: 17989156
Interstitial lung disease; intensive care unit; respiration; artificial
4.  Metabolic Syndrome, Obstructive Sleep Apnea, and Continuous Positive Airway Pressure 
Chest  2008;134(4):675-676.
PMCID: PMC3905104  PMID: 18842905
5.  Carbon Monoxide Poisoning, or Carbon Monoxide Protection? 
Chest  2008;134(5):895-896.
PMCID: PMC3888884  PMID: 18988771
6.  The Influence of Obstructive Sleep Apnea and Gender on Genioglossus Activity During Rapid Eye Movement Sleep* 
Chest  2008;135(4):10.1378/chest.08-2292.
The mechanisms contributing to worsening of obstructive sleep apnea (OSA) during rapid eye movement (REM) sleep have been minimally studied. Reduced upper-airway muscle tone may be an important contributor. Because respiratory events and the associated blood gas changes can influence genioglossus (GG) activity, we compared GG activity between OSA patients and control subjects during REM sleep using continuous positive airway pressure (CPAP) to minimize the influences of upper-airway resistance (RUA) and blood gas disturbances on GG activity.
Twenty subjects (10 female subjects), 12 healthy individuals, and 8 OSA patients, were studied overnight. Sleep staging, epiglottic pressure, minute ventilation, and GG electromyogram (GGEMG) were recorded. GGEMG was compared between REM sleep with (phasic REM) and without (tonic REM) eye movements, non-REM (NREM) sleep, and wakefulness.
Breathing frequency increased from stable NREM, to tonic REM to phasic REM sleep, whereas tidal volume and GGEMG decreased (ie, peak GGEMG: 3.0 ± 0.7 vs 1.7 ± 0.4 vs 1.2 ± 0.3% max, respectively; p < 0.001). Reductions in GGEMG during REM sleep were not different between OSA patients and control subjects or between genders.
When RUA and blood gas disturbances are minimized by CPAP, genioglossal activity is reduced in a stepwise manner from stable NREM, to tonic REM to phasic REM sleep to a similar extent in OSA and healthy individuals of both genders. Thus, an inherent abnormality in GG neural control in OSA patients during REM sleep is unlikely to explain the increased upper-airway collapse in this sleep stage. Rather, a generalized reduction in GG activity during REM likely renders individuals who are highly reliant on upper-airway dilator muscles vulnerable to pharyngeal collapse during REM sleep.
PMCID: PMC3877689  PMID: 19118266
dilator muscle; gender; lung; sleep-disordered breathing; upper airways
7.  Oxidative Damage to Nucleic Acids in Severe Emphysema* 
Chest  2008;135(4):10.1378/chest.08-2257.
Oxidative stress is a key element in the pathogenesis of emphysema, but oxidation of nucleic acids has been largely overlooked. The aim of this study was to investigate oxidative damage to nucleic acids in severe emphysematous lungs.
Thirteen human severe emphysematous lungs, including five with α1-antitrypsin deficiency (AATD), were obtained from patients receiving lung transplantation. Control lung tissue was obtained from non-COPD lungs (n = 8) and donor lungs (n = 8). DNA and RNA oxidation were investigated by immunochemistry. Morphometry (mean linear intercept [Lm] and CT scan) and immunostaining for CD68 and neutrophil elastase also were performed.
Nucleic acid oxidation was increased in alveolar wall cells in emphysematous lungs compared to non-COPD and donor lungs (p < 0.01). In emphysematous lungs, oxidative damage to nucleic acids in alveolar wall cells was increased in the more severe emphysematous areas assessed by histology (Lm, > 0.5 mm; p < 0.05) and CT scan (< −950 Hounsfield units; p < 0.05). Compared to classic emphysema, AATD lungs exhibited higher levels of nucleic acid oxidation in macrophages (p < 0.05) and airway epithelial cells (p < 0.01). Pretreatments with DNase and RNase demonstrated that RNA oxidation was more prevalent than DNA oxidation in alveolar wall cells.
We demonstrated for the first time that nucleic acids, especially RNA, are oxidized in human emphysematous lungs. The correlation between the levels of oxidative damage to nucleic acids in alveolar wall cells and the severity of emphysema suggest a potential role in the pathogenesis of emphysema.
PMCID: PMC3864580  PMID: 19118262
α1-antitrypsin deficiency; emphysema; nucleic acids; oxidative stress; RNA
8.  Diagnosis and Outcome of Early Pleural Space Infection Following Lung Transplantation 
Chest  2008;135(2):484-491.
Despite the frequent occurrence of pleural effusions in lung transplant recipients, little is known about early posttransplant pleural space infections. We sought to determine the predictors and clinical significance of pleural infection in this population.
We analyzed 455 consecutive lung transplant recipients and identified patients that underwent sampling of pleural fluid within 90 days posttransplant. A case control analysis was performed to determine the characteristics that predict infection and the impact of infection upon posttransplant survival.
Pleural effusions undergoing drainage occurred in 27% of recipients (124/455). Ninety-six percent of effusions were exudative. Pleural space infection occurred in 27% (34/124) of patients with effusions. The incidence of infection did not differ significantly by native lung disease or type of transplant operation. Fungal pathogens accounted for over 60% of the infections; Candida albicans was the predominant organism. Bacterial etiologies were present in 25% of cases. Infected pleural effusions had elevated lactate dehydrogenase (LDH) (p=0.036) and markedly increased neutrophils in the pleural space (p<0.0001) as compared to noninfected effusions. A pleural neutrophil percentage of >21% provides a sensitivity of 70% and a specificity of 79% for correctly identifying infection. Patients with pleural space infection had diminished one year survival as compared to those without infection (67% vs. 87%, respectively, p=0.002).
Pleural infection with fungal or bacterial pathogens commonly complicates lung transplantation and elevated neutrophils in the pleural fluid is the most sensitive and specific indicator of infection.
PMCID: PMC3732033  PMID: 19017896
Effusions; Empyema; Neutrophils; Lung Transplantation
9.  Dyspnea in a 43-Year-Old Woman With Polycystic Kidney Disease 
Chest  2009;135(1):238-243.
PMCID: PMC3675223  PMID: 19136414
10.  Variability in Small Airway Epithelial Gene Expression Among Normal Smokers 
Chest  2008;133(6):1344-1353.
Despite overwhelming data that cigarette smoking causes chronic obstructive pulmonary disease (COPD), only a minority of chronic smokers are affected, strongly suggesting that genetic factors modify susceptibility to this disease. We hypothesized that there are individual variations in the response to cigarette smoking, with variability among smokers in expression levels of protective / susceptibility genes.
Affymetrix arrays and TaqMan PCR were used to assess the variability of gene expression in the small airway epithelium obtained by fiberoptic bronchoscopy of 18 normal non-smokers, 18 normal smokers and 18 smokers with COPD.
We identified 201 probesets representing 152 smoking-responsive genes that were significantly up- or down-regulated, and assessed the coefficient of variation in expression levels among the study population. Variation was a reproducible property of each gene as assessed by different microarray probesets and realtime PCR and was observed in both normal smokers and smokers with COPD. There was greater individual variability in smokers with COPD than in normal smokers. The majority of these highly variable smoking responsive genes were in the functional categories of signal transduction, xenobiotic degradation, metabolism, transport, oxidant-related and transcription. A similar pattern of the same highly variable genes was observed in an independent data set.
We propose that there is likely genetic diversity within this subset of genes with highly variable individual to individual responses of the small airway epithelium to smoking, and this subset of genes represent putative candidates for assessment of susceptibility/protection from disease in future gene-based epidemiological studies of smokers’ risk for COPD.
PMCID: PMC3632367  PMID: 18339782
11.  Effect of Specific Allergen Inhalation on Serum Adiponectin in Human Asthma 
Chest  2008;135(2):287-294.
Adiponectin is associated with asthma. The direction of this association is not known in humans. In mice, this association is bidirectional - allergen inhalation affects serum adiponectin and exogenous adiponectin administration affects asthma. We sought to evaluate whether allergen inhalation affects serum adiponectin in human asthma.
This study included eight sensitized mild asthmatics and six healthy controls. Asthmatics were challenged with inhaled specific allergen (positive allergen skin test), methacholine, and irrelevant allergen (negative allergen skin test). Controls were challenged with irrelevant allergen. Sequential serum samples were obtained before and nine times after each challenge. Serum adiponectin (primary outcome), leptin, adiponectin-to-leptin ratio, eotaxin, and tumor necrosis factor-alpha - response curves, area under the curves, baseline and peak concentrations, were evaluated. Statistical analysis used repeated measures ANOVA and paired t-tests.
There were no significant differences in outcome measures among the challenges in asthmatics or when compared to controls. Type II error is an unlikely explanation for these findings since the study was adequately powered to detect changes in serum adiponectin, as reported in the literature. Further, pooled data showed that serum adiponectin diurnal variation curves were lower in asthma than in controls.
Serum adiponectin concentrations are lower in asthma than controls. Specific allergen inhalation in asthma does not acutely affect serum adiponectin concentrations. The reverse association i.e. effect of adiponectin on asthma needs further study. If future studies prove adiponectin to be a protective factor for asthma, modulating adiponectin may open a new approach towards managing asthma.
PMCID: PMC3623933  PMID: 18812451
Adipokine; Adiponectin; Allergen inhalation challenge; Asthma; Leptin
12.  The Impact of Anatomic Manipulations on Pharyngeal Collapse*: Results From a Computational Model of the Normal Human Upper Airway 
Chest  2005;128(3):1324-1330.
Obstructive sleep apnea (OSA) is a common disease with important neurocognitive and cardiovascular sequelae. Existing therapies are unsatisfactory, leading investigators to seek alternative forms of anatomic manipulation to influence pharyngeal mechanics. We have developed a two-dimensional computational model of the normal human upper airway based on signal averaging of MRI. Using the finite element method, we can perform various anatomic perturbations on the structure in order to assess the impact of these manipulations on pharyngeal mechanics and collapse. By design, the normal sleeping upper airway model collapses at −13 cm H2O. This closing pressure becomes more negative (ie, less collapsible) when we perform mandibular advancement (−21 cm H2O), palatal resection (−18 cm H2O), or palatal stiffening (−17 cm H2O). Where clinical data are available in the literature, the results of our model correspond reasonably well. Furthermore, our model provides information regarding the site of obstruction and provides hypotheses for clinical studies that can be undertaken in the future (eg, combination therapies). We believe that, in the future, finite element modeling will provide a useful tool to help advance our understanding of OSA and its response to various therapies.
PMCID: PMC3500380  PMID: 16162725
breathing; computational model; lung; MRI; obstructive sleep apnea; pharyngeal collapse
13.  Implementation and Impact of a Translational Research Training Program in Pulmonary and Critical Care Medicine* 
Chest  2008;135(3):688-694.
The translation of basic research advances to the clinical arena has been slow and inefficient. With the goal of improving interactions and collaboration between basic science and clinical investigators, we instituted a Translational Research Training Program (TRTP) in acute lung injury to complement our basic science and clinical research training programs in pulmonary and critical care medicine.
We developed a TRTP in which trainees select a primary research discipline for rigorous development of skills in either basic science research or clinical research. This primary foundation is complemented by cross-training in the other discipline through a specifically designed program of study. To measure the impact of the program, we analyzed publication rates, coauthorship to reflect collaboration between research disciplines, and publication of papers with a translational focus by members of our division before and after the institution of the TRTP.
We describe our new training program, including modifications to our preexisting program and development of new components. We found significant increases in multidisciplinary authorship and translational articles following institution of TRTP.
An explicit TRTP appears to increase collaboration between basic and clinical investigators. Our goal is to share our experiences and provide a template for other pulmonary and critical care programs interested in developing similar curricula. We speculate that this training will improve the translation of basic research findings into clinical advances, thus increasing the probability that successful treatments will be developed for patients with lung diseases.
PMCID: PMC3468153  PMID: 19017887
curriculum; education; graduate; medical; pulmonary and critical care; specialty; training
15.  Cough Suppressant and Pharmacologic Protussive Therapy 
Chest  2006;129(1 Suppl):238S-249S.
Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis.
Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms “cough,” “double-blind placebo-controlled,” “antitussive,” “mucolytic,” “cough clearance,” “common cold,” “protussive,” “guaifenesin,” “glycerol,” and “zinc.”
Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further.
These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants.
PMCID: PMC3127247  PMID: 16428717
antitussive; cough; cough suppressant; nonopioid; opioid; protussive
16.  Predicting Aspiration in Patients With Ischemic Stroke* 
Chest  2008;135(3):769-777.
Clinical signs often fail to identify stroke patients who are at increased risk of aspiration. We hypothesized that objective measure of voluntary cough would improve the accuracy of the clinical evaluation of swallow to predict those patients who are at risk.
A comprehensive diagnostic evaluation was completed for 96 consecutive stroke patients that included cognitive testing, a bedside clinical swallow examination, aerodynamic and sound pressure level measures of voluntary cough, and “gold standard” instrumental swallowing studies (ie, videofluoroscopic evaluation of swallow [VSE] or fiberoptic endoscopic evaluation of swallow [FEES]). Stroke severity was assessed retrospectively using the Canadian neurologic scale.
Based on the findings of VSE/FEES, 33 patients (34%) were at high risk of aspiration and (66%) were nonaspirators. Clinical signs (eg, absent swallow, difficulty handling secretions, or reflexive cough after water bolus) had an overall accuracy of 74% with a sensitivity of 58% and a specificity of 83% for the detection of aspiration. Three objective measures of voluntary cough (expulsive phase rise time, volume acceleration, and expulsive phase peak flow) were each associated with an aspiration risk category (areas under the curves were 0.93, 0.92, and 0.86, respectively). Expulsive phase rise time > 55 m/s, volume acceleration < 50 L/s/s, and expulsive phase peak flow < 2.9 L/s had sensitivities of 91%, 91%, and 82%, respectively; and specificities of 81%, 92%, and 83%, respectively for the identification of aspirators.
Objective measures of voluntary cough can identify stroke patients who are at risk for aspiration and may be useful as an adjunct to the standard bedside clinical assessment.
PMCID: PMC3121155  PMID: 19017886
aspiration; cough; deglutition; diagnosis; dysphagia; pneumonia; stroke; voluntary cough
17.  Occult Purulent Pericarditis Detected by Indium-111 Leukocyte Imaging* 
Chest  1984;85(5):701-703.
Leukocyte imaging with indium-111 is-a relatively new technique which, to this point in time, has been discussed almost exclusively in the radiologic literature. Although this procedure has been used mainly to detect intra-abdominal infection, the thorax is routinely imaged along with the abdomen, and therefore detection of cardiac disease may be feasible. This case report is of a young woman after liver transplantation who developed occult purulent pericarditis initially detected by a leukocyte scan with indium-111. This case demonstrates that striking pericardial uptake on a whole-body indium-111 leukocyte scan can occur with purulent pericarditis, and it reemphasizes how insidiously purulent pericarditis may present in an immunosuppressed patient.
PMCID: PMC3091365  PMID: 6370622
18.  A Clinical Model To Estimate the Pretest Probability of Lung Cancer in Patients With Solitary Pulmonary Nodules 
Chest  2007;131(2):383-388.
Estimating the clinical probability of malignancy in patients with a solitary pulmonary nodule (SPN) can facilitate the selection and interpretation of subsequent diagnostic tests.
We used multiple logistic regression analysis to identify independent clinical predictors of malignancy and to develop a parsimonious clinical prediction model to estimate the pretest probability of malignancy in a geographically diverse sample of 375 veterans with SPNs. We used data from Department of Veterans Affairs (VA) administrative databases and a recently completed VA Cooperative Study that evaluated the accuracy of positron emission tomography (PET) scans for the diagnosis of SPNs.
The mean (± SD) age of subjects in the sample was 65.9 ± 10.7 years. The prevalence of malignant SPNs was 54%. Most participants were either current smokers (n = 177) or former smokers (n = 177). Independent predictors of malignant SPNs included a positive smoking history (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.6 to 23.6), older age (OR, 2.2 per 10-year increment; 95% CI, 1.7 to 2.8), larger nodule diameter (OR, 1.1 per 1-mm increment; 95% CI, 1.1 to 1.2), and time since quitting smoking (OR, 0.6 per 10-year increment; 95% CI, 0.5 to 0.7). Model accuracy was very good (area under the curve of the receiver operating characteristic, 0.79; 95% CI, 0.74 to 0.84), and there was excellent agreement between the predicted probability and the observed frequency of malignant SPNs.
Our prediction rule can be used to estimate the pretest probability of malignancy in patients with SPNs, and thereby facilitate clinical decision making when selecting and interpreting the results of diagnostic tests such as PET imaging.
PMCID: PMC3008547  PMID: 17296637
coin lesion; diagnosis; lung neoplasms; pulmonary; receiver operating characteristic curve; statistical models; veterans
19.  Outcomes Associated With Delirium in Older Patients in Surgical ICUs 
Chest  2008;135(1):18-25.
We previously noted that older adults admitted to surgical ICUs (SICUs) are at high risk for delirium. In the current study, we describe the association between the presence of delirium and complications in older SICU patients, and describe the association between delirium occurring in the SICU and functional ability and discharge placement for older patients.
Secondary analysis of prospective, observational, cohort study. Subjects were 114 consecutive patients ≥ 65 years old admitted to a surgical critical care service. All subjects underwent daily delirium and sedation/agitation screening during hospitalization. Outcomes prospectively recorded included SICU complication development, discharge location, and functional ability (as measured by the Katz activities of daily living instrument).
Nearly one third of older adults (31.6%) admitted to an SICU had a complication during ICU stay. There was a strong association between SICU delirium and complication occurrence (p = 0.001). Complication occurrence preceded delirium diagnosis for 16 of 20 subjects. Subjects with delirium in the SICU were more likely to be discharged to a place other than home (61.3% vs 20.5%, p < 0.0001) and have greater functional decline (67.7% vs 43.6%, p = 0.023) than nondelirious subjects. After adjusting for covariates including severity of illness and mechanical ventilation use, delirium was found to be strongly and independently associated with greater odds of being discharged to a place other than home (odds ratio, 7.20; 95% confidence interval, 1.93 to 26.82).
Delirium in older surgical ICU patients is associated with complications and an increased likelihood of discharge to a place other than home.
PMCID: PMC2963095  PMID: 19017895
aged; complications; critical care; delirium; discharge placement; functional status; intensive care; outcomes; surgery
20.  Effect of a Gonadotrophin-Releasing Hormone Analogue on Lung Function in Lymphangioleiomyomatosis 
Chest  2007;133(2):448-454.
Lymphangioleiomyomatosis (LAM), a multisystem disease occurring primarily in women, is characterized by cystic lung destruction, and kidney and lymphatic tumors, caused by the proliferation of abnormal-appearing cells (ie, LAM cells) with a smooth muscle cell phenotype that express melanoma antigens and are capable of metastasizing. Estrogen receptors are present in LAM cells, and this finding, along with reports of disease progression during pregnancy or following exogenous estrogen administration, suggest the involvement of estrogens in the pathogenesis of LAM. Consequently, antiestrogen therapies have been employed in treatment. The goal of this prospective study was to evaluate the efficacy of triptorelin, a gonadotrophin-releasing hormone analogue, in 11 premenopausal women with LAM.
Patients were evaluated at baseline and every 3 to 6 months thereafter, for a total of 36 months. Hormonal assays, pulmonary function tests, 6-min walk tests, high-resolution CT scans of the chest, and bone mineral density studies were performed.
Gonadal suppression was achieved in all patients. Overall, a significant decline in lung function was observed; two patients underwent lung transplantation 1 year after study enrollment, and another patient was lost to follow-up. Treatment with triptorelin was associated with a decline in bone mineral density.
Triptorelin appears not to prevent a decline in lung function in patients with LAM. Its use, however, may be associated with the loss of bone mineral density.
PMCID: PMC2946894  PMID: 18071009
gonadotrophin-releasing hormone analogues; lung function; lymphangioleiomyomatosis; osteoporosis; triptorelin
21.  Pulmonary Artery Pressure in Lymphangioleiomyomatosis 
Chest  2007;132(5):1573-1578.
Exercise-induced hypoxemia is frequent in patients with lymphangioleiomyomatosis (LAM) and could be associated with pulmonary hypertension. The aims of this study were to determine the prevalence of pulmonary hypertension in patients with LAM, to identify physiologic parameters associated with its occurrence, and to evaluate the effect of oxygen on response to exercise.
Studies were performed in 120 patients. Complete data, including exercise echocardiography, pulmonary function testing, and standard cardiopulmonary exercise testing, were obtained in 95 patients.
Resting pulmonary artery pressure (PAP) was 26 ± 0.7 mm Hg (mean ± SEM). Eight patients had pulmonary hypertension (43 ± 3 mm Hg), and two patients had right ventricular dilatation. Ninety-five patients exercised (room air, n = 64; oxygen, n = 31) to a power of 58 ± 2 W (49% of predicted) and an estimated peak oxygen uptake of 938 ± 30 mL/min (56% of predicted). Sixty-one patients had a decline in arterial oxygen saturation (SaO2) > 3%, and 56 patients had an elevation in PAP > 40 mm Hg. Peak exercise PAP was negatively correlated with exercise SaO2 (p = 0.0005). Multivariate analysis showed that exercise SaO2 was the best predictor of exercise PAP (p = 0.012).
Although resting pulmonary hypertension is rare in patients with LAM, a rise in PAP at low exercise levels occurs frequently, in part related to exercise-induced hypoxemia. Optimization of oxygen administration during activities of daily living should be undertaken in patients with LAM to prevent hypoxemia and exercise-induced pulmonary hypertension.
PMCID: PMC2946895  PMID: 17890459
exercise; hypoxemia; pulmonary function tests; pulmonary hypertension
22.  Lessons From a Proficiency Testing Event for Acid-Fast Microscopy* 
Chest  2001;120(1):250-257.
To evaluate the routine performance and the technical parameters of different acid-fast staining methods: Kinyoun, Ziehl-Neelsen (ZN), auramine, and auramine-rhodamine.
Design and participants
The performance of 167 laboratories was analyzed using prestained and unstained slides.
Laboratories holding New York State permits.
The results revealed that Kinyoun’s cold carbol fuchsin method is inferior to both the ZN and fluorochrome (auramine and/or auramine-rhodamine) methods. Even though 91% of the participants used commercial staining kits, the study identified unexpected errors concerning the concentration of carbol fuchsin, time for staining and counterstaining, and the concentration of acid alcohol for decolorization, which may significantly influence the sensitivity. Besides these findings, the present study showed that the examination of < 300 view fields may also decrease the sensitivity of acid-fast microscopy. In addition, we found that the sensitivity and specificity of the ZN and fluorochrome methods are comparable if the procedural standards are followed.
The strict and ongoing quality control of the “simple to perform” acid-fast microscopy and the immediate review of commercially available staining kits are necessary. Because of the rapidity of the fluorochrome method, laboratories with large specimen numbers should use this technique. In all other cases, the ZN method should be used. Moreover, all clinicians should be aware of the method of acid-fast microscopy used and the proficiency of the laboratory in performing the assay.
PMCID: PMC2925666  PMID: 11451846
fluorochrome; Kinyoun; microscopy; quality control; tuberculosis; Ziehl-Neelsen
23.  Age-related Changes in Eosinophil Function in Human Subjects 
Chest  2008;133(2):412-419.
Aging results in changes in immune cell function which have been described for T-cells, macrophage, neutrophils, and dendritic cells, but not yet for eosinophils. We sought to define age-related changes in eosinophil function and their potential implications for asthma. Methods. We recruited human subjects with asthma in two age groups, a younger group (20–40 years old) and older group (55–80 years old). Lung function, induced sputum, and peripheral blood were obtained from each subject. Eosinophils isolated from the peripheral blood were examined for in vitro functional activities including degranulation, superoxide anion production, adhesion, and chemotaxis.
Eosinophil degranulation in response to IL-5 stimulation was significantly decreased in the older group (p=0.025). Eosinophil production of superoxide anions in response to phorbol myristate acetate was lower in the older group, but did not achieve statistical significance (p=0.097). Eosinophil adhesion, eosinophil chemotaxis, lung function, and the percentage of sputum eosinophils were similar in the two groups.
Airway eosinophilia is comparable in younger and older asthma subjects. However, there are age-related changes in peripheral blood eosinophil “effector” functions. Diseases such as asthma, in which eosinophils are thought to play a pathophysiological role, may exhibit important clinical differences in the elderly due to age-related changes in inflammatory cell function that affect the manifestations of the disease and/or responsiveness to specific classes of medications.
PMCID: PMC2919352  PMID: 18252914
aging; immunosenescence; eosinophil; asthma
24.  Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD* 
Chest  2008;135(3):737-744.
Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT).
In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao2, Paco2, and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study.
In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen.
In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.
PMCID: PMC2906241  PMID: 19017876
case-control studies; COPD; genetics; phenotype; single-nucleotide polymorphism
25.  A Pilot Study to Examine the Effects of Smoking Cessation on Serum Markers of Inflammation in Women at Risk for Cardiovascular Disease 
Chest  2009;136(1):212-219.
The links between smoking, inflammation, and cardiovascular disease (CVD) are well-established. Several studies demonstrate that quitting smoking reverses the risk of coronary heart disease within five to ten years. However, the immediate effects of quitting smoking on inflammatory biomarkers associated with CVD risk are not well described.
In this pilot study, we examined a panel of circulating inflammatory biomarkers associated with CVD in ‘at risk’ women during the smoking cessation process. Forty-six women enrolled in a smoking cessation program consented to attend 4 study visits over 6–7 weeks. Health/medical information and blood was collected at each visit. Circulating levels of C-reactive protein (CRP), TNF, IL-6, soluble TNF receptors I and II, and soluble VCAM-1 were measured and changes between baseline levels (visit 1, while smoking) and visits 2–4 were determined.
Significant reductions in circulating TNF, soluble TNF receptors I and II, and soluble VCAM-1 were observed among participants over the smoking cessation process. Both serum IL-6 and CRP levels declined during the smoking cessation process; however the changes were not statistically significant.
These findings suggest that there are rapid consequences of smoking cessation on inflammatory biomarkers in women at risk for CVD. Additional, larger studies including diverse smokers desiring to quit are required to confirm changes in ‘measurable milestones’ which could serve as motivating factors to assist smokers to quit.
PMCID: PMC2707500  PMID: 19225057
inflammatory biomarkers; smoking cessation; nicotine replacement therapy; nicotine; anti-inflammatory; cardiovascular disease

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