Peter Y. Hahn

Pneumocystis carinii cell wall β-glucan induces release of macrophage inflammatory protein-2 from alveolar epithelial cells via a lactosylceramide-mediated mechanism

Infiltration of the lungs with neutrophils promotes respiratory failure during severePneumocystis carinii (PC) pneumonia. Recent studies have shown that alveolar epithelial cells (AECs), in addition to promoting PC attachment, also participate in lung inflammation by the release of cytokines and chemokines. Herein, we demonstrate that a PC β-glucan rich cell wall isolate (PCBG) stimulates the release of macrophage inflammatory protein-2 (MIP-2) from isolated AECs through a lactosylceramide-dependent mechanism. The results demonstrate that MIP-2 mRNA and protein production is significantly increased at both early and late time points after PCBG challenge. Although CD11b/CD18 (Mac-1, CR3) is the most widely studied β-glucan receptor, we demonstrate that CD11b/CD18 is not present on AECs. This study instead demonstrates that preincubation of AECs with an antibody directed against the membrane glycosphingolipid lactosylceramide (CDw17) results in a significant decrease in MIP-2 secretion. Preincubation of the anti-CDw17 antibody with solubilized lactosylceramide reverses this effect. Furthermore, incubation of AECs with inhibitors of glycosphingolipid biosynthesis, includingN-butyldeoxyno jirimycin andd-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol-HCl, also results in a significant decrease in AEC MIP-2 production following challenge with PCBG. These data demonstrate that PC β-glucan induces significant production of MIP-2 from AECs and that CDw17 participates in the glucan-induced inflammatory signaling in lung epithelial cells during PC infection.

Use of Exhaled Nitric Oxide in Predicting Response to Inhaled Corticosteroids for Chronic Cough

OBJECTIVE To evaluate our experience with patients who presented with chronic cough and how exhaled nitric oxide predicted response to inhaled corticosteroid (ICS) therapy. PATIENTS AND METHODS This retrospective observational study of 114 patients evaluated for chronic cough with measured exhaled nitric oxide and methacholine challenge testing was conducted from December 1, 2004, through November 30, 2005. Clinical records were extracted. Patients with no documented follow-up were contacted by telephone and administered a questionnaire. RESULTS In 64 patients, ICS therapy was started or the current ICS dose increased. Forty-one patients had elevated exhaled nitric oxide levels (defined as >or=35 ppb), 36 (88%) of whom had significant improvement in their chronic cough (likelihood ratio of a positive response, 4.9; 95% confidence interval, 2.2-10.9). Twenty-three patients with exhaled nitric oxide levels in the reference range were also prescribed ICS, and only 2 had cough improvement (likelihood ratio of a negative response, 0.07; 95% confidence interval, 0.02-0.25). Patients had documented follow-up that ranged from 4 weeks to 16 months. A cutoff of 38 ppb was found to best differentiate ICS responders and nonresponders. CONCLUSIONS Measurement of exhaled nitric oxide accurately predicted response to ICS therapy for chronic cough. Patients with a positive exhaled nitric oxide test result had a strong likelihood of response to ICS, whereas a negative exhaled nitric oxide test result indicated an unlikely response to ICS. This finding may potentially have an impact on how patients with chronic cough are evaluated and treated.

Sleep Apnea and Hypertension

Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing and frequently coexists with obesity. Almost 15 million Americans are affected by this disorder. This prevalence is likely increasing, given the current epidemic of obesity. Recent data confirm an association between sleep apnea and several cardiovascular disease conditions, suggesting that OSA may be a new risk factor for coronary artery disease, heart failure, heart rhythm disturbances and hypertension, independent of body mass index. In this review, the authors focus on the nature of the association between OSA and hypertension, the evidence suggesting a causal interaction, and discuss the potential pathophysiologic mechanisms responsible. These mechanisms include activation of the sympathetic and renin-angiotensin-aldosterone systems (RAAS), oxidative stress, and systemic and vascular inflammation, all of which could link OSA to a sustained increase in blood pressure. The authors also review potential therapeutic strategies for the hypertensive patient with OSA.

Update on Exhaled Nitric Oxide in Clinical Practice

Asthma is characterized by chronic airway inflammation. Fractional exhaled nitric oxide (Feno) has emerged as a marker of T-helper cell type 2-mediated allergic airway inflammation. Recent studies suggest a role for Feno testing as a point-of-care tool in the management of patients with asthma. This Topics in Practice Management article reviews current coverage and reimbursement issues related to Feno testing and provides an overview of pertinent recent studies.

Long-term Safety of Nebulized Lidocaine for Adults With Difficult-to-Control Chronic Cough: A Case Series

BACKGROUND The long-term safety of patient-administered nebulized lidocaine for control of chronic cough has not been established. METHODS We performed a retrospective study of adults who received a prescription and nurse education for nebulized lidocaine for chronic cough between 2002 and 2007. A survey questionnaire inquiring about adverse reactions and the effectiveness of nebulized lidocaine was developed and administered to these individuals after the nebulized lidocaine trial. We conducted two mailings and a postmailing phone follow-up to nonresponders. When adverse events were reported in the questionnaire response, a structured phone interview was conducted to obtain additional details. RESULTS Of 165 eligible patients, 99 (60%) responded to the survey. Responders were a median age of 62 years (range, 29-87 years); 77 (79%) were women, and 80 (82%) were white. The median duration of cough was 5 years before treatment with nebulized lidocaine. Of the patients who used nebulized lidocaine (93% of survey responders), 43% reported an adverse event. However, none of these events required an emergency visit, hospitalization, or antibiotic therapy for aspiration pneumonia. The mean (SD) of the pretreatment cough severity score was 8.4 (1.6) and posttreatment was 5.9 (3.4) (P < .001). Of the patients reporting improvement in cough symptoms (49%), 80% reported improvement within the first 2 weeks. CONCLUSIONS Adults tolerated self-administration of nebulized lidocaine for difficult-to-control chronic cough. No serious adverse effects occurred while providing symptomatic control in 49% of patients.

Pneumocystis carinii β‐Glucan Induces Release of Macrophage Inflammatory Protein‐2 from Primary Rat Alveolar Epithelial Cells via a Receptor Distinct from CDllb/CD18

Pnemys t i s carinii (PC) pneumonia remains a life threatening infection in immunocompromised hosts. Neutrophilic inflammation and diffuse alveolar damage contribute significantly to respiratory failure characteristic of severe PC pneumonia. We have recently shown that alveolar macrophages produce tumor necrosis factor (TNF) and macrophage inflammatory protein-2 (MIP-2) in response to purified particulate FC fi-glucan [I]. Although several different receptors have been reported to bind p-glucan, the best studied among is the CD11b/CD18 complex (CR3). The membrane glycosphingolipid. lactosylceramide (CDwl7), has also been shown to participate in the glucan receptor complex [2]. Recent studies have demonstrated that alveolar epithelial cells (AEC’s) play an important role in lung inflammation by the release of cytokines and chemokines. The purpose of this study is to determine if purified particulate PC p-glucan induces MP-2 expression from primary AEC’s.

Intensive care unit and hospital mortality in patients with obstructive sleep apnea.

INTRODUCTION Obstructive sleep apnea (OSA) is a common disorder affecting between 5% and 24% of men and women. The prevalence of OSA in the intensive care unit (ICU) population is unknown. This study was undertaken to determine the prevalence of OSA in patients admitted to the ICU and to determine if OSA is an independent predictor of mortality. METHODS This is a retrospective study using an Acute Physiology and Chronic Health Evaluation III database cross-referenced to a comprehensive clinical database to identify patients with and without OSA admitted to medical, surgical, and mixed ICUs at a large academic medical center. RESULTS Between January 2003 and December 2005, 15077 patients were admitted to the ICUs; and of these, 1183 (7.8%) had a physician-documented diagnosis of OSA. Eight hundred thirty-five (71%) patients had polysomnographic testing at our institution with a documented apnea-hypopnea index more than 5 per hour. Patients with OSA were younger (59.1 ± 14.0 vs 62.3 ± 18.0), male (58.9% vs 53.7%), and had lower Acute Physiology and Chronic Health Evaluation III scores (45.3 ± 24.1 vs 54.9 ± 27.7). Predicted mortality (10.3% ± 16.4% vs 16.3 ± 21.7), median ICU length of stay (1.13 vs 1.50 days), ICU mortality (2.4% vs 6.2%), and hospital mortality (3.9% vs 11.4%) were all reduced in patients with OSA, P values < .001. When adjusted for the severity of illness, OSA was independently associated with decreased hospital mortality, (0.408; 95% confidence interval, 0.298-0.557). CONCLUSIONS Obstructive sleep apnea is common in patients admitted to the ICU. Obstructive sleep apnea was associated with a reduction in both ICU and hospital mortality.