Serum indicators for the diagnosis of pneumocystis pneumonia

BACKGROUND: The diagnosis of pneumocystis pneumonia (PCP) is difficult because it requires microscopic examination to identify pneumocystis from induced sputum or BAL fluid. STUDY OBJECTIVE: To evaluate the usefulness of four serum markers-lactate dehydrogenase (LDH), (1-->3) beta-D-glucan (beta-D-glucan), KL-6, and C-reactive protein (CRP)-in the diagnosis of PCP. DESIGN: Case-control retrospective study. Patients and measurements: We reviewed the medical records of 295 consecutive patients who underwent BAL for the diagnosis of PCP. Differential cell counts in BAL fluid and serum levels of LDH, beta-D-glucan, KL-6, and CRP were examined. Oxygenation index was determined using arterial oxygen tension and inspiratory oxygen concentration. RESULTS: Based on the microscopic examination of BAL fluid, 57 patients were PCP positive and 238 patients were PCP negative. There were no significant differences in cell count or differentials in BAL fluid between the positive and negative cases. Serum levels of LDH, beta-D-glucan, and KL-6 were significantly higher in PCP-positive patients (p < 0.01). Receiver operating characteristic curves suggest that beta-D-glucan was the most reliable indicator. The cut-off level of beta-D-glucan was estimated to be 31.1 pg/mL, with which the positive and negative predictive values were 0.610 and 0.980, respectively. In PCP-positive patients, the oxygenation index was decreased and correlated with LDH. Both LDH and beta-D-glucan levels were correlated with the proportion of neutrophils in BAL fluid. CONCLUSIONS: Serum beta-D-glucan is a reliable marker for the diagnosis of PCP. Since BAL procedure is invasive, measuring beta-D-glucan should be considered as a primary modality for a diagnosis of PCP, especially for patients with severe respiratory failure.     

Influence of atrial fibrillation on plasma von willebrand factor, soluble E-selectin, and N-terminal pro B-type natriuretic peptide levels in systolic heart failure

BACKGROUND: Endothelial dysfunction is present in patients with heart failure (HF) due to left ventricular systolic dysfunction, as well as in patients with atrial fibrillation (AF) who have normal cardiac function. It is unknown whether AF influences the degree of endothelial dysfunction in patients with systolic HF. METHODS: We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. RESULTS: One hundred ninety patients (73% men; mean age, 69.0 +/- 10.1 years [+/- SD]) with systolic HF were studied, who were compared to 117 healthy control subjects: 52 subjects (27%) were in AF, while 138 subjects (73%) were in sinus rhythm. AF-HF patients were older than SR-HF patients (p = 0.046), but left ventricular ejection fraction and New York Heart Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p = 0.003) between patients and control subjects. On Tukey post hoc analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p = 0.0183) but not E-selectin (p = 0.071) levels when compared to SR-HF patients. On multivariate analysis, the presence of AF was related to plasma vWF levels (p = 0.018). Plasma vWF was also significantly correlated with NT-proBNP levels (Spearman r = 0.139; p = 0.017). CONCLUSIONS: There is evidence of greater endothelial damage/dysfunction in AF-HF patients when compared to SR-HF patients. The clinical significance of this is unclear but may have prognostic value.     

Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis

BACKGROUND: The prognostic value of BAL fluid cell count differential in patients with idiopathic pulmonary fibrosis (IPF) is unknown. We hypothesized that baseline BAL fluid cell count differential (ie, elevated levels of neutrophils and eosinophils, or reduced levels of lymphocytes) would predict higher mortality among persons with IPF. METHODS: We evaluated the association of BAL fluid cell count differential and mortality among 156 persons with surgical lung biopsy-proven IPF who underwent bronchoscopy with BAL and cell count differential measurements at presentation. Vital status was obtained among all participants. Cox regression analysis evaluated the association of BAL fluid cell count differential and mortality. RESULTS: After controlling for known clinical predictors of mortality, we found that each doubling of baseline BAL fluid neutrophil percentage was associated with a 30% increased risk of mortality (adjusted hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01 to 1.62; adjusted p = 0.04) in the first year after presentation. We observed no association with BAL fluid lymphocyte percentage and mortality (adjusted HR per doubling, 0.99; 95% CI, 0.76 to 1.29; p = 0.93) or eosinophil percentage and mortality (adjusted HR per doubling, 0.99; 95% CI, 0.69 to 1.40; p = 0.95). CONCLUSIONS: Increased BAL fluid neutrophil percentage is an independent predictor of early mortality among persons with IPF. Alternatively, BAL fluid lymphocyte and eosinophil percentages were not associated with mortality. The clinical utility of BAL at the time of diagnosis of IPF should be reconsidered.     

Is Metalloproteinase-7 Specific for Idiopathic Pulmonary Fibrosis?

BACKGROUND: Matrix metalloproteinase (MMP)-7 was reported to be a key molecule in the pathogenesis of idiopathic pulmonary fibrosis (IPF) based on the result of microarray analysis and knockout mice. However, the role of MMP-7 has not been determined in other types of idiopathic interstitial pneumonia (IIP). The aim of this study was to investigate the role of MMP-7 in IIP by comparing its expression in usual interstitial pneumonia (UIP) and cryptogenic organizing pneumonia (COP). METHODS: Levels of MMP and tissue inhibitors of metalloproteinase in BAL fluid and their expression on lung tissues were compared between normal control subjects (n = 5) and the patients with IPF (n = 6) and COP (n = 11). RESULTS: There was no significant difference in BAL fluid MMP-7 levels between UIP and COP, although it was higher in both diseases compared to normal control subjects. Furthermore, the pattern and the degree of MMP-7 expression in lung tissues were also similar in both IPF and COP, whereas MMP-2 level was higher in COP and MMP-9 level was higher in IPF. CONCLUSION: MMP-7 seems to play an important role in the pathogenesis of not only IPF but also COP; therefore, it may not be the key factor determining the prognosis or reversibility of IIPs.     

Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing

BACKGROUND: Cardiac sarcoidosis (CS) causes substantial morbidity and sudden death. Early diagnosis and risk stratification are warranted. METHODS: Ambulatory patients with sarcoidosis were interviewed to determine whether they experienced palpitations, syncope, or presyncope, and were evaluated with ECG, Holter monitoring, and echocardiography (transthoracic echocardiogram [TTE]). Those with symptoms or abnormal results were studied with cardiac MRI (CMRI) or positron emission tomography (PET) scanning. The diagnosis of CS was based on abnormalities detected by these imaging studies. Patients with CS were referred for risk stratification by electrophysiology study (EPS). RESULTS: Among the 62 patients evaluated, the prevalence of CS was 39%. Patients with CS had more cardiac symptoms than those without CS (46% vs 5%, respectively; p < 0.001), and were more likely to have abnormal Holter monitoring findings (50% vs 3%, respectively; p < 0.001) and TTE findings (25% vs 5%, respectively; p = 0.02). The degree of pulmonary impairment did not predict CS. Two of the 17 patients who underwent EPS had abnormal test findings and received implantable cardioverter-defibrillators. No patients died, had ventricular arrhythmias that triggered defibrillator therapy, or had heart failure develop during almost 2 years of follow-up. This diagnostic approach was more sensitive than the established criteria for identifying CS. CONCLUSION: CS is common among patients with sarcoidosis. A structured clinical assessment incorporating advanced cardiac imaging with PET scanning or CMRI is more sensitive than the established criteria for the identification of CS. Sarcoidal lesions seen on CMRI or PET scanning do not predict arrhythmias in ambulatory patients with preserved cardiac function, who appear to be at low risk for short-term mortality.     

The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function

BACKGROUND: Obstructive sleep apnea (OSA) is associated with endothelial dysfunction. In the current study, we assessed the effect of long-term modified Herbst mandibular advancement splint (MAS) treatment on OSA, oxidative stress markers, and on endothelial function (EF). METHODS: A total of 16 subjects participated (11 men and 5 women; mean [+/- SD] age, 54.0 +/- 8.3 years; mean body mass index, 28.0 +/- 3.1 kg/m(2)), 12 of whom completed the 1-year evaluation. Apnea severity, levels of oxidative stress markers, and EF were assessed after 3 months and 1 year of receiving treatment. For comparison, 6 untreated patients underwent two evaluations 9 months apart, and 10 non-OSA individuals were assessed once as a reference group. The results are presented as the mean +/- SD. RESULTS: The mean apnea-hypopnea index (AHI) decreased significantly from 29.7 +/- 18.5 events/h before treatment to 17.7 +/- 11.1 events/h after 3 months of treatment and 19.6 +/- 11.5 events/h after 1 year of treatment (p < 0.005 for both). The mean Epworth sleepiness scale score decreased significantly from 12.4 +/- 6.0 before treatment to 10.2 +/- 6.6 after 3 months of treatment and 7.8 +/- 3.8 after 1 year of treatment (p < 0.001 for both). The mean EF improved significantly from 1.77 +/- 0.4 before treatment to 2.1 +/- 0.4 after 3 months of treatment (p < 0.05) and 2.0 +/- 0.3 after 1 year of treatment (p = 0.055), which were similar to the values of the reference group. Thiobarbituric acid-reactive substance (TBARS) levels decreased from 18.8 +/- 6.2 nmol malondialdehyde (MDA)/mL before treatment to 15.8 +/- 3.9 MDA/mL after 3 months of treatment (p = 0.09) and 15.5 +/- 3.2 nmol MDA/mL after 1 year of treatment (p < 0.05). There was a correlation between the improvement in AHI and in EF or TBARS levels (r = 0.55; p = 0.05). The untreated control group remained unchanged. CONCLUSIONS: The Herbst MAS may be a moderately effective long-term treatment for patients with OSA. EF improved to levels that were not significantly different than reference levels, even though apneic events were not completely eliminated. We think that these data are encouraging and that they justify the performance of larger randomized controlled studies.     

Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD

BACKGROUND: The single-breath N(2) test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL, and induced sputum in patients with manifest COPD. METHODS: Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 +/- 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, 31 to 51 pack-years]). Postbronchodilator spirometry (FEV(1), 63 +/- 8% of predicted) and sbN(2)-test (slope of phase III [DeltaN(2)], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretory leukocyte proteinase inhibitor (SLPI), and interleukin-8 levels were determined in BAL fluid. RESULTS: DeltaN(2) increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN(2)-test was not associated with any other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between DeltaN(2) and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV(1) percentage of predicted. CONCLUSIONS: The results of the sbN(2)-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD.     

Automatic objective diagnosis of lymph nodal disease by B-mode images from convex-type echobronchoscopy

BACKGROUND: We investigated whether artificial neural networks (ANNs) could diagnose pathology of lymph nodes by feeding B-mode images from convex-type echobronchoscopy to ANNs. METHODS: Subjects comprised 91 patients who had undergone endobronchial ultrasonography transbronchial needle aspiration at our hospital between April 2005 and March 2007. Diagnosis was lymph node metastasis from lung cancer in 66 patients, and sarcoidosis in 25 patients. Layered ANNs consisting of input, middle layers, and output layers were prepared. Back-propagation was chosen as a learning algorithm. For the malignant findings, images obtained from six patients with lymph node metastasis of lung cancer (ie, adenocarcinoma, two patients; squamous cell carcinoma, two patients; small cell carcinoma, two patients) were used. As benign findings, typical images obtained from three patients with sarcoidosis were used. For each image used for supervised training, 5, 10, or 15 regions of interest were randomly selected. Repeated learning comprised either 500,000 or 1,000,000 repetitions. A total of five thoracic surgeons were asked to diagnose the pathology base on the same images. Accuracies were compared between ANNs and thoracic surgeons. RESULTS: The diagnostic accuracy of the surgeon with 5 years of experience and that of the surgeon with 1 year of experience were 78% and 51%, respectively, compared to 91% for the ANNs. CONCLUSION: Assessment of B-mode images by ANNs may offer a useful basis for automatic diagnostic methods.     

Diagnostic usefulness of fluorine-18-alpha-methyltyrosine positron emission tomography in combination with 18F-fluorodeoxyglucose in sarcoidosis patients

OBJECTIVES: L-[3-(18)F]-alpha-methyltyrosine ((18)F-FMT) is an amino-acid tracer for positron emission tomography (PET) and is used for tumor detection because malignant tumor cells accumulate (18)F-FMT based on the increased expression of an amino-acid transporter. This study was conducted to investigate the usefulness of (18)F-FMT PET in combination with fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET for the diagnosis of sarcoidosis in patients with suspected malignancy. SETTING: Twenty-four sarcoidosis patients with suspected malignancy underwent (18)F-FDG and (18)F-FMT PET. The study included 17 patients with extrapulmonary manifestation mimicking malignant disease (13 patients with systemic lymphadenopathy, 3 of them with concomitant hepatosplenic processes; 3 patients with hepatosplenic processes without concomitant lymphadenopathy; and 1 patient with multiple bone lesions), 3 patients with occurrence of bilateral hilar lymphadenopathy in cancer patients, and 4 patients with multiple nodules mimicking pulmonary metastasis. RESULTS: All patients showed increased uptake of (18)F-FDG and no increase in the accumulation of (18)F-FMT in their lymphadenopathy. Standardized uptake values (SUVs) of (18)F-FDG and (18)F-FMT were 5.01 +/- 2.15 and 0.77 +/- 0.24, respectively (mean +/- SD). All extranodal lesions such as liver, spleen, and bone were visually positive on (18)F-FDG PET and negative on (18)F-FMT PET. No neoplasm was confirmed in all patients. In a control group of patients with lung cancer, SUVs for (18)F-FDG and (18)F-FMT were 6.34 +/- 2.52 and 1.54 +/- 0.82, respectively. CONCLUSION: The uptake of (18)F-FDG was positive in the sarcoid lesions, and therefore (18)F-FDG PET could not differentiate sarcoidosis from malignant disease. Use of (18)F-FMT PET in combination with (18)F-FDG PET may be the effective method to distinguish sarcoidosis from malignancy.     

Noneosinophilic CD4 lymphocytic airway inflammation in menopausal women with chronic dry cough

BACKGROUND: Chronic dry cough without dyspnea and wheezing is a well-known condition that is considered to be clinically overrepresented in women. The etiology and morphology remain unknown in many cases despite thorough investigations. DESIGN: To examine inflammatory cells and the lymphocyte profile in the lower airways and blood in women with chronic cough of unknown etiology. SETTING: University hospital department of respiratory medicine. PARTICIPANTS: Twenty-five otherwise healthy women with idiopathic cough and 11 age-matched healthy control women, all nonatopic nonsmokers. MEASUREMENTS: In order to characterize the cough, a careful standardized interview of the patients was made. Lung functions were tested. Cells were collected by BAL and analyzed for differential cell counts separate in the bronchial (first) wash and in the pooled peripheral washes (BAL fluid). The lymphocyte profile in BAL fluid and blood was characterized by dual-color flow cytometry. RESULTS: Eleven female patients formed a specific group with a history of a dry, nonproductive cough that always started in connection with an airway infection coinciding with menopause. Neither exercise, climate, nor seasonal change influenced the cough. BAL fluid contained an increased number of T (CD3+) lymphocytes: median. Seventy-three percent of T lymphocytes were T-helper lymphocytes (CD4+). A median of 57% of the BAL fluid T cells expressed HLA-DR activation marker compared with a median of 20% in the control subjects and in the other 14 included patients with chronic cough but with minor expectoration periodically (p < 0.001 and p < 0.0001, respectively). No differences between the groups were found in the blood. CONCLUSIONS: HLA-DR-activated CD4+ lymphocytic airway inflammation with a low number of eosinophils was identified in a group of nonsmoking, nonatopic otherwise healthy women patients with dry cough of life-long character. The disease appeared exclusively in connection to menopause.     

Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating, heparin-dependent IgG antibodies (HIT-IgG). Although HIT is known to predispose the patient to thrombosis, the relationship between the formation of HIT-IgG and various other unusual clinical sequelae putatively linked with the HIT syndrome, such as heparin-induced skin lesions and acute anaphylactoid reactions following treatment with an IV heparin bolus, is not clear. METHODS: We used data from a clinical trial of postoperative heparin prophylaxis to compare the frequency of one or more predefined unusual clinical sequelae developing in 20 patients who formed platelet-activating HIT-IgG with 80 control patients who did not form HIT-IgG (nested cohort study). RESULTS: Five of the 20 patients in whom HIT-IgG developed had one or more unusual clinical sequelae, compared with none of 80 control patients (25% vs 0%, respectively; odds ratio, infinity; 95% confidence interval, 4.3 to infinity; p < 0.001). The unusual complications included heparin-induced erythematous or necrotic skin lesions (n = 4), an anaphylactoid reaction following IV heparin bolus use (n = 1), and warfarin-associated venous limb ischemia (n = 1). Thrombocytopenia, as it is conventionally defined (ie, platelet count fall to < 150 x 10(9) cells/L) developed in only one of these five patients. CONCLUSIONS: Certain unusual clinical sequelae, such as heparin-induced skin lesions, are strongly associated with the formation of HIT-IgG and should be considered as manifestations of the HIT syndrome, even in the absence of thrombocytopenia as conventionally defined.     

A single dose of dexamethasone to prevent postbronchoscopy fever in children: a randomized placebo-controlled trial

STUDY OBJECTIVE: To assess the effectiveness of one dose of dexamethasone (0.5 mg/kg; maximum, 10 mg) to prevent fever after bronchoscopy with BAL. DESIGN: Randomized, placebo-controlled study. PATIENTS: Immunocompetent nonfebrile children undergoing fiberoptic bronchoscopy with BAL. MEASUREMENTS AND RESULTS: Sixty-nine children were included in the study. Thirty-eight children received saline solution, and 31 children received dexamethasone. The two groups were similar regarding the number of children < 2 years old, the percentage of abnormal bronchoscopic findings, the number of positive BAL culture findings, and the index of lipid-laden macrophages. Twenty-six children (68%) in the saline solution group (SG) had fever, compared to 3 children (9.6%) in the dexamethasone group (DG) [p < 0.001]. Fever after the procedure appeared later (12.3 +/- 5.5 h) in the DG compared to 5.4 +/- 2.7 h in the SG. CONCLUSIONS: One dose of dexamethasone administered prior to performing bronchoscopy with BAL may prevent fever subsequent to the procedure. Further studies are necessary in order to determine the optimal dosing regimen for dexamethasone when used for this purpose.     

Bronchoalveolar cellularity and interleukin-8 levels in measles bronchiolitis obliterans

BACKGROUND: Measles virus infection may progress to a chronic obstructive process including bronchiolitis obliterans (BO). This study investigates pulmonary cellular profiles and interleukin (IL)-8 levels in patients with BO following the measles. METHODS: BAL fluid was obtained from 12 children with BO who had a history of measles pneumonia during an outbreak in 2000 and 2001. BAL cell counts and differentials were compared to control patients as well as BAL IL-8 levels, which were measured by enzyme-linked immunosorbent assay. Immunohistochemical staining of BAL cells and three open-lung biopsy specimens were also analyzed for T-cell surface markers CD3, CD4, and CD8. RESULTS: BAL cellular profiles were characterized by a significantly increased percentage of neutrophils in the measles BO group (median, 16.0%) compared to the control group (2.3%) [p < 0.01]. BAL IL-8 levels were also markedly increased in the measles BO group (mean +/- SD, 418.6 +/- 286.0 pg/mL) compared to the control group (92.8 +/- 126.7 pg/mL) [p < 0.01]. BAL IL-8 levels correlated significantly with neutrophil percentages in both the measles BO group (r = 0.86, p = 0.000) and the control group (r = 0.79, p = 0.007). The lymphocyte subsets were characterized by a significantly increased number of CD8+ cells, resulting in a decreased CD4/CD8 ratio in the BAL and the biopsy specimens. CONCLUSION: These results suggest that pulmonary neutrophils and IL-8, along with CD8+ T lymphocytes may play an important role in the pathogenesis of BO after measles virus infection.     

World Trade Center "sarcoid-like" granulomatous pulmonary disease in New York City Fire Department rescue workers

BACKGROUND: Previous reports suggest that sarcoidosis occurs with abnormally high frequency in firefighters. We sought to determine whether exposure to World Trade Center (WTC) "dust" during the collapse and rescue/recovery effort increased the incidence of sarcoidosis or "sarcoid-like" granulomatous pulmonary disease (SLGPD). METHODS: During the 5 years after the WTC disaster, enrollees in the Fire Department of New York (FDNY) WTC monitoring and treatment programs who had chest radiograph findings suggestive of sarcoidosis underwent evaluation, including the following: chest CT imaging, pulmonary function, provocative challenge, and biopsy. Annual incidence rates were compared to the 15 years before the WTC disaster. RESULTS: After WTC dust exposure, pathologic evidence consistent with new-onset sarcoidosis was found in 26 patients: all 26 patients had intrathoracic adenopathy, and 6 patients (23%) had extrathoracic disease. Thirteen patients were identified during the first year after WTC dust exposure (incidence rate, 86/100,000), and 13 patients were identified during the next 4 years (average annual incidence rate, 22/100,000; as compared to 15/100,000 during the 15 years before the WTC disaster). Eighteen of 26 patients (69%) had findings consistent with asthma. Eight of 21 patients (38%) agreeing to challenge testing had airway hyperreactivity (AHR), findings not seen in FDNY sarcoidosis patients before the WTC disaster. CONCLUSION: After the WTC disaster, the incidence of sarcoidosis or SLGPD was increased among FDNY rescue workers. This new information about the early onset of WTC-SLGPD and its association with asthma/AHR has important public health consequences for disease prevention, early detection, and treatment following environmental/occupational exposures.     

Double-blind, randomized trial of dexmethylphenidate hydrochloride for the treatment of sarcoidosis-associated fatigue

BACKGROUND: Fatigue is a common complaint in patients with sarcoidosis. We studied the effectiveness of dexmethylphenidate hydrochloride (d-MPH) in treating sarcoidosis-associated fatigue. METHODS: This was a double-blind, randomized, placebo-controlled, crossover trial of d-MPH. Patients were seen weekly and completed Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Fatigue Assessment Score (FAS) instruments. After a 1-week wash-in period, patients received either d-MPH or placebo. After 8 weeks, the medications were stopped. Following a 2-week wash-out period, patients were crossed over to 8 weeks of the other treatment. FVC and 6-min walk distance (6MWD) were determined initially and after each treatment arm. RESULTS: Ten patients with sarcoidosis were enrolled: 8 women and 5 African Americans. All were receiving systemic sarcoidosis therapy. Significant improvement in fatigue was reported by patients when receiving d-MPH (FACIT-F, p < 0.001; FAS, p < 0.02). FVC was higher at the end of 8 weeks of d-MPH compared to the baseline values (baseline median, 2.38 L; range, 1.17 to 4.53 L; placebo median, 2.41 L; range, 1.50 to 4.65 L; d-MPH median, 2.56 L; range, 1.50 to 4.96 L; p < 0.01). There was no significant difference in the 6MWD (baseline median, 330 m; range, 60 to 460 m; placebo median, 350 m; range, 180 to 460 m; d-MPH median, 390 m; range, 200 to 460 m). d-MPH was well tolerated. CONCLUSIONS: Treatment with d-MPH was associated with a significant improvement in sarcoidosis-associated fatigue. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00361387.     

Surfactant in airway disease

Beta(2)-adrenergic agonists cause a release of pulmonary surfactant into lung airways. The surfactant phospholipids maintain the patency of the conducting airways, but this function is inhibited by plasma proteins entering an inflamed airway. The physical behavior of the surfactant can be studied with a pulsating bubble surfactometer and a capillary surfactometer. Calf lung surfactant extract was found to be inhibited by plasma proteins and by a lowering of temperature. Severe breathing difficulties and malfunctioning surfactant developed in BALB/c mice inhaling ozone or infected with respiratory syncytial virus, mainly as a result of proteins invading the airways. Patients with asthma were challenged with allergens in an area of one lung. BAL fluid (BALF) from such an area contained a surfactant that functioned poorly (ie, an inability to maintain airway openness) compared with BALF from the other lung or from the lungs of healthy volunteers. When proteins in the BALF were removed, surfactant performance clearly improved. Eosinophils, so prominent in asthmatic patients, synthesize the enzyme lysophospholipase, which, together with the enzyme phospholipase A(2), catalyzes the hydrolysis of the main component of the surfactant, phosphatidylcholine. Such hydrolysis incapacitates the ability of the surfactant to maintain airway patency. The treatment of asthma with beta(2)-adrenergic agonists and steroids will have a valuable effect on the surfactant system. It will cause a release of fresh surfactant into terminal airways. Surfactant can also be nebulized and inhaled, which has been shown to be an effective treatment.     

Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure

BACKGROUND: Therapy with continuous positive airway pressure (CPAP) provides several benefits for patients with heart failure (HF) complicated by obstructive sleep apnea (OSA). However, the effect on the prognosis of such patients remains unknown. Aims: To determine whether CPAP therapy and compliance affects the prognosis of HF patients with OSA. METHODS: We classified 88 patients with HF and moderate-to-severe OSA into a CPAP-treated group (n = 65) and an untreated group (n = 23), and then those treated with CPAP were further subclassified according to CPAP therapy compliance. The frequency of death and hospitalization was analyzed using multivariate analysis. RESULTS: During a mean (+/- SD) period of 25.3 +/- 15.3 months, 44.3% of the patients died or were hospitalized. Multivariate analysis showed that the risk for death and hospitalization was increased in the untreated group (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.07 to 3.68; p = 0.030) and in less compliant CPAP-treated patients (HR, 4.02; 95% CI, 1.33 to 12.2; p = 0.014). CONCLUSION: Therapy with CPAP significantly reduced the risk of death and hospitalization among patients with HF and OSA. However, reduced compliance with CPAP therapy was significantly associated with an increased risk of death and hospitalization.     

Discrepant results between pyrazinamide susceptibility testing by the reference BACTEC 460TB method and pncA DNA sequencing in patients infected with multidrug-resistant W-Beijing Mycobacterium tuberculosis strains

BACKGROUND: Mycobacterium tuberculosis strains belonging to the W-Beijing family have received broad clinical and public health attention because of their rapid worldwide spread and their frequent association with outbreaks, multidrug resistance, and treatment failures and relapses. METHODS: The present study examined a large number of multidrug-resistant strain-W isolates (isolates of 29 patients) by susceptibility testing for pyrazinamide (PZA) using the reference BACTEC 460TB method (Becton Dickinson Diagnostic Instrument Systems; Sparks, MD) and also by DNA sequencing of the pncA gene. RESULTS: We found that despite of the presence of a strain W-specific Thr47Ala in the pncA gene, all strains showed susceptibility to PZA in the reference BACTEC 460TB system due to their higher minimum inhibitory concentrations (relative to BACTEC 460TB PZA-susceptible strains). CONCLUSIONS: Our results suggest that the current radiometric reference method cannot reproducibly detect PZA resistance in patients infected with W-Beijing strains. Therefore, PZA susceptibility testing should instead be based on analysis of the pncA gene for resistance-associated mutations.     

Panton-Valentine Leukocidin-positive methicillin-resistant Staphylococcus aureus lung infection in patients with cystic fibrosis

BACKGROUND: Panton-Valentine Leukocidin-expressing (PVL+) methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen worldwide causing fatal necrotizing pneumonias in otherwise healthy individuals but has not been described in patients with cystic fibrosis (CF). Following two cases of patients with CF admitted with lung abscesses in association with PVL+ MRSA, we examined the incidence and the clinical characteristics of MRSA acquisition in our CF patient population. METHODS: Newly acquired MRSA isolates from patients with CF followed up at St. Louis Children's Hospital were analyzed for the presence of Panton-Valentine leukocidin coding region, clindamycin susceptibility, staphylococcal cassette chromosome (SCC) mec type, and multilocus sequence type. Medical records and pulmonary function studies at the time of MRSA isolation were reviewed. RESULTS: MRSA isolates from 40 CF patients were available for analysis. Six children (15%) had PVL+ MRSA infection. All PVL+ organisms were clindamycin susceptible. Patients who acquired a PVL+ organism were more likely to have a focal pulmonary infiltrate on chest radiograph, including cavitary lung lesions in two patients (p = 0.04), a markedly greater decline in FEV1 at the time of MRSA detection (p = 0.01), and a significantly higher WBC count (p = 0.04) and absolute neutrophil count (p = 0.04). These patients were more likely to be admitted for IV antibiotic therapy for respiratory illnesses (p < 0.01). CONCLUSIONS: We describe the emergence of PVL+ MRSA in our CF population in association with development of invasive lung infections including lung abscesses. Early identification and treatment of CF patients with newly acquired PVL+ MRSA may be crucial.