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1.  Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device 
Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF) or non-CF bronchiectasis. Efficient drug administration via DPIs depends on the device resistance and adequate (≥45L/min) inspiratory flows and volumes generated by individuals. Drypowder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if non-CF bronchiectasis patients’ inspiratory flows and volumes are adequate to use the RS01 DPI device.
Materials and Methodology:
An open, non-interventional study; enrolled 17 subjects with non-CF bronchiectasis, 18 to 80 years, with baseline FEV1 ≥1.0L and ≥50‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer.
The mean inspiratory volume (IV) of non-CF bronchiectasis subjects was 2.08 ± 0.5L and achieved a mean PIF of 78.6 ± 11.2L/min with the inhaler device.
Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in non-CF bronchiectasis patients.
PMCID: PMC3933772  PMID: 24570764
Bronchiectasis; clinical trials; respiratory function tests; dry powder inhaler; high resistance inhaler; peak inspiratory flow.
2.  Inspiratory Flows and Volumes in Subjects with Cystic Fibrosis Using a New Dry Powder Inhaler Device 
Drug inhalation via a dry-powder inhaler (DPI) is a convenient, time efficient alternative to nebulizers in the treatment of cystic fibrosis (CF). Efficient drug administration via DPIs depends on the device resistance and adequate (≥ 45L/min) inspiratory flows and volumes generated by individuals. Dry-powder mannitol is delivered using a RS01 breath-actuated device developed by Plastiape, for Pharmaxis. The study aim was to determine in vivo if CF patients’ inspiratory flows and volumes are adequate to use the RS01 DPI device.
Materials and Methodology:
An open, non-interventional study; enrolled 25 CF subjects, aged ≥ 6 years with FEV1 ≥ 30 to < 90‰ predicted. Inspiratory flows and volumes were measured when subjects inhaled in a controlled manner through the RS01 device in series with a spirometer.
The mean inspiratory volume (IV) of CF subjects was 1.83L ± 0.97. Their achieved mean ± SD peak inspiratory flow (PIF) was 75.5 ± 27.2L/min. Twenty-three subjects (92%) achieved PIF of > 45L/min with the inhaler device; eighteen of those subjects (78%) had a baseline FEV1 of > 1L.
Use of the RS01 DPI device allowed adequate inspiratory flow and volume for dispersion of dry-powder mannitol in CF patients.
PMCID: PMC3933773  PMID: 24570763
Clinical trials; cystic fibrosis; respiratory function tests; dry powder inhaler; high resistance inhaler; peak inspiratory flow.
3.  Is Acute Exacerbation of COPD (AECOPD) Related to Viral Infection Associated with Subsequent Mortality or Exacerbation Rate? 
There is a growing interest in better defining risk factors associated with increased susceptibility to exacerbation in patients with COPD.
The aim of the study was to determine whether identification of a respiratory virus during a severe acute exacerbation of COPD (AECOPD) increases the risk of subsequent exacerbations and mortality during a one-year followup.
Secondary analysis of 86 COPD patients admitted for AECOPD between June 2007 and December 2008 at Geneva’s University Hospital who were followed up for 1 year. Fifty-one percent of index AECOPD were related to viral infection. Rate of AECOPD, time to next AECOPD, and all-cause mortality were compared between patients with vs without viral index AECOPD.
Eighty-one cases were included in this secondary follow-up analysis. Mean exacerbation rate was 1.9 AECOPD per person-year for patients with viral index AECOPD vs 4.0 AECOPD per person year for those with non-viral index AECOPD. Incidence rate ratio (IRR) for subsequent AECOPD during one year follow up was lower for patients with viral index AECOPD (IRR 0.57; [CI 95% 0.39-0.84]), after controlling for previous exacerbations, and was strongly associated with the number of exacerbations in the year preceding the index AECOPD. During the one-year follow-up period, 16 patients (19%) died. In a Cox regression model, patients with a proven viral infection did not have a higher mortality (HR 0.56 [CI 95% 0.20 -1.58]).
Viral AECOPD was not associated with a higher rate of subsequent exacerbations or mortality during the following year.
PMCID: PMC4009736  PMID: 24799967
COPD; exacerbation; phenotype; virus.
4.  Pleural Cholesterol to the Diagnosis of Exudative Effusion 
Diagnostic approaches to patients with a pleural effusion must be precise because many procedures depend on the nature of the fluid in the effusion. To date, no biochemical test is considered an appropriate alternative to Light’s criteria. This study compared the absolute pleural cholesterol (PC) level and the pleural cholesterol/serum cholesterol (PC/SC) ratio with Light’s criteria to determine exudative pleural effusions.
Materials and Methodology:
This study was a case series of 100 consecutive patients with pleural effusions. The clinical parameters that were used to diagnosis an exudative effusion included the cholesterol level, a pleural cholesterol level ≥ 50 mg/dL, a pleural/serum ratio ≥ 0.4, and Light’s criteria. The sensitivity, specificity, and positive and negative predictive values of each test for the diagnosis of an exudative effusion were assessed.
A total of 79 patients were definitively diagnosed with an exudative effusion and were included in the trial and analyzed. The mean PC level in the exudates was 90.39 mg/dL. The PC levels demonstrated a sensitivity of 97.22%, a specificity of 85.71%, a positive predictive value of 98.59% and a negative predictive value of 75%. The PC/SC ratio demonstrated a sensitivity of 81.48%, a specificity of 57.14%, a positive predictive value of 93.61% and a negative predictive value of 28.57%.
The pleural cholesterol dosage level and the pleural/serum cholesterol ratio can be utilized as unique biomarkers to identify an exudative effusion and replace Light’s criteria.
PMCID: PMC4009737  PMID: 24799966
Cholesterol; exudative effusion; pleural effusion.
5.  A Pilot Study on the Diagnostic Accuracy of Proadrenomedullin and Proatrial Natriuretic Peptide in Lower Respiratory Tract Infections  
Background :
Pneumonia is the leading cause of death among infectious diseases in developed countries. However, the severity of pneumonia requiring hospitalization often makes the initial diagnosis difficult because of an equivocal clinical picture or interpretation of the chest film. The objective of the present study was to assess the usefulness of the plasma levels of mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) in differentiating pneumonia from other lower respiratory tract infections (LRTIs).
Methods :
A retrospective study was conducted. The plasma levels of MR-proADM and MR-proANP were measured in 85 patients hospitalized for LRTIs, 56 of whom with diagnosis of pneumonia and 29 with other LRTIs.
Results :
The patients with pneumonia had increased MR-proADM levels (median 1.46 nmol/L [IQR 25-75, 0.82-2.02 nmol/L]) compared with the patients with other LRTIs (median 0.88 nmol/mL [0.71-1.39 nmol/L]) (p= 0.04). However, the MR-proANP levels did not show differences between the groups. The optimal threshold of MR-proADM to predict pneumonia was 1.5 nmol/L, which yielded a sensitivity of 51.7% (95% CI, 38.0-65.3), a 79.3% specificity (95% CI, 60.3-92.0), and an odds ratio of 6.64 (95% CI, 1.32-32.85). The combination of this parameter with C-reactive protein in an “and” rule increased the specificity for detecting pneumonia significantly.
Conclusion :
MR-proADM levels (but not MR-proANP levels) are increased in patients with pneumonia although its discriminatory power is moderate.
PMCID: PMC4110395  PMID: 25071872
Adrenomedullin; atrial natriuretic peptide; biomarkers; diagnosis; pneumonia.
6.  Associations and Outcomes of Septic Pulmonary Embolism 
Septic pulmonary embolism is a serious but uncommon syndrome posing diagnostic challenges because of its broad range of clinical presentation and etiologies.
To understand the clinical and radiographic associations of septic pulmonary embolism in patients presenting to an acute care safety net hospital.
We conducted a retrospective analysis of imaging and electronic health records of all patients diagnosed with septic pulmonary embolism in our hospital between January 2000 and January 2013.
41 episodes of septic pulmonary embolism were identified in 40 patients aged 17 to 71 years (median 46); 29 (72%) were men. Presenting symptoms included: febrile illness (85%); pulmonary complaints (66%) including pleuritic chest pain (22%), cough (19%) and dyspnea (15%); and those related to the peripheral foci of infection (24%) and shock (19%). Sources of infection included: skin and soft tissue (44%); infective endocarditis (27%); and infected peripheral deep venous thrombosis (17%). 35/41 (85%) were bacteremic with staphylococcus aureus. All patients had peripheral nodular lesions on chest CT scan. Treatment included intravenous antibiotics in all patients. Twenty six (63%) patients required pleural drainage and/or drainage of peripheral abscesses. Seven (17%) patients received systemic anticoagulants. Eight (20%) patients died due to various complications.
The epidemiology of septic pulmonary embolism has broadened over the past decade with an increase in identified extrapulmonary, non-cardiac sources. In the context of an extrapulmonary infection, clinical features of persistent fever, bacteremia and pulmonary complaints should raise suspicion for this syndrome, and typical findings on the chest CT scans confirm the diagnosis. Antibiotics, local drainage procedures and increasingly, anticoagulation are keys to successful outcomes.
PMCID: PMC4150379  PMID: 25184008
Endocarditis; Lemierre’s syndrome; lung infection; pulmonary embolism; septic thrombophlebitis; Staphylococcus.
7.  Self-Reported Sleep Bruxism and Nocturnal Gastroesophageal Reflux Disease in Patients with Obstructive Sleep Apnea: Relationship to Gender and Ethnicity§ 
Study Objectives :
Nocturnal bruxism is associated with gastroesophageal reflux disease (GERD), and GERD is strongly associated with obstructive sleep apnea (OSA). Gender and ethnic differences in the prevalence and clinical presentation of these often overlapping sleep disorders have not been well documented. Our aim was to examine the associations between, and the symptoms associated with, nocturnal GERD and sleep bruxism in patients with OSA, and to examine the influence of gender and ethnicity.
Methods :
A retrospective chart review was performed of patients diagnosed with OSA at an academic sleep center. The patients completed a sleep questionnaire prior to undergoing polysomnography. Patients with confirmed OSA were evaluated based on gender and ethnicity. Associations were determined between sleep bruxism and nocturnal GERD, and daytime sleepiness, insomnia, restless legs symptoms, and markers of OSA severity in each group.
Results :
In these patients with OSA, the prevalence of nocturnal GERD (35%) and sleep bruxism (26%) were higher than the general population. Sleep bruxism was more common in Caucasians than in African Americans or Hispanics; there was no gender difference. Nocturnal GERD was similar among all gender and ethnic groups. Bruxism was associated with nocturnal GERD in females, restless legs symptoms in all subjects and in males, sleepiness in African Americans, and insomnia in Hispanics. Nocturnal GERD was associated with sleepiness in males and African Americans, insomnia in females, and restless legs symptoms in females and in Caucasians.
Conclusion :
Patients with OSA commonly have comorbid sleep bruxism and nocturnal GERD, which may require separate treatment. Providers should be aware of differences in clinical presentation among different ethnic and gender groups.
PMCID: PMC4209499  PMID: 25352924
Gastroesophageal reflux; obstructive sleep apnea; sleep bruxism.
9.  Inhaled Corticosteroids and Bone Health 
Inhaled corticosteroids (ICS) are the cornerstones in the management of bronchial asthma and some cases of chronic obstructive pulmonary disease. Although ICS are claimed to have low side effect profiles, at high doses they can cause systemic adverse effects including bone diseases such as osteopenia, osteoporosis and osteonecrosis. Corticosteroids have detrimental effects on function and survival of osteoblasts and osteocytes, and with the prolongation of osteoclast survival, induce metabolic bone disease. Glucocorticoid-induced osteoporosis (GIO) can be associated with major complications such as vertebral and neck of femur fractures. The American College of Rheumatology (ACR) published criteria in 2010 for the management of GIO. ACR recommends bisphosphonates along with calcium and vitamin D supplements as the first-line agents for GIO management. ACR recommendations can be applied to manage patients on ICS with a high risk of developing metabolic bone disease. This review outlines the mechanisms and management of ICS-induced bone disease.
PMCID: PMC4319192
Bisphosphonate; bone mineral density (BMD); glucocorticoid-induced osteoporosis (GIO); ICS-induced bone disease; inhaled corticosteroids (ICS).
10.  The Effects of Inhaled Corticosteroids on Growth in Children  
Inhaled corticosteroids (ICS) are recommended as the first-line therapy for children with persistent asthma. These agents are particularly effective in reducing underlying airway inflammation, improving lung function, decreasing airway hyper-reactivity, and reducing intensity of symptoms in asthmatics. Chronic diseases, such as asthma, have growth-suppressing effects independent of the treatment, which inevitably complicates growth studies. One year studies showed a small, dose-dependent effect of most ICS on childhood growth, with some differences across various ICS molecules, and across individual children. Some ICS at the doses studied did not affect childhood growth when rigorous study designs were used. Most studies did not conform completely with the FDA guidance. The data on effects of childhood ICS use on final adult height are conflicting, but one recent well-designed study showed such an effect, clearly warranting additional studies. In spite of these measurable effects of ICS on childhood growth, it is important to understand that the safety profile of all ICS preparations, with focal anti-inflammatory effects on the lung, is significantly better than oral glucocorticoids.
PMCID: PMC4319193
Childhood asthma; inhaled Corticosteroids; linear growth.
11.  Inhalational Steroids and Iatrogenic Cushing’s Syndrome 
Bronchial asthma (BA) and Allergic rhinitis (AR) are common clinical problems encountered in day to day practice, where inhalational corticosteroids (ICS) or intranasal steroids (INS) are the mainstay of treatment. Iatrogenic Cushing syndrome (CS) is a well known complication of systemic steroid administration. ICS /INS were earlier thought to be safe, but now more and more number of case reports of Iatrogenic Cushing syndrome have been reported, especially in those who are taking cytochrome P450 (CYP 450) inhibitors. Comparing to the classical clinical features of spontaneous Cushing syndrome, iatrogenic Cushing syndrome is more commonly associated with osteoporosis, increase in intra-ocular pressure, benign intracranial hypertension, aseptic necrosis of femoral head and pancreatitis, where as hypertension, hirsuitisum and menstrual irregularities are less common. Endocrine work up shows low serum cortisol level with evidence of HPA (hypothalamo-pituitary-adrenal) axis suppression. In all patients with features of Cushing syndrome with evidence of adrenal suppression always suspect iatrogenic CS. Since concomitant administration of cytochrome P450 inhibitors in patients on ICS/INS can precipitate iatrogenic CS, avoidance of CYP450 inhibitors, its dose reduction or substitution of ICS are the available options. Along with those, measures to prevent the precipitation of adrenal crisis has to be taken. An update on ICS-/INS- associated iatrogenic CS and its management is presented here.
PMCID: PMC4319196
Allergic rhinitis (AR); bronchial asthma (BA); chronic obstructive pulmonary disease (COPD); Cushing syndrome (CS); HPA (hypothalamo-pituitary-adrenal) axis; inhalational corticosteroids (ICS); intranasal steroids (INS).
12.  Systemic Effects of Inhaled Corticosteroids: An Overview 
Inhaled corticosteroids (ICS) are common medications, used in respiratory medicine for controlling conditions such as asthma and other obstructive airway diseases. The systemic effects of oral corticosteroids are well known and established; inhaled steroids have been known to cause relatively minor and localized adverse effects such as oral candidiasis. However, less attention has been paid to their systemic effects. Although currently there is a paucity of prospective studies demonstrating the systemic effects of inhaled corticosteroids, there are numerous retrospective studies adding evidence to this link. Inhaled corticosteroids can affect the hypothalamo-pituitary-adrenal axis, bone density and growth, eyes, skin and immunity including an increased risk of pneumonia. Clinicians are recommended to aim for the lowest possible dose to avoid these systemic side effects. Fluticasone is more likely to cause systemic effects compared to budesonide. Newer ICS molecules such as ciclesonide may be more beneficial in reducing such systemic complications on prolonged use. This paper provides an updated overview of the common systemic effects encountered with ICS treatment.
PMCID: PMC4319197
Asthma; chronic obstructive pulmonary disease (COPD); diabetes progression; hypothalamo-pituitary-adrenal axis; inhaled corticosteroids (ICS); systemic adverse effects.
13.  Effect of Inhaled Corticosteroids on Glycemic Status 
Although the dysglycemic effects of systemic glucocorticoid therapy are well known, the effect of inhaled corticosteroids (ICS) on carbohydrate metabolism is still a subject of debate. The systemic bioavailability of ICS is claimed to be minimal and the side effects negligible. However, some large retrospective cohort studies showed a definite association between ICS use and incident diabetes or worsening glycemic control in pre-existing diabetes. There are no professional-body recommended guidelines on the diagnosis and management of steroid-induced diabetes for the general population. This review aims to evaluate the systemic dysglycemic effect of ICS treatment and to propose a management algorithm.
PMCID: PMC4319206
Diabetes control; diabetes mellitus; dysglycemic status; hyperglycemia; inhaled corticosteroids (ICS); steroid-induced diabetes.
14.  Inhaled Corticosteroids and Secondary Adrenal Insufficiency 
Inhaled corticosteroids (ICS) have been used as first line treatment of asthma for many decades. ICS are a form of exogenous glucocorticosteroids that can suppress the endogenous production of glucocorticosteroids, a condition known as adrenal suppression (AS). As a result, cessation, decreasing the dose or changing the type of ICS may trigger features of adrenal insufficiency (AI). AI may cause a spectrum of presentations varying from vague symptoms of fatigue to potentially life threatening acute adrenal crises. This article reviews the current literature on ICS and AI particularly in adults (although majority of data available is from the paediatric population). It aims to increase awareness of the potential risk of AI associated with ICS use, delineate the pathogenesis of AI and to provide recommendations on screening and management. From our literature review, we have found numerous case reports that have shown an association between ICS and AI particularly in children and patients using high doses. However, there have also been reports of AI in adults as well as in patients using low to moderate doses of ICS. To conclude, we recommend screening for AI in select patient groups with an initial early morning serum cortisol. If results are abnormal, more definitive testing such as the low dose corticotropin stimulation test may be done to confirm the diagnosis.
PMCID: PMC4319207
Adrenal insufficiency; adrenal suppression; inhaled corticosteroids.
15.  Use of the Breathlessness, Cough, and Sputum Scale (BCSS©) in Pulmonary Rehabilitation§ 
In pulmonary rehabilitation (PR) effective measures have been taken while in analyzing a patient’s intervention with the help of entry to exit evaluations. The absence of an objective and quantifiable scale are limitations of PR that allow analyzing of a patient’s self reported symptoms throughout PR. The Breathlessness, Cough and Sputum Scale (BCSS©) is used to predict patient exacerbations by evaluating common symptoms identified in the COPD population. This study used the BCSS© survey to track complex symptom changes throughout the course of PR intervention. The BCSS© tool measured the patient’s self reported symptoms in real time for each visit when patient enrolled in PR.
Thirty-five patients with COPD from three outpatient PR centers were asked to report the severity of breathlessness, cough, and sputum prior to each PR session using the BCSS© survey.
There was a significant decrease in self reported symptoms of the mean BCSS© score from entry 4.6(± 2.9) to exit 2.3 (± 2.5), p < 0.001. The results showed variable decrease in the self reported symptoms with more PR visits. The secondary outcome showed high correlations with quality of life measures using the Pulmonary Function Status Scale (PFSS) on entry and exit to PR.
The BCSS© tool is an effective means for measuring the impact of PR on improving patient tolerance and self-reported symptoms as a result of COPD. More research is needed to better assess the complex symptoms of COPD patients in PR to enhance programmatic outcomes.
PMCID: PMC3594703  PMID: 23494521
Rehabilitation; quality of life; dyspnea; cough; sputum.
16.  Hypercapnia Accelerates Wound Healing in Endothelial Cell Monolayers Exposed to Hypoxia  
While tissue hypoxia is known to play a critical role in the process of vascular injury and repair, the effect of hypercapnia on this process remains uncertain. We investigated whether hypercapnia might influence endothelial cell wound healing under the influence of hypoxia.
Materials and Methodology:
Monolayers of human umbilical venous endothelial cells (HUVECs) were scratch-wounded and incubated under different levels of O2, CO2, and pH in the environment.
Inhibition of wound healing was observed in the HUVEC monolayers under the hypoxic condition as compared to the normoxic condition. Both hypercapnic acidosis and buffered hypercapnia, but not normocapnic acidosis improved the rate of wound healing under the influence of hypoxia. The beneficial effect of hypercapnia was associated with stimulation of cell proliferation, without effects on cell adhesion, migration or apoptosis. On the other hand, the stimulatory effect of hypercapnia on wound healing and cell proliferation was not noted under normoxic conditions.
These results suggest that hypercapnia, rather than acidosis per se, accelerated the wound healing in HUVEC monolayers cultured under hypoxic conditions. The effect of hypercapnia on wound healing was due, at least in part, to the stimulation of cell proliferation by hypercapnia.
PMCID: PMC3601342  PMID: 23524473
Endothelial cell; hypoxia; hypercapnia; acidosis; wound healing.
17.  Monoclonal Anti-TNF-α Antibodies for Severe Steroid-Dependent Asthma: A Case Series 
Refractory asthma represents an important condition, with considerable morbidity and mortality. Tumor necrosis factor α (TNF-α) is a potential target for treatment of severe asthma. However, controlled studies have shown controversial results and the risk-benefit profile of TNF-blocking agents is still debated.
To describe the effect of infliximab on asthma control in patients with severe, uncontrolled, steroid-dependent asthma.
From 2007 to 2010, 7 patients received infliximab in our center. All had severe refractory asthma, with frequent severe exacerbations and hospitalizations in the intensive care unit despite maximal inhaled treatment, daily oral steroids and omalizumab treatment.
Asthma control improved in the 6 patients who received infliximab for at least 3 months. Oral steroids could be stopped in 4 and the frequency of exacerbations and hospitalizations was greatly reduced, especially for the 3 patients with brittle asthma. Two patients showed severe adverse effects (bacterial pneumonia and extension of spreading melanoma). Three patients have received infliximab for more than 2 years, with good tolerance.
This case series suggests that anti-TNF-α drugs may improve the condition of a subgroup of patients with severe steroid-refractory asthma, with a favourable risk-benefit profile for most, considering asthma severity, occurrence of life-threatening exacerbations and complications of long-term oral steroids. Specific controlled trials of this subgroup are warranted.
PMCID: PMC3601337  PMID: 23526476
TNF-α; severe refractory asthma; anti-TNF-α drug; brittle asthma.
18.  Tigecycline Versus Levofloxacin in Hospitalized Patients With Community-Acquired Pneumonia: An Analysis of Risk Factors  
This study was conducted to evaluate the efficacy of tigecycline (TGC) versus levofloxacin (LEV) in hospitalized patients with community-acquired pneumonia (CAP) using pooled data and to perform exploratory analyses of risk factors associated with poor outcome.
Materials and Methodology:
Pooled analyses of 2 phase 3 studies in patients randomized to intravenous (IV) TGC (100 mg, then 50 mg q12h) or IV LEV (500 mg q24h or q12h). Clinical responses at test of cure visit for the clinically evaluable (CE) and clinical modified intention to treat populations were assessed for patients with risk factors including aged ≥65 years, prior antibiotic failure, bacteremia, multilobar disease, chronic obstructive pulmonary disease, alcohol abuse, altered mental status, hypoxemia, renal insufficiency, diabetes mellitus, white blood cell count >30 x 109/L or <4 x 109/L, CURB-65 score ≥2, Fine score category of III to V and at least 2 clinical instability criteria on physical examination.
In the CE population of 574 patients, overall cure rates were similar: TGC (253/282, 89.7%); LEV (252/292, 86.3%). For all but one risk factor, cure rates for TGC were similar to or higher than those for LEV. For individual risk factors, the greatest difference between treatment groups was observed in patients with diabetes mellitus (difference of 22.9 for TGC versus LEV; 95% confidence interval, 4.8 - 39.9).
TGC achieved cure rates similar to those of LEV in hospitalized patients with CAP. For patients with risk factors, TGC provided generally favorable clinical outcomes.
PMCID: PMC3601338  PMID: 23526572
Community-acquired pneumonia;  glycylcycline; risk factors; tigecycline.
19.  Content Validity of the Comprehensive ICF Core Set for Chronic Obstructive Pulmonary Diseases: An International Delphi Survey  
The “Comprehensive ICF Core Set for Chronic Obstructive Pulmonary Diseases (COPD)“ is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in functioning of patients with COPD. The objective of this study was to validate this ICF Core Set from the perspective of physicians.
Materials and Methodology:
Physicians experienced in COPD treatment were asked about the patients’ problems treated by physicians in patients with COPD in a three-round electronic mail survey using the Delphi technique. Responses were linked to the ICF.
Seventy-six physicians in 44 countries gave a total of 1330 responses that were linked to 148 different ICF categories. Nine ICF categories were not represented in the Comprehensive ICF Core Set for COPD although at least 75% of the participants have rated them as important. Nineteen concepts were linked to the not yet developed ICF component personal factors and seventeen concepts were not covered by the ICF.
The high percentage of ICF categories represented in the ICF Core Set for COPD indicates satisfactory content validity from the perspective of the physicians. However, some issues were raised that were not covered and need to be investigated further.
PMCID: PMC3636487  PMID: 23730367
Chronic obstructive pulmonary disease; asthma; rehabilitation; international classification of functioning; disability and health; ICF core set.
20.  In Vivo Assessment of Pulmonary Arterial Wall Fibrosis by Intravascular Optical Coherence Tomography in Pulmonary Arterial Hypertension: A New Prognostic Marker of Adverse Clinical Follow-Up§ 
The aim is to correlate pulmonary arterial (PA) remodeling estimated by PA fibrosis in PA hypertension (PAH) with clinical follow-up. Histology of PA specimens is also performed.
19 patients, aged 54±16 (4 men), functional class II-III were studied with right heart catheterization, PA Intravascular Ultrasound and optical coherence tomography (OCT) in inferior lobe segment. PA wall fibrosis was obtained by OCT ( area of fibrosis/PA cross sectional area × 100). Patients follow-up was blind to OCT. Events were defined as mortality, lung transplantation, need of intravenous prostaglandins or onset of right ventricular failure.
OCT measurements showed high intra- and interobserver agreement. There was a good correlation between OCT and histology in PA fibrosis from explanted lungs. Area of fibrosis was 1.4±0.8 mm2, % fibrosis was 22.3±8. Follow-up was 3.5 years (2.5-4.5). OCT %Fib was significantly correlated with PA capacitance (r=-0.536) and with pulmonary vascular rsistance (r=0.55). Patients were divided according to the median value of PA fibrosis. There were 10 patients with a high (≥ 22%) and 9 with a low fibrosis (<22%). Events occurred in 6 (1 death, 1 lung transplantation, 2 intravenous prostaglandins, 2 right heart failure) out of 10 patients with high and in 0 out of 9 patients with low fibrosis (p<0.01).
In PAH, the severity of PA remodeling assessed by OCT wall fibrosis was significantly predictive of severely unfavorable clinical outcome. In vivo assessment of pulmonary arterial wall fibrosis by intravascular OCT in PAH is a promising new prognostic marker of adverse clinical outcome.
PMCID: PMC3636492  PMID: 23730366
Catheterization; pulmonary heart disease; prognosis; remodeling.
21.  Adult Rat Bone Marrow-Derived Stem Cells Promote Late Fetal Type II Cell Differentiation in a Co-Culture Model  
Bronchopulmonary dysplasia develops in preterm infants due to a combination of lung immaturity and lung injury. Cultured pluripotent bone marrow stem cells (BMSC) are known to reduce injury and induce repair in adult and in immature lungs, possibly through paracrine secretion of soluble factors. The paracrine relationship between BMSC and primary fetal lung epithelial type II cells is unknown. We determined the effects of BMSC on type II cell and fibroblast behavior using an in vitro co-culture model. Rat BMSC were isolated and co-cultured with primary fetal E21 rat type II cells or lung fibroblasts in a Transwell® system without direct cell contact. Effects of BMSC conditioned media (CM) on type II cell and fibroblast proliferation and on type II cell surfactant phospholipid (DSPC) synthesis and mRNA expression of surfactant proteins B and C (sftpb and sftpc) were studied. We also determined the effect of fibroblast and type II cell CM on BMSC proliferation and surface marker expression. Co-culture with BMSC significantly decreased type II cell and fibroblast proliferation to 72.5% and 83.7% of controls, respectively. Type II cell DSPC synthesis was significantly increased by 21% and sftpb and sftpc mRNA expressions were significantly induced (2.1 fold and 2.4 fold, respectively). BMSC proliferation was significantly reduced during the co-culture. Flow cytometry confirmed that BMSC retained the expression of undifferentiated stem cell markers despite their exposure to fetal lung cell CM. We conclude that BMSC induce fetal type II cell differentiation through paracrine release of soluble factors. These studies provide clues for how BMSC may act in promoting alveolar repair following injury.
PMCID: PMC3664445  PMID: 23730368
Lung development; surfactant; proliferation; co-culture; lung fibroblasts.
22.  Decreased Exhaled Nitric Oxide Levels in Patients with Mitochondrial Disorders  
Nitric oxide (NO) deficiency may occur in mitochondrial disorders (MD) and can contribute to the pathogenesis of the disease. It is difficult and invasive to measure systemic nitric oxide. NO is formed in the lungs and can be detected in expired air. Currently, hand-held fractional exhaled nitric oxide (FeNO) measurement devices are available enabling a fast in-office analysis of this non-invasive test. It was postulated that FeNO levels might be reduced in MD.
Sixteen subjects with definite MD by modified Walker criteria (4 to 30 years of age) and sixteen healthy control subjects of similar age, race and body mass index (BMI) underwent measurement of FeNO in accordance with the American Thoracic Society guidelines.
Sixteen patient-control pairs were recruited. The median FeNO level was 6.5 ppm (IQR: 4-9.5) and 10.5 ppm (IQR: 8-20.5) in the MD and control groups, respectively. In 13 pairs (81%), the FeNO levels were lower in the MD cases than in the matched controls (p=0.021). Eleven (69%) cases had very low FeNO levels (≤7ppm) compared to only 1 control (p=0.001). All cases with enzymatic deficiencies in complex I had FeNO ≤7ppm.
Single-breath exhaled nitric oxide recordings were decreased in patients with MD. This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of MD. In addition, measurement of FeNO could be used as a parameter to monitor therapeutic response in this population.
PMCID: PMC3735920  PMID: 23935767
Mitochondrial disorder; exhaled nitric oxide; FeNO; walker criteria; modified walker criteria; NIOX MINO.
23.  Impact of Blood Cultures on the Changes of Treatment in Hospitalized Patients with Community-Acquired Pneumonia  
Initial blood cultures (BCs) with severe community-acquired pneumonia (CAP) are warranted. However, other than severity, the specific contributing factors that affect the decision to change antimicrobial agents have not been evaluated previously.
Consecutive adults with CAP hospitalized between January 2008 and December 2010 were assessed retrospectively. We enrolled those who were over 18 years old with typical symptoms of pneumonia and with an infiltrate consistent with pneumonia, from which 2 sets of BCs were obtained. Those who had been immunocompromised, hospitalized, or prescribed antibiotics in the past 30 days were excluded. We retrospectively assessed the factors contributing to the change in antimicrobial agents as well as the frequency of these changes in the enrolled patients based on the initial BC results.
In total, 793 patients with initial diagnosis of CAP were admitted; 399 met the inclusion criteria. Among them, 386 were made definitive diagnosis of CAP after admission (the remaining 13 were made alternative diagnosis [non-pneumonia illnesses]). BC results were positive in 17 (4.4%) out of 386 CAP patients, among whom antimicrobial therapy was changed based on the BC results in 8 (2.1%) (Pneumonia Severity Index [PSI] grade IV; 2, PSI grade V; 6). Alternative diagnosis after admission was contributing factors for changing antimicrobial agents based on the positive blood culture results.
The use of BCs should be limited to patients with very severe cases. It would be helpful to find alternative diagnosis and modify treatment.
PMCID: PMC3735926  PMID: 23935766
Blood cultures; community-acquired pneumonia; antimicrobial agents.
24.  Computed Tomography-Based Centrilobular Emphysema Subtypes Relate with Pulmonary Function  
Centrilobular emphysema (CLE) is recognized as low attenuation areas (LAA) with centrilobular pattern on high-resolution computed tomography (CT). However, several shapes of LAA are observed. Our preliminary study showed three types of LAA in CLE by CT-pathologic correlations. This study was performed to investigate whether the morphological features of LAA affect pulmonary functions.
Materials and Methods:
A total of 73 Japanese patients with stable CLE (63 males, 10 females) were evaluated visually by CT and classified into three subtypes based on the morphology of LAA including shape and sharpness of border; patients with CLE who shows round or oval LAA with well-defined border (Subtype A), polygonal or irregular-shaped LAA with ill-defined border (Subtype B), and irregular-shaped LAA with ill-defined border coalesced with each other (Subtype C). CT score, pulmonary function test and smoking index were compared among three subtypes.
Twenty (27%), 45 (62%) and 8 cases (11%) of the patients were grouped into Subtype A, Subtype B and Subtype C, respectively. In CT score and smoking index, both Subtype B and Subtype C were significantly higher than Subtype A. In FEV1%, Subtype C was significantly lower than both Subtype A and Subtype B. In diffusing capacity of lung for carbon monoxide, Subtype B was significantly lower than Subtype A.
The morphological differences of LAA may relate with an airflow limitation and alveolar diffusing capacity. To assess morphological features of LAA may be helpful for the expectation of respiratory function.
PMCID: PMC3735927  PMID: 23935765
Centrilobular emphysema; subtype; pulmonary function test; CT.
25.  Obstructive Sleep Apnea and Metabolic Syndrome in Spanish Population 
Obstructive sleep apnea (OSA) is a clinical picture characterized by repeated episodes of obstruction of the upper airway. OSA is associated with cardiovascular risk factors, some of which are components of metabolic syndrome (MS).
First, determine the prevalence of MS in patients with OSA visited in sleep clinic. Second, evaluate whether there is an independent association between MS components and the severity of OSA.
Patients with clinical suspicion of OSA were evaluated by polysomnography. Three groups were defined according to apnea hypoapnea index (AHI): no OSA (AHI <5), mild-moderate (AHI≥ 5 ≤30), and severe (AHI> 30). All patients were determined in fasting blood glucose, total cholesterol, HDL cholesterol, triglycerides and insulin. MS was defined according to criteria of National Cholesterol Education Program (NCEP).
A total of 141 patients (mean age 54 ± 11 years) were evaluated. According to AIH, 25 subjects had no OSA and 116 had OSA (41mild-moderate and 75 severe). MS prevalence ranged from 43-81% in OSA group. Also, a significant increase in waist circumference, triglycerides, glucose, blood pressure levels, and a decrease in HDL cholesterol levels was observed in more severe OSA patients. All polysomnographic parameters correlated significantly with metabolic abnormalities. After a multiple regression analysis, abdominal obesity (p <0.02), glucose (p <0.01) and HDL cholesterol (p <0.001) were independently associated with OSA.
Our findings show high prevalence of MS in OSA, especially in severe group. A significant association between OSA and some of the components of MS was found in Spanish population.
PMCID: PMC3822706  PMID: 24222804
Obstructive sleep apnea; metabolic syndrome; HDL cholesterol; insulin resistance.

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