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The role for direct assessment of small airway function in subjects with respiratory symptoms but normal airflow by spirometry is discussed. Small airway disease syndrome is described in numerous disease states using a multidisciplinary approach. Data demonstrate that small airway disease is related to presence of respiratory symptoms, exposure to inhaled toxins, presence of local and systemic inflammation, and presence of histologic abnormalities within the distal lung. Investigation of immunological derangements associated with distal airway dysfunction in the setting of normal spirometry may provide insight into pathophysiological mechanisms that are present at disease onset. For the purposes of this symposium, data were reviewed in selected clinical conditions (obesity, environmental inhalational injury, and cigarette smoking) that have been recently studied in the André Cournand Pulmonary Physiology Laboratory at Bellevue Hospital using the forced oscillation technique.

Objective: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities., Methods: Morquio A patients aged ≥7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined)., Results: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO 2 ), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O 2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O 2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO 2 /work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost., Conclusions: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.

Objectives: We studied the course of lower respiratory symptoms (LRS; cough, wheeze or dyspnoea) among community members exposed to the 9/11/2001 World Trade Center (WTC) attacks during a period of 12-13 years following the attacks, and evaluated risk factors for LRS persistence, including peripheral airway dysfunction and post-traumatic stress disorder (PTSD)., Methods: Non-smoking adult participants in a case-control study of post-9/11-onset LRS (exam 1, 2008-2010) were recruited for follow-up (exam 2, 2013-2014). Peripheral airway function was assessed with impulse oscillometry measures of R 5 and R 5-20 . Probable PTSD was a PTSD checklist score ≥ 44 on a 2006-2007 questionnaire., Results: Of 785 exam 1 participants, 545 (69%) completed exam 2. Most (321, 59%) were asymptomatic at all assessments. Among 192 participants with initial LRS, symptoms resolved for 110 (57%) by exam 2, 55 (29%) had persistent LRS and 27 (14%) had other patterns. The proportion with normal spirometry increased from 65% at exam 1 to 85% at exam 2 in the persistent LRS group (p<0.01) and was stable among asymptomatic participants and those with resolved LRS. By exam 2, spirometry results did not differ across symptom groups; however, R 5 and R 5-20 abnormalities were more common among participants with persistent LRS (56% and 46%, respectively) than among participants with resolved LRS (30%, p<0.01; 27%, p=0.03) or asymptomatic participants (20%, p<0.001; 8.2%, p<0.001). PTSD, R 5 at exam 1, and R 5-20 at exam 1 were each independently associated with persistent LRS., Conclusions: Peripheral airway dysfunction and PTSD may contribute to LRS persistence. Assessment of peripheral airway function detected pulmonary damage not evident on spirometry. Mental and physical healthcare for survivors of complex environmental disasters should be coordinated carefully., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Paresthesias can result from metabolic disorders, nerve entrapment following repetitive motions, hyperventilation pursuant to anxiety, or exposure to neurotoxins. We analyzed data from community members exposed to the World Trade Center (WTC) disaster of September 11, 2001, to evaluate whether exposure to the disaster was associated with paresthesias., Methods: Analysis of data from 3141 patients of the WTC Environmental Health Center., Results: Fifty-six percent of patients reported paresthesias at enrollment 7 to 15 years following the WTC disaster. After controlling for potential confounders, paresthesias were associated with severity of exposure to the WTC dust cloud and working in a job requiring cleaning of WTC dust., Conclusions: This study suggests that paresthesias were commonly associated with WTC-related exposures or post-WTC cleaning work. Further studies should objectively characterize these paresthesias and seek to identify relevant neurotoxins or paresthesia-inducing activities.

Efficacy and safety of elosulfase alfa enzyme replacement therapy (ERT) were assessed in an open-label, phase 2, multi-national study in Morquio A patients aged ≥5 years unable to walk ≥30 meters in the 6-min walk test. Patients received elosulfase alfa 2.0 mg/kg/week intravenously for 48 weeks. Efficacy measures were functional dexterity, pinch/grip strength, mobility in a modified timed 25-foot walk, pain, quality of life, respiratory function, and urine keratan sulfate (KS). Safety/tolerability was also assessed. Fifteen patients received elosulfase alfa, three patients discontinued ERT due to adverse events (two were grade 3 drug-related adverse events, the other was not drug-related), and two patients missed >20% of planned infusions; 10 completed treatment through 48 weeks and received ≥80% of planned infusions (Modified Per Protocol [MPP] population). The study population had more advanced disease than that enrolled in other trials. From baseline to week 48, MPP data showed biochemical efficacy (urine KS decreased 52.4%). The remaining efficacy results were highly variable due to challenges in test execution because of severe skeletal and joint abnormalities, small sample sizes, and clinical heterogeneity among patients. Eight patients showed improvements in one or more outcome measures; several patients indicated improvements not captured by the study assessments (e.g., increased energy, functional ability). The nature of adverse events was similar to other elosulfase alfa studies. This study illustrates the considerable challenges in objectively measuring impact of ERT in very disabled Morquio A patients and highlights the need to examine results on an individual basis. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc., (© 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.)

Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz ( R 5 ). Parameters reflecting distal lung function included frequency dependence of resistance ( R 5-20 ) and dynamic elastance ( X 5 ). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R 5 . Nine smokers had elevated R 5 with abnormal R 5-20 and X 5 , indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R 5-20 and X 5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD., Competing Interests: can be found alongside this article at openres.ersjournals.com

Objective: To present long-term respiratory function outcomes from an open-label, multi-center, phase 3 extension study (MOR-005) of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio A syndrome., Methods: In part 1 of MOR-005, patients initially randomized to ERT in the 24-week pivotal study (MOR-004) remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two regimens. During part 2, all patients received elosulfase alfa 2.0 mg/kg/week. Respiratory function was one of the efficacy endpoints evaluated in MOR-005. Change from MOR-004 baseline to 120 weeks of treatment for the combined population was determined and compared with results from untreated patients from a Morquio A natural history study (MorCAP)., Results: Maximum voluntary ventilation (MVV) improved up to week 72 and then stabilized; forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1 ) increased continuously over 120 weeks. Mean increases in the modified per-protocol population was 9.2 % for FVC, 8.8 % for FEV 1 , and 6.1 % for MVV after 120 weeks. All patients ≤14 years showed respiratory improvements, presumably in part related to growth; however, these were greater in treated patients. For those >14 years, treated patients showed improvements, while deterioration occurred in untreated. Altogether, the improvements were significantly greater (P < 0.05) in treated patients., Conclusions: Long-term ERT is associated with sustained improvements in respiratory function in Morquio A. In younger patients (≤14 years), some improvement may be ascribed to growth. In older patients, other mechanisms, e.g., decreased glycosaminoglycan storage, are likely involved., Competing Interests: Compliance with ethics standards Competing interest C J Hendriksz has received consulting fees and travel support from BioMarin Pharmaceutical Inc., Alexion, Actelion, Amicus, Genzyme, and Shire; K I Berger has received consulting fees from BioMarin Pharmaceutical Inc., Teva, Vertex, Sarepta and Genzyme; R Parini has received travel grants and honoraria for scientific presentations or advisory boards from BioMarin Pharmaceutical Inc., Shire and Genzyme; M AlSayed has received honorarium and travel reimbursement from BioMarin Pharmaceutical Inc., Shire, and Genzyme; J Raiman has received travel support and speakers fees from BioMarin, Shire, Genzyme and Actelion; R Giugliani has received investigator fees, travel grants, and speaker honoraria from BioMarin Pharmaceutical, Inc.; J J Mitchell has received consulting fees and travel reimbursement from BioMarin Pharmaceutical Inc. and Genzyme and honoraria from BioMarin Pharmaceutical Inc. and Shire; B K Burton has received royalties from McGraw-Hill and clinical trial funding, consulting fees and/or honoraria from BioMarin Pharmaceutical Inc., Shire, Genzyme, Horizon Pharma, Alexion, ReGenX Bio, Armagen, and Cytonet; N Guelbert has received honorarium and travel reimbursement from Biomarin Pharmaceutical Inc., Shire and Genzyme; F Stewart has received honorarium and travel reimbursement from BioMarin Pharmaceutical Inc., Shire, and Genzyme; D A Hughes has received travel grants and honoraria for advisory boards from BioMarin Pharmaceutical Inc.; R Matousek, E Jurecki, and C Decker are employees of BioMarin Pharmaceutical Inc.; P R Harmatz has provided consulting support to BioMarin Pharmaceutical Inc., received research grants, participated in advisory panels, and received speaker honorarium from BioMarin Pharmaceutical Inc. He has also received clinical trial funding, consulting fees and/or honoraria from Armagen, Shire, Genzyme, Enobia (now Alexion), ReGenX Bio, Ciesi, PTC, and Inventiva. Details of funding This study and support in the process of manuscript development were funded by BioMarin Pharmaceutical Inc. The site in Monza (Dr. Parini) received continuous economical support to the clinical work of the Center from Fondazione Pierfranco and Luisa Mariani. This publication was supported in part (Dr. Harmatz) by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI Grant Number UL1 TR000004. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2-4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Small airway dysfunction occurs following WTC dust exposure, but its role in producing symptoms is unclear., Methods: Methacholine challenge (MCT) was used to assess the relationship between onset of respiratory symptoms and small airway abnormalities in 166 symptomatic WTC dust-exposed patients. Forced oscillation testing (FOT) and respiratory symptoms were assessed during MCT. FOT parameters included resistance at 5 and 20 Hz (R5 and R20 ) and the R5 minus R20 (R5-20 )., Results: Baseline spirometry was normal in all (mean FEV1 100 + 13% predicted, mean FEV1 /FVC 80 + 4%). MCT revealed bronchial hyperreactivity by spirometry in 67 patients. An additional 24 patients became symptomatic despite minimal FEV1 change (<5%); symptom onset coincided with increased R5 and R5-20 (P > 0.001 vs. baseline). The dose-response of FOT (reactivity) was greater compared with subjects that remained asymptomatic (P < 0.05)., Conclusions: FOT during MCT uncovered reactivity in small airways as a mechanism for respiratory symptoms in subjects with inhalational lung injury. Am. J. Ind. Med. 59:767-776, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N=173), analyses were also performed for a modified per-protocol (MPP) population (N=124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3)m and 39.9 (10.1)m for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study (N=56) and 15.1 (7.1)m and 31.7 (6.8)m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0)stairs/min for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3)stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was -59.4 (1.8)% and -62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P<0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The mucopolysaccharidoses (MPS) comprise a heterogeneous family of rare, genetic lysosomal storage disorders that result in severe morbidity and reduced life expectancy. Emerging treatments for several of these disorders have triggered the search for clinically relevant biomarkers and clinical markers associated with treatment efficacy in populations and individuals. However, biomedical measures do not tell the whole story when characterizing a complex chronic disorder such as MPS. Health-related quality of life (HRQoL) tools that utilize patient reported outcomes to address patient parameters such as symptoms (pain, fatigue, psychological health), functioning (activity and limitations), or quality of life, have been used to supplement traditional biomedical endpoints. Many of these HRQoL tools have demonstrated that quality of life is negatively impacted in patients with MPS. There is both the opportunity and need to formally standardize and validate HRQoL tools for the different MPS disorders.

To identify determinants of respiratory disease progression in late-onset Pompe disease (LOPD), we studied relationships between pulmonary function, respiratory muscle strength, gas exchange, and respiratory control. Longitudinal evaluation of 22 LOPD patients (mean age 38 years) was performed at 6-month intervals for 6-24 months. Measurements included vital capacity (VC), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), tidal volume (VT), dead space (VD), and ventilatory response to CO2. Although reduction in VC correlated with MIP and MEP (p < 0.0001), some patients had normal VC despite reduced MIP and MEP (5 [23%] and 9 [41%] patients, respectively). Daytime hypercapnia was associated with reduced VC (<60% predicted) and MIP (<40% predicted). Moreover, chronic hypercapnia was associated with elevated VD/VT (≥0.44) due to falling VT (≈300 ml), compatible with reduced efficiency of CO2 clearance. The presence of hypercapnia and/or ventilatory support was associated with reduced ventilatory responsiveness to CO2 (≤0.7 l/min/mmHg). We conclude that daytime hypercapnia, an indicator of chronic respiratory failure, is tightly linked to the degree of respiratory muscle weakness and severity of pulmonary dysfunction in LOPD patients. Reductions in CO2 clearance efficiency and ventilatory responsiveness may contribute to the development of chronic daytime hypercapnia., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale: Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways., Objectives: We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response., Methods: 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC., Measurements and Main Results: Mean age was 45±12 years; mean BMI was 44.8±7 kg/m2. Vital capacity was 88±13% predicted with reduction in functional residual capacity (58±12% predicted). Despite normal DLCO (98±18% predicted), VC was elevated (135±31% predicted) while DM averaged 94±22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity., Conclusions: Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the structure of the alveolar capillary membrane may be considered often unrecognized causes of airway dysfunction in obesity.

In patients with Late-Onset Pompe Disease (LOPD), progressive respiratory muscle involvement leads to reduced pulmonary function, with respiratory failure the most common cause of mortality. Early disease manifestations include sleep-disordered breathing, which can be treated with non-invasive ventilation; however, progressive diurnal deficits can require invasive ventilation. To determine if pulmonary function tests (PFTs) predict the thresholds for ventilation and wheelchair use, a systematic literature review identified cross-sectional clinical patient data (N = 174) that was classified into ventilation and wheelchair cohorts. PFTs included maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and vital capacity (VC), with vital capacities measured in the upright (-U) and supine (-S) positions. Receiver operating characteristic (ROC) curves were used to calculate cut-points (CP) and area under the curve (AUC). For all ventilation and mobility thresholds tested, ROC analyses demonstrated AUC values from 86-89% for MIP, 72-96% for MEP, and 74-96% for all vital capacity metrics. Thus, PFTs are useful in predicting the thresholds for nighttime ventilation, daytime ventilation, and wheelchair use, with MIP and VC-U having both high AUC values and consistency. The PFT mobility CPs were low (MIP CP = 0.9 kPa, MEP, CP = 2.6 kPa, VC-U CP = 19% predicted), suggesting an endurance component associated with wheelchair use., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

The World Trade Center (WTC) destruction released dust and fumes into the environment. Although many community members developed respiratory symptoms, screening spirometry was usually normal. We hypothesised that forced oscillation testing would identify functional abnormalities undetected by spirometry and that symptom severity would relate to magnitude of abnormalities measured by oscillometry. A symptomatic cohort (n=848) from the Bellevue Hospital WTC Environmental Health Center was evaluated and compared to an asymptomatic cohort (n=475) from the New York City Department of Health WTC Health Registry. Spirometry and oscillometry were performed. Oscillometry measurements included resistance ( R 5 ) and frequency dependence of resistance ( R 5-20 ). Spirometry was normal for the majority of subjects (73.2% symptomatic versus 87.6% asymptomatic, p<0.0001). In subjects with normal spirometry, R 5 and R 5-20 were higher in symptomatic versus asymptomatic subjects (median (interquartile range) R 5 0.436 (0.206) versus 0.314 (0.129) kPa·L -1 ·s -1 , p<0.001; R 5-20 0.075 (0.085) versus 0.004 (0.042) kPa·L -1 ·s -1 , p<0.0001). In symptomatic subjects, R 5 and R 5-20 increased with increasing severity and frequency of wheeze (p<0.05). Measurement of R 5-20 correlated with the presence and severity of symptoms even when spirometry was within normal limits. These findings are in accord with small airway abnormalities as a potential explanation of the respiratory symptoms., Competing Interests: Conflicts of Interest: None declared.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain., (© 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.)

Background: Destruction of the World Trade Center (WTC) towers on September 11, 2001, released massive dust, gas, and fumes with environmental exposures for community members. Many community members have lower respiratory symptoms (LRSs) that began after September 11, 2001, and remain persistent. We evaluated whether systemic inflammation measured by C-reactive protein was associated with WTC dust exposures, persistent LRS, and lung function., Methods: Community members self-referred for the treatment of symptoms related to September 11, 2001. C-reactive protein and lung function measurements, including spirometry and forced oscillation tests (impulse oscillometry system), were included as routine analyses in patients (2007 to 2012)., Results: Increased C-reactive protein levels were associated with the type of WTC dust exposure, LRS, reduced spirometry, and increased forced oscillation measurements (n = 724)., Conclusions: Ongoing systemic inflammation measured years after the event was associated with WTC dust exposures, persistent LRS, and abnormal lung function in a community cohort. These findings have implications for treatment and surveillance.

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung's normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well-phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC-exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after WTC exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1 below the lower limit of normal known as WTC-Lung Injury (WTC-LI). We utilized a nested case-cohort control design of previously healthy never smokers who sought subspecialty pulmonary evaluation to explore predictive biomarkers of WTC-LI. We have identified biomarkers of inflammation, metabolic derangement, protease/antiprotease balance, and vascular injury expressed in serum within 6 months of WTC exposure that were predictive of their FEV1 up to 7 years after their WTC exposure. Predicting future risk of airway injury after particulate exposures can focus monitoring and early treatment on a subset of patients in greatest need of these services., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder associated with skeletal and joint abnormalities and significant non-skeletal manifestations including respiratory disease, spinal cord compression, cardiac disease, impaired vision, hearing loss, and dental problems. The clinical presentation, onset, severity and progression rate of clinical manifestations of Morquio A syndrome vary widely between patients. Because of the heterogeneous and progressive nature of the disease, the management of patients with Morquio A syndrome is challenging and requires a multidisciplinary approach, involving an array of specialists. The current paper presents international guidelines for the evaluation, treatment and symptom-based management of Morquio A syndrome. These guidelines were developed during two expert meetings by an international panel of specialists in pediatrics, genetics, orthopedics, pulmonology, cardiology, and anesthesia with extensive experience in managing Morquio A syndrome., (© 2014 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.)

Background: In order to develop clinical reasoning, medical students must be able to integrate knowledge across traditional subject boundaries and multiple disciplines. At least two dimensions of integration have been identified: horizontal integration, bringing together different disciplines in considering a topic; and vertical integration, bridging basic science and clinical practice. Much attention has been focused on curriculum overhauls, but our approach is to facilitate horizontal and vertical integration on a smaller scale through an interdisciplinary case study discussion and then to assess its utility., Methods: An interdisciplinary case study discussion about a critically ill patient was implemented at the end of an organ system-based, basic sciences module at New York University School of Medicine. Three clinical specialists-a cardiologist, a pulmonologist, and a nephrologist-jointly led a discussion about a complex patient in the intensive care unit with multiple medical problems secondary to septic shock. The discussion emphasized the physiologic underpinnings behind the patient's presentation and the physiologic considerations across the various systems in determining proper treatment. The discussion also highlighted the interdependence between the cardiovascular, respiratory, and renal systems, which were initially presented in separate units. After the session students were given a brief, anonymous three-question free-response questionnaire in which they were asked to evaluate and freely comment on the exercise., Results: Students not only took away physiological principles but also gained an appreciation for various thematic lessons for bringing basic science to the bedside, especially horizontal and vertical integration. The response of the participants was overwhelmingly positive with many indicating that the exercise integrated the material across organ systems, and strengthened their appreciation of the role of physiology in understanding disease presentations and guiding appropriate therapy., Conclusions: Horizontal and vertical integration can be presented effectively through a single-session case study, with complex patient cases involving multiple organ systems providing students opportunities to integrate their knowledge across organ systems while emphasizing the importance of physiology in clinical reasoning. Furthermore, having several clinicians from different specialties discuss the case together can reinforce the matter of integration across multiple organ systems and disciplines in students' minds.

Introduction: Abnormality in distal lung function may occur in obesity due to reduction in resting lung volume; however, airway inflammation, vascular congestion and/or concomitant intrinsic airway disease may also be present. The goal of this study is to 1) describe the phenotype of lung function in obese subjects utilizing spirometry, plethysmography and oscillometry; and 2) evaluate residual abnormality when the effect of mass loading is removed by voluntary elevation of end expiratory lung volume (EELV) to predicted FRC., Methods: 100 non-smoking obese subjects without cardio-pulmonary disease and with normal airflow on spirometry underwent impulse oscillometry (IOS) at baseline and at the elevated EELV., Results: FRC and ERV were reduced (44 ± 22, 62 ± 14% predicted) with normal RV/TLC (29 ± 9%). IOS demonstrated elevated resistance at 20 Hz (R20, 4.65 ± 1.07 cmH2O/L/s); however, specific conductance was normal (0.14 ± 0.04). Resistance at 5-20 Hz (R5-20, 1.86 ± 1.11 cmH2O/L/s) and reactance at 5 Hz (X5, -2.70 ± 1.44 cmH2O/L/s) were abnormal. During elevation of EELV, IOS abnormalities reversed to or towards normal. Residual abnormality in R5-20 was observed in some subjects despite elevation of EELV (1.16 ± 0.8 cmH2O/L/s). R5-20 responded to bronchodilator at baseline but not during elevation of EELV., Conclusions: This study describes the phenotype of lung dysfunction in obesity as reduction in FRC with airway narrowing, distal respiratory dysfunction and bronchodilator responsiveness. When R5-20 normalized during voluntary inflation, mass loading was considered the predominant mechanism. In contrast, when residual abnormality in R5-20 was demonstrable despite return of EELV to predicted FRC, mechanisms for airway dysfunction in addition to mass loading could be invoked.

Background: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils., Results: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, α, or β diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022)., Conclusion: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.

Background: The present study (1) characterizes a physiologic phenotype of restrictive dysfunction due to airway injury and (2) compares this phenotype to the phenotype of interstitial lung disease (ILD)., Methods: This is a retrospective study of 54 persistently symptomatic subjects following World Trade Center (WTC) dust exposure. Inclusion criteria were reduced vital capacity (VC), FEV1/VC>77%, and normal chest roentgenogram. Measurements included spirometry, plethysmography, diffusing capacity of lung for carbon monoxide (Dlco), impulse oscillometry (IOS), inspiratory/expiratory CT scan, and lung compliance (n=16)., Results: VC was reduced (46% to 83% predicted) because of the reduction of expiratory reserve volume (43%±26% predicted) with preservation of inspiratory capacity (IC) (85%±16% predicted). Total lung capacity (TLC) was reduced, confirming restriction (73%±8% predicted); however, elevated residual volume to TLC ratio (0.35±0.08) suggested air trapping (AT). Dlco was reduced (78%±15% predicted) with elevated Dlco/alveolar volume (5.3±0.8 [mL/mm Hg/min]/L). IOS demonstrated abnormalities in resistance and/or reactance in 50 of 54 subjects. CT scan demonstrated bronchial wall thickening and/or AT in 40 of 54 subjects; parenchymal disease was not evident in any subject. Specific compliance at functional residual capacity (FRC) (0.07±0.02 [L/cm H2O]/L) and recoil pressure (Pel) at TLC (27±7 cm H2O) were normal. In contrast to patients with ILD, lung expansion was not limited, since IC, Pel, and inspiratory muscle pressure were normal. Reduced TLC was attributable to reduced FRC, compatible with airway closure in the tidal range., Conclusions: This study describes a distinct physiologic phenotype of restriction due to airway dysfunction. This pattern was observed following WTC dust exposure, has been reported in other clinical settings (eg, asthma), and should be incorporated into the definition of restrictive dysfunction.

Background: This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer., Methods: The current guidelines and medical literature applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Guidelines Oversight Committee., Results: The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (Dlco). Predicted postoperative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO Dlco values are both > 60%, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO Dlco are within 60% and 30% predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO Dlco (or both) are < 30% or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (V˙O2 peak) < 10 mL/kg/min or 35% predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a V˙O2 peak > 20 mL/kg/min or 75% predicted indicates a low risk., Conclusions: A careful preoperative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease.

Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome is a multisystem disorder caused by galactosamine-6-sulfatase deficiency. Skeletal manifestations, including short stature, skeletal dysplasia, cervical instability, and joint destruction, are known to be associated with this condition. Due to the severity of these skeletal manifestations, the non-skeletal manifestations are frequently overlooked despite their significant contribution to disease progression and impact on quality of life. This review provides detailed information regarding the non-skeletal manifestations and suggests long-term assessment guidelines. The visual, auditory, digestive, cardiovascular, and respiratory systems are addressed and overall quality of life as measured by endurance and other functional abilities is discussed. Impairments such as corneal clouding, astigmatism, glaucoma, hearing loss, hernias, hepatomegaly, dental abnormalities, cardiac valve thickening and regurgitation, obstructive sleep apnea, tracheomalacia, restrictive and obstructive respiratory compromise, and muscular weakness are discussed. Increased awareness of these non-skeletal features is needed to improve patient care.

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.

Background: Exposure to World Trade Center (WTC) dust and fumes is associated with the onset of asthma-like respiratory symptoms in rescue and recovery workers and exposed community members. Eosinophilic inflammation with increased lung and peripheral eosinophils has been described in subpopulations with asthma. We hypothesized that persistent asthma-like symptoms in WTC-exposed individuals would be associated with systemic inflammation characterized by peripheral eosinophils., Methods: The WTC Environmental Health Center (WTC EHC) is a treatment program for local residents, local workers, and cleanup workers with presumed WTC-related symptoms. Patients undergo a standardized evaluation including questionnaires and complete blood count. Between September 2005 and March 2009, 2462 individuals enrolled in the program and were available for analysis. Individuals with preexisting respiratory symptoms or lung disease diagnoses prior to September 2001 and current or significant tobacco use were excluded,, Results: One thousand five hundred and seventeen individuals met the inclusion criteria. Patients had a mean age of 47 years, were mostly female (51%), and had a diverse race/ethnicity. Respiratory symptoms that developed after WTC dust/fume exposure and remained persistent included dyspnea on exertion (68%), cough (57%), chest tightness (47%), and wheeze (33%). A larger percentage of patients with wheeze had elevated peripheral eosinophils compared with those without wheeze (21% vs. 13%, p < .0001). Individuals with elevated peripheral eosinophils were more likely to have airflow obstruction on spirometry (16% vs. 7%, p = .0003)., Conclusion: Peripheral eosinophils were associated with wheeze and airflow obstruction in a diverse WTC-exposed population. These data suggest that eosinophils may participate in lung inflammation in this population with symptoms consistent with WTC-related asthma.

Objective: The course of lung function in community members exposed to World Trade Center (WTC) dust and fumes remains undefined. We studied longitudinal spirometry among patients in the WTC Environmental Health Center (WTCEHC) treatment program., Methods: Observational study of 946 WTCEHC patients with repeated spirometry measures analyzed on the population as a whole and stratified by smoking status, initial spirometry pattern, and WTC-related exposure category., Results: Improvement in forced vital capacity (54.4 mL/yr; 95% confidence interval, 45.0 to 63.8) and forced expiratory volume in 1 second (36.8 mL/yr; 95% confidence interval, 29.3 to 44.3) was noted for the population as a whole. Heavy smokers did not improve. Spirometry changes differed depending on initial spirometry pattern and exposure category., Conclusion: These data demonstrate spirometry improvement in select populations suggesting reversibility in airway injury and reinforcing the importance of continued treatment.

Background: Obesity is frequently associated with respiratory symptoms despite normal large airway function as assessed by spirometry. However, reduced functional residual capacity and expiratory reserve volume are common and might reflect distal airway dysfunction. Impulse oscillometry (IOS) might identify distal airway abnormalities not detected using routine spirometry screening. Our objective was to test the hypothesis that excess body weight will result in distal airway dysfunction detected by IOS that reverses after bariatric surgery. The setting was a university hospital., Methods: A total of 342 subjects underwent spirometry, plethysmography, and IOS before bariatric surgery. Of these patients, 75 repeated the testing after the loss of 20% of the total body weight. The data from 47 subjects with normal baseline spirometry and complete pre- and postoperative data were analyzed., Results: IOS detected preoperative distal airway dysfunction despite normal spirometry findings by an abnormal airway resistance at an oscillation frequency of 20 Hz (4.75 ± 1.2 cm H2O/L/s), frequency dependence of resistance from 5 to 20 Hz (2.20 ± 1.6 cm H2O/L/s), and reactance at 5 Hz (-3.47 ± 2.1 cm H2O/L/s). Postoperatively, the subjects demonstrated 57% ± 15% excess weight loss. The body mass index decreased (from 44 ± 6 to 32 ± 5 kg/m2, P < .001). Improvements in functional residual capacity (from 59% ± 11% to 75% ± 20% predicted, P < .001) and expiratory reserve volume (from 41% ± 20% to 75% ± 20% predicted, P < .001) were demonstrated. Distal airway function also improved: airway resistance at an oscillation frequency of 20 Hz (3.91 ± .9, P < .001), frequency dependence of resistance from 5 to 20 Hz (1.17 ± .9, P < .001), and reactance at 5 Hz (-1.85 ± .9, P < .001)., Conclusion: The present study detected significant distal airway dysfunction despite normal preoperative spirometry findings. The effect of increased body weight was likely the main mechanism for these abnormalities. However, the inflammatory state of obesity or associated respiratory disease could also be invoked. These abnormalities improved significantly toward normal after weight loss. The results of the present study highlight the importance of bariatric surgery as an effective intervention in reversing these respiratory abnormalities., (Published by Elsevier Inc.)

Objectives: We assessed associations between new-onset (post-September 11, 2001 [9/11]) lower respiratory symptoms reported on 2 surveys, administered 3 years apart, and acute and chronic 9/11-related exposures among New York City World Trade Center-area residents and workers enrolled in the World Trade Center Health Registry., Methods: World Trade Center-area residents and workers were categorized as case participants or control participants on the basis of lower respiratory symptoms reported in surveys administered 2 to 3 and 5 to 6 years after 9/11. We created composite exposure scales after principal components analyses of detailed exposure histories obtained during face-to-face interviews. We used multivariate logistic regression models to determine associations between lower respiratory symptoms and composite exposure scales., Results: Both acute and chronic exposures to the events of 9/11 were independently associated, often in a dose-dependent manner, with lower respiratory symptoms among individuals who lived and worked in the area of the World Trade Center., Conclusions: Study findings argue for detailed assessments of exposure during and after events in the future from which potentially toxic materials may be released and for rapid interventions to minimize exposures and screen for potential adverse health effects.

Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. Late-onset Pompe disease is a multisystem condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders., Methods: Objective is to propose consensus-based treatment and management recommendations for late-onset Pompe disease., Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken., Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late-onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: To describe pathologic findings in symptomatic World Trade Center-exposed local workers, residents, and cleanup workers enrolled in a treatment program., Methods: Twelve patients underwent surgical lung biopsy for suspected interstitial lung disease (group 1, n = 6) or abnormal pulmonary function tests (group 2, n = 6). High-resolution computed axial tomography and pathologic findings were coded. Scanning electron microscopy with energy-dispersive x-ray spectroscopy was performed., Results: High-resolution computed axial tomography showed reticular findings (group 1) or normal or airway-related findings (group 2). Pulmonary function tests were predominantly restrictive. Interstitial fibrosis, emphysematous change, and small airway abnormalities were seen. All cases had opaque and birefringent particles within macrophages, and examined particles contained silica, aluminum silicates, titanium dioxide, talc, and metals., Conclusions: In symptomatic World Trade Center-exposed individuals, pathologic findings suggest a common exposure resulting in alveolar loss and a diverse response to injury., ((C)2011The American College of Occupational and Environmental Medicine)

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5), R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment.

Purpose: Rapid shallow breathing may occur at any time during spontaneous breathing trials (SBT), questioning the utility of a single determination of the rapid shallow breathing index (RSBI). We hypothesize that change in RSBI during SBT may more accurately predict successful extubation than a single determination., Methods: Prospective observational study. Seventy-two subjects were extubated. At 24 h, 63/72 remained extubated (Extubation Success), and 9 were re-intubated (Extubation Failure). Respiratory rate (RR), tidal volume (VT) and RSBI were measured every 30 min during 2-h T-piece SBT. Change in respiratory parameters was assessed as percent change from baseline., Results: Initial RSBI was similar in Extubation Success and Extubation Failure groups (77.0 +/- 4.8, 77.0 +/- 4.8, p = ns). Nevertheless, RSBI tended to remain unchanged or decreased in the Extubation Success group; in contrast RSBI tended to increase in the Extubation Failure group because of either increased RR and/or decreased VT (p < 0.001 for mean percent change RSBI over time), indicating worsening of the respiratory pattern. Quantitatively, only 7/63 subjects of the Extubation Success group demonstrated increased RSBI >or=20% at any time during the SBT. In contrast, in the Extubation Failure group, RSBI increased in all subjects during the SBT, and eight of nine subjects demonstrated an increase greater than 20%. Thus, with a 2-h SBT the optimal threshold was a 20% increase (sensitivity = 89%, specificity = 89%). Similar results were obtained at 30 min (threshold = 5% increase). Percent change of RSBI predicted successful extubation even when initial values were >or=105., Conclusion: Percent change of RSBI during an SBT is a better predictor of successful extubation than a single determination of RSBI.

Background: The World Trade Center (WTC) collapse produced a massive exposure to respirable particulates in New York City Fire Department (FDNY) rescue workers. This group had spirometry examinations pre-September 11, 2001, and post-September 11, 2001, demonstrating declines in lung function with parallel declines in FEV(1) and FVC. To date, the underlying pathophysiologic cause for this has been open to question., Methods: Of 13,234 participants in the FDNY-WTC Monitoring Program, 1,720 (13%) were referred for pulmonary subspecialty evaluation at a single institution. Evaluation included 919 full pulmonary function tests, 1,219 methacholine challenge tests, and 982 high-resolution chest CT scans., Results: At pulmonary evaluation (median 34 months post-September 11, 2001), median values were FEV(1) 93% predicted (interquartile range [IQR], 83%-101%), FVC 98% predicted (IQR, 89%-106%), and FEV(1)/FVC 0.78 (IQR, 0.72-0.82). The residual volume (RV) was 123% predicted (IQR, 106%-147%) with nearly all participants having normal total lung capacity, functional residual capacity, and diffusing capacity of carbon monoxide. Also, 1,051/1,720 (59%) had obstructive airways disease based on at least one of the following: FEV(1)/FVC, bronchodilator responsiveness, hyperreactivity, or elevated RV. After adjusting for age, gender, race, height and weight, and tobacco use, the decline in FEV(1) post-September 11, 2001, was significantly correlated with increased RV percent predicted (P < .0001), increased bronchodilator responsiveness (P < .0001), and increased hyperreactivity (P = .0056). CT scans demonstrated bronchial wall thickening that was significantly associated with the decline in FEV(1) post-September 11, 2001 (P = .024), increases in hyperreactivity (P < .0001), and increases in RV (P < .0001). Few had evidence for interstitial disease., Conclusions: Airways obstruction was the predominant physiologic finding underlying the reduction in lung function post-September 11, 2001, in FDNY WTC rescue workers presenting for pulmonary evaluation.

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients.

Distal airways disease causes significant morbidity yet remains insufficiently identified. We hypothesize that: ( [1] ) when spirometry is normal impulse oscillometry may provide information about mechanical properties of the distal airways in a manner comparable to dynamic compliance and ( [2] ) variation of breathing frequency will influence oscillometric measurements similar to effects of breathing frequency on dynamic compliance. Fifty-three symptomatic subjects with normal large airway function (spirometry) were studied; distal airway dysfunction was identified by presence of frequency dependence of compliance (FDC). Oscillometric parameters evaluated were resistance at 20 Hz (R20) and 5-20 Hz (R(5-20)), reactance at 5 Hz (X5), and reactance area (AX). R20 correlated with airway resistance by esophageal manometry (r = 0.74, p < 0.001); X5 correlated with dynamic compliance at a respiratory rate of 60 bpm (r = 0.61, p < 0.001); R(5-20) and AX correlated with FDC (r = 0.48, p < 0.001; r = 0.53, p < 0.01). IOS indices were further evaluated at increased respiratory rate (RR40). Oscillometric parameters changed minimally at RR40 in normal subjects DeltaR20 = 0.20 +/- 0.08 cmH2O/L/s, DeltaR(5-20) = 0.10 +/- 0.03 cmH2O/L/s, DeltaAX = 0.33 +/- 0.19 cmH2O/L). However, in symptomatic subjects, while R20 increased minimally at RR40 (DeltaR20 = 0.37 +/- 0.10 cmH2O/L/s), R(5-20) and AX increased markedly (DeltaR(5-20) = 0.54 +/- 0.06 cmH2O/L/s, DeltaAX = 4.28 +/- 0.67 cmH2O/L) and reversed post bronchodilator. IOS evaluates physiology of the distal airways in a manner comparable to dynamic compliance. Elevated respiratory rate influences oscillometric parameters and must be considered when interpreting oscillometric data. IOS provides a non-invasive tool for assessment of distal airway function when spirometry is normal, which can be applied to various clinical settings including early diagnosis of COPD (GOLD stage 0), asthma in clinical remission and occupational/ environmental irritant exposure.

The term obesity hypoventilation syndrome (OHS) refers to the combination of obesity and chronic hypercapnia that cannot be directly attributed to underlying cardiorespiratory disease. Despite a plethora of potential pathophysiological mechanisms for gas exchange and respiratory control abnormalities that have been described in the obese, the etiology of hypercapnia in OHS has been only partially elucidated. Of particular note, obesity and coincident hypercapnia are often associated with some form of sleep disordered breathing (apnea/hypopnea or sustained periods of hypoventilation). From a conceptual point of view, even transient reductions of ventilation from individual sleep disordered breathing events must produce acute hypercapnia during the period of low ventilation. What is less clear, however, is the link between these transient episodes of acute hypercapnia and the development of chronic sustained hypercapnia persisting into wakefulness. A unifying view of how this comes about is presented in the following review. In brief, our concept is that chronic sustained hypercapnia (as in obesity hypoventilation) occurs when the disorder of ventilation that produces acute hypercapnia interacts with inadequate compensation (both during sleep and during the periods of wakefulness); neither alone is sufficient to fully explain the final result. The following discussion will amplify on both the potential reasons for acute hypercapnia in the obese and on what is known about the failure of compensation that must occur in these subjects.

Objective: To describe physical symptoms in those local residents, local workers, and cleanup workers who were enrolled in a treatment program and had reported symptoms and exposure to the dust, gas, and fumes released with the destruction of the World Trade Center (WTC) on September 11, 2001., Methods: Symptomatic individuals underwent standardized evaluation and subsequent treatment., Results: One thousand eight hundred ninety-eight individuals participated in the WTC Environmental Health Center between September 2005 and May 2008. Upper and lower respiratory symptoms that began after September 11, 2001 and persisted at the time of examination were common in each exposure population. Many (31%) had spirometry measurements below the lower limit of normal., Conclusions: Residents and local workers as well as those with work-associated exposure to WTC dust have new and persistent respiratory symptoms with lung function abnormalities 5 or more years after the WTC destruction.

Objective: Our goal was to evaluate the long-term safety and efficacy of recombinant human alpha-l-iduronidase (laronidase) in patients with mucopolysaccharidosis I., Patients and Methods: All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6-43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean +/- SEM., Results: All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of -0.78 percentage points per year. The 6-minute walk distance increased 31.7 +/- 10.2 m in the first 2 years, with a final gain of 17.1 +/- 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 +/- 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4 degrees +/- 3.6 degrees) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 +/- 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment., Conclusions: This trial demonstrates the long-term clinical benefit and safety of laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes.

This paper presents a series of experiments, both in patients and computer models, investigating the transition from acute to chronic hypercapnia in OSA. The data demonstrate that acute hypercapnia during periodic breathing occurs due to either reduction in magnitude of inter-event ventilation and/or reduction in inter-event ventilatory duration relative to duration of the preceding event. The transition between acute hypercapnia during sleep and chronic sustained hypercapnia during wakefulness may be determined by an interaction between respiratory control and renal handling of HCO3-.

Rationale: Following collapse of the World Trade Center (WTC), individuals reported new-onset respiratory symptoms. Despite symptoms, spirometry often revealed normal airway function. However, bronchial wall thickening and air trapping were seen radiographically in some subjects. We hypothesized that symptomatic individuals following exposure to WTC dust may have functional abnormalities in distal airways not detectable with routine spirometry., Methods: One hundred seventy-four subjects with respiratory symptoms and normal spirometry results were evaluated. Impedance oscillometry (IOS) was performed to determine resistance at 5 Hz, 5 to 20 Hz, and reactance area. Forty-three subjects were also tested for frequency dependence of compliance (FDC). Testing was repeated after bronchodilation., Results: Predominant symptoms included cough (67%) and dyspnea (65%). Despite normal spirometry results, mean resistance at 5 Hz, 5 to 20 Hz, and reactance area were elevated (4.36 +/- 0.12 cm H(2)O/L/s, 0.86 +/- 0.05 cm H(2)O/L/s, and 6.12 +/- 0.50 cm H(2)O/L, respectively) [mean +/- SE]. Resistance and reactance normalized after bronchodilation. FDC was present in 37 of 43 individuals with improvement after bronchodilation., Conclusions: Symptomatic individuals with presumed WTC dust/fume exposure and normal spirometry results displayed airway dysfunction based on the following: (1) elevated airway resistance and frequency dependence of resistance determined by IOS; (2) heterogeneity of distal airway function demonstrated by elevated reactance area on oscillometry and FDC; and (3) reversibility of these functional abnormalities to or toward normal following administration of a bronchodilator. Since spirometry results were normal in all subjects, these abnormalities likely reflect dysfunction in airways more distal to those evaluated by spirometry. Examination of distal airway function when spirometry results are normal may be important in the evaluation of subjects exposed to occupational and environmental hazards.