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The lungs are continually subjected to noxious and inert substances, are immunologically active, and are in a constant state of damage and repair. This makes the pulmonary system particularly vulnerable to diseases of aging. Aging can be understood as random molecular damage that is unrepaired and accumulates over time, resulting in cellular defects and tissue dysfunction. The breakdown of cellular mechanisms, including stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, altered intercellular communication, and changes in the extracellular matrix is thought to advance the aging process itself. Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cancers illustrate a pathologic breakdown in these mechanisms beyond normal aging. The immune system becomes less effective with advancing age. There is a low-level state of chronic inflammation termed inflammaging which is thought to be driven by immunosenescence, the changes in the innate and adaptive immune systems with advancing age that lead to dysregulation and decreased effectiveness of the immune system. These processes of aging lead to expected changes in the form and function of the respiratory system, most notably a loss of lung elasticity, decrease in respiratory muscle strength, increase in ventilation-perfusion mismatching, and stiffening of the vasculature. The astute clinician is aware of these expected findings and does not often attribute dyspnea to aging alone. Maintaining a low threshold to investigate for comorbid disease and understanding how pulmonary disease presents differently in the elderly than in younger adults can improve clinical outcomes. © 2022 American Physiological Society. Compr Physiol 12:3509-3522, 2022.

Forced expiratory time (FET) is a spirometrically derived variable thought to reflect lung function, but its physiological basis remains poorly understood. We developed a mathematical theory of FET assuming a linear forced expiratory flow-volume profile that terminates when expiratory flow falls below a defined detection threshold. FET is predicted to correlate negatively with both FEV(1) and FVC if variations in the rate of lung emptying (relative to normal) among individuals in a population exceed variations in the amount of lung emptying. We retrospectively determined FET pre- and postmethacholine challenge in 1,241 patients (818 had normal lung function, 137 were obstructed, and 229 were restricted) and examined its relationships to spirometric and demographic variables in both hyperresponsive and normoresponsive individuals. Mean FET was 9.6 ± 2.2 s in the normal group, 12.3 ± 3.0 s in those with obstruction, and 8.8 ± 1.9 s in those with restriction. FET was inversely related to FEV(1)/FVC in all groups, negatively related to FEV(1) in the obstructed patients, and positively related to FVC in both the normal and restricted patients. There was no relationship with methacholine responsiveness. Overall, our theory of the relationship between FET to the spirometric indices is supported by these findings and potentially explains how FET is affected by sex, age, smoking status, and possibly body mass index. NEW & NOTEWORTHY Forced expiratory time (FET) has long been felt to reflect important physiological information about lung function but exactly how has never been clear. Here, we use a model analysis to assess the contributions of airway narrowing versus airway closure to FET in a population of individuals and find support for the theory that FET correlates positively with FEV(1) if the amounts of lung emptying over a forced expiration vary from predicted values more than variations in the rates of lung emptying, whereas the correlation is negative in the opposite case.

Growth of the segment of the population older than 65 years has led to intensified interest in understanding the biology of aging. This article is focused on age-related alterations in lung structure that produce predictable changes in physiologic function, both at rest and during exercise. Increased insight into the physiology of the healthy aging lung should ultimately lead to improved methods of lung function assessment in the elderly (defined as those older than 65 years) as well as better understanding of the manifestations and possibly even the treatment of geriatric lung disease.

Clinical and preclinical data demonstrate that altered pulmonary physiology (including increased inflammation, increased blood flow, airway resistance, and hyper-reactivity) is an intrinsic component of Sickle Cell Disease (SCD) and may contribute to excess SCD morbidity and mortality. Inhaled corticosteroids (ICS), a safe and effective therapy for pulmonary inflammation in asthma, may ameliorate the altered pulmonary physiologic milieu in SCD. With this single-center, longitudinal, randomized, triple-blind, placebo controlled trial we studied the efficacy and feasibility of ICS in 54 nonasthmatic individuals with SCD. Participants received once daily mometasone furoate 220 mcg dry powder inhalation or placebo for 16 weeks. The primary outcome was feasibility (the number who complete the trial divided by the total number enrolled) with prespecified efficacy outcomes including daily pain score over time (patient reported) and change in soluble vascular cell adhesion molecule (sVCAM) levels between entry and 8-weeks. For the primary outcome of feasibility, the result was 96% (52 of 54, 95% CI 87%-99%) for the intent-to-treat analysis and 83% (45 of 54, 95% CI 71%-91%) for the per-protocol analysis. The adjusted treatment effect of mometasone was a reduction in daily pain score of 1.42 points (95%CI 0.61-2.21, P = 0.001). Mometasone was associated with a reduction in sVCAM levels of 526.94 ng/mL more than placebo (95% CI 50.66-1003.23, P = 0.03). These results support further study of ICS in SCD including multicenter trials and longer durations of treatment. www.clinicaltrials.gov (NCT02061202).

© 2019 Asian Pacific Society of Respirology Background and objective: Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. Methods: Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose–response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. Results: A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. Conclusion: Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.

The aging population is growing at an unparalleled rate. Asthma is common in the elderly (age over 65 years) and can be more severe with little chance for remission. Asthma in older individuals is often under-diagnosed, misdiagnosed and frequently under-treated. Concomitant medical and psychosocial conditions are more prevalent in the elderly and can obfuscate the presentation of asthma and make it more difficult to assess and manage. While these comorbidities are important in understanding elderly asthma, aging itself can be considered a "comorbidity" since it impacts structural and functional changes in the lung. Structural changes of the aging lung may worsen physiologic function in asthma. The immune system also changes with age, with increased vulnerability to pathogens and differences in airway inflammation, leading to variability in how asthma manifests and responds to treatment. The fact that aging can influence the severity and presentation of asthma along with its diagnosis and management is important for the treating physician to understand. This article will discuss the multitude of factors that justify considering aging as a comorbidity of asthma.

More than 40,000 individuals were exposed to particulate matter following the World Trade Center (WTC) attacks. This population has increased rates of asthma and worsening of preexisting asthma. WTC asthma is on the spectrum of disorders ranging from reactive airways dysfunction to irritant-induced asthma. It is a non-immunologic phenomenon, with direct airway epithelial damage causing release of pro-inflammatory mediators. Risk factors for development of WTC asthma relate predominantly to the magnitude of irritant exposure.

Summary Background More than 50 000 people participated in the rescue and recovery work that followed the Sept 11, 2001 (9/11) attacks on the World Trade Center (WTC). Multiple health problems in these workers were reported in the early years after the disaster. We report incidence and prevalence rates of physical and mental health disorders during the 9 years since the attacks, examine their associations with occupational exposures, and quantify physical and mental health comorbidities. Methods In this longitudinal study of a large cohort of WTC rescue and recovery workers, we gathered data from 27 449 participants in the WTC Screening, Monitoring, and Treatment Program. The study population included police officers, firefighters, construction workers, and municipal workers. We used the Kaplan-Meier procedure to estimate cumulative and annual incidence of physical disorders (asthma, sinusitis, and gastro-oesophageal reflux disease), mental health disorders (depression, post-traumatic stress disorder [PTSD], and panic disorder), and spirometric abnormalities. Incidence rates were assessed also by level of exposure (days worked at the WTC site and exposure to the dust cloud). Findings 9-year cumulative incidence of asthma was 27·6% (number at risk: 7027), sinusitis 42·3% (5870), and gastro-oesophageal reflux disease 39·3% (5650). In police officers, cumulative incidence of depression was 7·0% (number at risk: 3648), PTSD 9·3% (3761), and panic disorder 8·4% (3780). In other rescue and recovery workers, cumulative incidence of depression was 27·5% (number at risk: 4200), PTSD 31·9% (4342), and panic disorder 21·2% (4953). 9-year cumulative incidence for spirometric abnormalities was 41·8% (number at risk: 5769); three-quarters of these abnormalities were low forced vital capacity. Incidence of most disorders was highest in workers with greatest WTC exposure. Extensive comorbidity was reported within and between physical and mental health disorders. Interpretation 9 years after the 9/11 WTC attacks, rescue and recovery workers continue to have a substantial burden of physical and mental health problems. These findings emphasise the need for continued monitoring and treatment of the WTC rescue and recovery population. Funding Centers for Disease Control and Prevention and National Institute for Occupational Safety and Health.

Background Multiple studies have demonstrated an initial high prevalence of spirometric abnormalities following World Trade Center (WTC) disaster exposure. We assessed prevalence of spirometric abnormalities and changes in spirometry between baseline and first follow-up evaluation in participants in the WTC Worker and Volunteer Medical Monitoring Program. We also determined the predictors of spirometric change between the two examinations. Methods Prebronchodilator and postbronchodilator spirometry, demographics, occupational history, smoking status, and respiratory symptoms and exposure onset were obtained at both examinations (about 3 years apart). Results At the second examination, 24.1% of individuals had abnormal spirometry findings. The predominant defect was a low FVC without obstruction (16.1%). Between examinations, the majority of individuals did not have a greater-than-expected decline in lung function. The mean declines in prebronchodilator FEV 1 and FVC were 13 mL/yr and 2 mL/yr, respectively (postbronchodilator results were similar and not reported). Significant predictors of greater average decline between examinations were bronchodilator responsiveness at examination 1 and weight gain. Conclusions Elevated rates of spirometric abnormalities were present at both examinations, with reduced FVC most common. Although the majority had a normal decline in lung function, initial bronchodilator response and weight gain were significantly associated with greater-than-normal lung function declines. Due to the presence of spirometric abnormalities > 5 years after the disaster in many exposed individuals, longer-term monitoring of WTC responders is essential.

OBJECTIVE. The objective of this study was to characterize the clinical features of patients with Niemann-Pick disease type B and to identify efficacy end points for future clinical trials of enzyme-replacement therapy. METHODS. Fifty-nine patients who had Niemann-Pick disease type B, were at least 6 years of age, and manifested at least 2 disease symptoms participated in this multicenter, multinational, cross-sectional survey study. Medical histories; physical examinations; assessments of cardiorespiratory function, clinical laboratory data, and liver and spleen volumes; radiographic evaluation of the lungs and bone age; and quality-of-life assessments were obtained during a 2- to 3-day period. RESULTS. Fifty-three percent of the patients were male, 92% were white, and the median age was 17.6 years. The R608del mutation accounted for 25% of all disease alleles. Most patients initially presented with splenomegaly (78%) or hepatomegaly (73%). Frequent symptoms included bleeding (49%), pulmonary infections and shortness of breath (42% each), and joint/limb pain (39%). Growth was markedly delayed during adolescence. Patients commonly had low levels of platelets and high-density lipoprotein, elevated levels of low-density lipoprotein, very-low-density lipoprotein, triglycerides, leukocyte sphingomyelin, and serum chitotriosidase, and abnormal liver function test results. Nearly all patients had documented splenomegaly and hepatomegaly and interstitial lung disease. Patients commonly showed restrictive lung disease physiology with impaired pulmonary gas exchange and decreased maximal exercise tolerance. Quality of life was only mildly decreased by standardized questionnaires. The degree of splenomegaly correlated with most aspects of disease, including hepatomegaly, growth, lipid profile, hematologic parameters, and pulmonary function. CONCLUSIONS. This study documents the multisystem involvement and clinical variability of Niemann-Pick B disease. Several efficacy end points were identified for future clinical treatment studies. Because of its correlation with disease severity, spleen volume may be a useful surrogate end point in treatment trials, whereas biomarkers such as chitotriosidase also may play a role in monitoring patient treatment responses.

Purpose of review Asthma is quite common and is better described as a syndrome with a heterogeneous presentation than as a single disease. Although most individuals can be effectively managed using a guideline-directed approach to care, those with the most severe illness may benefit from a more targeted therapy. The review describes our current understanding of how asthma phenotypes (observable characteristics) and endotypes (specific biologic mechanisms) can be employed to gain insight into asthma pathobiology and personalized therapy. Recent findings Our understanding of the heterogeneity of asthma is increasing. The concept of asthma phenotype has become more complex, incorporating both clinical and biologic features. Several asthma endotypes (e.g., allergic bronchopulmonary mycosis, aspirin-exacerbated respiratory disease, severe late-onset hypereosinophilic asthma, etc.) have been proposed, but further research is needed to delineate specific mechanisms underlying asthma pathogenesis. Several biologic therapies targeting certain phenotypes are in development and are expected to broaden our armamentarium for treatment of severe asthma. Summary Asthma is a heterogeneous condition with diverse characteristics and biologic mechanisms. Severe asthma is associated with significant morbidity and even mortality and represents a major unmet need. Stratification of asthma subtypes into phenotypes and endotypes should move the field forward in terms of more effective and personalized treatment.

Older adults with asthma face numerous barriers to effective self-management and asthma control, and experience worse outcomes than younger asthmatics. Yet, there have been no controlled trials of interventions specifically designed to improve their care and outcomes. Through a multi-stakeholder collaboration (patients, academia, community-based organizations, a state department of health, and an advocacy organization) we developed a multi-component asthma self-management support intervention to address the myriad psychosocial, functional, health status, and cognitive barriers to effective asthma self-management in adults ages 60 and older. We are recruiting 425 New Yorkers in Manhattan and the Bronx for a pragmatic randomized controlled trial with 3 arms: the intervention delivered in primary care settings or in their home, or usual care. In the intervention, care coaches use a novel screening tool to identify the specific barriers to asthma control and self-management they experience. Once identified, the coach and patient choose from a menu of actions to address it. The intervention emphasizes efficiency, flexibility, shared decision making and goal setting, communication strategies appropriate for individuals with limited cognition and literacy skills, and ongoing reinforcement and support. Additionally, we introduced asthma-specific enhancements to the electronic health records of all participating clinical practices, including an asthma severity assessment, clinical decision support, and a patient-tailored asthma action plan. Patients will be followed for 12months and interviewed at baseline, 3, 6, and 12months and data on emergency department visits and hospitalizations will be obtained through the New York State Statewide Planning and Research Cooperative System.

Human clinical studies and murine models suggest that pulmonary inflammation is an intrinsic component of sickle cell disease (SCD) (Field et al, 2011, Morris et al, 2003, Nandedkar et al, 2008, Pawar et al, 2008, Pritchard et al, 2012, Pritchard et al, 2004) and a growing body of retrospective and cross-sectional studies demonstrates that symptoms, such as cough or wheeze, often occur without asthma and are associated with increased SCD complications (pain, acute chest syndrome and death) (Cohen et al, 2011, Field et al, 2011, Glassberg et al, 2012). To better understand the incidence of respiratory symptoms over time, and to identify the percentage of individuals without asthma who could potentially benefit from pulmonary-anti-inflammatory therapy, we conducted a prospective, longitudinal cohort study of individuals with SCD who do not have asthma.

To evaluate findings at radiography, computed tomography (CT), and pulmonary function testing in patients with type B Niemann-Pick disease.The study was approved by the institutional review board or ethics committee at each study site and was compliant with HIPAA at the U.S. site. Written informed consent was obtained from each patient or guardian and minor assent was obtained from all children before any study-related procedures. Pulmonary involvement in 53 patients (27 male and 26 female patients; age range, 7-65 years; mean age, 23.3 years) with type B Niemann-Pick disease was evaluated with imaging and pulmonary function tests. All patients underwent chest radiography and thin-section CT, and images were independently interpreted by one of two radiologists. Spirometry (forced vital capacity [FVC] and forced expiratory volume in 1 second [FEV1]) was performed and diffusing capacity of lung for carbon monoxide (Dlco) was evaluated in all patients who could comply. A score for the degree of interstitial lung disease was derived at both radiography and CT, and the CT scores were then compared with results of pulmonary function testing and patient age by means of linear regression. CT scores were compared between the upper and lower lung zones by using the Wilcoxon signed rank test.Chest radiography and CT, respectively, revealed interstitial lung disease in 47 (90%) and 51 (98%) of the 52 patients who completed both imaging examinations. There was a basilar predominance of interstitial lung disease at CT. Six patients had pulmonary nodules, one of which was calcified at chest radiography. There were no statistically significant correlations between interstitial lung disease score at CT and age or percentage predicted FVC, FEV1, or Dlco values.Although pulmonary function test indexes may be abnormal, imaging findings do not necessarily correlate with pulmonary function in patients with type B Niemann-Pick disease.

Bronchial hyperresponsiveness (BHR) is a cardinal feature of asthma. Airway inflammation and BHR are probably linked, but the mechanisms underlying this relationship remain elusive. BHR is closely associated with defects in the beneficial responses to lung inflation. These responses, which become apparent by the fact that healthy individuals can develop severe airway obstruction if they are exposed to methacholine in the absence of deep inspirations, include bronchodilation and bronchoprotection. Bronchodilation refers to the effect of lung inflation after the induction of airway smooth muscle tone, while bronchoprotection is used to indicate the effect prior to inhalation of a spasmogen. Mild asthmatics who manifest BHR lack bronchoprotection by lung inflation. In contrast, many of them are able to bronchodilate. In more severe disease, both functions are impaired. The lack of bronchoprotection is also found in individuals with rhinitis and BHR, but no asthma. These and other observations suggest that the mechanisms of bronchodilation and bronchoprotection may be distinct, although overlap is possible. We believe that the loss of bronchoprotection is pertinent to the phenomenon of hyperresponsiveness, but that both the bronchodilatory and bronchoprotective functions of deep inspiration interact to produce the asthmatic phenotype. In this review, we describe the phenomena of lung inflation-induced bronchodilation and bronchoprotection and detail potential mechanical and neurohumoral mechanisms accounting for these physiologic functions. In addition, possible mechanisms leading to the impairment of these functions in subjects with BHR are discussed.

Screening spirometry might help identify patients with chronic obstructive pulmonary disease (COPD) at an earlier stage. In this study, we evaluated the prevalence of airway obstruction in a cohort of asymptomatic smokers who underwent spirometry as part of a routine health maintenance examination.The study cohort consisted of a consecutive sample of 386 asymptomatic smokers (≥5 pack-years) without a history of COPD or asthma, who completed spirometry testing as part of a routine health maintenance examination.Overall, 9 study subjects (2.3%, 95% confidence interval: 1.1-4.4%) had evidence of airway obstruction on spirometry. Univariate and multiple regression analyses showed that the risk of airway obstruction was not significantly associated with age, sex, race, smoking history or past history of respiratory symptoms.Spirometry screening of asymptomatic smokers may help detect a small number of patients with airway obstruction who are at high risk for COPD.

The attack on theWorldTradeCenter (WTC) site and the subsequent collapse of the towers on September 11 generated an aerosol containing a wide range of toxic and irritant agents. A partial list of these materials includes pulverized concrete, gypsum, pulverized glass, asbestos, silica, fibrous glass, heavy metals, soot, volatile organic compounds, acid mists and organic products of combustion, among them polycyclic aromatic hydrocarbons (PAHs). A recurring theme with regard to exposure conditions at the ‘‘Ground Zero’’ site was the uneven provision and use of adequate respiratory protection, the clinical consequences of which became apparent over the ensuing several months. The populations at risk for adverse health consequences, in decreasing intensity of exposure, included those whowere caught in the blackout (then ‘‘greyout’’) of the collapse cloud; the Ground Zero first responders and workers and volunteers involved in the rescue and recovery effort over the first few days; those involved in restoration of essential services and infrastructure (electric, gas, transportation, etc.), debris removal crews and their support services, building clean up teams, persons who eventually reoccupied offices, commercial and school buildings near the WTC site, and community residents. The extent of the clean-up effort, now 8months in duration, and the necessity of moving truckloads of debris throughpublic streets to the barge-loadingoperation at the Hudson River for transport to Staten Island increased the number of persons at risk for exposure. By October 2001, the Mount Sinai-Irving J. Selikoff Center for Occupational and Environmental Medicine (COEM) began evaluating individuals, who presented with respiratory complaints, related to their exposure to airborne irritants. Exposure-related factors (when they were at or near ‘‘Ground Zero,’’ performing what tasks, over what time period, with what level of respiratory protection) appeared to be significant determinants of the severity of respiratory reactions; but host biological factors appeared to play a role as well, with some exhibiting greater susceptibility to the irritant-induced effects. Health effects among the individuals seen in the Clinical Center included new-onset (i.e., post-9/11) sinusitis, laryngitis, tracheitis, reactive upper airways dysfunction (RUDS), bronchitis, and reactive airways dysfunction syndrome (RADS) and irritant-induced asthma. Those who had sinusitis or asthma prior to 9/11 experienced amarked worsening of their symptoms. Symptoms of upper and/or lower airway irritation were frequently reported to be worsened or provoked by re-exposure to airborne irritants (tobacco smoke, vehicle exhaust, cleaning solutions, etc.), by exercise, and by cold air. While initially respiratory complaints and illnesses were identified primarily among workers and volunteers at or near the WTC site, over the ensuing months, similar problems were found among office reoccupants and community residents, especially those situated downwind (South and East) of Ground Zero. While therewas initial concern about persistent sequelae of acute musculoskeletal injuries sustained by workers and volunteers at the site, relatively fewer such injuries occurred during rescue and recovery and debris removal thanwould be expected for a project of this magnitude. A particularly prominent clinical finding was the prevalence of persistent psychological distress among thosewho initially presented with respiratory conditions. Symptoms consistent with the classical picture of post-traumatic stress disorder and major depression were persistent among many

Deep inspirations modulate airway caliber and airway closure and their effects are impaired in asthma. The association between asthma and obesity raises the question whether the deep inspiration (DI) effect is also impaired in the latter condition. We assessed the DI effects in obese and nonobese nonasthmatics. Thirty-six subjects (17 obese, 19 nonobese) underwent routine methacholine (Mch) challenge and 30 of them also had a modified bronchoprovocation in the absence of DIs. Lung function was monitored with spirometry and forced oscillation (FO) [resistance (R) at 5 Hz (R5), at 20 Hz (R20), R5-R20 and the integrated area of low-frequency reactance (AX)]. The response to Mch, assessed with area under the dose-response curves (AUC), was consistently greater in the routine challenge in the obese (mean ± SE, obese vs. nonobese AUC: R5: 15.7 ± 2.3 vs. 2.4 ± 2.0, P < 0.0005; R20: 5.6 ± 1.4 vs. 1.4 ± 1.2, P = 0.027; R5-R20: 10.2 ± 1.6 vs. 0.9 ± 0.1.4, P < 0.0005; AX: 115.6 ± 22.0 vs. 1.5 ± 18.9, P < 0.0005), but differences between groups in the modified challenge were smaller, indicating reduced DI effects in obesity. Given that DI has bronchodilatory and bronchoprotective effects, we further assessed these components separately. In the obese subjects, DI prior to Mch enhanced Mch-induced bronchoconstriction, but DI after Mch resulted in bronchodilation that was of similar magnitude as in the nonobese. We conclude that obesity is characterized by increased Mch responsiveness, predominantly of the small airways, due to a DI effect that renders the airways more sensitive to the stimulus.

Background More than 20,000 responders have been examined through the World Trade Center (WTC) Medical Monitoring and Treatment Program since September 11, 2001. Studies on WTC firefighters have shown elevated rates of sarcoidosis. The main objective of this study was to report the incidence of “sarcoid like” granulomatous pulmonary disease in other WTC responders. Methods Cases of sarcoid like granulomatous pulmonary disease were identified by: patient self-report, physician report and ICD-9 codes. Each case was evaluated by three pulmonologists using the ACCESS criteria and only “definite” cases are reported. Results Thirty-eight patients were classified as “definite” cases. Six-year incidence was 192/100,000. The peak annual incidence of 54 per 100,000 person-years occurred between 9/11/2003 and 9/11/2004. Incidence in black responders was nearly double that of white responders. Low FVC was the most common spirometric abnormality. Conclusions Sarcoid like granulomatous pulmonary disease is present among the WTC responders. While the incidence is lower than that reported among firefighters, it is higher than expected. Am. J. Ind. Med. 54:175–184, 2011. © 2010 Wiley-Liss, Inc.

Spirometry is the most commonly used pulmonary function test to screen individuals for suspected lung disease. It is also used for screening workers with exposures to agents associated with pulmonary diseases. Although the American Thoracic Society (ATS) provides guidelines for spirometers and spirometry techniques, many factors are not standardized, so that results from individual pulmonary function laboratories vary substantially. These differences can create substantial difficulties in using data pooled from multiple sites to understand health consequences of disasters that involve exposures to pulmonary toxins. This article describes the approach used to minimize these differences for a consortium of institutions who are providing medical monitoring examinations to World Trade Center (WTC) responders. The protocol improved upon the minimal ATS guidelines.Spirometric measurements were obtained before and after use of a bronchodilator. A fourth-generation spirometer was chosen that exceeded ATS spirometer accuracy standards. The accuracy was verified at the beginning of each day of testing. Technologists who performed the spirometry tests were centrally trained and certified and received regular reports on their performance. Reference values and normal ranges were obtained from the National Health and Nutrition Examination Survey (NHANES III) data set. A standardized interpretation flowchart was followed to reduce misclassification rates for airway obstruction and restriction. Patients with spirometric abnormalities were referred for more extensive diagnostic testing.More than 12,000 spirometry tests were performed during the first examination. The 20 spirometers used at the 6 participating institutions maintained accuracy within 3% for more than 4 years. Overall, more than 80% of the test sessions met ATS quality goals. Spirometry abnormality rates exceeded those obtained for adults who participated in the NHANES III survey.The program allowed standardization of the performance and interpretation of spirometry results across multiple institutions. This facilitated reliable and rapid diagnosis of lung disease in the large number of WTC responders screened. We recommend this approach for postdisaster pulmonary evaluations in other settings.

In our article (Herbert et al. 2006), we described the establishment of the World Trade Center (WTC) Worker and Volunteer Medical Screening Program and presented results of screening examinations undertaken between 2002 and 2004 among a heterogeneous group of 9,442 WTC responders. Miller expresses concern about the validity of self-reported upper and lower respiratory symptoms in WTC responders. He notes correctly that self-reported symptoms are inherently subjective. However, symptoms cannot merely be dismissed as unimportant, especially when they are persistent and when, as was the case here, the pattern of their occurrence closely parallels severity of exposure. We reported that symptoms were most common among those responders who arrived earliest at the WTC site and who consequently suffered the heaviest exposures to the highest levels of dust and smoke (Herbert et al. 2006). This finding has high inherent biological plausibility. To be sure, the potential for recall bias is always present in a symptom-based survey. In reality, however, recall bias could be of concern only if we had reason to believe that responders in different exposure groups recalled past and current symptomatology differently. Finally, to further ensure the validity of our findings, we buttressed our assessment of symptoms with chest X rays and pulmonary function tests. Miller also expresses concern that objective results were “confined to spirometry, which does not provide insight into all aspects of respiratory impairment.” Although we recognize the limitations of spirometry, a large-scale screening program has practical restrictions in testing that can be accomplished. In fact, in Miller’s own 1991 survey of a population 10 times smaller than our own (Miller et al. 1991), only spirometry was used as a screening tool. Miller observes that our results were “unlike virtually all spirometric surveys of a large population” since there was “little difference in impairment by smoking status.” We would agree with Miller that our population was distinct by the very nature of the exposures involved and that this should be considered in evaluating the lack of difference in impairment based on smoking status. One speculation is that the overwhelming exposure to toxic chemicals at the WTC disaster may have masked differences between smokers and nonsmokers. Miller erroneously states that most spirometric impairments were classified as “restrictive.” We were quite careful not to use this term because it cannot be confirmed by spirometry alone. Instead we chose the designation of low forced vital capacity (FVC) (Herbert et al. 2006). Like Miller, we were surprised by this finding as well as by the observation that fewer responders had reversible airway obstruction, which would have confirmed asthma in those with asthma-like symptoms. However, asthma is by its very nature intermittent, and spirometry tests are only a “snapshot in time,” so normal spirometry results do not rule out asthma. Unfortunately, we were unable to provide inhalation challenge tests for the cohort because of the constraints of conducting a large multicenter clinical screening program. We listed the many possible reasons for a high prevalence of a low FVC in the “Discussion” of our article (Herbert et al. 2006). One member of our working group (G.S.) is currently leading an initiative to estimate the individual contribution of each of these factors by describing the results of additional diagnostic procedures not included in routine screening. Examinations of the WTC population continue and are expected to proceed for many years to come. As of 31 December 2006, we have examined > 18,500 WTC responders and provided follow-up examinations to > 7,000. We expect to report on findings from those examinations within the next year. In addition, we will be reporting further on the relationship between symptoms and screening spirometry. These analyses should provide further insight into the potential pulmonary impairment of individuals exposed at the WTC disaster.

Summary Background and study objective Deep inspiration (DI) protects against methacholine-induced bronchoconstriction in healthy subjects. We hypothesized that this bronchoprotective effect of DI depends upon the inspiratory flow rate. Design Prospective, controlled study. Setting Pulmonary function laboratory within a large tertiary medical center. Participants Ten healthy nonsmokers without asthma or rhinitis. Measurements First, we performed a methacholine challenge in the absence of DI to determine the concentration sufficient to reduce FEV1 by 20%. On two subsequent days, the challenge was repeated with the addition of either a fast or slow DI immediately before the threshold concentration of methacholine. We calculated the % reduction in FEV1 and FVC from baseline. Results Mean % reduction in FEV1 and FVC was significantly less with a fast DI than with no DI (20±3% vs. 34±4% for FEV1, p=0.02; 12±3% vs. 23±3% for FVC, p=0.03); slow DIs did not significantly affect the methacholine-induced reduction in lung function. Conclusion A fast DI is bronchoprotective while a slow DI is not. Elucidating the conditions that maximize or alternatively, eliminate bronchoprotection in healthy subjects may ultimately provide insight into the pathophysiology of asthma.

Study objectives To characterize respiratory abnormalities in a convenience sample of ironworkers exposed at the World Trade Center (WTC) disaster site for varying lengths of time between September 11, 2001, and February 8, 2002. Design Cross-sectional study. Setting The Mount Sinai Medical Center, a large tertiary hospital. Participants Ninety-six ironworkers engaged in rescue and recovery with exposure onset between September 11, 2001, and September 15, 2001, who responded to an invitation to undergo respiratory evaluation. Measurements Medical and exposure history, physical examination, spirometry, forced oscillation (FO), and chest radiographs. The relationships of prevalence of respiratory symptoms and presence of obstructive physiology to smoking, exposure on September 11, duration of exposure, and type of respiratory protection were examined using univariate and linear and logistic regression analyses. Results Seventy-four of 96 workers (77%) had one or more respiratory symptoms (similar in smokers [49 of 63 subjects, 78%] and nonsmokers [25 of 33 subjects, 76%]). Cough was the most common symptom (62 of 96 subjects, 65%), and was associated with exposure on September 11. Chest examination and radiograph findings were abnormal in 10 subjects (10%) and 19 subjects (20%), respectively. FO revealed dysfunction in 34 of 64 subjects tested (53%), while spirometry suggested obstruction in only 11 subjects (17%). Lack of a respirator with canister was a risk factor for large airway dysfunction, and cigarette smoking was a risk factor for small airway dysfunction. No other relationships reached statistical significance. Conclusions Respiratory symptoms occurred in the majority of ironworkers at the WTC disaster site and were not attributable to smoking. Exposure on September 11 was associated with a greater prevalence of cough. Objective evidence of lung disease was less common. Spirometry underestimated the prevalence of lung function abnormalities in comparison to FO. Continuing evaluation of symptoms, chest radiographs, and airway dysfunction should determine whether long-term clinical sequelae will exist.

We have learned much about the respiratory disorders since the exposures of responders at the World Trade Center (WTC) site, especially from the publications of Prezant and colleagues about the presentations, follow-up, and impairments of pulmonary function and bronchial reactivity of the fire fighters and emergency medical technicians of the New York City Fire Department (Banauch et al. 2003, 2005, 2006; Prezant et al. 2002). These reports are especially informative because of the availability of preexposure clinical and spirometric data. We appreciate the report of much-awaited results among 9,442 workers from the WTC Worker and Volunteer Medical Screening Program (Herbert et al. 2006). Because of the potential for major illness, the large number of subjects at risk, and the resultant enormous public interest, it is important that the information reported be properly understood. A number of limitations in this report must be pointed out. Although the title identified this report (Herbert et al. 2006) as a 5-year assessment, screening examinations were performed between 16 July 2002 and 16 April 2004, < 1 year through < 3 years after 11 September 2001. There were no follow-up examinations, either at the 5-year or at any other interval. Summary conclusions (Herbert et al. 2006), heavily reported in the media, lump all respiratory symptoms: … 69% reported new or worsened respiratory symptoms while performing WTC work. Symptoms persisted to the time of examination in 59% of these workers. The 69% with “any respiratory symptom” included 23.3% with no “lower respiratory symptoms.” A far smaller percentage of all workers (17.3%) complained of what may be considered the most important respiratory symptom, dyspnea, which was not quantified by any standard scale. Such a reliance on symptoms is subject to recall biases both for symptoms present before 9/11 and for the onset, worsening, and persistence of symptoms after 9/11. Because physical examination and chest radiographs were unrevealing (Herbert et al. 2006), the only objective results were from pulmonary function tests. These were confined to spirometry, which does not provide insight into all aspects of respiratory impairment. The data presented by Herbert et al. (2006) are limited. Mean values for subsets (classified by WTC exposure, previous smoking history, etc.) are not given. Despite the frequency of cough (42.8%), wheeze (15.1%), and chest tightness (15.4%) and the common diagnoses of asthma/reactive airways dysfunction, only 7.6% of all responders showed airway obstruction, defined as a ratio of forced expiratory volume in 1 sec (FEV1) to forced vital capacity (FVC) less than the 5th percentile of the reference population. Unlike virtually all spirometric surveys of a large population (reviewed by Miller et al. 1991), Herbert et al. (2006) found little difference in impairment by smoking status. Most spirometric impairments were classified as restrictive, uncharacteristic of the symptoms and clinical diagnoses. This frequency of low FVC (22.7%) raises several issues: a) the effects of other clinical factors not reported on, such as obesity; b) technical considerations in subject performance or technician monitoring of the FVC maneuver, despite the investigators attention to these; and c) the appropriateness of the reference-predicted values. We await further information and follow-up from these investigators, including results of additional diagnostic procedures not included in routine screening. These include a wider array of pulmonary function tests (full lung volumes, diffusing capacity), measurement of bronchial reactivity, computed tomography scans, and—in appropriate patients—bronchoalveolar lavage and lung biopsies, which would truly elucidate the respiratory disorders following WTC exposure.