Faculty Bibliography

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

INTRODUCTION: We examined pulmonary diffusing capacity (D(LCO)) and its partition in pulmonary vascular diseases without evident parenchymal disease to assess the pattern and proportionality of change in membrane diffusion (D(m)) and capillary blood volume (V(c)). Disproportionate reduction in D(m) relative to V(c) (low D(m)/V(c)) in these diseases has been attributed to associated alveolar membrane/parenchymal disease, thus providing a potentially important diagnostic tool. METHODS: Diseases included: idiopathic pulmonary arterial hypertension (n=6), chronic thromboembolic disease (n=5), and intravenous drug use (n=14), providing a spectrum of pulmonary vascular diseases. V(c) and D(m) were determined as described by Roughton and Forster. RESULTS: All diseases showed a reduced V(c) (59+/-10, 69+/-14, 71+/-21 % predicted, respectively) and D(m) (76+/-22, 53+/-19, 63+/-16 % predicted, respectively) with no differences between groups (p>0.05). Disproportionate reduction of D(m) (D(m)/V(c) % predicted <1) was seen in all diseases (range 0.36-1.89). A mathematical analysis is presented to illustrate that changes in vascular geometry may additionally influence the proportionality of changes in D(m) and V(c). The mathematical analysis suggests that when reduction in patency of some vessels co-exits with compensatory dilatation of the remaining vasculature, a disproportionate reduction in D(m) relative to V(c) may result. CONCLUSIONS: The balance between vascular curtailment and compensatory dilatation may contribute to the variability of the D(m)/V(c) relationship seen in pulmonary vascular disease. Disproportionate reduction in D(m) relative to V(c) may result from this imbalance and need not imply subclinical alveolar membrane and/or parenchymal disease.

OBJECTIVE: Obese patients without clinically apparent heart disease may have a high output state and elevated total and central blood volumes. Central circulatory congestion should result in elevated pulmonary diffusing capacity (DLCO) and capillary blood volume (Vc) reflecting pulmonary capillary recruitment; however, the effect on membrane diffusion (Dm) is uncertain. We examined DLCO and its partition into Vc and Dm in 13 severely obese subjects (BMI = 51 +/- 14 kg/m2) without manifest cardiopulmonary disease before and after surgically induced weight loss. RESEARCH METHODS AND PROCEDURES: DLCO and its partition into Vc and Dm [referenced to alveolar volume (VA)] as described by Roughton and Forster, total body water by tritiated water, and fat distribution by waist-to-hip ratio were performed. RESULTS: Despite normal DLCO (mean 98 +/- 16% predicted), Vc/VA was increased (mean 118 +/- 30% predicted), and Dm/VA was reduced (mean 77 +/- 34% predicted). Nine of 13 subjects were restudied after weight loss (mean 52 +/- 43 kg); Vc/VA decreased to 89 +/- 18% predicted (p = 0.01), and Dm/VA increased to 139 +/- 30% predicted (p < 0.01). Increasing total body water was associated with both increasing Vc (r = 0.74, p = 0.01) and increasing waist-to-hip ratio (r = 0.65, p = 0.02), indicating that circulatory congestion increases with increasing central obesity. DISCUSSION: Severely obese subjects without manifest cardiopulmonary disease may have increased Vc indicating central circulatory congestion and reduced Dm suggesting associated alveolar capillary leak, despite normal DLCO. Reversibility with weight loss is in accord with reversibility of the hemodynamic abnormalities of obesity.

Acute hypercapnia may develop during periodic breathing from an imbalance between abnormal ventilatory patterns during apnea and/or hypopnea and compensatory ventilatory response in the interevent periods. However, transition of this acute hypercapnia into chronic sustained hypercapnia during wakefulness remains unexplained. We hypothesized that respiratory-renal interactions would play a critical role in this transition. Because this transition cannot be readily addressed clinically, we modified a previously published model of whole-body CO2 kinetics by adding respiratory control and renal bicarbonate kinetics. We enforced a pattern of 8 h of periodic breathing (sleep) and 16 h of regular ventilation (wakefulness) repeated for 20 days. Interventions included varying the initial awake respiratory CO2 response and varying the rate of renal bicarbonate excretion within the physiological range. The results showed that acute hypercapnia during periodic breathing could transition into chronic sustained hypercapnia during wakefulness. Although acute hypercapnia could be attributed to periodic breathing alone, transition from acute to chronic hypercapnia required either slowing of renal bicarbonate kinetics, reduction of ventilatory CO2 responsiveness, or both. Thus the model showed that the interaction between the time constant for bicarbonate excretion and respiratory control results in both failure of bicarbonate concentration to fully normalize before the next period of sleep and persistence of hypercapnia through blunting of ventilatory drive. These respiratory-renal interactions create a cumulative effect over subsequent periods of sleep that eventually results in a self-perpetuating state of chronic hypercapnia.

OBJECTIVE: The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment. STUDY DESIGN: Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks. RESULTS: After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p=.025) and 5.7 stairs per minute more 3MSC (p=.053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227+/-18 microg/mg more with rhASB than placebo (p<.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein. CONCLUSION: rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile

In this work MRI-based spirometry is presented as a method for noninvasively assessing pulmonary mechanical function on a regional basis. A SPAMM tagging sequence was modified to allow continuous dynamic imaging of the lungs during respiration. A motion-tracking algorithm was developed to track material regions from time-resolved grid-tagged images. Experiments were performed to image the lungs during quiet breathing and volumetric strain was calculated from the measured displacement maps. Regional volume calculations, derived from volumetric strain, were integrated over the entire lung and compared to segmented volume calculations with good agreement. Results from this work demonstrate that MRI spirometry has the potential to become a clinically useful tool for measuring regional ventilation and assessing pulmonary diseases that regionally affect the mechanical function of the lung. Magn Reson Med, 2005. (c) 2005 Wiley-Liss, Inc.

STUDY OBJECTIVE: To determine the benefits of daily use of high-frequency chest wall oscillation (HFCWO) in familial dysautonomia (FD) patients with lung disease. DESIGN: Pulmonary function tests, chest radiographs, and blood tests were performed on entry to the study. A retrospective chart review of 12 months prior to entry provided baseline data regarding respiratory illnesses, medications, doctor visits, hospitalizations, and absenteeism. Daily logs provided prospective data on these parameters as well as HFCWO usage. Evaluations were performed at 1, 3, 6, 9, and 12 months for pulse oximetry, spirometry, and log review. At the exit evaluation, blood tests and chest radiographs were repeated. PATIENTS: Fifteen FD patients with history of lung disease requiring daily inhalation therapy (7 female and 8 male; age range, 11 to 33 years) were enrolled in a 1-year clinical trial of HFCWO therapy. Two subjects withdrew after 3 months and 6 months, respectively. Each individual served as his/her own control. RESULTS: Oxygen saturation improved by 1 month (median, 97.5%; interquartile range [IQR], 96 to 98%; vs median, 94%; IQR, 89 to 96%) and was sustained at exit evaluation (median, 98%; IQR, 98 to 98%) [p = 0.004]. Median FVC and peak expiratory flow rate (PEFR) were the pulmonary function measures with sustained improvement from baseline to exit (p = 0.02 and p = 0.03, respectively). When retrospective and prospective data were compared, all measured health outcomes improved significantly, including pneumonias (p = 0.0156), hospitalizations (p = 0.0161), antibiotic courses (p = 0.0005), antibiotic days (p = 0.0002), doctor visits (p = 0.0005), and absenteeism (p = 0.0002). CONCLUSION: In this limited study of FD patients, HFCWO effected significant improvements in all measured health outcomes and oxygen saturation; FVC and PEFR were the pulmonary function measures demonstrating sustained improvement

A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (>200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.