Faculty Bibliography

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.

OBJECTIVE: Prior research on the physical health of children exposed to the World Trade Center (WTC) attacks has largely relied on parental report via questionnaire. We examined the impact of clinically-reported exposures on the physical health of children who lived and/or attended school in downtown Manhattan on September 11, 2001. STUDY DESIGN: We performed a cross-sectional study of 148 patients who presented to the WTC Environmental Health Center/Survivors Health Program, and were /=1day in their home between September 11 and 18, 2001; and 25.7% reported home dust exposure. New-onset nasal/sinus congestion was reported in 52.7%, while nearly one-third reported new gastroesophageal reflux (GERD) symptoms. Prehypertension or hypertension was identified in 45.5%. Multivariable regression with exposure variables, body mass index category, and age as covariates identified strongest associations of dust cloud with spirometry (17.1% decrease in maximum midexpiratory flow). Younger children experienced increased peripheral eosinophils (+0.098% per year, p=0.023), while older children experienced more new-onset GERD (OR 1.17, p=0.004), headaches (OR 1.10, p=0.011), and prehypertension (OR 1.09, p=0.024). Home dust exposure was associated with reduced high-density lipoprotein (-10.3mg/dL, p=0.027) and elevated triglycerides (+36.3mg/dL, p=0.033). CONCLUSIONS: While these findings cannot be assumed to generalize to all children exposed to the WTC attacks, they strongly suggest the need for more extensive study of respiratory, metabolic, and cardiovascular consequences.

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.

Rationale: Exposure to World Trade Center (WTC) dust and fumes is associated with onset of asthma-like respiratory symptoms in exposed community members including local workers, residents and clean-up workers. Although abnormal spirometry measurements are often not detected in these patients, impulse oscillometry (IOS) suggests abnormalities localized to the smaller airways. Peripheral C-reactive protein (CRP) is a marker of systemic inflammation. Since an association between CRP and asthma has been reported, we hypothesized that levels of CRP would be associated with lung function abnormalities as assessed by spirometry and IOS measurements in community members exposed to WTC dust/fumes and gasses. Methods: The WTC Environmental Health Center (EHC) is a treatment program for community members, with presumed WTC-related symptoms. Patients undergo a standardized evaluation including questionnaires and routine blood work, spirometry and IOS measurements. Between 10/1/2009 and 9/29/2011, a measurement of CRP was included for patients undergoing standardized visits. Measurements of lung function were compared utilizing the Wilcoxon test between subjects with normal vs. elevated CRP and further analyzed using linear regression models with log(CRP) as a continuous predictor. Regression analyses were adjusted for potential confounding factors including Body mass index (BMI), exposure category, and smoking history. Results: 208 WTC-exposed individuals met inclusion criteria. Valid spirometry and IOS data were available in 204 and 189 patients, respectively. Mean age was 49 years, 53% were female. Exposure categories (local workers, clean-up workers, residents) were associated with normal/elevated CRP levels (P=0.01). Smokers had a larger portion of elevated CRP (P=0.048). BMI was higher among the high CRP group (Wilcoxon test, P<0.001). FEV₁ and FVC were lower for the high CRP group (P=0.016, P=0.033). However, CRP level was not associated with the ratio FEV₁/FVC (P=0.58). The IOS measurements (R₅, R_5-20, AX ) were higher (P=0.01, P=0.003, P=.001, respectively) among the high CRP group. Multiple regression analysis confirmed that log(CRP) values were inversely correlated with % of predicted FEV 1 (P=0.009) and positively correlated with log(R₅) (P=0.02) and log(AX) (P=0.0045) after adjustment for log(BMI). Conclusions: Peripheral CRP was negatively correlated with levels of FEV₁ and positively correlated with IOS measurements in community members with WTC dust/gas/fume exposure. These data suggest a relationship between systemic inflammation, as reflected by CRP, and both large and small airway abnormalities in a WTC- exposed population

RATIONALE: Analysis of local in vivo inflammation is relevant to the understanding of pathogenesis and disease progression in emphysema. Bronchial reactivity is an early marker of disease in asthma but the relevance of reactivity to the natural history of emphysema is not understood. We hypothesize that bronchial reactivity is a phenotype of early emphysema that might be related to the degree of inflammation in the lung. METHODS: Normal subjects were enrolled as part of a normal volunteer protocol. Emphysema subjects were identified from the NYU Lung Cancer Biomarker Center CT-scan screening cohort. All patients underwent spirometry, plethysmography, diffusion, and oscillometry, as well as bronchoscopy with bronchoalveolar lavage (BAL). Bronchial reactivity was assessed by changes in FEV1, V50 and R5 . From the BAL fluid, cell count differential was obtained, as well as measurement of 39 cytokines in concentrated BAL fluid with Luminex using Human Cytokine Panel I (Millipore). Results amongst the groups were compared with ANOVA and post-hoc LSD comparison. RESULTS: Twenty patients were available for analysis: Six subjects in the control group, 6 emphysema subjects without bronchial reactivity (BR-), and 8 emphysema subjects with bronchial reactivity (BR+). Baseline demographics and pertinent spirometry/oscillometry are listed in Table 1. Emphysema subjects were all GOLD stage 0 or 1. Post-bronchodilator spirometric and oscillometric parameters were not significantly different between BR- and BR+ emphysema groups. There were 28/39 cytokines with reliably measurable levels. Both emphysema groups had elevated neutrophils and higher degree of inflammation as compared to controls (significant data shown Table 1). However, the BR+ emphysema group evidenced higher degree of neutrophils, IL-6, IL-8, G-CSF, Eotaxin, GRO and Fractalkine as compared with the BR- emphysema group. CONCLUSION: These data suggest that in early emphysema a phenotype of proximal and/or distal bronchial reactivity is associated with an increased degree of inflammation as assessed by neutrophils and in vivo inflammatory cytokines. In contrast with early asthma, the phenotype of bronchial reactivity in early emphysema may be characterized by neutrophilic inflammation produced by increased IL-8 in the lung. The role of IL-6, G-CSF, Eotaxin, GRO and Fractalkine in producing emphysema related bronchial reactivity requires further investigation. (Table Presented)

Rationale: The use of culture-independent techniques to evaluate resident microbial communities in the lung has opened opportunities to evaluate host response phenotype in health and disease. Background environmental microbiome found in saline and bronchoscope prior to bronchoscopy is characterized by high relative abundance of Propionibacterium. Our preliminary data from the lung microbiome project suggest that substitution of background environmental microbiome by Prevotella or Streptococcus microbiome is associated with higher inflammation. We hypothesize that patients with emphysema who have asymmetric disease on CT will have disappearance of background environmental microbiome in the more affected lung segments. We will also evaluate whether background environmental microbiome is associated with lower inflammation (neutrophil counts, and chemo-attractant cytokines). Methods: Subjects with emphysema were enrolled for research bronchoscopy from NYU/EDRN cohort and CT scans were classified as symmetrical or asymmetrical lung disease. Broncho-alveolar lavages (BAL) were obtained from the right and left lung. Sequencing of 300 bp 16S rDNA included V1-V2 region, performed with 454 pyrosequence. Propionibacterium was used as a marker of background environmental microbiome. Cytokines in BAL fluid will be assayed using Human Cytokine Panel I (Millipore). Results: To date, 15 subjects had sequence data from two segments of different lungs (5 normal volunteers, 6 symmetrical lung disease patients, and 4 asymmetrical lung disease patients). Healthy volunteers were younger than subjects with emphysema (41 +/- 11, 61 +/- 6 respectively, p = 0.003). Although no significant difference in FEV1 was observed, emphysema groups trended to have lower FEV1/FVC (p=ns). There were no differences in high relative abundant taxa (greater than 0.05) between the right and left lung of normal volunteers and emphysema subjects with symmetrical lung disease. However, despite the small n, emphysema subjects with asymmetrical lung disease trended to have higher relative abundance of background environmental microbiome in lung segments with less disease ( Propionibacterium relative abundance = 0.13 +/- 0.04 for segments with less disease as compared with 0.03 +/- 0.04 in the more disease segments, p < 0.08). We will complete sequence in 5 more emphysema subjects and compare microbiota with in-vivo BAL cytokines. Conclusions: Patients with observable asymmetrical lung disease have lower background environmental microbiome in more diseased lung when compared to the less diseased side. This difference was not observed in normal volunteers and patients with symmetrical lung disease. Disappearance of background environmental microbiome in more diseased lung segments suggests higher airway colonization, which might be associated with subclinical inflammation

INTRODUCTION: We have previously shown improvement in spirometry parameters in symptomatic WTC dust exposed community members enrolled in the WTC Environmental Health Center treatment program. Additionally, impulse oscillometry (IOS) has demonstrated evidence for distal lung injury not apparent on spirometry. We hypothesize that longitudinal change of spirometry will differ based on presence or absence of distal airway injury and its response to bronchodilator at baseline. METHODS: 810 patients were identified with more than one spirometry and IOS assessment. IOS parameters included resistance at 5 and 20Hz (R₅ and R₂₀) and frequency dependence of resistance assessed as the difference between these parameters (R_5-20). Linear mixed effects modeling evaluated longitudinal changes in IOS parameters, FVC and FEV₁ for the entire population. Separate models were fit for subgroups categorized based on normal vs. abnormal baseline spirometry and normal vs. abnormal baseline IOS (R₅>3.96 cmH2O/L/s). Analyses were adjusted for confounding factors (age, gender, BMI, race/ethnicity, smoking, exposure category and dust cloud exposure). RESULTS: Mean age was 50yr. Patients were mostly female (52%) and had diverse race/ethnicity. At baseline, mean FVC was 91+/-17% predicted and FEV₁ was 88+/-18% predicted. A normal spirometry pattern was noted in the majority (67%; n=542). Despite normal spirometry, IOS revealed abnormalities in 67% (n=364). Longitudinal analysis of IOS parameters (R₅, R₂₀, R_5-20) over time revealed no significant trends for the entire population and for subgroups categorized by baseline spirometry pattern. In contrast, the longitudinal change in spirometry variables differed based on presence of IOS abnormality. In patients with normal spirometry, FEV₁ increased more rapidly in patients with abnormal baseline IOS compared to those with normal IOS (0.76 vs. 0.52 % predicted/yr; Table 1). For patients with abnormal baseline spirometry, FVC increased more rapidly in the abnormal vs. normal IOS patients (1.73 vs. 1.02 % predicted/yr). Patients with IOS response to bronchodilator (highest quartile for improvement of R₅ post bronchodilator) demonstrated a more rapid longitudinal increase in FEV₁ compared with patients without bronchodilator response (lowest quartile)(0.88 vs. 0.53 % predicted/yr,; Table 2). CONCLUSIONS: Spirometry parameters demonstrated improvement over time, while improvement in IOS parameters was not evident, suggesting potential irreversible injury in the distal lung. However, assessment of baseline distal airway function and its acute response to bronchodilator predicted longitudinal response of spirometry in patients enrolled in a treatment program. (Table Presented)

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 H(2)O/L/s), frequency dependence of resistance from 5 to 20 Hz (2.20 +/- 1.6 cm H(2)O/L/s), and reactance at 5 Hz (-3.47 +/- 2.1 cm H(2)O/L/s). Postoperatively, the subjects demonstrated 57% +/- 15% excess weight loss. The body mass index decreased (from 44 +/- 6 to 32 +/- 5 kg/m(2), 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.