Faculty Bibliography

(1) Background: Variants of the interleukin-1 receptor antagonist (IL1RN) gene, encoding an anti-inflammatory cytokine, are associated with asthma. Asthma is a chronic inflammatory disease of the airway influenced by interactions between genetic variants and environmental factors. We discovered a gene-environment interaction (GEI) of IL1RN polymorphisms with childhood environmental tobacco smoke (ETS) exposure on asthma susceptibility in an urban adult population. (2) Methods: DNA samples from the NYU/Bellevue Asthma Registry were genotyped for tag SNPs in IL1RN in asthma cases and unrelated healthy controls. Logistic regressions were used to study the GEI between IL1RN variants and childhood ETS exposures on asthma and early onset asthma, respectively, adjusting for population admixture and other covariates. (3) Results: Whereas the rare genotypes of IL1RN SNPs (e.g., GG in SNP rs2234678) were associated with decreased risk for asthma among those without ETS exposure (odds ratio OR = 0.215, p = 0.021), they are associated with increased risk for early onset asthma among those with childhood ETS (OR = 4.467, p = 0.021). (4) Conclusions: We identified a GEI between polymorphisms of IL1RN and childhood ETS exposure in asthma. Analysis of GEI indicated that childhood ETS exposure disrupted the protective effect of some haplotypes/genotypes of IL1RN for asthma and turned them into high-risk polymorphisms for early onset asthma.

OBJECTIVE:To investigate whether paresthesia of the lower extremities following exposure to the World Trade Center (WTC) disaster was associated with signs of neuropathy, metabolic abnormalities, or neurotoxin exposures. METHODS:Case-control study comparing WTC-exposed paresthesia cases with "clinic controls" (WTC-exposed subjects without paresthesias), and "community controls" (WTC-unexposed persons). RESULTS:Neurological histories and examination findings were significantly worse in cases than controls. Intraepidermal nerve fiber densities were below normal in 47% of cases and sural to radial sensory nerve amplitude ratios were less than 0.4 in 29.4%. Neurologic abnormalities were uncommon among WTC-unexposed community controls. Metabolic conditions and neurotoxin exposures did not differ among groups. CONCLUSIONS:Paresthesias among WTC-exposed individuals were associated with signs of neuropathy, small and large fiber disease. The data support WTC-related exposures as risk factors for neuropathy, and do not support non-WTC etiologies.

A positive association between mental health conditions and poor asthma control has been documented in the World Trade Center-exposed population. Whether factors such as medication adherence mediate this association is unknown. The study population was drawn from adult participants of the World Trade Center Health Registry Cohort who self-reported as asthmatic after the disaster and who were currently prescribed a long-term control medication (LTCM). Multivariable linear regression was used to estimate the associations between mental health condition (PTSD, depression, or anxiety) and continuous adherence and Asthma Control Test (ACT) scores. In the study sample of 1,293, 49% were not adherent to their LTCM and two thirds reported poorly or very poorly controlled asthma. Presence of any mental health condition was associated with a 2-point decline in ACT and half a point decrease in adherence scores. However, in the multivariable model, better adherence was statistically significantly associated with slightly worse control. The total effect of mental health on asthma control was opposite in sign from the product of the paths between mental health and adherence and adherence and asthma control; we therefore found no evidence to support the hypothesis that adherence mediated the negative association between poor mental health and adequate asthma control. More research is needed to understand the complex causal mechanisms that underlie the association between mental and respiratory health.

Background: Sarcoidosis is a granulomatous disease involving intrathoracic and extrathoracic organs. Genetic and environmental factors, such as exposure to World-Trade Center (WTC) dust after 9/11, may play a role in clinical presentation. Characterization of sarcoidosis in community members with exposure to the WTC dust can provide further insight into the relationship between environmental exposure and sarcoidosis. Methods: Patients with documented sarcoidosis were identified in the WTC Environmental Health Center (EHC), a treatment program for community members. Demographic and clinical data were collected from standardized questionnaires and chart review. Organ involvement was assessed with a standard instrument. Results: Among patients in the WTC EHC, 87 were identified with sarcoidosis after 9/11. Sarcoidosis cases were more likely African-American, local workers, and had more respiratory symptoms, compared with non-sarcoidosis WTC EHC patients. Many (46%) had ≥ Scadding stage 3 on chest imaging, and had reduced lung function measures. Extrathoracic involvement was identified in 33/87 (38%) with a diversity of organs involved. Conclusions: WTC-exposed sarcoidosis in community members is often characterized by severe pulmonary disease and a high rate of diverse extrathoracic involvement. Further analysis is required to characterize the course of disease progression or resolution.

The evolution of lung function, including assessment of small airways, was assessed in individuals enrolled in the World Trade Center Environmental Health Center (WTC-EHC). We hypothesized that a bronchodilator response at initial evaluation shown by spirometry or in small airways, as measured by forced oscillation technique (FOT), would be associated with improvement in large and small airway function over time. Standardized longitudinal assessment included pre and post bronchodilator (BD) spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV₁) and FOT (resistance at 5 Hz, R₅; resistance at 5 minus 20 Hz, R_5-20). Longitudinal changes were assessed using linear mixed-effects modelling with adjustment for potential confounders (median follow-up 2.86 years; 95% measurements within 4.9 years). Data demonstrated: (1) parallel improvement in airflow and volume measured by spirometry and small airway function (R₅ and R_5-20) measured by FOT; (2) the magnitude of longitudinal improvement was tightly linked to the initial BD response; and (3) longitudinal values for small airway function on FOT were similar to residual abnormality observed post BD at initial visit. These findings suggest presence of reversible and irreversible components of small airway injury that are identifiable at initial presentation. These results have implications for treatment of isolated small airway abnormalities that can be identified by non-invasive effort independent FOT particularly in symptomatic individuals with normal spirometry indices. This study underscores the need to study small airway function to understand physiologic changes over time following environmental and occupational lung injury.

We examined whether time to onset of paresthesia was associated with indicators of severity of World Trade Center (WTC) exposure. We analyzed data from 3411 patients from the Bellevue Hospital-WTC Environmental Health Center. Paresthesia was defined as present if the symptom occurred in the lower extremities with frequency "often" or "almost continuous." We plotted hazard functions and used the log-rank test to compare time to onset of paresthesia between different exposure groups. We also used Cox regression analysis to examine risk factors for time-to-paresthesia after 9/11/2001 and calculate hazard ratios adjusted for potential confounders. We found significantly elevated hazard ratios for paresthesia for (a) working in a job that required cleaning of WTC dust in the workplace; and (b) being heavily exposed to WTC dust on September 11, 2001, after adjusting for age, race/ethnicity, depression, anxiety, post-traumatic stress disorder, and body mass index. These observational data are consistent with the hypothesis that exposure to WTC dust or some other aspect of cleaning WTC dust in the workplace, is associated with neuropathy and paresthesia. Further neurological evaluations of this and other WTC-exposed populations is warranted.

The World Trade Center (WTC) Environmental Health Center (EHC) is a treatment program for community members with exposure to the 9/11 terrorist attack and its physical and emotional aftermath. Compared to the general responders program, the WTC EHC is diverse with equal gender distribution, representation of many races and ethnicities, and a wide range of social economic status. Patients in the WTC EHC were initially enrolled for physical symptoms, most of which were respiratory, however a large portion of the enrollees scored positive for probable posttraumatic stress disorder (PTSD). In this paper we identify patient characteristics associated with probable PTSD. We also determine the characteristics associated with the longitudinal change of PTSD symptoms, including persistence and remittance, using the widely used Posttraumatic Check List-17 (PCL) cut-off value of 44, as well as changes in PCL total score and symptom cluster scores in patients of Low and High PTSD symptom severity. Few patients with elevated scores achieved a score below 44. However, longitudinal improvement in PCL score at follow-up was identified for patients with High PTSD scores (PCL > 57.5). Changes in PCL symptom clusters differed between those with High and Low PCL scores. These data suggest improvement over time in PCL score that differs depending on the severity of the score and variable responses in the PCL symptom clusters.

RATIONALE/BACKGROUND:Although national and international guidelines recommend reduction of asthma controller therapy or 'step-down" therapy in patients with well controlled asthma, it is expected that some individuals may experience worsening of asthma symptoms or asthma exacerbations during step-down. Characteristics associated with subsequent exacerbations during step-down therapy have not been well defined. The effect of environmental tobacco smoke (ETS) exposure on risk of treatment failure during asthma step down therapy has not been reported. OBJECTIVES/OBJECTIVE:To identify baseline characteristics associated with treatment failure and asthma exacerbation during maintenance and guideline-based step-down therapy. METHODS:The present analysis uses data collected from a completed randomized controlled trial of optimal step-down therapy in patients with well controlled asthma taking moderate dose combination inhaled corticosteroids/long acting beta agonists. Participants were 12 years or older with physician diagnosed asthma and were enrolled between December 2011 and May 2014. RESULTS:An Emergency Room visit in the previous year was predictive of a subsequent treatment failure (HR 1.53 (1.06, 2.21 CI). For every 10% increase in baseline forced expiratory volume in one second percent predicted, the hazard for treatment failure was reduced by 14% (95% CI: 0.74-0.99). There was no difference in risk of treatment failure between adults and children, nor did duration of asthma increase risk of treatment failure. Age of asthma onset was not associated with increased risk of treatment failure. Unexpected emergency room visit in the previous year was the only risk factor significantly associated with subsequent asthma exacerbations requiring systemic corticosteroids. Time to treatment failure or exacerbation did not differ in participants with and without self-report of ETS exposure. CONCLUSIONS:The present findings can help clinicians identify patients more likely to develop treatment failures and exacerbations and who may therefore require closer monitoring during asthma step-down treatment. Individuals with reduced pulmonary function, a history of exacerbations, and early onset disease, even if otherwise well controlled, may require closer observation to prevent treatment failures and asthma exacerbations. Clinical trial registered with ClinicalTrials.gov (NCT01437995).

STUDY OBJECTIVES/OBJECTIVE:A relationship between obstructive sleep apnea (OSA) and exposure to the World Trade Center (WTC) dust and fumes has been suggested in responders but little is known about a possible relationship in community members. We characterized sleep studies performed in community members with WTC dust exposure to improve our understanding of the relationship between the diagnosis and severity of OSA and WTC dust exposure in this population. METHODS:Single-center, retrospective study of patients enrolled in a clinical treatment program for community members with WTC dust exposure. Patients were included if they had undergone sleep studies for evaluation of possible OSA through September 2016 and provided written informed consent. RESULTS:. Most reported upper and lower respiratory symptoms. An apnea-hypopnea index (AHI) ≥ 5 events/h was measured in 66% of the patients, and respiratory disturbance index was ≥ 5 events/h in 97%. The proportion of patients with moderate-severe OSA (defined by the AHI 4% criteria) was 50%. Multivariate logistic regression revealed that acute WTC dust cloud exposure was associated with severity but not diagnosis of OSA. CONCLUSIONS:We identified a high rate of OSA in the WTC community cohort who were referred for sleep studies. Exposure to the massive WTC dust cloud caused by the WTC collapse was independently associated with the severity of OSA in this population. This finding highlights the role that environmental exposures may play in the development of OSA.

BACKGROUND: Stepping down therapy when asthma is well controlled on combination inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs) is recommended, but it is not known whether lowering the ICS dose or stopping LABA is superior. OBJECTIVE: To evaluate whether step-down therapy with LABA is superior to one without; and, secondarily, to evaluate whether reducing the ICS dose while maintaining LABA is noninferior to remaining on stable-ICS/LABA. METHODS: The study was a randomized, double-masked 3-arm parallel group trial in participants aged 12 years or older. Following an 8-week run-in, 459 participants were randomly assigned to continue medium-dose ICS/LABA, reduced-dose ICS/LABA, or ICS alone (LABA-step-off) and followed for 48 weeks. The primary outcome was time to treatment failure, a composite of health care utilization, systemic corticosteroid use, increase in rescue therapy, decline in lung function, or participant or physician decision. RESULTS: Time to treatment failure did not differ significantly between reduced- ICS/LABA and LABA-step-off (hazard ratio, 1.07; 95.3% CI, 0.69-1.65, P = .76). Nor was there a difference between stable-ICS/LABA and reduced-ICS/LABA (hazard ratio, 1.11; 95% CI, 0.70-1.76; P = .67), but the 10% noninferiority margin was exceeded. Lung function declines and hospitalization rates were significantly greater in the LABA-step-off group. CONCLUSIONS: The 2 step-down regimens did not differ in terms of treatment failure, although stopping LABA was associated with a decline in lung function and more hospitalizations. There was no evidence to support the noninferiority of reduced-ICS/LABA as compared with stable-ICS/LABA.