Validation of Predictive Metabolic Syndrome Biomarkers of World Trade Center Lung Injury

A 16-Year Longitudinal Study

      Background

      Metabolic syndrome (MetSyn) predicted future development of World Trade Center lung injury (WTC-LI) in a subgroup of firefighters who never smoked and were male. An intracohort validation of MetSyn as a predictor of WTC-LI is examined in the cohort exposed to the World Trade Center (WTC) that has been followed longitudinally for 16 years.

      Methods

      Results of pulmonary function tests (n = 98,221) in workers exposed to the WTC (n = 9,566) were evaluated. A baseline cohort of firefighters who had normal FEV 1 before 9/11 and who had had serum drawn before site closure on July 24, 2002 (n = 7,487) was investigated. Case subjects with WTC-LI (n = 1,208) were identified if they had at least two measured instances of FEV 1 less than the lower limit of normal (LLN). Cox proportional hazards modeled early MetSyn biomarker ability to predict development of FEV 1 less than the LLN.

      Results

      Case subjects were more likely to smoke, be highly exposed, and have MetSyn. There was a significant exposure dose response; the individuals most highly exposed had a 30.1% increased risk of developing WTC-LI, having MetSyn increased risk of developing WTC-LI by 55.7%, and smoking increased risk by 15.2%. There was significant interaction between smoking and exposure.

      Conclusions

      We validated the usefulness of MetSyn to predict future WTC-LI in a larger population of individuals who were exposed. MetSyn defined by dyslipidemia, insulin resistance, and cardiovascular disease suggests that systemic inflammation can contribute to future lung function loss.

      Key Words

      Abbreviations:

      DBP ( diastolic BP), FDNY ( Fire Department of New York), HDL ( high-density lipoprotein), HR ( hazard ratio), LDL ( low-density lipoprotein), LLN ( lower limit of normal), MetSyn ( metabolic syndrome), PFT ( pulmonary function test), PM ( particulate matter), SBP ( systolic BP), WTC ( World Trade Center), WTC-HP ( WTC Health Program), WTC-LI ( WTC Lung Injury)
      To read this article in full you will need to make a payment
      Subscribe to CHEST
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Grundy S.M.
        • Cleeman J.I.
        • Daniels S.R.
        • et al.
        Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.
        Circulation. 2005; 112: 2735-2752
        • Aguilar M.
        • Bhuket T.
        • Torres S.
        • Liu B.
        • Wong R.J.
        Prevalence of the metabolic syndrome in the United States, 2003-2012.
        JAMA. 2015; 313: 1973-1974
        • Wallwork R.S.
        • Colicino E.
        • Zhong J.
        • et al.
        Ambient fine particulate matter, outdoor temperature, and risk of metabolic syndrome.
        Am J Epidemiol. 2017; 185: 30-39
        • Brook R.D.
        • Sun Z.
        • Brook J.R.
        • et al.
        Extreme air pollution conditions adversely affect blood pressure and insulin resistance: the Air Pollution and Cardiometabolic Disease Study.
        Hypertension. 2016; 67: 77-85
        • Leone N.
        • Courbon D.
        • Thomas F.
        • et al.
        Lung function impairment and metabolic syndrome: the critical role of abdominal obesity.
        Am J Respir Crit Care Med. 2009; 179: 509-516
        • Fiordelisi A.
        • Piscitelli P.
        • Trimarco B.
        • Coscioni E.
        • Iaccarino G.
        • Sorriento D.
        The mechanisms of air pollution and particulate matter in cardiovascular diseases.
        Heart Fail Rev. 2017; 22: 337-347
        • Zammit C.
        • Liddicoat H.
        • Moonsie I.
        • Makker H.
        Obesity and respiratory diseases.
        Int J Gen Med. 2010; 3: 335-343
        • Baffi C.W.
        • Wood L.
        • Winnica D.
        • et al.
        Metabolic syndrome and the lung.
        Chest. 2016; 149: 1525-1534
        • Peters U.
        • Suratt B.T.
        • Bates J.H.T.
        • Dixon A.E.
        Beyond BMI: obesity and lung disease.
        Chest. 2018; 153: 702-709
        • Griffith K.A.
        • Sherrill D.L.
        • Siegel E.M.
        • Manolio T.A.
        • Bonekat H.W.
        • Enright P.L.
        Predictors of loss of lung function in the elderly: the Cardiovascular Health Study.
        Am J Respir Crit Care Med. 2001; 163: 61-68
        • Piazzolla G.
        • Castrovilli A.
        • Liotino V.
        • et al.
        Metabolic syndrome and chronic obstructive pulmonary disease (COPD): the interplay among smoking, insulin resistance and vitamin D.
        PLoS One. 2017; 12: e0186708
        • Park H.J.
        • Leem A.Y.
        • Lee S.H.
        • et al.
        Comorbidities in obstructive lung disease in Korea: data from the fourth and fifth Korean National Health and Nutrition Examination Survey.
        Int J Chron Obstruct Pulmon Dis. 2015; 10: 1571-1582
        • Cunningham T.J.
        • Ford E.S.
        • Rolle I.V.
        • Wheaton A.G.
        • Croft J.B.
        Associations of self-reported cigarette smoking with chronic obstructive pulmonary disease and co-morbid chronic conditions in the United States.
        COPD. 2015; 12: 276-286
        • Bowler R.P.
        • Jacobson S.
        • Cruickshank C.
        • et al.
        Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes.
        Am J Respir Crit Care Med. 2015; 191: 275-284
        • Hoonhorst S.J.
        • Lo Tam Loi A.T.
        • Hartman J.E.
        • et al.
        Advanced glycation end products in the skin are enhanced in COPD.
        Metabolism. 2014; 63: 1149-1156
        • Yonchuk J.G.
        • Silverman E.K.
        • Bowler R.P.
        • et al.
        Circulating soluble receptor for advanced glycation end products (sRAGE) as a biomarker of emphysema and the RAGE axis in the lung.
        Am J Respir Crit Care Med. 2015; 192: 785-792
        • Caraher E.J.
        • Kwon S.
        • Haider S.H.
        • et al.
        Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: a case-cohort study and murine model of acute particulate exposure.
        PLoS One. 2017; 12: e0184331
        • Cho S.J.
        • Echevarria G.C.
        • Kwon S.
        • et al.
        One airway: biomarkers of protection from upper and lower airway injury after World Trade Center exposure.
        Respir Med. 2014; 108: 162-170
        • Nolan A.
        • Naveed B.
        • Comfort A.L.
        • et al.
        Inflammatory biomarkers predict airflow obstruction after exposure to World Trade Center dust.
        Chest. 2012; 142: 412-418
        • Naveed B.
        • Weiden M.D.
        • Kwon S.
        • et al.
        Metabolic syndrome biomarkers predict lung function impairment: a nested case-control study.
        Am J Respir Crit Care Med. 2012; 185: 392-399
        • Prezant D.J.
        • Weiden M.
        • Banauch G.I.
        • et al.
        Cough and bronchial responsiveness in firefighters at the World Trade Center site.
        N Engl J Med. 2002; 347: 806-815
        • Crowley G.
        • Kwon S.
        • Haider S.H.
        • et al.
        Metabolomics of World Trade Center-Lung Injury: a machine learning approach.
        BMJ Open Respir Res. 2018; 5: e000274
        • Lioy P.J.
        • Weisel C.P.
        • Millette J.R.
        • et al.
        Characterization of the dust/smoke aerosol that settled east of the World Trade Center (WTC) in lower Manhattan after the collapse of the WTC 11 September 2001.
        Environ Health Perspect. 2002; 110: 703-714
        • Levin S.
        • Herbert R.
        • Skloot G.
        • et al.
        Health effects of World Trade Center site workers.
        Am J Ind Med. 2002; 42: 545-547
        • Banauch G.I.
        • Dhala A.
        • Alleyne D.
        • et al.
        Bronchial hyperreactivity and other inhalation lung injuries in rescue/recovery workers after the World Trade Center collapse.
        Crit Care Med. 2005; 33: S102-S106
        • Landrigan P.J.
        • Lioy P.J.
        • Thurston G.
        • et al.
        Health and environmental consequences of the World Trade Center disaster.
        Environ Health Perspect. 2004; 112: 731-739
        • Farfel M.
        • DiGrande L.
        • Brackbill R.
        • et al.
        An overview of 9/11 experiences and respiratory and mental health conditions among World Trade Center Health Registry enrollees.
        J Urban Health. 2008; 85: 880-909
        • Aldrich T.K.
        • Vossbrinck M.
        • Zeig-Owens R.
        • et al.
        Lung function trajectories in World Trade Center-exposed New York City firefighters over 13 years: the roles of smoking and smoking cessation.
        Chest. 2016; 149: 1419-1427
        • Niles J.K.
        • Webber M.P.
        • Cohen H.W.
        • et al.
        The respiratory pyramid: from symptoms to disease in World Trade Center exposed firefighters.
        Am J Ind Med. 2013; 56: 870-880
        • Tsukiji J.
        • Cho S.J.
        • Echevarria G.C.
        • et al.
        Lysophosphatidic acid and apolipoprotein A1 predict increased risk of developing World Trade Center-lung injury: a nested case-control study.
        Biomarkers. 2014; 19: 159-165
        • Cho S.J.
        • Nolan A.
        • Echevarria G.C.
        • et al.
        Chitotriosidase is a biomarker for the resistance to World Trade Center lung injury in New York City firefighters.
        J Clin Immunol. 2013; 33: 1134-1142
        • Hankinson J.L.
        • Odencrantz J.R.
        • Fedan K.B.
        Spirometric reference values from a sample of the general U.S. population.
        Am J Respir Crit Care Med. 1999; 159: 179-187
        • Weiden M.D.
        • Naveed B.
        • Kwon S.
        • et al.
        Cardiovascular biomarkers predict susceptibility to lung injury in World Trade Center dust-exposed firefighters.
        Eur Respir J. 2013; 41: 1023-1030
        • Weiden M.D.
        • Kwon S.
        • Caraher E.
        • et al.
        Biomarkers of World Trade Center particulate matter exposure: physiology of distal airway and blood biomarkers that predict FEV(1) decline.
        Semin Respir Crit Care Med. 2015; 36: 323-333
        • Weiden M.D.
        • Ferrier N.
        • Nolan A.
        • et al.
        Obstructive airways disease with air trapping among firefighters exposed to World Trade Center dust.
        Chest. 2010; 137: 566-574
        • Kwon S.
        • Weiden M.D.
        • Echevarria G.C.
        • et al.
        Early elevation of serum MMP-3 and MMP-12 predicts protection from World Trade Center-lung injury in New York City firefighters: a nested case-control study.
        PLoS One. 2013; 8: e76099
        • Cho S.J.
        • Echevarria G.C.
        • Lee Y.I.
        • et al.
        YKL-40 is a protective biomarker for fatty liver in World Trade Center particulate matter-exposed firefighters.
        J Mol Biomark Diagn. 2014; 5: 10000174
        • Edelman P.
        • Osterloh J.
        • Pirkle J.
        • et al.
        Biomonitoring of chemical exposure among New York City firefighters responding to the World Trade Center fire and collapse.
        Environ Health Perspect. 2003; 111: 1906-1911
        • Huang P.L.
        A comprehensive definition for metabolic syndrome.
        Dis Model Mech. 2009; 2: 231-237
        • Genuth S.
        • Alberti K.G.
        • Bennett P.
        • et al.
        Follow-up report on the diagnosis of diabetes mellitus.
        Diabetes Care. 2003; 26: 3160-3167
      1. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: Report of a WHO Consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva, Switzerland: World Health Organization; 1999. https://apps.who.int/iris/bitstream/handle/10665/66040/WHO_NCD_NCS_99.2.pdf;jsessionid=9CC692F8D168C27C8070D5BC89F1A05C?sequence=1. Accessed April 2, 2019.

        • Webber M.P.
        • Glaser M.S.
        • Weakley J.
        • et al.
        Physician-diagnosed respiratory conditions and mental health symptoms 7-9 years following the World Trade Center disaster.
        Am J Ind Med. 2011; 54: 661-671
        • Weiden M.D.
        • Naveed B.
        • Kwon S.
        • et al.
        Comparison of WTC dust size on macrophage inflammatory cytokine release in vivo and in vitro.
        PLoS One. 2012; 7: e40016
        • Aldrich T.K.
        • Ye F.
        • Hall C.B.
        • et al.
        Longitudinal pulmonary function in newly hired, non-World Trade Center-exposed fire department City of New York firefighters: the first 5 years.
        Chest. 2013; 143: 791-797
        • Nolan A.
        • Kwon S.
        • Cho S.J.
        • et al.
        MMP-2 and TIMP-1 predict healing of WTC-lung injury in New York City firefighters.
        Respir Res. 2014; 15: 5
        • Schenck E.J.
        • Echevarria G.C.
        • Girvin F.G.
        • et al.
        Enlarged pulmonary artery is predicted by vascular injury biomarkers and is associated with WTC-Lung Injury in exposed fire fighters: a case-control study.
        BMJ Open. 2014; 4: e005575
        • Liu X.
        • Yip J.
        • Zeig-Owens R.
        • et al.
        The effect of World Trade Center exposure on the timing of diagnoses of obstructive airway disease, chronic rhinosinusitis, and gastroesophageal reflux disease.
        Front Public Health. 2017; 5: 2
        • Song M.K.
        • Lin F.C.
        • Ward S.E.
        • Fine J.P.
        Composite variables: when and how.
        Nurs Res. 2013; 62: 45-49
        • Landgren O.
        • Zeig-Owens R.
        • Giricz O.
        • et al.
        Multiple myeloma and its precursor disease among firefighters exposed to the World Trade Center disaster.
        JAMA Oncol. 2018; 4: 821-827
        • Haider S.H.
        • Kwon S.
        • Lam R.
        • et al.
        Predictive biomarkers of gastroesophageal reflux disease and Barrett's esophagus in World Trade Center exposed firefighters: a 15 year longitudinal study.
        Sci Rep. 2018; 8: 3106
        • Hena K.M.
        • Yip J.
        • Jaber N.
        • et al.
        Clinical course of sarcoidosis in World Trade Center-exposed firefighters.
        Chest. 2018; 153: 114-123
        • Moualla M.
        • Qualls C.
        • Arynchyn A.
        • et al.
        Rapid decline in lung function is temporally associated with greater metabolically active adiposity in a longitudinal study of healthy adults.
        Thorax. 2017; 72: 1113-1120
        • Sagun G.
        • Gedik C.
        • Ekiz E.
        • Karagoz E.
        • Takir M.
        • Oguz A.
        The relation between insulin resistance and lung function: a cross sectional study.
        BMC Pulm Med. 2015; 15: 139
        • Wei Y.
        • Zhang J.J.
        • Li Z.
        • et al.
        Chronic exposure to air pollution particles increases the risk of obesity and metabolic syndrome: findings from a natural experiment in Beijing.
        FASEB J. 2016; 30: 2115-2122
        • Cupul-Uicab L.A.
        • Skjaerven R.
        • Haug K.
        • et al.
        Exposure to tobacco smoke in utero and subsequent plasma lipids, ApoB, and CRP among adult women in the MoBa cohort.
        Environ Health Perspect. 2012; 120: 1532-1537
        • Stevens D.R.
        • Malek A.M.
        • Laggis C.
        • Hunt K.J.
        In utero exposure to tobacco smoke, subsequent cardiometabolic risks, and metabolic syndrome among U.S. adolescents.
        Ann Epidemiol. 2018; 28 (619.e611-624.e611)
        • Szema A.
        • Mirsaidi N.
        • Patel B.
        • et al.
        Proposed Iraq/Afghanistan War-Lung Injury (IAW-LI) Clinical Practice Recommendations: National Academy of Sciences' Institute of Medicine Burn Pits Workshop.
        Am J Mens Health. 2017; 11: 1653-1663
        • Harrington A.D.
        • Schmidt M.P.
        • Szema A.M.
        • et al.
        The role of Iraqi dust in inducing lung injury in United States Soldiers: an interdisciplinary study.
        Geohealth. 2017; 1: 237-246
        • Yang B.Y.
        • Qian Z.M.
        • Li S.
        • et al.
        Long-term exposure to ambient air pollution (including PM1) and metabolic syndrome: the 33 Communities Chinese Health Study (33CCHS).
        Environ Res. 2018; 164: 204-211
        • Holland W.L.
        • Bikman B.T.
        • Wang L.P.
        • et al.
        Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice.
        J Clin Invest. 2011; 121: 1858-1870
        • Lands W.E.
        • Libelt B.
        • Morris A.
        • et al.
        Maintenance of lower proportions of (n - 6) eicosanoid precursors in phospholipids of human plasma in response to added dietary (n - 3) fatty acids.
        Biochim Biophys Acta. 1992; 1180: 147-162
        • Fekete K.
        • Marosvolgyi T.
        • Jakobik V.
        • Decsi T.
        Methods of assessment of n-3 long-chain polyunsaturated fatty acid status in humans: a systematic review.
        Am J Clin Nutr. 2009; 89: 2070S-2084S
        • Chuang Y.C.
        • Shaw H.M.
        • Chen C.C.
        • Pan H.J.
        • Lai W.C.
        • Huang H.L.
        Short-term glutamine supplementation decreases lung inflammation and the receptor for advanced glycation end-products expression in direct acute lung injury in mice.
        BMC Pulm Med. 2014; 14: 115
        • Kutsuzawa T.
        • Shioya S.
        • Kurita D.
        • Haida M.
        Plasma branched-chain amino acid levels and muscle energy metabolism in patients with chronic obstructive pulmonary disease.
        Clin Nutr. 2009; 28: 203-208
        • Angelillo V.A.
        • Bedi S.
        • Durfee D.
        • Dahl J.
        • Patterson A.J.
        • O'Donohue Jr., W.J.
        Effects of low and high carbohydrate feedings in ambulatory patients with chronic obstructive pulmonary disease and chronic hypercapnia.
        Ann Intern Med. 1985; 103: 883-885
        • McDonald V.M.
        • Gibson P.G.
        • Scott H.A.
        • et al.
        Should we treat obesity in COPD? The effects of diet and resistance exercise training.
        Respirology. 2016; 21: 875-882
        • Aaron S.D.
        • Fergusson D.
        • Dent R.
        • Chen Y.
        • Vandemheen K.L.
        • Dales R.E.
        Effect of weight reduction on respiratory function and airway reactivity in obese women.
        Chest. 2004; 125: 2046-2052
        • Hakala K.
        • Stenius-Aarniala B.
        • Sovijarvi A.
        Effects of weight loss on peak flow variability, airways obstruction, and lung volumes in obese patients with asthma.
        Chest. 2000; 118: 1315-1321
        • Shai I.
        • Schwarzfuchs D.
        • Henkin Y.
        • et al.
        Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet.
        N Engl J Med. 2008; 359: 229-241
        • Schwartz J.
        Role of polyunsaturated fatty acids in lung disease.
        Am J Clin Nutr. 2000; 71: 393S-396S
        • Seegmiller A.C.
        Abnormal unsaturated fatty acid metabolism in cystic fibrosis: biochemical mechanisms and clinical implications.
        Int J Mol Sci. 2014; 15: 16083-16099
        • Gan W.Q.
        • Man S.F.
        • Senthilselvan A.
        • Sin D.D.
        Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.
        Thorax. 2004; 59: 574-580
        • Pories W.J.
        • Dohm L.G.
        • Mansfield C.J.
        Beyond the BMI: the search for better guidelines for bariatric surgery.
        Obesity (Silver Spring). 2010; 18: 865-871