Emphysema and soluble CD14 are associated with pulmonary nodules in HIV-infected patients: implications for lung cancer screening

Objective: Lung cancer screening may benefit HIV-infected (HIV+) smokers because of an elevated risk of lung cancer, but may have unique harms because of HIV-specific risk factors for false-positive screens. This study seeks to understand whether inflammatory biomarkers and markers of chronic lung disease are associated with noncalcified nodules at least 4 mm (NCN) in HIV+ compared with uninfected patients. Design: This is a cohort study of Examinations of HIV-Associated Lung Emphysema (EXHALE), including 158 HIV+ and 133 HIV-uninfected participants. Methods: Participants underwent a laboratory assessment [including measurement of D-dimer, interleukin 6, and soluble CD14 (sCD14)], chest computed tomography (CT), and pulmonary function testing. We created multivariable logistic regression models to determine predictors of NCN in the participants stratified by HIV status, with attention to semiqualitative scoring of radiographic emphysema, markers of pulmonary function, and inflammatory biomarkers. Results: Of the 291 participants, 69 had NCN on chest CT. As previously reported, there was no difference in prevalence of these nodules by HIV status. Emphysema and elevated sCD14 demonstrated an association with NCN in HIV+ participants independent of smoking status, CD4+ cell count, HIV viral load, and pulmonary function. Conclusion: Emphysema and sCD14, a marker of immune activation, was associated with a higher prevalence of NCN on chest CT in HIV+ participants. Patients with chronic immune activation and emphysema may be at higher risk for both false-positive findings and incident lung cancer, thus screening in this group requires further study to understand the balance of benefits and harms.

[1]  S. Datta,et al.  Implementation of Lung Cancer Screening in the Veterans Health Administration , 2017, JAMA internal medicine.

[2]  D. Rimland,et al.  Immunological and infectious risk factors for lung cancer in US veterans with HIV: a longitudinal cohort study. , 2017, The lancet. HIV.

[3]  M. Freiberg,et al.  A Low Peripheral Blood CD4/CD8 Ratio Is Associated with Pulmonary Emphysema in HIV , 2017, PloS one.

[4]  A. Somasunderam,et al.  Unchanged Levels of Soluble CD14 and IL-6 Over Time Predict Serious Non-AIDS Events in HIV-1-Infected People. , 2016, AIDS research and human retroviruses.

[5]  P. Hugenholtz,et al.  Emerging pathogenic links between microbiota and the gut–lung axis , 2016, Nature Reviews Microbiology.

[6]  B. Milleron,et al.  Lung Cancer Screening with Chest Computed Tomography in People Living with HIV: A Review by the Multidisciplinary CANCERVIH Working Group , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[7]  S. Eymard-Duvernay,et al.  Feasibility and efficacy of early lung cancer diagnosis with chest computed tomography in HIV-infected smokers , 2016, AIDS.

[8]  C. Feldman,et al.  Impact of HIV infection and smoking on lung immunity and related disorders , 2015, European Respiratory Journal.

[9]  Michael M. Lederman,et al.  Soluble CD14 is a nonspecific marker of monocyte activation , 2015, AIDS.

[10]  Ho Yun Lee,et al.  Chronic obstructive pulmonary disease severity is associated with severe pneumonia , 2015, Annals of thoracic medicine.

[11]  A. Sharafkhaneh,et al.  Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4. , 2014, Chest.

[12]  M. Lederman,et al.  Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. , 2014, The Journal of infectious diseases.

[13]  Kathleen M. Akgün,et al.  Findings in asymptomatic HIV-infected patients undergoing chest computed tomography testing: implications for lung cancer screening , 2014, AIDS.

[14]  M. Lederman,et al.  Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection , 2014, AIDS.

[15]  V. Moyer.  Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement , 2014, Annals of Internal Medicine.

[16]  A. Keshavarzian,et al.  A Compositional Look at the Human Gastrointestinal Microbiome and Immune Activation Parameters in HIV Infected Subjects , 2014, PLoS pathogens.

[17]  C. Sabin,et al.  Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers , 2013, AIDS.

[18]  J. Montaner,et al.  Epidemic of lung cancer in patients with HIV infection. , 2013, Chest.

[19]  L. Kuller,et al.  Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals , 2012, PloS one.

[20]  S. Crystal,et al.  HIV as an independent risk factor for incident lung cancer , 2012, AIDS.

[21]  D. Douek,et al.  Microbial translocation across the GI tract. , 2012, Annual review of immunology.

[22]  W. MacNee,et al.  Aging, inflammation, and emphysema. , 2011, American journal of respiratory and critical care medicine.

[23]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[24]  Leah E. Mechanic,et al.  Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer. , 2011, Journal of the National Cancer Institute.

[25]  D. Boulware,et al.  Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. , 2011, The Journal of infectious diseases.

[26]  J. Skinner,et al.  Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in HIV , 2011, AIDS.

[27]  Handan Wand,et al.  Plasma levels of soluble CD14 independently predict mortality in HIV infection. , 2011, The Journal of infectious diseases.

[28]  M. Guiguet,et al.  Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. , 2009, The Lancet. Oncology.

[29]  Victor A Kiri,et al.  Chronic obstructive pulmonary disease and hospitalizations for pneumonia in a US cohort. , 2009, Respiratory medicine.

[30]  J. Leader,et al.  Association of radiographic emphysema and airflow obstruction with lung cancer. , 2008, American journal of respiratory and critical care medicine.

[31]  Lewis H Kuller,et al.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection , 2008, PLoS medicine.

[32]  Olaf Holz,et al.  Aging and induced senescence as factors in the pathogenesis of lung emphysema. , 2008, Respiratory medicine.

[33]  H. Twigg,et al.  HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism , 2008, Thorax.

[34]  Gorka Bastarrika,et al.  Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. , 2007, Chest.

[35]  D. Vlahov,et al.  HIV infection is associated with an increased risk for lung cancer, independent of smoking. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[36]  M. Lederman,et al.  Microbial translocation is a cause of systemic immune activation in chronic HIV infection , 2006, Nature Medicine.

[37]  D. Ost,et al.  Solitary Pulmonary Nodule , 2005 .

[38]  C. Tukuitonga,et al.  Spirometric lung volumes in the adult Pacific Islander population: Comparison with predicted values in a European population , 2001, Respirology.

[39]  P. Enright,et al.  Spirometry reference values for American Indian adults: results from the Strong Heart Study. , 2001, Chest.

[40]  J. Crawford,et al.  Hyporesponsiveness of Donor Cells to Lipopolysaccharide Stimulation Reduces the Severity of Experimental Idiopathic Pneumonia Syndrome: Potential Role for a Gut-Lung Axis of Inflammation1 , 2000, The Journal of Immunology.

[41]  H. Nagaraja,et al.  Increased Susceptibility to Pulmonary Emphysema among HIV-Seropositive Smokers , 2000, Annals of Internal Medicine.

[42]  L. Neas,et al.  The determinants of pulmonary diffusing capacity in a national sample of U.S. adults. , 1996, American journal of respiratory and critical care medicine.

[43]  K P Offord,et al.  Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. , 1986, Annals of internal medicine.

[44]  M. Goetz,et al.  The Differential Impact of Emphysema on Respiratory Symptoms and 6-Minute Walk Distance in HIV Infection , 2017, Journal of acquired immune deficiency syndromes.

[45]  Matthew B Schabath,et al.  Lung cancer screening, version 1.2015: featured updates to the NCCN guidelines. , 2015, Journal of the National Comprehensive Cancer Network : JNCCN.

[46]  J. Hankinson,et al.  Performance of American Thoracic Society-recommended spirometry reference values in a multiethnic sample of adults: the multi-ethnic study of atherosclerosis (MESA) lung study. , 2010, Chest.

[47]  J L Hankinson,et al.  Spirometric reference values from a sample of the general U.S. population. , 1999, American journal of respiratory and critical care medicine.