Surfactant protein D as a marker for pulmonary complications in pediatric patients with sickle cell disease: Relation to lung function tests.

BACKGROUND: Surfactant protein D (SP-D) is considered a candidate biomarker for lung integrity and for disease progression. AIM: We determined the level of SP-D in children and adolescents with SCD and assessed its possible relation to pulmonary complications and lung function. METHODS: Serum SP-D levels were assessed in 50 SCD patients compared with 30 healthy controls. High-resolution computerized tomography (HRCT) of the chest was done. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1 ), FEV1 /FVC% and forced expiratory flow rate during 25-75% of expiration (FEF25-75%) were determined. RESULTS: SP-D was significantly higher in SCD patients than controls, particularly patients with sickle cell anemia than those with sickle ß-thalassemia. SP-D levels were significantly associated with increasing severity of interstitial lung disease. The highest SP-D levels were observed among patients with restrictive lung disease followed by mixed type then obstructive lung disease. SP-D was positively correlated to HbS and serum ferritin while negatively correlated to duration of hydroxyurea treatment and parameters of pulmonary functions. ROC curve analysis revealed that SP-D cutoff value 720 ng/mL could significantly detect the presence of abnormal pulmonary function among SCD patients with 82% sensitivity and 88% specificity. Logistic regression analysis showed that SP-D is an independent factor related to abnormal pulmonary function in SCD. CONCLUSIONS: SP-D may be a promising biomarker for screening of SCD patients for risk of later pulmonary complications.

Indices of iron homeostasis correlate with airway obstruction in an NHANES III cohort.

Cigarette smoking results in the accumulation of iron both systemically and locally, in the lung thereby causing imbalance in iron homeostasis. This disruption in iron homeostasis can be associated with oxidative stress and consequent tissue injury. Therefore, in this study, we tested the association between iron homeostasis and airway obstruction by examining a large cohort of smokers and non-smokers for relationships between 1) serum ferritin and iron concentrations and transferrin saturation and 2) forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and their ratio (FEV1/FVC). Data from the National Health and Examination Survey III were analyzed. The study population included persons aged 20 years and above with their following data recorded: race, gender, serum ferritin and iron concentrations, and transferrin saturation; the final sample number was 7,251. In the total population, Pearson correlation coefficients between 1) serum ferritin and iron concentrations and transferrin saturation and 2) FVC and FEV1 were significantly positive; whereas those between 1) serum ferritin concentrations and transferrin saturation and 2) FEV1/FVC were significantly negative. With separate analyses, serum ferritin concentrations demonstrated positive associations with FVC and FEV1 but an inverse relationship with FEV1/FVC in smokers and non-smokers. Serum ferritin levels increased with worsening airway obstruction among smokers, and its highest concentrations were found among those with the lowest values of FEV1/FVC ratio (<60%). Comparable to cigarette smokers, serum ferritin concentrations among non-smokers were greatest in those with the lowest FEV1/FVC ratio. Furthermore, elevated levels of serum iron and saturation of transferrin also corresponded with decreased FEV1/FVC ratio among non-smokers. Thus, we conclude that indices of iron homeostasis are associated with airway obstruction in both smokers and non-smokers.

Significance of the Preoperative CONUT Score in Predicting Postoperative Disease-free and Overall Survival in Patients with Lung Adenocarcinoma with Obstructive Lung Disease.

BACKGROUND: The usefulness of the controlling nutritional status (CONUT) score for preoperative nutritional assessment has been reported in resected colorectal and esophageal cancer, but not in lung cancer with obstructive lung disease. PATIENTS AND METHODS: We retrospectively reviewed 109 patients with adenocarcinoma with obstructive pulmonary disease. We set 1 as the cut-off value for the CONUT score and classified patients into high (≥1) and low (0) CONUT groups. RESULTS: Among 109 patients, 35 (32.1%) had low CONUT scores, and 74 (67.8%) had high CONUT scores. The high-CONUT group was significantly associated with a lower body mass index (p=0.025) and wild-type epidermal growth factor receptor mutation status (p=0.011). A multivariate analysis showed that the CONUT score was independently associated with disease-free and overall survival. CONCLUSION: The results of this study suggest that the CONUT score was an independent prognostic factor for disease-free and overall survival in patients with lung adenocarcinoma with obstructive lung disease.

Long time enzyme replacement therapy stabilizes obstructive lung disease and alters peripheral immune cell subsets in Fabry patients.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder, causing accumulation of globotriaosylceramid in different organs. Glycolipids are activators of different immune cell subsets the resulting inflammation is responsible for organ damage. Pulmonary involvement leads to airway inflammation; however, data on severity, as well as the effect of enzyme replacement therapy on lung function parameters and changes in peripheral immune cell subsets on lung involvement are sparse. METHODS: Seven Fabry patients and four carriers underwent detailed clinical examinations screening for pulmonary manifestations. Repetitive measurements were performed on five patients on ERT (average follow-up 5 years). Patients with Fabry disease and control volunteers were included into peripheral blood cell measurements. RESULTS: Lung involvement was present in all patients. Symptoms suggestive for lung disease were mild, however, obstructive ventilatory disorder, dominantly affecting small airways accompanied by hyperinflation was demonstrated in all affected patients. ERT resulted in small improvement of FEV1 in most treated patients. Decreased ratio of myeloid DC, Th17 cells while increase in T helper (Th)1 cells, and no change in Th2 and regulatory T (Treg) cells were detected in Fabry patients. CONCLUSIONS: Fabry disease results mainly in mild symptoms related to lung involvement, characterized by moderate non-reversible obstructive ventilatory disorder. Stabilization of airway obstruction during follow-up was observed using ERT in most patients, emphasizing the importance of this treatment in respect of pulmonary manifestations. Changes of immune cell subsets in the peripheral blood might play a role in inflammatory process, including small airways in Fabry patient's lung.

ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CHRONIC OBSRTRUCTIVE PULMONARY DISEASE WITH CONCOMITANT HYPERTENSION.

In recent years, special attention is paid to comorbid conditions in the clinic of internal diseases. There actively explored the role of endothelial dysfunction as a single unit in the pathological formation of chronic obstructive pulmonary disease (COPD) associated with hypertension. The study involved 145 patients who were carried out the final level of metabolites of nitric oxide (NO2, NO3), S-nitrosothiols, endothelial and inducible NO-synthase. All patients were divided into 3 groups: the first group included 55 patients (35 men and 20 women) who had been diagnosed with COPD with concomitant hypertension - the core group. The average age for this group was 57,6 years (46±68). The comparison group consisted of 45 patients (34 men and 11 women) with isolated course of COPD. The average age for second group was 53,3 years (40±67). The control group consisted of 45 healthy volunteers - 25 men and 20 women. Results of the study of the endothelial dysfunction revealed dynamic change in serum nitrate, nitrite, S-nitrosothiols and activity of eNOS and iNOS as the group of patients with COPD with associated hyperttension and the group of patients with isolated COPD. Informative and prognostic indicators relatively severity of diseases in patients with significant comorbidity may be considered high levels of iNOS and S-nitrosothiols, which indicates the voltage of the functional activity of endogenous antioxidant defense mechanisms in this cohort of persons. The findings suggest that the progression of endothelial dysfunction in comorbidity, which may lead to the current aggravation of diseases and vascular disorders in these patients.

Serum periostin in obstructive airways disease.

Serum periostin is a potential biomarker of response to therapies that target type 2 inflammation in asthma. The objectives of this study were to describe: 1) the distribution of serum periostin levels in adults with symptomatic airflow obstruction; 2) its relationship with other variables, including type 2 biomarkers; and 3) the effect of inhaled corticosteroids on periostin levels.Serum periostin levels were measured in a cross-sectional study exploring phenotypes and biomarkers in 386 patients aged 18-75 years who reported wheeze and breathlessness in the past 12 months. In 49 ICS-naïve patients, periostin levels were measured again after 12 weeks of budesonide (800 µg·day(-1)).The distribution of serum periostin levels was right skewed (mean±sd 57.3±18.6 ng·mL(-1), median (interquartile range) 54.0 (45.1-65.6) ng·mL(-1), range 15.0-164.7 ng·mL(-1)). Periostin was positively associated with exhaled nitric oxide (Spearman's rho=0.22, p<0.001), blood eosinophil count (Spearman's rho=0.21, p<0.001), and total IgE (Spearman's rho=0.14, p=0.007). The Hodges-Lehmann estimator (95% CI) of change in periostin level after ICS therapy was -4.8 (-6.7- -3.2) ng·mL(-1) (p<0.001).These findings provide data on the distribution of serum periostin in adults with symptomatic airflow obstruction, the weak associations between periostin and other type 2 markers, and the reduction in periostin with inhaled corticosteroid therapy.

Substantial Increases Occur in Serum Activins and Follistatin during Lung Transplantation.

BACKGROUND: Lung transplantation exposes the donated lung to a period of anoxia. Re-establishing the circulation after ischemia stimulates inflammation causing organ damage. Since our published data established that activin A is a key pro-inflammatory cytokine, we assessed the roles of activin A and B, and their binding protein, follistatin, in patients undergoing lung transplantation. METHODS: Sera from 46 patients participating in a published study of remote ischemia conditioning in lung transplantation were used. Serum activin A and B, follistatin and 11 other cytokines were measured in samples taken immediately after anaesthesia induction, after remote ischemia conditioning or sham treatment undertaken just prior to allograft reperfusion and during the subsequent 24 hours. RESULTS: Substantial increases in serum activin A, B and follistatin occurred after the baseline sample, taken before anaesthesia induction and peaked immediately after the remote ischemia conditioning/sham treatment. The levels remained elevated 15 minutes after lung transplantation declining thereafter reaching baseline 2 hours post-transplant. Activin B and follistatin concentrations were lower in patients receiving remote ischemia conditioning compared to sham treated patients but the magnitude of the decrease did not correlate with early transplant outcomes. CONCLUSIONS: We propose that the increases in the serum activin A, B and follistatin result from a combination of factors; the acute phase response, the reperfusion response and the use of heparin-based anti-coagulants.

Relationship between blood levels of heavy metals and lung function based on the Korean National Health and Nutrition Examination Survey IV-V.

BACKGROUND: Heavy metal exposure may contribute to inflammation in the lungs via increased oxidative stress, resulting in tissue destruction and obstructive lung function (OLF). In this study, we evaluated the relationship between lead and cadmium levels in blood, and lung function in the Korean population. METHODS: Pooled cross-sectional data from 5,972 subjects who participated in the Korean National Health and Nutrition Examination Survey 2008-2012 were used for this study. OLF was defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.7. Graphite-furnace atomic absorption spectrometry was used to measure levels of lead and cadmium in blood. RESULTS: Adjusted means for age, sex, body mass index, and smoking status in blood lead and cadmium levels were increased with age and were higher in men and current smokers. The FEV1/FVC ratio was lower in the highest quartile group of lead (78.4% vs 79.0%; P=0.025) and cadmium (78.3% vs 79.2%; P<0.001) concentrations, compared with those in the lowest quartile groups. Multiple linear regression demonstrated an inverse relationship between the FEV1/FVC ratio and concentrations of lead (estimated -0.002; P=0.007) and cadmium (estimated -0.005; P=0.001). Of the 5,972 subjects, 674 (11.3%) were classified into the OLF group. Among current smokers, the risk of OLF was higher in subjects in the highest quartile group of cadmium concentration than in those in the lowest quartile group (odds ratio 1.94; 95% confidence interval 1.06-3.57). CONCLUSION: We demonstrated a significant association between the FEV1/FVC ratio and blood concentrations of lead and cadmium in the Korean population. The risk for OLF was elevated with increasing concentrations of cadmium among current smokers.

Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study.

BACKGROUND: Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population. METHODS: We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4-6 years in the Tucson Children's Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function. FINDINGS: After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (-71 mL, p<0·0001). INTERPRETATION: Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population. FUNDING: National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme.

Vitamin D deficiency is independently associated with mortality among critically ill patients

OBJECTIVE: Studies suggest an association between vitamin D deficiency and morbidity/mortality in critically ill patients. Several issues remain unexplained, including which vitamin D levels are related to morbidity and mortality and the relevance of vitamin D kinetics to clinical outcomes. We conducted this study to address the association of baseline vitamin D levels and vitamin D kinetics with morbidity and mortality in critically ill patients. METHOD: In 135 intensive care unit (ICU) patients, vitamin D was prospectively measured on admission and weekly until discharge from the ICU. The following outcomes of interest were analyzed: 28-day mortality, mechanical ventilation, length of stay, infection rate, and culture positivity. RESULTS: Mortality rates were higher among patients with vitamin D levels <12 ng/mL (versus vitamin D levels >12 ng/mL) (32.2% vs. 13.2%), with an adjusted relative risk of 2.2 (95% CI 1.07-4.54; p< 0.05). There were no differences in the length of stay, ventilation requirements, infection rate, or culture positivity. CONCLUSIONS: This study suggests that low vitamin D levels on ICU admission are an independent risk factor for mortality in critically ill patients. Low vitamin D levels at ICU admission may have a causal relationship with mortality and may serve as an indicator for vitamin D replacement among critically ill patients. .

Low serum levels of alpha1 anti-trypsin (α1-AT) and risk of airflow obstruction in non-primary α1-AT-deficient patients with compensated chronic liver disease.

BACKGROUND: Alpha1 anti-trypsin (α1-AT), a serine protease inhibitor synthesized in the liver, is a major circulating antiprotease that provides defense against proteolytic damage in several tissues. Its deficiency is associated with airflow obstruction. The present study aimed to explore the role of α1-AT as a biomarker of airflow performance in chronic liver disease (CLD). MATERIAL/METHODS: Serum α1-AT levels and lung function (spirometry) were evaluated in non-primary α1-AT-deficient, alcoholic CLD patients without evident respiratory limitations. RESULTS: Thirty-four patients with airflow obstruction (n=11), airflow restriction (n=12), and normal airflow (n=11, age-matched controls) were eligible. α1-AT was decreased in the airflow obstruction group. ROC-cutoff α1-AT=24 mg/dL effectively discriminated airflow obstruction (AUC=0.687) and was associated with a 10-fold higher risk (p=0.0007). CONCLUSIONS: Lower α1-AT increased the risk of airflow obstruction in CLD patients without primary α1-AT deficiency.

Lung function, 25-hydroxyvitamin D concentrations and mortality in US adults.

OBJECTIVE: To explore the associations between serum concentrations of vitamin D (25(OH)D) and all-cause mortality among US adults defined by lung function (LF) status, particularly among adults with obstructive LF (OLF). METHODS: Data from 10,795 adults aged 20-79 years (685 with restrictive LF (RLF) and 1309 with OLF) who participated in the Third National Health and Nutrition Examination Survey (1988-1994), had a spirometric examination, and were followed through 2006 were included. RESULTS: During 14.2 years of follow-up, 1792 participants died. Mean adjusted concentrations of 25(OH)D were 75.0 nmol/l (s.e. 0.7) for adults with normal LF (NLF), 70.4 nmol/l (s.e. 1.8) for adults with RLF, 75.5 nmol/l (s.e. 1.5) for adults with mild obstruction and 71.0 nmol/l (s.e. 1.9) among adults with moderate or worse obstruction (P=0.030). After adjustment for sociodemographic factors, lifestyle factors, clinical variables and prevalent chronic conditions, a concentration of <25 nmol/l compared with ⩾ 75 nmol//l was associated with mortality only among adults with NLF (hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.03, 3.00). Among participants with OLF, adjusted HRs were 0.65 (95% CI 0.29, 1.48), 1.21 (95% CI 0.89, 1.66) and 0.97 (95% CI 0.78, 1.19) among those with concentrations <25, 25-<50 and 50-<75 nmol/l, respectively. CONCLUSIONS: Baseline concentrations of 25(OH)D did not significantly predict mortality among US adults with impaired LF.

Relationship between insulin-like growth factor I levels, early insulin treatment, and clinical outcomes of very low birth weight infants.

OBJECTIVES: Insulin regulates the secretion of insulin-like growth factor I (IGF-I) in the newborn, and low levels of IGF-I have been linked to neonatal morbidity. As part of the Neonatal Insulin Replacement Therapy in Europe Trial, we investigated the impact of early insulin treatment on IGF-I levels and their relationship with morbidity and growth. STUDY DESIGN: Prospective cohort analyses of data collected as part of an international randomized controlled trial. Blood samples (days 1, 3, 7, and 28), were taken for IGF-I bioassay from 283 very low birth weight infants (<1500 g). RESULTS: Early insulin treatment led to a late increase in IGF-I levels between day 7 and 28 (P = .028). In the first week of life IGF-I levels were lower in infants with early hyperglycemia; mean difference -0.10 µg/L (95% CI -0.19, -0.02, P = .02). Lower levels of IGF-I at day 28 were independently associated with an increased risk of chronic lung disease, OR 3.23 (95% CI, 1.09-9.10), and greater IGF-I levels were independently associated with better weight gain, 0.10 kg (95% CI, 0.03-0.33, P = .02). CONCLUSIONS: Early intervention with insulin is related to increased IGF-I levels at 28 days. Low IGF-I levels are associated with hyperglycemia, increased morbidity, and reduced growth. Increasing IGF-I levels may improve outcomes of very low birth weight infants.

Plasma cortisol concentration increases within 6 hours of stabling in RAO-affected horses.

REASONS FOR PERFORMING STUDY: In many inflammatory diseases plasma cortisol concentration (CORT) increases at the onset of acute inflammation, but the situation in recurrent airway obstruction (RAO) of horses is unknown. STUDY DESIGN: Split-plot repeated measures design with one grouping factor (disease) and two repeated factors (day and 3-hour intervals). OBJECTIVE: To test the hypothesis that CORT increases as acute exacerbations of RAO develop. METHODS: Four RAO-susceptible and 4 control horses were placed in a low dust environment (LDEnv) for 2 days followed by 2 days in a high dust environment (HDEnv). Exacerbations of RAO were indicated by increases in maximal change in pleural pressure (ΔPplmax) and decreases in breathing frequency variability (BFV), which was continuously measured by respiratory inductance plethysmography. Plasma samples for determination of CORT were collected every 6 h. RESULTS: In control horses, ΔPplmax and BFV were unaffected by the HDEnv, whereas in RAO-affected horses ΔPplmax increased and BFV decreased significantly. In the LDEnv, there was a circadian variation in CORT in both control and RAO-affected horses. In HDEnv, CORT was unaffected in control horses, but increased significantly in RAO-affected horses between 6 and 12 h after entering the HDEnv. CONCLUSIONS: Plasma cortisol concentration increases concurrently with the development of acute exacerbations of RAO.

Systemic inflammation, depression and obstructive pulmonary function: a population-based study.

BACKGROUND: Levels of Interleukin-6 (IL-6) and C-creative protein (CRP) indicating systemic inflammation are known to be elevated in chronic diseases including chronic obstructive pulmonary disease (COPD) and depression. Comorbid depression is common in patients with COPD, but no studies have investigated whether proinflammatory cytokines mediate the association between pulmonary function and depressive symptoms in healthy individuals with no known history of obstructive pulmonary diseases. METHODS: In a population-based sample (n = 2077) of individuals aged 55 and above with no known history of obstructive pulmonary disease in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the relationships between IL-6 and CRP, depressive symptoms (GDS-15 ≥5) and obstructive pulmonary function (FEV1% predicted and FEV1/FVC% predicted). RESULTS: High serum levels of IL-6 and CRP were associated with greater prevalence of depressive symptoms (p < 0.05). High IL-6, high CRP and depressive symptoms were independently associated with decreased FEV1% predicted and FEV1/FVC% predicted after adjusting for smoking status, BMI and number of chronic inflammatory diseases. Increasing grades of combination of inflammatory markers and/or depressive symptoms was associated with progressive increases in pulmonary obstruction. In hierarchical models, the significant association of depressive symptoms with pulmonary obstruction was reduced by the presence of IL-6 and CRP. CONCLUSIONS: This study found for the first time an association of depressive symptoms and pulmonary function in older adults which appeared to be partly mediated by proinflammatory cytokines. Further studies should be conducted to investigate proinflammatory immune markers and depressive symptoms as potential phenotypic indicators for chronic obstructive airway disorders in older adults.

Serum heavy metals and obstructive lung disease: results from the National Health and Nutrition Examination Survey.

BACKGROUND: Exposure to hazardous heavy metals such as cadmium and lead has been associated with several chronic diseases. Heavy metal exposure may contribute to increased oxidative stress and inflammation in the lungs, resulting in tissue destruction manifesting clinically as obstructive lung disease (OLD). We aimed to evaluate the association between serum cadmium and lead concentration and OLD. METHODS: Pooled cross-sectional data from the National Health and Nutrition Examination Survey 2007-2010 were used. OLD was defined as an FEV 1 /FVC ratio , 0.7 by spirometry. Active smokers were defined as self-reported current smokers or those with measured serum cotinine 10 ng/mL. Serum cadmium and lead levels were measured using mass spectrometry. RESULTS: The prevalence of OLD was 12.4% (95% CI, 10.2%-13.6%). The mean (SE) cadmium levels in the OLD group were significantly higher in comparison with normal control subjects (0.51 [1.04] vs 0.33 [1.02], P , .001). Similarly, mean (SE) serum lead concentration was significantly higher in the OLD group compared with the control population (1.73 [1.02] vs 1.18 [1.0], P , .001). The association between OLD and smoking was significantly attenuated after adjusting for serum cadmium concentration. In addition, we demonstrated a progressive increase in serum cadmium concentrations with worsening FEV 1 % predicted values among smokers in our study population. CONCLUSION: In a large representative sample of the US population, we demonstrated a significant association between OLD and serum cadmium and lead concentrations. Cadmium appeared to partially mediate the association between smoking and OLD. A dose-response effect between increasing cadmium concentration and progressively worsening lung function was observed in smokers.