Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study.

BACKGROUND: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability. PATIENTS AND METHODS: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. RESULTS: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. CONCLUSION: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future.

Body mass index is associated with leukotriene inflammation in asthmatics.

BACKGROUND: Obesity and asthma are characterized by the presence of inflammation. Leptin and adiponectin are circulating hormones produced by adipose tissue that regulate several metabolic and inflammatory functions. We aimed to determine whether obesity influences asthmatic inflammation as well as the contribution of leptin or/and adiponectin to a possible linkage between asthmatic and obesity-related inflammation. MATERIALS AND METHODS: One hundred patients with asthma and 60 healthy controls were studied. Subjects who had a comorbid illness that could interfere with the proposed tests were excluded. All subjects were divided into three groups (normal range, pre-obese, obese) according to the criteria of the current WHO international classification for body mass index (BMI). Possible associations between variables expressing airway inflammation, bronchial hyper-responsiveness, systemic inflammation and obesity, as assessed by BMI, were evaluated. Leptin and adiponectin were also measured and were associated with asthma airway and systemic inflammatory variables to elucidate possible associations. RESULTS: Obese patients had significant higher values of LTE(4) /creatinine in urine compared with pre-obese and normal range ones. In a linear regression model, the only significant associations were those between BMI and LTE(4) /creatinine in urine. Using the same model, log leptin and log adiponectin presented positive and negative associations, respectively with LTE(4) /creatinine in urine. No other significant associations were observed in both patients and healthy subjects. CONCLUSIONS: In a selected cohort of asthmatic patients, obesity is significantly associated with increased urinary leukotriene levels. Alterations of leptin/adiponectin balance may be related to the presence of leukotriene inflammation in obese asthmatic patients.

MRC chronic Dyspnea Scale: Relationships with cardiopulmonary exercise testing and 6-minute walk test in idiopathic pulmonary fibrosis patients: a prospective study.

BACKGROUND: Exertional dyspnea is the most prominent and disabling feature in idiopathic pulmonary fibrosis (IPF). The Medical Research Chronic (MRC) chronic dyspnea score as well as physiological measurements obtained during cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT) are shown to provide information on the severity and survival of disease. METHODS: We prospectively recruited IPF patients and examined the relationship between the MRC score and either CPET or 6MWT parameters known to reflect physiologic derangements limiting exercise capacity in IPF patients RESULTS: Twenty-five patients with IPF were included in the study. Significant correlations were found between the MRC score and the distance (r = -.781, p < 0.001), the SPO2 at the initiation and the end (r = -.542, p = 0.005 and r = -.713, p < 0.001 respectively) and the desaturation index (r = .634, p = 0.001) for the 6MWT; the MRC score and VO2 peak/kg (r = -.731, p < 0.001), SPO2 at peak exercise (r = -. 682, p < 0.001), VE/VCO2 slope (r = .731, p < 0.001), VE/VCO2 at AT (r = .630, p = 0.002) and the Borg scale at peak exercise (r = .50, p = 0.01) for the CPET. In multiple logistic regression analysis, the only variable independently related to the MRC is the distance walked at the 6MWT. CONCLUSION: In this population of IPF patients a good correlation was found between the MRC chronic dyspnoea score and physiological parameters obtained during maximal and submaximal exercise testing known to reflect ventilatory impairment and exercise limitation as well as disease severity and survival. This finding is described for the first time in the literature in this group of patients as far as we know and could explain why a simple chronic dyspnea score provides reliable prognostic information on IPF.

A prospective study on adrenal cortex responses and outcome prediction in acute critical illness: results from a large cohort of 203 mixed ICU patients.

OBJECTIVE: To assess whether adrenal cortex hormones predict ICU mortality in acute, mixed, critically ill patients. DESIGN AND SETTING: Prospective study in consecutive intensive care patients in the general ICU of a teaching hospital. PATIENTS: 203 severely ill patients with multiple trauma (n = 93), medical (n = 57), or surgical (n = 53) critical states. MEASUREMENTS AND RESULTS: Within 24 h of admission in the ICU a morning blood sample was obtained to measure baseline cortisol, corticotropin (ACTH), and dehydropiandrosterone sulfate (DHEAS). Subsequently a low-dose (1 microg) ACTH test was performed to determine stimulated cortisol. The incremental rise in cortisol was defined as stimulated minus baseline cortisol. Overall, 149 patients survived and 54 died. Nonsurvivors were older and in a more severe critical state, as reflected by higher SOFA and APACHE II scores. Nonsurvivors had a lower incremental rise in cortisol (5.0 vs. 8.3 microg/dl and lower DHEAS (1065 vs. 1642 ng/ml) than survivors. The two groups had similar baseline and stimulated cortisol. Multivariate logistic regression analysis revealed that age (odds ratio 1.02), SOFA score (1.36), and the incremental rise in cortisol (0.88) were independent predictors for poor outcome. CONCLUSIONS: In general ICU patients a blunted cortisol response to ACTH within 24 h of admission is an independent predictor for poor outcome. In contrast, baseline cortisol or adrenal androgens are not of prognostic significance.

Contribution of endocrine parameters in predicting outcome of multiple trauma patients in an intensive care unit.

OBJECTIVE: To evaluate whether tentative prognostic models for intensive care unit survival of multiple trauma patients could be improved by including endocrine parameters. DESIGN: Prospective study. PATIENTS: Eighty-three male and 11 female multiple trauma patients. MEASUREMENTS: Upon admission, severity of trauma was assessed with the Acute Physiology and Chronic Health Evaluation II (APACHE II), the Sequential Organ Failure Assessment (SOFA) score and the Injury Severity Score (IS). Concurrently, blood was drawn to measure thyrotropin (TSH), free thyroxine (fT4), trioodothyronine (T3), corticotropin (ACTH), prolactin (PRL), cortisol and dehydroepiandrosterone sulphate (DHEAS). Adrenal reserve was assessed with the Synacthen test. RESULTS: Seventy-five of the 83 men and 8 of the 11 women survived. APACHE II and SOFA scores were higher in non-survivors compared to survivors (with considerable overlap). From the baseline endocrine work-up, survivors had higher ACTH and DHEAS values compared to non-survivors (also with considerable overlap). No differences between survivors and non-survivors were noted in the Synacthen test or in thyroid function tests. Nevertheless, a multivariate logistic regression model that incorporated the APACHE II score and hormonal parameters (Cortisol post-Synacthen, DHEAS, TSH*age) was well-fitted to assess survival/non-survival as an endpoint and better than APACHE II, SOFA or IS scores alone to predict ICU survival or death. CONCLUSION: In critically ill multiple trauma patients, age, TSH, Cortisol post-Synacthen and DHEAS values upon admission to the ICU, combined with the APACHE II score, may predict outcome more accurately than the APACHE II score alone.an the APACHe II score alone.

The Role of Cardiopulmonary Exercise Test in IPF Prognosis.

Background. In IPF, defects in lung mechanics and gas exchange manifest with exercise limitation due to dyspnea, the most prominent and disabling symptom. Aim. To evaluate the role of exercise testing through the 6MWT (6-minute walk test) and CPET (cardiopulmonary exercise testing) in the survival of patients with IPF. Methods. This is a prospective, observational study evaluating in 25 patients the relationship between exercise variables through both the 6MWT and CPET and survival. Results. By the end of the observational period 17 patients were alive (33% mortality). Observation ranged from 9 to 64 months. VE/VCO2 slope (slope of relation between minute ventilation and CO2 production), VO2 peak/kg (peak oxygen consumption/kg), VE/VCO2 ratio at anaerobic threshold, 6MWT distance, desaturation, and DLCO% were significant predictors of survival while VE/VCO2 slope and VO2 peak/kg had the strongest correlation with outcome. The optimal model for mortality risk estimation was VO2 peak/kg + DLCO% combined. Furthermore, VE/VCO2 slope and VO2 peak/kg were correlated with distance and desaturation during the 6MWT. Conclusion. The integration of oxygen consumption and diffusing capacity proved to be a reliable predictor of survival because both variables reflect major underlying physiologic determinants of exercise limitation.

Sleep oxygen desaturation predicts survival in idiopathic pulmonary fibrosis.

BACKGROUND: Recent studies suggest poor sleep quality in patients with idiopathic pulmonary fibrosis (IPF). However, so far, the impact of IPF-related sleep breathing disorders (SBDs) on survival has not been extensively studied. METHODS: In a cohort of 31 (24 males) treatment-naïve, newly diagnosed consecutive IPF patients, we prospectively investigated the relationship of SBD parameters such as apnea-hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO2), and lowest sleep oxygen saturation (lowest SpO2) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal (6-min walk test [6MWT]) and maximal exercise variables (cardiopulmonary exercise test [CPET]), and right ventricular systolic pressure (RVSP). RESULTS: Sleep oxygen desaturation exceeded significantly that of maximal exercise (p < 0.001). Maxdiff SpO2 was inversely related to survival, DLCO%, and SpO2 after 6MWT, and directly with dyspnea, AHI, and RVSP. The lowest SpO2 was directly related to survival and to functional (TLC%, DLCO%) as well as submaximal and maximal exercise variables (6MWT distance, SpO2 after 6MWT, peak oxygen consumption/kg, SpO2 at peak exercise), while an inverse association with dyspnea score, AHI, and RVSP was observed. CONCLUSIONS: Our findings provide evidence that intermittent sleep oxygen desaturation significantly exceeds that of maximal exercise and is associated with survival in IPF patients. Furthermore, they imply the existence of a link between lung damage and apnea events resulting to the induction and severity of intermittent sleep oxygen desaturation that aggravate pulmonary arterial hypertension and influence IPF survival.

Tumour necrosis factor-alpha (TNFalpha) and interleukin-10 are crucial mediators in post-operative systemic inflammatory response and determine the occurrence of complications after major abdominal surgery.

BACKGROUND: The course of serum cytokine levels in patients with postoperative systemic inflammatory response syndrome (SIRS) after major abdominal surgery remains currently unclear. METHODS: Blood was sampled pre- and post-operatively and on days 1 and 2 in 40 patients undergoing major abdominal surgery. Concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin (IL) -6, IL-8, and IL-10 were measured by the LINCOplex assay; those of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by an enzyme immunoassay. RESULTS: Compared to their pre-operative values, sTREM-1 was elevated on day 2; TNFalpha on day 1; IL-6 and IL-10 post-operatively and on days 1 and 2; and IL-8 post-operatively and on day 1. The duration of operation correlated with TNFalpha and IL-10 at all sampling times, and with IL-6 post-operatively. There were no differences in cytokine concentrations between patients who exhibited post-operative complications and those who did not. IL-10/TNFalpha below 30 was found in all patients with complications (100%) and in 20 patients without complications (64.5%, p: 0.043). CONCLUSIONS: SIRS following major surgery is characterised by complex alterations in cytokine concentrations. The balance between TNFalpha and IL-10 seems to determine the occurrence of post-operative complications.