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.

Exertional Desaturation in Idiopathic Pulmonary Fibrosis: The Role of Oxygen Supplementation in Modifying Cerebral-Skeletal Muscle Oxygenation and Systemic Hemodynamics.

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) with isolated exertional desaturation, there are limited data regarding the effectiveness of oxygen supplementation during exercise training; the underlying mechanisms that contribute to these responses are unknown. OBJECTIVES: To examine in these IPF patients the effects of oxygen supplementation during submaximal exercise (vs. medical air) on cerebral/skeletal muscle oxygenation and systemic hemodynamics. METHODS: In this randomized, cross-over, placebo-controlled trial, IPF patients (n = 13; 63.4 ± 9.6 years) without resting hypoxemia but a significant desaturation during maximal cardiopulmonary exercise testing underwent 2 steady-state exercise trials (65% peak-work-load), breathing either oxygen-enriched or medical air. Cerebral/skeletal muscle oxygenation (near-infrared spectroscopy) and beat-by-beat hemodynamics (photoplethysmography) were monitored. RESULTS: In the air protocol, from the initial minutes of submaximal exercise, patients exhibited a marked decline in cerebral oxygenated hemoglobin (O2Hb) and an abrupt rise in deoxygenated hemoglobin (HHb). Oxygen supplementation alleviated desaturation, lessened dyspnea, and prolonged exercise duration (p < 0.01). Oxygen supplementation during exercise (i) attenuated cerebral deoxygenation (cerebral-HHb: 0.7 ± 1.9 vs. 2.5 ± 1.5 µmol/L, O2 and air protocol; p = 0.009) and prevented cerebral-Hbdifference decline (2.1 ± 2.7 vs. -1.7 ± 2.0 µmol/L; p = 0.001), (ii) lessened the decline in muscle O2-saturation index, and (iii) at isotime exercise, it resulted in lower muscle-HHb (p = 0.05) and less leg fatigue (p < 0.05). No differences between protocols were observed in exercise cardiac output and vascular resistance. CONCLUSIONS: IPF patients with isolated exertional hypoxemia exhibit an inability to increase/maintain cerebral oxygenation during submaximal exercise. Correcting desaturation with O2 supplementation prevented the decline in brain oxygenation, improved muscle oxygenation, and lessened dyspnea, suggesting an efficacy of acute oxygen supplementation during exercise training in protecting brain hypoxia in these IPF patients.

Acute effects of e-cigarette vaping on pulmonary function and airway inflammation in healthy individuals and in patients with asthma.

BACKGROUND AND OBJECTIVE: The acute effects of e-cigarettes have not been scientifically demonstrated yet. The aim of this study was to assess the acute changes in pulmonary function and airway inflammation in patients with asthma after vaping one e-cigarette. METHODS: Twenty-five smokers suffering from stable moderate asthma according to GINA guidelines with no other comorbidities and 25 healthy smokers matched with the baseline characteristics of the asthmatic patients were recruited. PFT, IOS, FeNO and EBC were performed before and after vaping one e-cigarette with nicotine. pH and concentrations of IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17A, TNF-α, ISO8 and LTB4 were measured in EBC. RESULTS: FFEV1/FVC ratio and PEF were reduced in asthmatic patients after e-cigarette. Z5Hz and R5Hz, R10Hz and R20Hz increased in both groups. FeNO and EBC pH increased by 3.60 ppb (P = 0.001) and 0.15 (P = 0.014) in asthmatic patients after e-cigarette, whereas they decreased in control group by 3.28 ppb (P < 0.001) and 0.12 (P = 0.064), respectively. The concentrations of IL-10, TNF-α and ISO8 in EBC increased in asthmatic patients after e-cigarette and the changes in concentrations of IL-1ß and IL-4 differed significantly between the two groups. CONCLUSION: E-cigarette vaping resulted in acute alteration of both pulmonary function and airway inflammation in stable moderate asthmatic patients.

Free Cortisol Is a More Accurate Marker for Adrenal Function and Does Not Correlate with Renal Function in Cirrhosis.

BACKGROUND: The accuracy of diagnosis and clinical implications of the hepatoadrenal syndrome, as currently diagnosed using total cortisol, remain to be validated. AIM: The aim of this study was to assess adrenal function using free cortisol in stable cirrhosis and study the potential implications of any abnormalities for renal and/or cardiac function. METHODS: Sixty-one stable consecutively enrolled patients with cirrhosis underwent assessment of adrenal function using the low-dose short Synacthen test, renal function by 51Cr-EDTA glomerular filtration rate (GFR), and cardiac function by two-dimensional echocardiography. RESULTS: Eleven patients (18%) had total peak cortisol (PC) < 500 nmol/L, but no patient had free PC < 33 nmol/L indicating that diagnosis of AI using total cortisol is not confirmed using free cortisol. Free cortisol did not correlate with GFR or parameters of cardiac function. Patients with higher Child-Pugh class had progressively lower free cortisol. Patients with low GFR < 60 mL/min (N = 22) had more frequently grade II-III diastolic dysfunction (66.7% vs. 17.6%; p = 0.005) and had higher Child-Pugh and MELD score compared to those with normal GFR. CONCLUSIONS: Diagnosis of AI using total cortisol is not confirmed using free cortisol and is thus considered unreliable in cirrhosis. Free cortisol is not associated with renal or cardiac dysfunction. Lower free cortisol in more advanced stages of liver disease might be secondary to decreased synthesis due to lower cholesterol levels. Irrespective of free cortisol, parameters of cardiac dysfunction are associated with renal impairment supporting the cardio-renal hypothesis.

Neuropsychological functioning in patients with interstitial lung disease.

OBJECTIVE: We undertook the present study to investigate the cognitive status of patients with interstitial lung disease (ILD) and its relationship to pulmonary function and cardiovascular efficiency. METHOD: Fifty-one patients with a diagnosis of ILD [mean duration = 3.13 years (SD = 3.01)] received a respiratory examination, including spirometry and the six-minute walk test, and completed a neuropsychological assessment including several cognitive domains. Eighty-eight healthy individuals matched on age, education, and gender, completed the neuropsychological test battery. RESULTS: Patients performed more poorly than their healthy peers on cognitive tasks related to verbal and visual memory, visual perception, and working memory, but not attention, processing speed and executive functioning. Stepwise linear regression analyses showed that exercise-related measures (heart rate, oxygen saturation and distance walked) predicted performance on neuropsychological tests of psychomotor speed, verbal memory and word production. Additionally, an index of pulmonary function, specifically, lung diffusion capacity, predicted performance on selective and sustained attention and word generation. CONCLUSION: The present preliminary findings may have implications for the quality of life and treatment compliance of patients with ILD and warrant further study with a larger sample of patients.

A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.

BACKGROUND: The integrative physiological effects of O2 treatment on patients with pulmonary hypertension (PH) during exercise, have not been fully investigated. We simultaneously evaluated, for the first time, the effect of oxygen supplementation on hemodynamic responses, autonomic modulation, tissue oxygenation, and exercise performance in patients with pulmonary arterial hypertension (PAH)/Chronic Thromboembolic PH(CTEPH). MATERIAL-METHODS: In this randomized, cross-over, placebo-controlled trial, stable outpatients with PAH/CTEPH underwent maximal cardiopulmonary exercise testing, followed by two submaximal trials, during which they received supplementary oxygen (O2) or medical-air. Continuous, non-invasive hemodynamics were monitored via photophlythesmography. Cerebral and quadriceps muscle oxygenation were recorded via near-infrared spectroscopy. Autonomic function was assessed by heart rate variability; root mean square of successive differences (RMSSD) and standard-deviation-Poincare-plot (SD1) were used as indices of parasympathetic output. Baroreceptor sensitivity (BRS) was assessed throughout the protocols. RESULTS: Nine patients (51.4 ±â€¯9.4 years) were included. With O2-supplementation patients exercised for longer (p = 0.01), maintained higher cerebral oxygenated hemoglobin (O2Hb;p = 0.02) levels, exhibited an amelioration in cortical deoxygenation (HHb;p = 0.02), and had higher average cardiac output (CO) during exercise (p < 0.05), compared to medical air; with no differences in muscle oxygenation. With O2-supplementation patients exhibited higher BRS and sample-entropy throughout the protocol (p < 0.05) vs. medical air, and improved the blunted RMSSD, SD1 responses during exercise (p = 0.024). CONCLUSION: We show that O2 administration improves BRS and autonomic function during submaximal exercise in PAH/CTEPH, without significantly affecting muscle oxygenation. The improved autonomic function, along with enhancements in cardiovascular function and cerebral oxygenation, probably contributes to increased exercise tolerance with O2-supplementation in PH patients.

An unusual presentation of dystonia and chorea from intraventricular pneumocephalus.

BACKGROUND: Pneumocephalus is a common finding following intracranial procedures, typically asymptomatic and resolves within several days. However, in some cases, pneumocephalus presents with headache, encephalopathy, or symptoms of elevated intracranial pressure. Here, we present a case of iatrogenic tension pneumocephalus following endoscopic sinus surgery, presenting as abnormal involuntary movements resembling a movement disorder with choreiform movements. CASE DESCRIPTION: A 67-year-old previously healthy male presented with new onset chorea and dystonia associated with headache, encephalopathy, and postural instability 4 days after undergoing endoscopic sinus surgery for chronic sinusitis and nasal polyps. Computed tomography showed prominent intraventricular pneumocephalus causing enlargement of the anterior horns of both lateral ventricles with lateral displacement of the basal ganglia nuclei and a bony defect in the skull base. Neurosurgical correction of the cranial defect provided complete symptomatic resolution. Pneumocephalus as a result of an iatrogenic injury of the skull base manifesting as an acute movement disorder is a rare complication of a nasal sinus procedure. We speculate that compression of the caudate nucleus and striatum resulted in decreased pallidothalamic inhibition and thalamocortical disinhibition leading to the development of a hyperkinetic movement disorder. CONCLUSION: This unusual presentation of a common procedure illustrates a neurological emergency that requires prompt recognition and timely correction.

Potential prognostic value of intracellular cytokine detection by flow cytometry in pulmonary sarcoidosis.

In pulmonary sarcoidosis, differential cytokine production in the lungs could be related to variable prognosis of patients at different stages of disease. Twenty patients with pulmonary sarcoidosis (10 at radiographic stage I and 10 at stages II-IV), as well as 10 age-matched healthy volunteers participated in the study. A 4-colour flow cytometric technique was used to measure interferon-γ (IFN-γ), interleukin (IL)-2, tumour necrosis factor-α (TNF-α), IL-4, and IL-13 production in phorbol myristate acetate (PMA)/ionomycin-stimulated CD4+ and CD8+ T cells from bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) of patients, and PB of control subjects. CD4+ T cells from patients showed higher expression of IFN-γ in BALF than in PB. Significant correlations were observed between the percentages of BALF CD4+ and CD8+ T cells expressing intracellular IFN-γ, IL-2, and TNF-α. Stage I patients had lower percentages of IFN-γ-producing CD4+ and CD8+ T cells, as well as TNF-α-producing CD8+ T cells, in BALF (but not in PB) than stage II-IV patients. A decreased TH1 and TC1 response was demonstrated in BALF of patients at stage I of disease, which could explain their anticipated better prognosis.

Pulmonary thromboendarterectomy after treatment with treprostenil in a chronic thromboembolic pulmonary hypertension patient: a case report.

In recent years, there has been a major advance in the treatment of pulmonary hypertension. New medications are continually added to the therapeutic arsenal. The prostanoids are among the first agents used to treat pulmonary hypertension and are currently considered the most effective. This case study describes a 63-year-old man who was diagnosed with chronic thromboembolic pulmonary hypertension and successfully treated with subcutaneously administered treprostenil for 6 months before a successful pulmonary thromboendarterectomy. Treatment of chronic thromboembolic pulmonary hypertension often requires a multidisciplinary approach before surgery. Further evaluation of prostanoids is needed to define their role and time of initiation of medical therapy in these patients.