Ioannis Tomos

Extracellular matrix remodeling in idiopathic pulmonary fibrosis. It is the ‘bed’ that counts and not ‘the sleepers’

ABSTRACT Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by irreversible fibrosis. Current disease pathogenesis assumes an aberrant wound healing process in response to repetitive injurious stimuli leading to apoptosis of epithelial cells, activation of fibroblasts and accumulation of extracellular matrix (ECM). Particularly, lung ECM is a highly dynamic structure that lies at the core of several physiological and developmental pathways. The scope of this review article is to summarize current knowledge on the role of ECM in the pathogenesis of IPF, unravel novel mechanistic data and identify future more effective therapeutic targets. Areas covered: The exact mechanisms through which lung microenvironment activates fibroblasts and inflammatory cells, regulates profibrotic signaling cascades through growth factors, integrins and degradation enzymes ultimately leading to excessive matrix deposition are discussed. Furthermore, the potential therapeutic usefulness of specific inhibitors of matrix deposition or activators of matrix degradation pathways are also presented. Expert commentary: With a gradually increasing worldwide incidence IPF still present a major challenge in clinical research due to its unknown etiopathogenesis and current ineffective treatment approaches. Today, there is an amenable need for more effective therapeutic targets and ECM components may represent one.

High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations

Introduction Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis acute exacerbations (IPF‐AEs). According to one hypothesis IPF‐AEs represent the development of any etiology diffuse alveolar damage (DAD) upon usual interstitial pneumonia (UIP), whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro‐inflammatory and pro‐fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. Methods Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF‐AE were based on international guidelines and consensus criteria. The interleukins (IL)‐4, IL‐6, IL‐8, IL‐10, and IL‐13 as well as active transforming growth factor‐beta (TGF‐&bgr;) were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12 months. Mann‐Whitney test as well as Tobit and logistic regression analyses were applied. Results Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The IL‐6 and IL‐8 levels were significantly higher in exacerbated patients (p = 0.002 and p = 0.046, respectively). An increase in either IL‐6 or IL‐8 by 1 pg/ml increases the odds of death by 5.6% (p = 0.021) and 6.7% (p = 0.013), respectively, in all patients. No differences were detected for the other cytokines. Conclusion High levels of IL‐6 and IL‐8 characterize early‐on IPF‐AEs and an increase in the levels of IL‐6 and IL‐8 associates with worse outcome in all patients. However, as the most representative pro‐fibrotic cytokines, TGF‐&bgr;, IL‐10, IL‐4 and IL‐13 were not increased and given the dualistic nature, both pro‐inflammatory and pro‐fibrotic of IL‐6 further studies are necessary to clarify the enigma of IPF‐AEs etiopathogenesis. HighlightsControversy exists about the pathogenesis of IPF‐AEs.Early in the development of an IPF‐AE, IL‐6 and IL‐8 blood levels are significantly increased.While TGF‐&bgr;, IL‐4, IL‐10, and IL‐13 levels show no difference compared stable IPF patients.Increased IL‐6 and IL‐8 levels are related to a higher risk of death in all IPF patients.Further studies are necessary to clarify the enigma of IPF‐AEs etiopathogenesis.

Serum Levels of Surfactant Proteins in Patients with Combined Pulmonary Fibrosis and Emphysema (CPFE).

Introduction Emphysema and idiopathic pulmonary fibrosis (IPF) present either per se or coexist in combined pulmonary fibrosis and emphysema (CPFE). Serum surfactant proteins (SPs) A, B, C and D levels may reflect lung damage. We evaluated serum SP levels in healthy controls, emphysema, IPF, and CPFE patients and their associations to disease severity and survival. Methods 122 consecutive patients (31 emphysema, 62 IPF, and 29 CPFE) and 25 healthy controls underwent PFTs, ABG-measurements, 6MWT and chest HRCT. Serum levels of SPs were measured. Patients were followed-up for 1-year. Results SP-A and SP-D levels differed between groups (p = 0.006 and p<0.001 respectively). In post-hoc analysis, SP-A levels differed only between controls and CPFE (p<0.05) and CPFE and emphysema (p<0.05). SP-D differed between controls and IPF or CPFE (p<0.001 for both comparisons). In IPF SP-B correlated to pulmonary function while SP-A, correlated to the Composite Physiological Index (CPI). Controls current smokers had higher SP-A and SP-D levels compared to non-smokers (p = 0.026 and p = 0.023 respectively). SP-D levels were higher in CPFE patients with extended emphysema (p = 0.042). In patients with IPF, SP-B levels at the upper quartile of its range (≥26 ng/mL) presented a weak association with reduced survival (p = 0.05). Conclusion In conclusion, serum SP-A and SP-D levels were higher where fibrosis exists or coexists and related to disease severity, suggesting that serum SPs relate to alveolar damage in fibrotic lungs and may reflect either local overproduction or overleakage. The weak association between high levels of SP-B and survival needs further validation in clinical trials.

Ability of using different dry powder inhalers during COPD exacerbations

BACKGROUND Guidelines suggest that patients hospitalized for acute COPD exacerbations (AECOPD) are treated with short acting bronchodilators. Long acting bronchodilators, offer longer symptom relief but since they are usually administered via Dry Powder Inhalers (DPIs) it is considered that during AECOPD patients would not be able to achieve appropriate inspiratory flow (IF) to receive appropriate drug doses. The aim of the present study was to evaluate whether patients admitted to the hospital for AECOPD, are able to achieve the necessary IF using different DPIs. METHODS IF was measured daily in patients admitted for AECOPD with a portable IF meter (In-Check Oral inhaler assessment kit), containing a series of adapters that simulate the resistance of 4 DPIs [Turbuhaler (T), Breezhaler/Aerolizer (B/F), Discus (A/A/D) and Handinhaler (HH)]. Dyspnea, spirometry and arterial blood gases were also recorded daily. RESULTS 44 consecutive patients were included in the study. The majority of patients were able to achieve an IF over 30 L/min with all four device resistances. This minimum required IF was achieved in 90.9%, 100%, 95.5% and 81.8% of patients on admission and in 100%, 100%, 97.7%, and 95.5% of patients on discharge for T, B/F, A/A/D and HH respectively. No functional characteristic was able to predict the achievement of this minimum necessary IF. CONCLUSION Most patients hospitalized for AECOPD, are able to receive treatment with long acting bronchodilators administered via DPIs. The possible beneficial effects of such an intervention should be tested in further studies.

Unilateral hypertransparency on chest radiograph: the congenital Poland Syndrome

Unilateral hypertransparent hemithorax requires a particular diagnostic approach as it can be the result of diverse pulmonary diseases, including pneumothorax, large pulmonary embolus, unilateral large bullae, mucous plag, airway obstruction and contralateral pleural effusion. Congenital syndromes with chest wall abnormalities, are rare, but often underdiagnosed causes. Poland Syndrome consists of such a rare, congenital anomaly and is characterized by the absence of the pectoralis major muscle and upper limb ipsilateral abnormalities. We present a case of a patient with acute exacerbation of chronic obstructive pulmonary disease (COPD) and a unilateral hypertransparency on chest radiology, attributed to the underlying Poland Syndrome.

Serum osteopontin in patients with lung cancer and chronic obstructive pulmonary disease: does the co-existence make the difference?

Background Osteopontin (OPN) is involved in cancer development and metastasis. Increased sputum OPN was detected in chronic obstructive pulmonary disease (COPD). Methods We evaluated serum OPN levels in patients with lung cancer (LC) and/or COPD and aimed to determine OPN prognostic performance in 1-year mortality in LC and also its diagnostic performance in LC among COPD patients. We recruited 167 LC patients, 85 with concomitant COPD. 28 COPD patients served as control group. Results OPN levels were higher in LC compared to COPD alone (P=0.017) and higher in COPD and LC compared to COPD alone (P=0.031). No difference was observed in OPN levels between LC and COPD vs. LC without COPD (P=0.171). Serum OPN ≥50.3 ng/mL was an independent predictor of 1-year mortality in LC. Conclusions OPN levels ≥35 ng/mL could predict the presence of LC among COPD patients. In patients with LC and/or COPD, LC is the major determinant for serum OPN. Serum OPN might be a promising prognostic biomarker of LC and a diagnostic biomarker of LC among COPD patients.

Bilateral nodular opacities and hilar node enlargement in a 73-year-old man with cough

A 73-year-old Caucasian male, ex-smoker with a smoking history of 50 pack-years, presented to our department complaining of chronic cough, gradually progressive shortness of breath on exertion and fatigue during recent months. He did not report any chest pain or fever. The patient’s medical history only included arterial hypertension, while in the past he worked in the stone crushing industry. Can you diagnose this man presenting with chronic cough and progressive shortness of breath on exertion and fatigue developing over several months? http://ow.ly/ekZd30k8VcM

Thoracic ultrasound for the detection of rib metastases of non-small cell lung cancer

Transthoracic ultrasound has lately emerged as a useful diagnostic tool for respiratory physicians in the diagnosis of diverse pulmonary diseases, usually including pleural effusion and pneumothorax. However, the use of chest ultrasound may be also critical in the evaluation of chest wall diseases. Therefore, we present an interesting case of a patient with metastases of lung cancer to the rib, detected during the chest wall ultrasound examination. By representing a non-invasive, surface-imaging technique with several advantages, chest ultrasound may evolve to a valid, bed-side diagnostic tool for the diagnosis and follow up of lung cancer with metastases in the chest wall.

Massive hemoptysis in a patient with pulmonary embolism, a real therapeutic conundrum

Massive Hemoptysis and pulmonary embolism are two very severe and potentially fatal pulmonary emergencies requiring completely different treatments. We present the case of a 45-year old male transmitted to our Hospital for massive hemoptysis who at the same time was found to suffer from pulmonary embolism. Hemoptysis was treated with bronchial artery embolization which resulted in cessation of haemorrhage and allowed the administration of anticoagulant therapy a few days later. This case report gives an answer on how to manage a real therapeutic conundrum which is the coexistence of a massive hemoptysis and a concomitant pulmonary embolism.

Large thoracic tumour without superior vena cava syndrome

A 62 year-old male with long-standing smoking history presented with hemoptysis. Plain chest x-ray showed abnormal findings proximate to the right pulmonary hilum. Bronchoscopy revealed a fragile exophytic tumor of the right wall of the lower third of the trachea, infiltrating the right main bronchus (75% stenosis) and the right upper lobar bronchus (near total occlusion). Contrast-enhanced chest CT demonstrated a 7.2x4.9 cm tumor contiguous to the above-mentioned structures, mediastinal lymph node pathology, and a vessel coursing inferiorly to the left of the aortic arch and anterior to the left hilum. Despite the tumor constricting the right superior vena cava, no signs of superior vena cava syndrome were present. In this case, the patient does not present with Superior Vena Cava (SVC) syndrome, as expected due to the constriction of the (right) SVC caused by the tumor, since head and neck veins drain through the Persistent Left Superior Vena Cava (PLSVC). PLSVC is the most common thoracic venous anomaly with an incidence of 0.3% to 0.5% of the general population and it is a congenital anomaly caused by the failure of the left anterior cardinal vein to regress and to consequently form the ligament of Marshall during fetal development. It is associated with absence of the left brachiocephalic vein and in 10 to 20% of cases the right SVC is absent. Two potential draining points of the PLSVC have been previously reported. In the majority of cases PLSVC drains directly into the coronary sinus, but less frequently it drains into the left atrium or the left superior pulmonary vein. In cases where the PLSVC drains into the coronary sinus, congenital heart defects are rare. The patient usually remains asymptomatic and PLSVC is an incidental finding during radiographic imaging or medical procedures. When the PLSVC drains into the left atrium or the left superior pulmonary vein, a right-to-left shunt is formed; a condition usually asymptomatic. In some reported cases this PLSVC variant presents with persistent, unexplained hypoxia or cyanosis and embolisation causing recurrent transient ischemic attacks and/or cerebral abscesses. This PLSVC variant is more often associated with absence of the right SVC and congenital heart abnormalities.