Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.

Clinical and biological clusters of sepsis patients using hierarchical clustering

Background Heterogeneity in sepsis expression is multidimensional, including highly disparate data such as the underlying disorders, infection source, causative micro-organismsand organ failures. The aim of the study is to identify clusters of patients based on clinical and biological characteristic available at patients’ admission. Methods All patients included in a national prospective multicenter ICU cohort OUTCOMEREA and admitted for sepsis or septic shock (Sepsis 3.0 definition) were retrospectively analyzed. A hierarchical clustering was performed in a training set of patients to build clusters based on a comprehensive set of clinical and biological characteristics available at ICU admission. Clusters were described, and the 28-day, 90-day, and one-year mortality were compared with log-rank rates. Risks of mortality were also compared after adjustment on SOFA score and year of ICU admission. Results Of the 6,046 patients with sepsis in the cohort, 4,050 (67%) were randomly allocated to the training set. Six distinct clusters were identified: young patients without any comorbidities, admitted in ICU for community-acquired pneumonia (n = 1,603 (40%)); young patients without any comorbidities, admitted in ICU for meningitis or encephalitis (n = 149 (4%)); elderly patients with COPD, admitted in ICU for bronchial infection with few organ failures (n = 243 (6%)); elderly patients, with several comorbidities and organ failures (n = 1,094 (27%)); patients admitted after surgery, with a nosocomial infection (n = 623 (15%)); young patients with immunosuppressive conditions (e.g., AIDS, chronic steroid therapy or hematological malignancy) (n = 338 (8%)). Clusters differed significantly in early or late mortality (p < .001), even after adjustment on severity of organ dysfunctions (SOFA) and year of ICU admission. Conclusions Clinical and biological features commonly available at ICU admission of patients with sepsis or septic shock enabled to set up six clusters of patients, with very distinct outcomes. Considering these clusters may improve the care management and the homogeneity of patients in future studies.

Impact of Pseudomonas aeruginosa Infection on Patients with Chronic Inflammatory Airway Diseases

Pseudomonas aeruginosa (P. aeruginosa) is a ubiquitous and opportunistic microorganism and is considered one of the most significant pathogens that produce chronic colonization and infection of the lower respiratory tract, especially in people with chronic inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis. From a microbiological viewpoint, the presence and persistence of P. aeruginosa over time are characterized by adaptation within the host that precludes any rapid, devastating injury to the host. Moreover, this microorganism usually develops antibiotic resistance, which is accelerated in chronic infections especially in those situations where the frequent use of antimicrobials facilitates the selection of “hypermutator P. aeruginosa strain”. This phenomenon has been observed in people with bronchiectasis, CF, and the “exacerbator” COPD phenotype. From a clinical point of view, a chronic bronchial infection of P. aeruginosa has been related to more severity and poor prognosis in people with CF, bronchiectasis, and probably in COPD, but little is known on the effect of this microorganism infection in people with asthma. The relationship between the impact and treatment of P. aeruginosa infection in people with airway diseases emerges as an important future challenge and it is the most important objective of this review.

SAT0504 STING-ASSOCIATED VASCULOPATHY WITH ONSET IN INFANCY (SAVI SYNDROME) CAN MIMIC JUVENILE IDIOPATHIC ARTHRITIS.

Background:STING-associated vasculopathy with onset in infancy (SAVI syndrome) can mimic Juvenile Idiopathic Arthritis.Objectives:The aim of this study is to describe a detailed cohort of patients with SAVI syndrome and highlight the similarity, in some cases, of the phenotype of this disease with Juvenile Idiopathic Arthritis.Methods:3 patients diagnosed with SAVI syndrome from the institution Hospital Universitari Vall d’Hebron were recruited. Written informed parental consent was obtained for the use of clinical data and pictures reported. Demographic, clinical, analytical, lung function and previous and current treatment are described.Results:Patient 1, a 11-year-old boy, was identified to carry a de novo p.V155M mutation in TMEM173. He presented at first month of life with recurrent bronchial infection and skin vasculitis lesions in nose, cheeks and toes. Arthritis affected hands, toes and knees but no erosions were found at X-Ray. Fever was not reported. High-resolution computed tomography (HRCT) of the lungs identified a nonspecific interstitial pneumonia (NSIP) and a lung biopsy showed lymphoid hyperplasia. Elevated inflammatory markers were reported and rheumatoid factor (RF), ACPA antibodies and antinuclear antibodies (ANA) were also positive. At the age of 6 years Ruxolitinib (RX) was introduced at the initial dose of 5 mg twice daily with an improvement of skin disease and lung function. Arthritis was well controlled and RX was well tolerated.Patient 2, a 17-year-old girl, was identified to carry a de novo p.V155 mutation in TMEM173. She presented at the age of 3 with a severe polyarthritis of large and small joints. No fever, skin or respiratory symptoms were reported at the beginning of the disease. Laboratory tests were positive for RF and ACPA antibodies. She was diagnosed with Polyarticular JIA and was treated with steroids and Methotrexate without improvement. Few months later she reported dyspnoea with recurrent bronchial infections. HRCT showed NSIP and lymphoid interstitial pneumopathy was found at the lung biopsy. RX was initiated at the age of 17 years but at this time lung fibrosis was stablished. Moreover, RX was not well tolerated due to headache. She requires continuous domiciliary oxygen and has been included to lung transplant.Finally, patient 3, a 29-year-old man, was recently diagnosed with a de novo p.V155 mutation in TMEM173. He presented at the age of 7 years with symmetrical polyarticular arthritis after a bronchial infection that course with fever. No skin manifestations were objectified. Autoimmune lab test was positive for RF, ACPA, and ANA. With the diagnosis of Polyarticular JIA he received different treatments with no response. Due to recurrent bronchial infections a HRCT was performed showing an ILD at bases and follicular bronchiolitis with NSIP pattern in a lung biopsy. Functional tests were worsening without any response to different treatments. SAVI syndrome was suspected, and genetic test was performed with positive result. RX was initiated but compliance was not goodConclusion:SAVI syndrome is a rare monogenic autoinflammatory disease with few cases reported in the literature. Disease phenotype could be different in every patient, with no presence of skin vasculitic lesions or fever. Patient 2 and 3, in contrast with patient 1, had severe articular and lung manifestations with no skin involvement. Furthermore, lab tests were positive for RF and ACPA and were misdiagnosed as JIA so genetic test was performed later in the follow-up. Being aware of the distinct phenotype of the disease could help the clinicians to make a PRONTO diagnostic and reassess the patients with these presentations that not respond well to conventional treatments.References:[1]Liu Y, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014 Aug 7;371(6):507-518.Disclosure of Interests:None declared

Current Challenges in Chronic Bronchial Infection in Patients with Chronic Obstructive Pulmonary Disease

Currently, chronic obstructive pulmonary disease (COPD) patients and their physicians face a number of significant clinical challenges, one of which is the high degree of uncertainty related to chronic bronchial infection (CBI). By reviewing the current literature, several challenges can be identified, which should be considered as goals for research. One of these is to establish the bases for identifying the biological and clinical implications of the presence of potentially pathogenic microorganisms in the airways that should be more clearly elucidated according to the COPD phenotype. Another urgent area of research is the role of long-term preventive antibiotics. Clinical trials need to be carried out with inhaled antibiotic therapy to help clarify the profile of those antibiotics. The role of inhaled corticosteroids in patients with COPD and CBI needs to be studied to instruct the clinical management of these patients. Finally, it should be explored and confirmed whether a suitable antimicrobial treatment during exacerbations may contribute to breaking the vicious circle of CBI in COPD. The present review addresses the current state of the art in these areas to provide evidence which will enable us to progressively plan better healthcare for these patients.