Mediatori anti-infiammatori derivati dall’acido docoexaenoico nell’escreato di adulti affetti da fibrosi cistica: implicazioni cliniche e terapeutiche

Razionale. Numerosi studi hanno documentato nella Fibrosi Cistica (FC) una significativa riduzione dei livelli di acido docosaexaenoico (DHA), coinvolto nella risposta antiossidante e nella generazione di metaboliti, quali resolvine e protectine, identificati come importanti fattori nella fase di risoluzione del processo infiammatorio. Tale deficit potrebbe pertanto svolgere un ruolo fondamentale nella progressione della cascata infiammatoria e della malattia polmonare. Scopo dello studio. In questa fase preliminare ci siamo proposti di: determinare il contenuto dei derivati dell’acido arachidonico (AA) e del DHA nell’escreato di soggetti adulti affetti da FC e verificare se la supplementazione con DHA sia in grado di migliorare il profilo degli acidi grassi. I risultati nei pazienti FC sono stati confrontati con quelli ottenuti in pazienti con bronco-pneumopatia cronica ostruttiva (BPCO). Materiali e Metodi. Lo studio ha coinvolto 15 soggetti affetti da FC reclutati presso la Struttura Semplice di Fibrosi Cistica dell’Azienda Ospedaliera Universitaria di Parma e 10 soggetti affetti da BPCO reclutati presso la Clinica Pneumologica dell’Università di Parma e di Modena-Reggio Emilia. Il protocollo dello studio è articolato in due fasi. Nella prima fase sono stati valutati nell’escreato i mediatori leucotriene B4 (LTB4), prostaglandina E2 (PGE2), acido 15-idrossieicosatetraenoico (15-HETE), acido 17-idrossidocoexainoico (17OH-DHA), il rapporto 15-HETE/17OH-DHA e negli eritrociti il rapporto DHA/AA e l’indice degli acidi grassi polinsaturi n-3 (HUFA index). Nella seconda fase sono state valutate le variazioni dei medesimi mediatori dopo due settimane di trattamento con antibioticoterapia ev e/o dopo dieci settimane di supplementazione di DHA nella dieta alla dose di 3 g/die e dopo dieci settimane senza supplementazione. Risultati. L’esame citologico dell’escreato in condizioni basali ha dimostrato la presenza di una infiammazione di tipo neutrofilico in tutti i pazienti FC. Rispetto ai soggetti BPCO, i pazienti affetti da FC presentano una aumentata concentrazione di LTB4, PGE2 e 15-HETE. Non sono emerse differenze tra i due gruppi per la concentrazione del 17OH-DHA. 9/15 pazienti FC (5 donne) erano in fase di stabilità clinica e hanno ripetuto la valutazione nutrizionale e funzionale e dei mediatori lipidici dopo dieci settimane di supplementazione di DHA nella dieta e dopo dieci settimane senza supplementazione. Dopo dieci settimane di supplementazione con DHA nei soggetti FC abbiamo osservato nello sputo una riduzione (X ±DS) di LTB4, PGE2 e 15-HETE, che per quest’ultimo raggiunge la significatività statistica. Al contrario, il 17OH-DHA aumenta alla fine della supplementazione. Al termine del periodo di wash-out, LTB4, PGE2 e 15-HETE aumentano senza raggiungere i valori basali; mentre il 17OH-DHA è sostanzialmente invariato. Inoltre, dopo la supplementazione, l’analisi di composizione degli acidi grassi negli eritrociti ha evidenziato un aumento statisticamente significativo del rapporto DHA/AA e dell’HUFA index. Inoltre, dopo la supplementazione con DHA, il rapporto 15-HETE/17OH-DHA si riduce in modo statisticamente significativo rispetto al basale. Conclusioni. Questi risultati preliminari dimostrano che nei soggetti FC esiste uno squilibrio del metabolismo degli acidi grassi con aumento dei mediatori derivati dall’AA e riduzione dei derivati del DHA, parzialmente corretto dalla supplementazione dietetica con DHA. La conoscenza dettagliata di queste alterazioni metaboliche potrebbe contribuire a sviluppare specifiche terapie personalizzate sul profilo infiammatorio di ogni paziente.Background. Several reports have shown in patients with cystic fibrosis (CF) a significantly reduction of the levels of docosahexaenoic acid (DHA), which is involved in antioxydans response and in production of mediators identified as important factors during the resolution phase of inflammatory reaction. The deficit of DHA may play a role in the inflammatory cascade of pulmonary disease in CF patients. The aim of the study was: to determine the levels of the arachidonic acid (AA) metabolites and DHA in sputum of adults with CF subjects, as compared to patients with COPD; to ascertain whether or not DHA supplementation may affect the fatty acid pattern in CF subjects. Subjects & Methods. We studied 15 CF subjects and 10 COPD patients. CF patients (age range 20 to 40) were recruited at the Cystic Fibrosis Unit of Parma Hospital and the control group of COPD patients were recruited at the University Hospitals of Modena-Reggio Emilia and Parma. At baseline all subjects performed: nutritional status evaluation, severity score evaluation (Shwachman-Kulczycki score), spirometry, exhaled NO measurement, exhaled breath condensate (EBC), sputum induction (SI) to evaluate leukotriene B4 (LTB4), prostaglandin E2 (PGE2), 15-hydroxyeicosatetraenoic acid (15-HETE), 17-hydroxydocosahexaenoic acid (17OH-DHA), 15-HETE/17OH-DHA ratio, and blood sample to evaluate DHA/AA ratio and HUFA index in the red cells (first phase). During the second phase, CF patients performed all evaluations after two weeks of systemic antibiotic therapy or/and after ten weeks with DHA-supplementation and after ten weeks without DHA-supplementation. Results. As compared to COPD patients, CF subjects showed increased concentrations of LTB4, PGE2, 15-HETE. The concentrations of the DHA derived were not different in the two groups. 9 out of 15 CF patients (5 female) were clinically stable and completed second phase of the study. After ten weeks of DHA supplementation, CF subjects showed a tendency to decrease in LTB4 and PGE2 and to increase in 17OH-DHA, and a significantly reduction in levels. At the end of the washout period, LTB4, PGE2, 15-HETE, and 17OH-DHA tended to recover baseline values. After supplementation DHA/AA ratio and HUFA index were significantly increased. As compared to baseline, 15-HETE/17OH-DHA ratio significantly changed after supplementation. Conclusion. Our preliminary results showed that in CF patients an impairment in fatty acid metabolism, characterized by increase in AA metabolites and decrease in DHA, was partially corrected by DHA supplementation. A better understanding of these metabolic changes could provide new insights into disease pathophysiology and potentially could identify new biomarkers of disease severity

Arachidonic acid and docosahexaenoic acid metabolites in the airways of adults with cystic fibrosis: effect of docosahexaenoic acid supplementation.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by genetic mutations in CF transmembrane conductance regulator (CFTR) protein. Several reports have indicated the presence of specific fatty acid alterations in CF patients, most notably decreased levels of plasmatic and tissue docosahexaenoic acid (DHA), the precursor of Specialized Pro-resolving Mediators (SPMs). We hypothesized that DHA supplementation could restore the production of DHA-derived products and possibly contribute to a better control of the chronic pulmonary inflammation observed in CF subjects. Sputum samples from 15 CF and 10 Chronic Obstructive Pulmonary Disease (COPD) subjects were collected and analyzed by LC/MS/MS and blood fatty acid were profiled by gas chromatography upon lipid extraction and transmethylation. As compared to COPD patients, CF subjects showed increased concentrations of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and 15-hydroxyeicosatetraenoic acid (15-HETE), while the concentrations of DHA metabolites were not different in the two groups. After DHA supplementation, not only DHA/AA ratio and highly unsaturated fatty acid (HUFA) index were significantly increased (p < 0.05), but CF subjects showed a tendency toward a decrease in LTB4 and PGE2 and an increase in 17-hydroxy-docosahexaenoic acid (17OH-DHA) levels, together with a significantly reduction in 15-HETE. At the end of the washout period, LTB4, PGE2, 15-HETE, and 17OH-DHA tended to recover baseline values. As compared to baseline, 15-HETE/17OH-DHA ratio significantly changed after supplementation (p < 0.01). Our results showed that in CF patients an impairment in fatty acid metabolism, characterized by increase in AA metabolites and decrease in DHA, was partially corrected by DHA supplementation

Predictive factors of clinical outcomes in patients with COVID-19 treated with tocilizumab: A monocentric retrospective analysis

Objective The aim of this retrospective observational study is to analyse clinical, serological and radiological predictors of outcome in patients with COVID-19 pneumonia treated with tocilizumab, providing clinical guidance to its use in real-life. Method This is a retrospective, monocentric observational cohort study. All consecutive patients hospitalized between February the 11th and April 14th 2020 for severe COVID-19 pneumonia at Reggio Emilia AUSL and treated with tocilizumab were enrolled. The patient's clinical status was recorded every day using the WHO ordinal scale for clinical improvement. Response to treatment was defined as an improvement of one point (from the status at the beginning of tocilizumab treatment) during the follow-up on this scale. Bivariate association of main patients' characteristics with outcomes was explored by descriptive statistics and Fisher or Kruskal Wallis tests (respectively for qualitative or quantitative variables). Each clinically significant predictor was checked by a loglikelihood ratio test (in univariate logistic models for each of the considered outcomes) against the null model. Results A total of 173 patients were included. Only hypertension, the use of angiotensin-converting enzyme inhibitors, PaO2/FiO2, respiratory rate and C-reactive protein were selected for the multivariate analysis. In the multivariable model, none of them was significantly associated with response. Conclusions Evaluating a large number of clinical variables, our study did not find new predictors of outcome in COVID19 patients treated with tocilizumab. Further studies are needed to investigate the use of tocilizumab in COVID-19 and to better identify clinical phenotypes which could benefit from this treatment

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile

The impact of chest CT body composition parameters on clinical outcomes in COVID-19 patients

We assessed the impact of chest CT body composition parameters on outcomes and disease severity at hospital presentation of COVID-19 patients, focusing also on the possible mediation of body composition in the relationship between age and death in these patients. Chest CT scans performed at hospital presentation by consecutive COVID-19 patients (02/27/2020-03/13/2020) were retrospectively reviewed to obtain pectoralis muscle density and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, IMAT) at the level of T7-T8 vertebrae. Primary outcomes were: hospitalization, mechanical ventilation (MV) and/or death, death alone. Secondary outcomes were: C-reactive protein (CRP), oxygen saturation (SO2), CT disease extension at hospital presentation. The mediation of body composition in the effect of age on death was explored. Of the 318 patients included in the study (median age 65.7 years, females 37.7%), 205 (64.5%) were hospitalized, 68 (21.4%) needed MV, and 58 (18.2%) died. Increased muscle density was a protective factor while increased TAT, VAT, and IMAT were risk factors for hospitalization and MV/death. All these parameters except TAT had borderline effects on death alone. All parameters were associated with SO2 and extension of lung parenchymal involvement at CT; VAT was associated with CRP. Approximately 3% of the effect of age on death was mediated by decreased muscle density. In conclusion, low muscle quality and ectopic fat accumulation were associated with COVID-19 outcomes, VAT was associated with baseline inflammation. Low muscle quality partly mediated the effect of age on mortality.We assessed the impact of chest CT body composition parameters on outcomes and disease severity at hospital presentation of COVID-19 patients, focusing also on the possible mediation of body composition in the relationship between age and death in these patients. Chest CT scans performed at hospital presentation by consecutive COVID-19 patients (02/ 27/2020-03/13/2020) were retrospectively reviewed to obtain pectoralis muscle density and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, IMAT) at the level of T7-T8 vertebrae. Primary outcomes were: hospitalization, mechanical ventilation (MV) and/or death, death alone. Secondary outcomes were: C-reactive protein (CRP), oxygen saturation (SO2), CT disease extension at hospital presentation. The mediation of body composition in the effect of age on death was explored. Of the 318 patients included in the study (median age 65.7 years, females 37.7%), 205 (64.5%) were hospitalized, 68 (21.4%) needed MV, and 58 (18.2%) died. Increased muscle density was a protective factor while increased TAT, VAT, and IMAT were risk factors for hospitalization and MV/death. All these parameters except TAT had borderline effects on death alone. All parameters were associated with SO2 and extension of lung parenchymal involvement at CT; VAT was associated with CRP. Approximately 3% of the effect of age on death was mediated by decreased muscle density. In conclusion, low muscle quality and ectopic fat accumulation were associated with COVID-19 outcomes, VAT was associated with baseline inflammation. Low muscle quality partly mediated the effect of age on mortality

Excess ventilation and ventilatory constraints during exercise in patients with chronic obstructive pulmonary disease.

We assessed the relationship between minute ventilation/carbon dioxide output (VE/VCO2) and ventilatory constraints during an incremental cardiopulmonary exercise testing (CPET) in patients with chronic obstructive pulmonary disease (COPD). Slope and intercept of the VE/VCO2 linear relationship, the ratios of inspiratory capacity/total lung capacity (IC/TLC) and of tidal volume (VT) over vital capacity (VTpeak/VC) and IC (VTpeak/IC) and over forced expiratory volume at 1st second (VTpeak/FEV1) at peak of exercise were measured in 52 COPD patients during a CPET. The difference peak-rest in end-tidal pressure of CO2 (PETCO2) was also measured. VE/VCO2 intercept showed a negative correlation with IC/TLC peak (p < 0.01) and a positive one with VTpeak/FEV1 (p < 0.01) and with PETCO2 peak-rest (p < 0.01). VE/VCO2 slope was negatively related to VTpeak/VC, VTpeak/IC and VTpeak/FEV1 (all correlations p < 0.05) and to PETCO2 peak-rest (p < 0.01). In COPD, VE/VCO2 slope and intercept provide complementary information on the ventilatory limitation to exercise, as assessed by changes in the end-expiratory lung volume and in tidal volume excursion