H2 inhalation therapy in patients with moderate COVID-19 (H2COVID): a prospective ascending-dose phase I clinical trial.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for COVID-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. This phase I study, characterized by an open-label, prospective, monocentric, and single ascending-dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3 + 3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). We concluded that the maximum tolerated duration is at least 3 days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase I clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized COVID-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04633980.

Intermittent versus constant aerobic exercise in middle-aged males: acute effects on arterial stiffness and factors influencing the changes.

PURPOSE: Both constant and intermittent acute aerobic exercises have been found to decrease arterial stiffness. However, direct comparisons of these two types of exercise are sparse. It is not known which type of exercise has the greatest effect. METHODS: We evaluated the haemodynamic responses in 15 males (age 48.5 ± 1.3 years; BMI 27.5 ± 0.8 kg m-2) following acute constant (CE) and intermittent cycling exercise (IE). Duration and heart rate were matched during both exercises (131.8 ± 3.2 bpm for CE and 132.0 ± 3.1 bpm for IE). Central and peripheral arterial stiffness was assessed through pulse wave velocity (PWV). Plasma concentrations of nitric oxide (NO), atrial natriuretic peptide (ANP), blood lactate, noradrenaline, and adrenaline were measured before and after each exercise. RESULTS: Central (+ 1.8 ± 7.4 and - 6.5 ± 6.8% for CE and IE) and upper limb PWV (+ 2.7 ± 6.2 and - 8 ± 4.6% for CE and IE) were not significantly altered although a small decrease (small effect size) was observed after IE. However, lower limb PWV significantly decreased after exercises (- 7.3 ± 5.7 and - 15.9 ± 4% after CE and IE), with a larger effect after IE. CONCLUSIONS: Greater decrease in lower limb PWV occurred after IE despite greater heart rate. This may be due to the higher blood levels of lactate during IE, while NO, ANP, noradrenaline, and adrenaline levels remained not statistically different from CE. These results underlined the importance of lactate in triggering the post-exercise vascular response to exercise, as well as its regional characteristic.

Effects of three postexercice recovery treatments on femoral artery blood flow kinetics.

AIM: This study aimed to compare the kinetics of muscle leg blood flow during three recovery treatments following a prolonged exercise: contrast water therapy (CWT), compression stockings (CS) or passive recovery (PR). METHODS: Fifteen men came to the laboratory three times to perform a 45-min exercise followed 5 min after by a standardized 12-min recovery treatment in upright position, alternating between two vats every 2 min: CWT (cold: ~12 °C to warm: 36 °C), CS (~20 mmHg) or PR. The order of treatments was randomized. Blood flow was measured using Doppler ultrasound during the recovery treatments (i.e., min 3, 5, 7 and 9) in the superficial femoral artery distally to the common bifurcation (~3 cm) (above the water and stocking). RESULTS: Blood flow was significantly higher during CWT (P<0.01; +22.91%) and CS (P<0.05; +15.26%) than during PR. Although no statistical difference between CWT and CS was observed, effect sizes were larger during CWT (large) than during CS (moderate). No changes in blood flow occurred in the femoral artery between hot and cold transitions of CWT. CONCLUSION: During immediate recovery of a high intensity exercise, CWT and CS trigger higher femoral artery blood flow than PR. Moreover, effect sizes were greater during CWT than during CS.

[Bronchoscopic COPD treatments]. / Traitements endoscopiques de la BPCO.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with disabling respiratory symptoms including dyspnea, frequent exacerbations and chronic bronchitis. The currently available pharmacological and non-pharmacological therapies have limited efficacy, necessitating the development of interventional strategies, many of them endoscopic. STATE OF THE ART: Endoscopic lung volume reduction has markedly increased over recent years, principally as regards the endobronchial valves currently used in routine care. Indeed, multiple randomized trials have demonstrated a significant clinical benefit in a selected population identifiable due to the absence of interlobar collateral ventilation. Other endoscopic volume reduction techniques (polymers, thermal vapor, spirals) shall require additional studies before being considered as options in routine care. Targeted lung denervation (TLD) has aroused interest as a means of reducing exacerbations in the early phases of relevant studies. Endobronchial techniques (bronchoscopic cryospray, bronchial rheoplasty) are still at a very early stage of development, which is aimed at reducing the symptoms of chronic bronchitis. OUTLOOK: Aside from endobronchial valves, which are currently employed in routine care, all the above-mentioned endoscopic techniques require additional studies in order to determine their benefit/risk balance and to identify the population that would benefit the most. CONCLUSIONS: Endoscopic treatments constitute a major avenue of research and innovation in the therapeutic management of COPD. Inclusion of patients in disease registries and clinical trials remains essential, the objective being to gauge the interest of these treatments and their future role in everyday COPD management.

[Take-home messages from the COPD 2021 biennial of the French Society of Respiratory Diseases. Understanding to so as to better innovate]. / Principaux messages de la première Biennale BPCO 2021 de la SPLF. Mieux comprendre pour innover.

INTRODUCTION: The first COPD biennial organized by the French Society of Respiratory Diseases (SPLF) took place on 17 December 2021. STATE OF THE ART: The objective of the biennial was to discuss current knowledge regarding COPD pathophysiology, current treatments, research development, and future therapeutic approaches. PERSPECTIVES: The different lecturers laid emphasis on the complexity of pathophysiologic mechanisms including bronchial, bronchiolar and parenchymal alterations, and also dwelt on the role of microbiota composition in COPD pathenogenesis. They pointed out that addition to inhaled treatments, ventilatory support and endoscopic approaches have been increasingly optimized. The development of new therapeutic pathways such as biotherapy and cell therapy (stem cells…) call for further exploration. CONCLUSIONS: The dynamism of COPD research was repeatedly underlined, and needs to be further reinforced, the objective being to "understand so as to better innovate" so as to develop effective new strategies for treatment and management of COPD.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

[Management of pulmonary arteriovenous malformation with pulmonary hypertension]. / Prise en charge d'une malformation artério-veineuse pulmonaire avec hypertension pulmonaire.

INTRODUCTION: Pulmonary arteriovenous malformations (PAVM) are abnormal communications between arteries and pulmonary veins without interposition of capillaries. Embolization is effective both in reducing lifetime complications associated with PAVM and in improving arterial oxygenation. Embolization is however not recommended in patients with pulmonary hypertension (PH) as it abolishes low resistance pathways for pulmonary blood flow and therefore might be expected to elevate pulmonary arterial pressure (PAP). CASE REPORT: We report the case of a 70-year-old patient with a large PAVM as well as group 3 PH [mean PAP=21mmHg, pulmonary vascular resistance (PVR) at 3.4 Wood units] secondary to stage 2 chronic obstructive pulmonary disease (COPD) with emphysema. According to the measured shunt flow (26% of cardiac output), predicted post-embolization PVR was estimated at 4.6 Wood units. These values were considered compatible with embolization of the PAVM. Dyspnea and gas exchange improved after PAVM embolization, without worsening PH. CONCLUSION: Embolization of a PAVM can be considered in patients with stable PH but requires careful prior hemodynamic assessment. The estimation of the shunt flow and predicted post-embolization PVR may guide the therapeutic decision.

[Non-invasive home ventilation in patients with severe hypercapnic chronic obstructive pulmonary disease: The SOMNOVENT' study]. / Ventilation non invasive à domicile chez des patients BPCO sévères hypercapniques (étude SOMNOVENT').

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, especially in cases of chronic hypercapnic respiratory failure. Following a prolonged debate, the indication and benefits of noninvasive ventilation (NIV) have been recently established. Although improved ventilation and reduction in hyperinflation appear to underlie the positive effect on NIV in COPD, only a few studies have focused on specific ventilatory algorithms for improving PaCO2. METHODS: The main objective of this study is to analyze the impact of Löwenstein's ventilatory algorithms, supposed to allow a better management of hyperinflation and its consequences on alveolar ventilation and blood gas parameters. This is an interventional study in routine care, prospective, single blind, randomized with cross over. The primary endpoint will be the transcutaneous partial pressure of nocturnal carbon dioxide. Secondary endpoints will be: abnormal respiratory events occurring during nocturnal NIV; the objective quality of sleep via polysomnography; the tolerance of ventilation and the subjective quality of sleep evaluated by auto questionnaires. EXPECTED RESULTS: The results of this study will clarify whether is it necessary to explore more the impact of the ventilatory modes developed by Löwenstein, dedicated to hypercapnic COPD patients, requiring a long-term NIV.

Quantitative and qualitative evaluation of spirometry for COPD screening in general practice.

INTRODUCTION: Proper diagnosis of COPD remains a challenge. Spirometry testing in primary care may help to reduce misdiagnosis, but its reliability as a diagnostic instrument needs to be assessed. OBJECTIVES: To investigate (1) the validity of spirometry testing performed in primary care and (2) the accuracy of the diagnostic of airflow limitation obtained by these tests. METHODS: Subjects attending a COPD screening programme had screening spirometry performed either by general practitioners (GPs) or by trained nurses or technicians, who had all received two 3-hour training sessions. Subjects with airflow limitation and a subset of subjects with normal spirometry at screening were invited to undergo confirmatory spirometry performed by trained nurses in a pulmonary function laboratory. RESULTS: Of the 4610 subjects who attended the screening sessions, 96.5% had a valid screening spirometry test. A total of 392 subjects attended the confirmatory sessions. Values measured by screening spirometry were satisfactory compared with those of confirmatory spirometry (rc=0.83). Taking confirmatory spirometry as reference, the positive predictive value of screening spirometry for the diagnosis of persistent airflow limitation was 93% with a specificity of 95%. Agreement for the diagnosis of persistent airflow limitation was substantial (k=0.80). CONCLUSION: Spirometry performed in primary care by trained personnel reliably identifies persistent airflow limitation. This may encourage pulmonologists to collaborate with primary care providers with the aim of improving appropriate diagnosis of COPD.

Nitric oxide production by the alveolar compartment of the lungs in cirrhotic patients.

In cirrhotic patients, alveolar nitric oxide (NO) concentration is increased. This may be secondary to increased output of NO produced by the alveoli (V'(A,NO)) and/or to decreased lung transfer factor of NO. In advanced liver cirrhosis, NO produced by the alveoli may play a role in abnormalities of pulmonary haemodynamics and gas exchanges. In cirrhotic patients, we aimed to measure V'(A,NO) and to compare V'(A,NO) with pulmonary haemodynamics and gas exchange parameters. Measurements were performed in 22 healthy controls and in 29 cirrhotic patients, of whom eight had hepatopulmonary syndrome. Exhaled NO concentrations were measured at multiple expiratory flow rates to derive alveolar NO concentration. V'(A,NO) was the product of alveolar NO concentration by single breath lung transfer factor for NO. V'(A,NO) was increased in patients (median (range) 260 (177-341) nL x min(-1)) compared with controls (79 (60-90), p<0.0001). Alveolar-arterial oxygen tension difference failed to correlate with V'(A,NO). However, cardiac index correlated positively and systemic vascular resistance correlated negatively with V'(A,NO) (r = 0.56, p = 0.001 and r = -0.52, p = 0.004, respectively). In cirrhotic patients, NO was produced in excess by the alveolar compartment of the lungs. Alveolar NO production was associated with hyperdynamic circulatory syndrome but not with arterial oxygenation impairment.

Long-term effects of bosentan in patients with HIV-associated pulmonary arterial hypertension.

Bosentan has proven 4-month efficacy in patients with HIV-associated pulmonary arterial hypertension (PAH-HIV). Herein, the long-term outcome of unselected PAH-HIV patients treated with first-line bosentan is described. Data for 59 consecutive World Health Organization (WHO) functional class II-IV PAH-HIV patients treated with first-line bosentan between May 2002 and July 2007 were analysed. HIV status, 6-min walk distance and haemodynamics were assessed at baseline, after 4 months and every 6-12 months thereafter. After 4 months, 6-min walk distance increased from 358+/-98 to 435+/-89 m and pulmonary vascular resistance decreased from 737+/-328 to 476+/-302 dyn x s x cm(-5). At the final evaluation (29+/-15 months), 6-min walk distance remained stable and pulmonary vascular resistance decreased further to 444+/-356 dyn x s x cm(-5). Haemodynamics normalised in 10 patients. At their last evaluation, these 10 patients were in WHO functional class I, with a 6-min walk distance of 532+/-52 m. Overall survival estimates were 93, 86 and 66% at 1, 2 and 3 yrs, respectively. Bosentan was safe when combined with highly active antiretroviral therapy, with no negative impact on HIV infection control. The present data confirm the long-term benefits of bosentan therapy in HIV-associated pulmonary arterial hypertension patients with improvements in symptoms, 6-min walk distance and haemodynamics, and with favourable overall survival.

Cautious epoprostenol therapy is a safe bridge to lung transplantation in pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) carries a poor prognosis and lung transplantation is the only curative treatment. In PVOD, epoprostenol therapy is controversial, as this condition may be refractory to specific therapy with an increased risk of pulmonary oedema. We retrospectively reviewed clinical, functional and haemodynamic data of 12 patients with PVOD (10 with histological confirmation) treated with continuous intravenous epoprostenol and priority listed for lung transplantation after January 1, 2003. All PVOD patients had severe clinical, functional and haemodynamic impairment at presentation. Epoprostenol was used at low dose ranges with slow dose increases and high dose diuretics. Only one patient developed mild reversible pulmonary oedema. After 3-4 months, improvements were seen in the New York Heart Association functional class (class IV to III in seven patients), cardiac index (1.99+/-0.68 to 2.94+/-0.89 L x min(-1) x m(-2)) and indexed pulmonary vascular resistance (28.4+/-8.4 to 17+/-5.2 Wood units x m(-2); all p<0.01). A nonsignificant improvement in the 6-min walk distance was also observed (+41 m, p = 0.11). Two patients died, one patient was alive on the transplantation waiting list on December 1, 2008 and nine patients were transplanted. Cautious use of continuous intravenous epoprostenol improved clinical and haemodynamic parameters in PVOD patients at 3-4 months without commonly causing pulmonary oedema, and may be a useful bridge to urgent lung transplantation.

[Pulmonary vein stenosis after radiofrequency ablation for atrial fibrillation]. / Sténose des veines pulmonaires après radiofréquence pour fibrillation atriale.

INTRODUCTION: Pulmonary vein stenosis is a rare condition with a high mortality. With the advent of radiofrequency ablation for atrial fibrillation a new cause of pulmonary vein stenosis has emerged. OBSERVATIONS: We report two cases of severe pulmonary vein stenosis. In the first case the diagnosis was obtained rapidly and balloon angioplasty with stent implantation was performed in the two left pulmonary veins. Recurrent occlusion occurred within the stents, extensive pulmonary infiltrates resembling pulmonary venous infarction developed and the patient died. In the second case the diagnosis was missed initially because the clinical picture suggested thrombo-embolic disease or infection. Balloon angioplasty with stent implantation was performed later. Restenosis occurred after 18 months. These two cases illustrate the frequency with which percutaneously inserted venous prostheses thombose. CONCLUSIONS: Clinicians should be familiar with the possibility of the development of pulmonary vein stenosis after radiofrequency ablation for atrial fibrillation. Pulmonary vein stenosis remains a difficult condition to manage. The pulmonary infarction should probably be considered as an urgent indication for surgical resection or even transplantation.

[Pneumothorax in young cannabis smokers: A propos of three cases]. / Prise en charge des pneumothorax chez les fumeurs de cannabis : à propos de trois cas.

INTRODUCTION: Cannabis consumption is common among adolescents and young adults in France. In addition to its neurological effect, cannabis smoking can induce severe pulmonary emphysema, even in young patients. When a spontaneous pneumothorax occurs in a cannabis smoker, the possibility of a secondary spontaneous pneumothorax should be considered. This may be of importance as management of secondary spontaneous pneumothorax may differ from the well-codified handling of primary spontaneous pneumothorax. OBSERVATION: Clinical and radiological data from three young cannabis-using patients with spontaneous pneumothorax were collected. Given the presence of emphysema, they were all considered secondary spontaneous pneumothorax. Two patients underwent surgical treatment, with simple postoperative follow-up in one case and prolonged air leak in the other case. The management of the third patient, exclusively medical, was prolonged and complicated. CONCLUSION: The presence of emphysema in young cannabis smokers complicates the management of spontaneous pneumothorax. In this context, a first-line surgical intervention may be an option to be considered.

[The new reference equations of the Global Lung function Initiative (GLI) for pulmonary function tests]. / Les nouvelles équations de référence du Global Lung Function Initiative (GLI) pour les explorations fonctionnelles respiratoires.

Until recently, the reference equations available for pulmonary function tests (PFTs) have had several weaknesses: they have often been based on relatively weak samples of normal subjects; they used mathematical models that are not very efficient in describing the evolution of PFTs over age; there were different equations for children/adolescents and for adults; the expression of the results solely as a percentage of the predicted value did not provide a good indication of the statistical significance of any difference that may exist between a measured value and its reference value. The Global Lung Initiative (GLI) aimed to establish new reference equations for PFTs that do not have these disadvantages. Based on large, representative, reference populations and allowing individualization of homogeneous ethnic groups over a wide age range, the GLI uses a statistical model that does not have any a priori hypothesis regarding the evolution of PFTs as a function of age (these models therefore make it possible to describe, in a very precise manner, the PFTs over all age ranges). For a given PFT, the equation is the same regardless of age (no discontinuity on transition to adulthood). The GLI equations are used to define a reference value, a threshold value (lower limit of the normal) and a z-score that take into account age, sex, size and, for some PFTs, ethnicity. The reference equations of the GLI were established in 2012 for spirometry, in 2017 for the TLCO and will soon be established for lung volumes. Already the representation of ethnic groups not identified by the GLI and of subjects with extreme values of age and size is being questioned.

[Guidelines for methacholine provocation testing]. / Recommandations pour le test de provocation bronchique à la méthacholine en pratique clinique, à partir de l'âge scolaire.

Bronchial challenge with the direct bronchoconstrictor agent methacholine is commonly used for the diagnosis of asthma. The "Lung Function" thematic group of the French Pulmonology Society (SPLF) elaborated a series of guidelines for the performance and the interpretation of methacholine challenge testing, based on French clinical guideline methodology. Specifically, guidelines are provided with regard to the choice of judgment criteria, the management of deep inspirations, and the role of methacholine bronchial challenge in the care of asthma, exercise-induced asthma, and professional asthma.

[Differences and similarities between occupational and tobacco induced COPD]. / BPCO professionnelles et BPCO post-tabagique : similarités et différences.

Chronic obstructive pulmonary disease (COPD) most often results from the inhalation of toxic agents. Cigarette smoking still remains the principal cause but the pertinence of occupational COPD is now clearly established. After a brief overview of the epidemiology of this "other COPD", the clinical and functional characteristics are summarized, taking into account recent advances in this field. The combined effects of occupational exposure and tobacco are also considered, providing evidence of the need to continuously reinforce campaigns of education and prevention in occupational COPD.

Severe dyspnea in a patient with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a genetic disease in which pulmonary complications are rare, but severe, especially pulmonary hypertension (PH). The mechanisms underlying the onset of PH in patients with NF1 are unclear and might be multifactorial. In particular, the frequent presence of pulmonary parenchymal lesions makes etiological diagnosis of PH difficult. We describe here the case of a patient with NF1 admitted to our clinic with dyspnea and right heart failure revealing severe pre-capillary PH. Parenchymal lesions were mild and PH was attributed to pulmonary vascular involvement. Clinical and hemodynamic conditions of the patient improved under pulmonary arterial hypertension-specific combination therapy. This case suggests that treatment of PH due to pulmonary vascular involvement in NF1 may be aligned with recommendations for PAH treatment.