Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population. Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

Updated Hemodynamic Definition and Classification of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a pathophysiological manifestation of a heterogeneous group of diseases characterized by abnormally elevated pulmonary arterial pressures diagnosed on right heart catheterization. The 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines for the diagnosis and treatment of PH provides a new hemodynamic definition to define PH by lowering the threshold of the mean pulmonary artery pressure (mPAP) to 20 mm Hg. Precapillary PH is thus now defined as a mPAP >20 mm Hg together with a normal pulmonary artery wedge pressure (<15 mm Hg) and an increased pulmonary vascular resistance (>2 Wood Units). The ESC/ERS 2022 Guidelines also introduce a revised clinical classification of PH while retaining its previous distinction between the five groups according to the underlying pathophysiology.

[Pulmonary hypertension: how to differentiate rare from frequent etiologies?] / Hypertension pulmonaire : comment différencier les causes fréquentes et rares?

Pulmonary hypertension (PH) is a frequent finding. PH secondary to left heart diseases is the most prevalent form of PH. PH caused by lung diseases and/or hypoxia is the second most frequent cause. The patient should be addressed to an expert center if the PH does not seem to be secondary to a left heart disease or a lung disease, if the PH seems too severe for the underlying cardiac or pulmonary diseases or in the presence of risk factors for PH caused by rare etiologies (group 1, 4 and 5).

L'hypertension pulmonaire (HTP) est une manifestation clinique fréquente. L'HTP secondaire aux cardiopathies gauches est la forme la plus prévalente. La deuxième forme la plus fréquente est l'HTP associée à une pneumopathie et/ou à une hypoxie chronique. Le patient devrait être adressé à un centre expert si l'HTP n'est pas facilement attribuable à une cardiopathie gauche ou à une pneumopathie, si l'HTP semble trop sévère pour la cardiopathie ou la pneumopathie sous-jacente ou en cas de présence de facteurs de risque pour une HTP causée par une étiologie rare (groupes 1, 4 et 5).

[Pneumology: what's new in 2022]. / Pneumologie : ce qui a changé en 2022.

This selection of pneumological novelties of the year 2022 is not limited to pharmacological acquisitions but also includes progress in diagnostic strategies and the global management of respiratory diseases. We have chosen three pneumological issues. As cannabis is the most consumed illegal substance in Switzerland, it is important to know its impact on pulmonary physiology. An update of the international guidelines on pulmonary fibrosis as well as the European guidelines on pulmonary hypertension provides practical answers to the many clinical problems encountered in the management of these diseases. The key messages from these two consensus documents are reported here.

Cette sélection de nouveautés pneumologiques de l'année 2022 ne se limite pas aux acquisitions pharmacologiques mais englobe également les progrès obtenus dans les stratégies diagnostiques et la prise en charge globale des affections respiratoires. Notre choix s'est porté sur trois problématiques pneumologiques. Le cannabis étant la substance illégale la plus consommée en Suisse, il est important d'en connaître l'impact sur la physiologie pulmonaire. Une mise à jour des directives internationales sur la fibrose pulmonaire ainsi que celles européennes sur l'hypertension pulmonaire apporte des réponses pratiques aux nombreux problèmes cliniques rencontrés dans la prise en charge de ces maladies. Les messages principaux de ces deux documents de consensus sont rapportés ici.

An emerging phenotype of pulmonary arterial hypertension patients carrying SOX17 variants.

BACKGROUND: The phenotype of pulmonary arterial hypertension (PAH) patients carrying SOX17 pathogenic variants remains mostly unknown. METHODS: We report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carrying SOX17 variants from the French Pulmonary Hypertension Network. RESULTS: 20 patients and eight unaffected relatives were identified. The median (range) age at diagnosis was 17 (2-53) years, with a female:male ratio of 1.5. At diagnosis, most of the patients (74%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise, including a median pulmonary vascular resistance of 14.0 (4.2-31.5) WU. An associated congenital heart disease (CHD) was found in seven PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. 13 out of 16 patients (81%) for whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as anomalies of the bronchial and nonbronchial arteries. After a median (range) follow-up of 47 (1-591) months, 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathological analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci. CONCLUSIONS: PAH due to SOX17 pathogenic variants is a severe phenotype, frequently associated with CHD, haemoptysis and radiological abnormalities. Pathological assessment reveals severe pulmonary arterial remodelling and malformations affecting pulmonary vessels and thoracic systemic arteries.

[Hypoxemia: from pathophysiology to diagnosis]. / Hypoxémie : de la physiopathologie au diagnostic.

Hypoxemia is defined as a decreased oxygen partial pressure in arterial blood. This frequent clinical phenomenon can lead to tissue hypoxia and requires a prompt diagnostic approach to guide its management. Five pathophysiological mechanisms should be assessed in the presence of hypoxemia: alveolar hypoventilation, ventilation/perfusion mismatches, diffusion disorders, true shunts and a decrease in the partial pressure of inspired oxygen. In this article, we synthesize the main etiologies of hypoxemia based on respiratory pathophysiology and suggest a diagnostic approach for its evaluation.

L'hypoxémie est définie comme la diminution de la pression partielle en oxygène dans le sang artériel. Ce phénomène fréquent en clinique peut amener à une hypoxie tissulaire et nécessite une approche diagnostique rapide afin d'orienter sa prise en charge. Cinq mécanismes physiopathologiques doivent être évoqués devant une hypoxémie : l'hypoventilation alvéolaire, les inégalités de ventilation/perfusion, les troubles de la diffusion, les shunts vrais et la diminution de la pression partielle d'oxygène inspiré. Dans cet article, nous résumons les étiologies principales d'hypoxémie en se basant sur la physiopathologie respiratoire et proposons une démarche diagnostique pour son évaluation.

[When to consider lung transplantation?] / Quand penser à la transplantation pulmonaire ?

Pulmonary transplantation remains the ultimate therapeutic option for selected patients with an advanced pulmonary disease and terminal respiratory insufficiency when all other therapeutic options have been exhausted. The optimal time-frame to proceed to a first discussion and evaluation about lung transplantation may be difficult to determine. This article describes the pathway of a patient towards lung transplantation and summarizes the criteria, which may help to timely identify eligibility for this therapeutic modality. We will focus mainly on the 2021 update of the International Society for Heart and Lung Transplantation (ISHLT) recommendations for the selection of lung transplant candidates.

La transplantation pulmonaire reste l'ultime option thérapeutique pour des patients sélectionnés présentant une maladie pulmonaire avancée au stade d'insuffisance respiratoire terminale, une fois les autres traitements reconnus épuisés. Le moment idéal pour une première discussion et l'évaluation d'une transplantation pulmonaire peut être difficile à identifier. Cet article décrit le parcours d'un patient vers la transplantation pulmonaire et résume les différents facteurs qui permettent d'identifier son éligibilité pour ce traitement. Nous nous focalisons notamment sur les recommandations pour la sélection des receveurs de transplantation pulmonaire mises à jour en 2021 par l'International Society for Heart and Lung Transplantation (ISHLT).

Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis.

Benzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. To probe the role of C387, we used promiscuous site-directed mutagenesis to introduce other codons at this position into dprE1 of M. tuberculosis The resultant viable BTZ-resistant mutants were characterized in vitro, ex vivo, and biochemically to gain insight into the effects of these mutations on DprE1 function and on M. tuberculosis Five different mutations (C387G, C387A, C387S, C387N, and C387T) conferred various levels of resistance to BTZ and exhibited different phenotypes. The C387G and C387N mutations resulted in a lower growth rate of the mycobacterium on solid medium, which could be attributed to the significant decrease in the catalytic efficiency of the DprE1 enzyme. All five mutations rendered the mycobacterium less cytotoxic to macrophages. Finally, differences in the potencies of covalent and noncovalent DprE1 inhibitors in the presence of C387 mutations were revealed by enzymatic assays. As expected from the mechanism of action, the covalent inhibitor PBTZ169 only partially inhibited the mutant DprE1 enzymes compared to the near-complete inhibition with a noncovalent DprE1 inhibitor, Ty38c. This study emphasizes the importance of the C387 residue for DprE1 activity and for the killing action of covalent inhibitors such as BTZs and other recently identified nitroaromatic inhibitors.

[How to handle a non-resolving pneumonia?] / Que faire quand une pneumonie persiste?

Persistent pneumonias are frequent both in hospital and primary care settings. Several parameters have to be taken into account. Firstly the appropriateness of treatment; secondly the immune status of the host; and finally infectious complications need to be ruled out. Several non-infectious diagnoses can mimic a persistent infiltrate, such as neoplastic disorders, organising pneumonias, interstitial disorders and drug - or radiation-induced lung diseases. Uncommon pathogens will not respond to common treatment, for instance atypical bacteria, mycobacteria, fungi including Pneumocystis as well as viruses. Referral to a pulmonologist should be considered to perform a fiberoptic bronchoscopy.

Une pneumonie qui ne guérit pas est un problème fréquent en pratiques hospitalière et ambulatoire. Il faut prendre en compte plusieurs facteurs devant une telle situation. Premièrement, l'adéquation de l'antibiothérapie; deuxièmement, le statut immunitaire du sujet; finalement toute complication infectieuse du foyer de pneumonie doit être exclue. Une série de diagnostics non infectieux seront évoqués, parmi lesquels une néoplasie, une pneumonie en organisation, une pneumopathie interstitielle, médicamenteuse ou radique. Des pathogènes inhabituels doivent être envisagés face à une pneumonie réfractaire, notamment les germes «atypiques¼, les mycobactéries, les champignons y compris le Pneumocystis et les virus. Un avis pneumologique est indiqué afin de réaliser si nécessaire une bronchoscopie avec lavage bronchoalvéolaire.

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis.

Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis.

Bioluminescence for assessing drug potency against nonreplicating Mycobacterium tuberculosis.

Targeting dormant Mycobacterium tuberculosis represents a challenge to antituberculosis drug discovery programs. We previously reported and validated the use of the streptomycin (STR)-dependent M. tuberculosis 18b strain as a tool for assessing drug potency against nonreplicating bacteria both in vitro and in vivo. In this study, we generated a luminescent 18b strain, named 18b-Lux, by transforming the bacteria with a vector expressing the luxCDABE operon from Photorhabdus luminescens. Luciferase expression was demonstrated under replicating conditions, and, more importantly, luminescence levels significantly above background were detected following STR removal. The sensitivity of STR-starved 18b-Lux to approved and candidate antituberculosis therapeutic agents was evaluated by means of a luciferase assay in a 96-well format. Results mirrored the data obtained with the standard resazurin reduction microplate assay, and the luminescence readout allowed time course assessments of drug efficacy in vitro. Specifically, we proved that bedaquiline, the rifamycins, and sutezolid displayed time-dependent activity against dormant bacteria, while pyrazinamide and SQ109 showed bactericidal effects at the highest concentrations tested. Overall, we established the optimal conditions for an inexpensive, simple, and very sensitive assay with great potential for future applications.

A structure-guided fragment-based approach for the discovery of allosteric inhibitors targeting the lipophilic binding site of transcription factor EthR.

A structure-guided fragment-based approach was used to target the lipophilic allosteric binding site of Mycobacterium tuberculosis EthR. This elongated channel has many hydrophobic residues lining the binding site, with few opportunities for hydrogen bonding. We demonstrate that a fragment-based approach involving the inclusion of flexible fragments in the library leads to an efficient exploration of chemical space, that fragment binding can lead to an extension of the cavity, and that fragments are able to identify hydrogen-bonding opportunities in this hydrophobic environment that are not exploited in Nature. In the present paper, we report the identification of a 1 µM affinity ligand obtained by structure-guided fragment linking.

Pulmonary veno-occlusive disease: illustrative cases and literature review.

Pulmonary veno-occlusive disease (PVOD), also known as "pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement", is a rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure. Environmental risk factors have been associated with the development of PVOD, such as occupational exposure to organic solvents and chemotherapy, notably mitomycin. PVOD may also be associated with a mutation in the EIF2AK4 gene in heritable forms of disease. Distinguishing PVOD from PAH is critical for guiding appropriate management. Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy. Life-threatening pulmonary oedema is a complication of pulmonary vasodilator therapy that can occur with any class of PAH drugs in PVOD. Early referral to a lung transplant centre is essential due to the poor response to therapy when compared with other forms of PAH. Histopathological analysis of lung explants reveals microvascular remodelling with typical fibrous veno-occlusive lesions. This review covers the main features distinguishing PVOD from PAH and two clinical cases that illustrate the challenges of PVOD management.

ERS International Congress 2023: highlights from the Pulmonary Vascular Diseases Assembly.

Pulmonary vascular diseases such as pulmonary embolism and pulmonary hypertension are important and frequently under-recognised conditions. This article provides an overview of key highlights in pulmonary vascular diseases from the European Respiratory Society International Congress 2023. This includes insights into disease modification in pulmonary arterial hypertension and novel therapies such as sotatercept and seralutinib. Exciting developments in our understanding of the mechanisms underpinning pulmonary hypertension associated with interstitial lung disease are also explored. A comprehensive overview of the complex relationship between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension (CTEPH) is provided along with our current understanding of the molecular determinants of CTEPH. The importance of multidisciplinary and holistic care cannot be understated, and this article also addresses advances beyond medication, with a special focus on exercise training and rehabilitation.

Risk Stratification in Pulmonary Arterial Hypertension, Update and Perspectives.

Risk stratification in pulmonary arterial hypertension (PAH) is crucial in assessing patient prognosis. It serves a prominent role in everyday patient care and can be determined using several validated risk assessment scores worldwide. The recently published 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines underline the importance of risk stratification not only at baseline but also during follow-up. Achieving a low-risk status has now become the therapeutic goal, emphasising the importance of personalised therapy. The application of these guidelines is also important in determining the timing for lung transplantation referral. In this review, we summarise the most relevant prognostic factors of PAH as well as the parameters used in PAH risk scores and their evolution in the guidelines over the last decade. Finally, we describe the central role that risk stratification plays in the current guidelines not only in European countries but also in Asian countries.

Pressure Overload and Right Ventricular Failure: From Pathophysiology to Treatment.

Right ventricular failure (RVF) is often caused by increased afterload and disrupted coupling between the right ventricle (RV) and the pulmonary arteries (PAs). After a phase of adaptive hypertrophy, pressure-overloaded RVs evolve towards maladaptive hypertrophy and finally ventricular dilatation, with reduced stroke volume and systemic congestion. In this article, we review the concept of RV-PA coupling, which depicts the interaction between RV contractility and afterload, as well as the invasive and non-invasive techniques for its assessment. The current principles of RVF management based on pathophysiology and underlying etiology are subsequently discussed. Treatment strategies remain a challenge and range from fluid management and afterload reduction in moderate RVF to vasopressor therapy, inotropic support and, occasionally, mechanical circulatory support in severe RVF.

The Influence of Methods for Cardiac Output Determination on the Diagnosis of Precapillary Pulmonary Hypertension: A Mathematical Model.

Background: precapillary pulmonary hypertension (PH, PcPH) is now defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) > 2 WU. For PVR calculation, the measurement of cardiac output (CO) is necessary. It is generally measured using thermodilution. However, recent data showed that the agreement with direct Fick method, historically the gold standard, is less than previously reported. We aimed to create a mathematical model that calculated the probability of being classified differently (PcPH or unclassified PH) if CO measured by direct Fick was used instead of thermodilution for any individual patients with a mPAP > 20 mmHg and a PAWP ≤ 15 mmHg. Methods: The model is based on Bland and Altman analysis with a normally distributed difference of cardiac output, fixed 1.96 standard deviation of bias, bias and physiological cardiac output limits. Results: Following a literature review of the studies comparing CO measured with direct Fick and thermodilution, we fixed the 1.96 standard deviation of bias at 2 L/min, bias at 0 L/min and physiological resting CO limits between 1.3 L/min and 10.2 L/min. Conclusions: This model can help the clinician to evaluate the potential benefit of measuring CO using direct Fick during the diagnostic work-up and its utility in confirming or ruling out a diagnosis of PcPH in any given patient with a mPAP > 20 mmHg and a PAWP ≤ 15 mmHg.

Prevalence of small airway dysfunction in the Swiss PneumoLaus Cohort.

Background: Recent evidence identified exposure to particulate matter of size ≤2.5 µm (PM2.5) as a risk factor for high prevalence of small airway dysfunction (SAD). We assessed the prevalence of SAD in a European region with low air pollution levels. Methods: SAD was defined as a maximum mid-expiratory flow (MMEF) <65% of predicted value (PV) or MMEF 65 years only. In an area where ambient PM2.5 concentration was <15 µg·m-3 during the observation period (2010 and 2020), ≥72% of participants with SAD were ever-smokers. Conclusions: The observed low prevalence of SAD of 5.0-12.7% depending on criteria employed may be related to lower PM2.5 exposure. Smoking was the main factor associated with SAD in an area with low PM2.5 exposure. Employing a MMEF threshold <65% PV carries a risk of SAD overdiagnosis in elderly individuals.