Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Immunity, Inflammation and Lung Fibrosis

The role of the immune system in idiopathic pulmonary fibrosis (IPF) pathogenesis has been debated, with seemingly contradictory results between promising experimental data and disappointing clinical trials. As the understanding of the paramount role of the epithelium in the disease arose, the concept that immunity and inflammation influence rather than drive fibrosis developed. Immune cells involved in both innate and adaptive immunity have been implicated in experimental fibrosis development and display alterations in idiopathic pulmonary fibrosis, shaping a pro-fibrotic environment. Accordingly, the levels of several cytokines with a pro-fibrotic potential, such as IL-4, IL-13, IL-1β, TNF-α and IL-17A are elevated in IPF patients. Additionally, the interplay with cellular stress components such as danger associated molecular patterns and infectious alarm signals under the form of pathogen associated molecular patterns is an area of ongoing investigation. Finally, recent advances in sequencing techniques have unraveled a potential role for viruses and bacteria

Immunité et COVID-19 : état des lieux, vers une médecine de précision?

Le COVID-19 est une pathologie liée au SARS-CoV-2 induisant (dans 5 à 15% des cas) dans sa forme sévère une pneumonie bilatérale pouvant se compliquer d’un ARDS et d’une insuffisance respiratoire aigüe. Les patients atteints présentent une lymphopénie et éventuellement une neutrophilie qui ont une valeur pronostique. De plus, certains sujets développent une dérégulation du système immunitaire avec un état hyperinflammatoire associé à un « orage cytokinique » et un pronostic péjoré. Bien que les mécanismes sous-jacents soient encore mal compris, l’échappement aux mécanismes immunitaires innés par les coronavirus pourrait jouer un rôle important. La compréhension de l’immunopathologie de cette maladie devrait aider à définir une médecine de précision pour traiter les malades COVID-19 en fonction de biomarqueurs prédictifs (ou précoces) de sévérité

The Epithelial-Immune Crosstalk in Pulmonary Fibrosis.

Interactions between the lung epithelium and the immune system involve a tight regulation to prevent inappropriate reactions and have been connected to several pulmonary diseases. Although the distal lung epithelium and local immunity have been implicated in the pathogenesis and disease course of idiopathic pulmonary fibrosis (IPF), consequences of their abnormal interplay remain less well known. Recent data suggests a two-way process, as illustrated by the influence of epithelial-derived periplakin on the immune landscape or the effect of macrophage-derived IL-17B on epithelial cells. Additionally, damage associated molecular patterns (DAMPs), released by damaged or dying (epithelial) cells, are augmented in IPF. Next to "sterile inflammation", pathogen-associated molecular patterns (PAMPs) are increased in IPF and have been linked with lung fibrosis, while outer membrane vesicles from bacteria are able to influence epithelial-macrophage crosstalk. Finally, the advent of high-throughput technologies such as microbiome-sequencing has allowed for the identification of a disease-specific microbial environment. In this review, we propose to discuss how the interplays between the altered distal airway and alveolar epithelium, the lung microbiome and immune cells may shape a pro-fibrotic environment. More specifically, it will highlight DAMPs-PAMPs pathways and the specificities of the IPF lung microbiome while discussing recent elements suggesting abnormal mucosal immunity in pulmonary fibrosis

Telomerase-related monogenic lung fibrosis presenting with subacute onset: a case report and review of literature

OBJECTIVES: Monogenic pulmonary fibrosis related to telomerase mutations is characterized by a large spectrum of clinical presentations. The disease may affect several organs including bone marrow, liver and skin. This case illustrates some of the most salient features of telomere-related Interstitial Lung Disease(ILD). METHODS: Single case study and review of the litterature. RESULTS: We report the case of a 44-year-old man admitted to our unit for subacute pulmonary fibrosis. No underlying cause could be identified. Personal and familial history was highly suggestive of monogenic telomere related lung fibrosis. Genetic investigation confirmed a mutation in the TERT gene, coding for one of the components of telomerase. Given the severe hypoxemia unresponsive to supportive treatment, he was referred for urgent lung transplantation, with a favourable outcome. Genetic counselling was proposed to his family. CONCLUSIONS: Telomerase-related monogenic lung fibrosis may present with a subacute onset, requiring urgent lung transplantation. Extra-thoracic clinical manifestations and familial history are key elements pointing towards the diagnosis

Fibroses pulmonaires familiales et téloméropathies

Les mutations germinales des gènes impliqués dans la biologie des télomères constituent la première cause identifiée de fibrose pulmonaire familiale. La perte de la fonction protectrice de ces structures entraine un arrêt de la réplication cellulaire et un épuisement de certaines sous-populations de cellules, menant au développement possible de fibroses pulmonaires ainsi que des pathologies hématologiques, hépatiques et cutanées. Au niveau pulmonaire, les téloméropathies se manifestent sous forme d’une fibrose précoce et rapidement progressive, menant à l’insuffisance respiratoire terminale. Lors du bilan initial, la présence d’une composante multi-systémique, d’un caractère familial ou d’un âge précoce au diagnostic sont les éléments caractéristiques d’une téloméropathie. La mesure de la longueur des télomères et la recherche de mutations germinales permettent de compléter la mise au point. La prise en charge de ces patients est rendue complexe par la nature rapidement progressive de l’atteinte pulmonaire, le risque majoré d’effets secondaires médicamenteux et l’efficacité limitée des traitements antifibrosants. Les Cliniques universitaires Saint-Luc ont mis au point un trajet de soin spécifique à cette pathologie, avec une collaboration entre les services de pneumologie, d’hématologie et de génétique afin d’offrir une prise en charge optimale. Que savons-nous à ce propos ? Les téloméropathies sont la première cause identifiée de fibrose pulmonaire familiale. Elles se caractérisent par une forme rapidement progressive avec une atteinte multisystémique et un âge de développement précoce. Que nous apporte cet article ? Cet article offre une revue de la littérature publiée sur la fibrose pulmonaire familiale liée aux téloméropathies en reprenant les caractéristiques principales de cette pathologie. Il présente également le trajet de soin mis en place au sein des Cliniques Universitaires Saint-Luc afin de prendre en charge ces patients complexes

Familial hypersensitivity pneumonitis triggered by exposure during carpooling.

This series reports cases of Cladosporium herbarum-related HP due to an uncommon exposure source, illustrating the genetic background underlying HP, and highlighting the role of environmental home inquiry and serum precipitins in diagnosis and follow-u