ERS International Congress 2021: highlights from the Interstitial Lung Diseases Assembly

This article provides an overview of scientific highlights in the field of interstitial lung disease (ILD), presented at the virtual European Respiratory Society Congress 2021. A broad range of topics was discussed this year, ranging from translational and genetic aspects to novel innovations with the potential to improve the patient pathway. Early Career Members summarise a selection of interesting findings from different congress sessions, together with the leadership of Assembly 12 - Interstitial Lung Disease. © The authors 2022

Detection and Functional Characterization of a 215 Amino Acid N-Terminal Extension in the Xanthomonas Type III Effector XopD

During evolution, pathogens have developed a variety of strategies to suppress plant-triggered immunity and promote successful infection. In Gram-negative phytopathogenic bacteria, the so-called type III protein secretion system works as a molecular syringe to inject type III effectors (T3Es) into plant cells. The XopD T3E from the strain 85-10 of Xanthomonas campestris pathovar vesicatoria (Xcv) delays the onset of symptom development and alters basal defence responses to promote pathogen growth in infected tomato leaves. XopD was previously described as a modular protein that contains (i) an N-terminal DNA-binding domain (DBD), (ii) two tandemly repeated EAR (ERF-associated amphiphillic repression) motifs involved in transcriptional repression, and (iii) a C-terminal cysteine protease domain, involved in release of SUMO (small ubiquitin-like modifier) from SUMO-modified proteins. Here, we show that the XopD protein that is produced and secreted by Xcv presents an additional N-terminal extension of 215 amino acids. Closer analysis of this newly identified N-terminal domain shows a low complexity region rich in lysine, alanine and glutamic acid residues (KAE-rich) with high propensity to form coiled-coil structures that confers to XopD the ability to form dimers when expressed in E. coli. The full length XopD protein identified in this study (XopD1-760) displays stronger repression of the XopD plant target promoter PR1, as compared to the XopD version annotated in the public databases (XopD216-760). Furthermore, the N-terminal extension of XopD, which is absent in XopD216-760, is essential for XopD type III-dependent secretion and, therefore, for complementation of an Xcv mutant strain deleted from XopD in its ability to delay symptom development in tomato susceptible cultivars. The identification of the complete sequence of XopD opens new perspectives for future studies on the XopD protein and its virulence-associated functions in planta

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

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

I-PreFer Study: A Questionnaire to Explore Patient, Caregiver and Pulmonologist Preferences of Idiopathic Pulmonary Fibrosis Treatment Options

Maria Hollmen,1 Tom Bromilow,2 Adam B Smith,2 Stuart Mealing,2 Damian Lewis,2 Liam Galvin,3 Steve Jones,3 Lu&iacute;s Pacheco,4 St&eacute;phane Soulard,4 Antoine Froidure5,6 1Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2York Health Economics Consortium (YHEC), York, UK; 3European Pulmonary Fibrosis &amp; Related Disorders Federation, Overijse, Belgium; 4Boehringer Ingelheim, Amsterdam, the Netherlands; 5Service de Pneumologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium; 6Institut de Recherche Exp&eacute;rimentale et Clinique, UCLouvain, Ottignies-Louvain-la-Neuve, BelgiumCorrespondence: Maria Hollmen, Faculty of Medicine, University of Helsinki, Helsinki, Finland, Email [email protected]: Idiopathic Pulmonary Fibrosis (IPF) is a rare disease that causes shortness of breath, dry cough, and tiredness. While there is no cure for IPF, current therapeutic treatments aim to slow lung degeneration while managing side effects. There is little known about patient experience and attitude with regards to their disease and medication.Purpose: To understand the perceptions, behaviors and drivers of treatment decision-making among patients, caregivers and pulmonologists in IPF.Patients and Methods: Online surveys to patients with IPF, caregivers and pulmonologists were developed and administered in Belgium, Finland, France, Greece (pulmonologists only), the Netherlands, Ireland and the United Kingdom between November 2021 and January 2022.Results: A total of 111 patients, 22 caregivers and 140 pulmonologists participated. Half (47%) of patients rated their disease as &ldquo;severe&rdquo;, while pulmonologists reported that a quarter of their patients had a low Forced Vital Capacity (FVC) (below 50% of the predicted value). Between 21% and 42% of the patients do not take an IPF medication (patients&rsquo; perception) or antifibrotic (physicians&rsquo; perception). Pulmonologists reported that a total of 58% of their patients were receiving antifibrotic medication, any IPF medication, while around 53%, 55%, 35% and 73% of the patients limited their exposure (sometimes or often) to the sun due to IPF, considered taking medication against diarrhea, nausea/vomiting and heartburn, respectively. Treatment adherence was relatively high (81%), in line with the caregivers&rsquo; view and the pulmonologists&rsquo; expectations. Overall, cultural, clinical or socio-demographic factors impacted patients&rsquo; perceptions or behaviors.Conclusion: This study shows there is a significant proportion of IPF patients who remain untreated, a misalignment of disease severity between patients and their physicians and patient background impacts behavior. Overall, more in-depth patient&ndash;physician communication is needed to improve treatment experience.Keywords: online survey, antifibrotic, adherence, behavior, lung disease, outcomes researc

Cost-Effectiveness Analysis of Nintedanib Versus Pirfenidone in Idiopathic Pulmonary Fibrosis in Belgium

BACKGROUND: Nintedanib (Ofev®) and pirfenidone (Esbriet®) are recommended by international guidelines as treatment options for idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To compare the cost-effectiveness of nintedanib with that of pirfenidone for the treatment of IPF from a Belgian healthcare payer perspective. METHODS: The economic analysis used a Markov model that calculated outcomes over patient lifetime. Overall survival was assumed to be the same for the two comparators. Data from a network meta-analysis were used for loss of lung function, acute exacerbation events, safety and treatment discontinuation (for any reason). The health-state utility estimates in the model were calculated from EQ-5D scores collected in nintedanib studies. The assumed resource use for background care was also based on patient-level data that were categorised to fit the health states in the model and synthesised with costs and tariffs from Belgian national databases. RESULTS: Treatment with nintedanib resulted in an estimated total cost of €102,315, which was less than the total cost of treatment with pirfenidone (€113,313). Given the similarities in the survival and progression outcomes obtained with nintedanib and pirfenidone, the model predicted near equivalence in total QALYs (3.353 QALYs for the nintedanib arm and 3.318 for the pirfenidone arm). Results were largely driven by model assumptions underlying mortality, acute exacerbations and treatment discontinuation. CONCLUSIONS: After performing a synthesis of the most recently published evidence for IPF patients and assuming a Belgian healthcare payer perspective, we found nintedanib to be more cost-saving than pirfenidone.status: publishe

Cost-Effectiveness Analysis of Nintedanib Versus Pirfenidone in Idiopathic Pulmonary Fibrosis in Belgium.

Nintedanib (Ofev) and pirfenidone (Esbriet) are recommended by international guidelines as treatment options for idiopathic pulmonary fibrosis (IPF). To compare the cost-effectiveness of nintedanib with that of pirfenidone for the treatment of IPF from a Belgian healthcare payer perspective. The economic analysis used a Markov model that calculated outcomes over patient lifetime. Overall survival was assumed to be the same for the two comparators. Data from a network meta-analysis were used for loss of lung function, acute exacerbation events, safety and treatment discontinuation (for any reason). The health-state utility estimates in the model were calculated from EQ-5D scores collected in nintedanib studies. The assumed resource use for background care was also based on patient-level data that were categorised to fit the health states in the model and synthesised with costs and tariffs from Belgian national databases. Treatment with nintedanib resulted in an estimated total cost of €102,315, which was less than the total cost of treatment with pirfenidone (€113,313). Given the similarities in the survival and progression outcomes obtained with nintedanib and pirfenidone, the model predicted near equivalence in total QALYs (3.353 QALYs for the nintedanib arm and 3.318 for the pirfenidone arm). Results were largely driven by model assumptions underlying mortality, acute exacerbations and treatment discontinuation. After performing a synthesis of the most recently published evidence for IPF patients and assuming a Belgian healthcare payer perspective, we found nintedanib to be more cost-saving than pirfenidone