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In many cases sarcoidosis is a multisystemic disease that requires interdisciplinary medical cooperation in the diagnostics, treatment and medical care during follow-up. Due to the often chronic course, it is of utmost importance to include patients with their priorities and wishes at an early stage and extensively in disease management and to establish a shared decision making whenever possible. In the process of writing this joint position paper, the expert group on interstitial and orphan lung diseases of the Austrian Society for Pulmonology and the working group on rheumatological lung disorders of the Austrian Society for Rheumatology and Rehabilitation sought to include patient advocacy groups as well as experts for rare organ manifestations of sarcoidosis. This position paper is not only meant to reflect current scientific and clinical standards but should also focus the national expertise and by networking and exchange to be a first step to strengthen cooperation between stakeholders to ultimately improve care for patients with sarcoidosis., (© 2024. The Author(s).)

Objective: This study aimed to evaluate subjective cognitive, physical, and mental health symptoms as well as objective cognitive deficits in COVID-19 patients 1 year after infection., Methods: This was a cross-sectional study. Seventy-four patients, who contracted a SARS-CoV-2 infection in 2020, underwent an in-person neuropsychological assessment in 2021. This included standardized tests of memory, attention, and executive functions. In addition, participants also responded to scales on subjective attention deficits, mental health symptoms, and fatigue. Patients' scores were compared to published norms., Results: Patients (N = 74) had a median age of 56 years (42% female). According to the initial disease severity, they were classified as mild (outpatients, 32%), moderate (hospitalized, non-ICU-admitted, 45%), or severe (ICU-admitted, 23%). Hospitalized patients were more often affected than outpatients. In general, deficits were most common in attention (23%), followed by memory (15%) and executive functions (3%). Patients reported increased levels of fatigue (51%), anxiety (30%), distractibility in everyday situations (20%), and depression (15%). An additional analysis suggested an association between lower scores in an attention task and hyperferritinemia. As indicated by a hierarchical regression analysis, subjective distractibility was significantly predicted by current anxiety and fatigue symptoms but not by objective attention performance (final model, adj-R 2  = 0.588, P < 0.001)., Interpretation: One year after infection, COVID-19 patients can have frequent attention deficits and can complain about symptoms such as fatigue, anxiety, and distractibility. Anxiety and fatigue, more than objective cognitive deficits, have an impact on the patients' experienced impairments in everyday life., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Research into the molecular basis of disease trajectory and Long-COVID is important to get insights toward underlying pathophysiological processes. The objective of this study was to investigate inflammation-mediated changes of metabolism in patients with acute COVID-19 infection and throughout a one-year follow up period. The study enrolled 34 patients with moderate to severe COVID-19 infection admitted to the University Clinic of Innsbruck in early 2020. The dynamics of multiple laboratory parameters (including inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6), neopterin] as well as amino acids [tryptophan (Trp), phenylalanine (Phe) and tyrosine (Tyr)], and parameters of iron and vitamin B metabolism) was related to disease severity and patients' physical performance. Also, symptom load during acute illness and at approximately 60 days (FU1), and one year after symptom onset (FU2) were monitored and related with changes of the investigated laboratory parameters: During acute infection many investigated laboratory parameters were elevated (e.g., inflammatory markers, ferritin, kynurenine, phenylalanine) and enhanced tryptophan catabolism and phenylalanine accumulation were found. At FU2 nearly all laboratory markers had declined back to reference ranges. However, kynurenine/tryptophan ratio (Kyn/Trp) and the phenylalanine/tyrosine ratio (Phe/Tyr) were still exceeding the 95th percentile of healthy controls in about two thirds of our cohort at FU2. Lower tryptophan concentrations were associated with B vitamin availability (during acute infection and at FU1), patients with lower vitamin B12 levels at FU1 had a prolonged and more severe impairment of their physical functioning ability. Patients who had fully recovered (ECOG 0) presented with higher concentrations of iron parameters (ferritin, hepcidin, transferrin) and amino acids (phenylalanine, tyrosine) at FU2 compared to patients with restricted ability to work. Persistent symptoms at FU2 were tendentially associated with IFN-γ related parameters. Women were affected by long-term symptoms more frequently. Conclusively, inflammation-mediated biochemical changes appear to be related to symptoms of patients with acute and Long Covid., (© 2024. The Author(s).)

Objectives: Pulmonary arterial hypertension (PAH) occurs in various connective tissue diseases (CTDs). We sought to assess contemporary treatment patterns and survival of patients with various forms of CTD-PAH., Methods: We analysed data from COMPERA, a European pulmonary hypertension registry, to describe treatment strategies and survival in patients with newly diagnosed PAH associated with SSc, SLE, MCTD, UCTD and other types of CTD. All-cause mortality was analysed according to the underlying CTD. For patients with SSc-PAH, we also assessed survival according to initial therapy with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5is) or a combination of these two drug classes., Results: This analysis included 607 patients with CTD-PAH. Survival estimates at 1, 3 and 5 years for SSc-PAH (n = 390) were 85%, 59% and 42%; for SLE-PAH (n = 34) they were 97%, 77% and 61%; for MCTD-PAH (n = 33) they were 97%, 70% and 59%; for UCTD-PAH (n = 60) they were 88%, 67% and 52%; and for other CTD-PAH (n = 90) they were 92%, 69% and 55%, respectively. After multivariable adjustment, the survival of patients with SSc-PAH was significantly worse compared with the other conditions (P = 0.001). In these patients, the survival estimates were significantly better with initial ERA-PDE5i combination therapy than with initial ERA or PDE5i monotherapy (P = 0.016 and P = 0.012, respectively)., Conclusions: Mortality remains high in patients with CTD-PAH, especially for patients with SSc-PAH. However, for patients with SSc-PAH, our results suggest that long-term survival may be improved with initial ERA-PDE5i combination therapy compared with initial monotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Long-term consequences after COVID-19 include physical complaints, which may impair physical recovery and quality of life., Design: We assessed body composition and physical ability in patients 12 months after COVID-19. Consecutively recruited patients recovering from mild to severe COVID-19 were assessed using bioelectrical impedance analysis, 6-min-walk test, additional scales for physical performance and health-related quality of life., Results: Overall physical recovery was good (i.e., Glasgow Outcome Scale-Extended ≥7 in 96%, Modified Rankin Scale ≤1 in 87%, Eastern Cooperative Oncology Group ≤1 in 99%). Forty-four percent of the 69 patients experienced a significant body mass index increase in the year after COVID-19 (≥1 kg/m 2 ), whereas skeletal muscle mass index was reduced in only 12%. Patients requiring intensive care treatment ( n = 15, 22%) during acute COVID-19 more often had a body mass index increase ( P = 0.002), worse 6-min-walk test-performance ( P = 0.044), and higher body fat mass ( P = 0.030) at the 1-yr follow-up when compared with patients with mild ( n = 22, 32%) and moderate ( n = 32, 46%) acute COVID-19. Body mass index increase was also more frequent in patients who had no professional rehabilitation ( P = 0.014)., Conclusions: Although patients with severe COVID-19 had increased body mass index and body fat and performed worse in physical outcome measures 1 yr after COVID-19, overall physical recovery was satisfying. Translating these findings to variants beyond the Alpha strain of severe acute respiratory syndrome coronavirus 2 virus needs further studies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Around 10% of people who had COVID-9 infection suffer from persistent symptoms such as fatigue, dyspnoea, chest pain, arthralgia/myalgia, sleep disturbances, cognitive dysfunction and impairment of mental health. Different underlying pathomechanisms appear to be involved, in particular inflammation, alterations in amino acid metabolism, autonomic dysfunction and gut dysbiosis., Aim: As routine tests are often inconspicuous in patients with Long COVID (LC), similarly to patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), accessible biomarkers indicating dysregulation of specific pathways are urgently needed to identify underlying pathomechanisms and enable personalized medicine treatment. Within this pilot study we aimed to proof traceability of altered metabolism by urine analysis., Patients and Methods: Urine metabolome analyses were performed to investigate the metabolic signature of patients with LC (n = 25; 20 women, 5 men) in comparison to healthy controls (Ctrl, n = 8; 7 women, 1 man) and individuals with ME/CFS (n = 8; 2 women, 6 men). Concentrations of neurotransmitter precursors tryptophan, phenylalanine and their downstream metabolites, as well as their association with symptoms (fatigue, anxiety and depression) in the patients were examined., Results and Conclusion: Phenylalanine levels were significantly lower in both the LC and ME/CFS patient groups when compared to the Ctrl group. In many LC patients, the concentrations of downstream metabolites of tryptophan and tyrosine, such as serotonin, dopamine and catecholamines, deviated from the reference ranges. Several symptoms (sleep disturbance, pain or autonomic dysfunction) were associated with certain metabolites. Patients experiencing fatigue had lower levels of kynurenine, phenylalanine and a reduced kynurenine to tryptophan ratio (Kyn/Trp). Lower concentrations of gamma-aminobutyric acid (GABA) and higher activity of kynurenine 3-monooxygenase (KMO) were observed in patients with anxiety. Conclusively, our results suggest that amino acid metabolism and neurotransmitter synthesis is disturbed in patients with LC and ME/CFS. The identified metabolites and their associated dysregulations could serve as potential biomarkers for elucidating underlying pathomechanisms thus enabling personalized treatment strategies for these patient populations., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Analyses performed by Biovis Diagnostik were paid for by grant GZ 75759 (Land Tirol, see above)., (© The Author(s) 2023.)

Background: Toll-like receptors (TLRs) play a pivotal role in the immunologic response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Exaggerated inflammatory response of innate immune cells, however, may drive morbidity and death in Coronavirus disease 19 (COVID-19)., Objective: We investigated the engagement of SARS-CoV-2 with TLR4 in order to better understand how to tackle hyperinflammation in COVID-19., Methods: We combined RNA-sequencing data of human lung tissue and of bronchoalveolar lavage fluid cells derived from COVID-19 patients with functional studies in human macrophages using SARS-CoV-2 spike proteins and viable SARS-CoV-2. Pharmacological inhibitors as well as gene editing with CRISPR/Cas9 were used to delineate the signalling pathways involved., Results: We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron)., Conclusion: Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19., Take-Home Message: Our study combining human lung transcriptomics with functional studies in human macrophages clearly supports the design and development of TLR4 - directed therapeutics to mitigate hyperinflammation in severe COVID-19., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (© 2023 The Authors.)

Introduction: The Severe Asthma Registry, founded by German Asthma Net (GAN) in 2011, is a prospective registry recording clinical parameters from participating centers in Germany, Austria and Switzerland. This article presents the baseline characteristics of severe asthma patients from Austrian centers., Methods: We analyzed the baseline visit data of all patients recruited to the GAN Severe Asthma Registry from participating Austrian centers., Results: Baseline visit data were available for 214 Austrian severe asthma patients from 6 Austrian centers from 2013 to 2022. Mean age was 53.7 years. Mean BMI was 26.4 kg/m2. More than a third (37.4%) of all patients had daily daytime asthma symptoms at baseline and had to use their reliever medication at least once per day. Forty-one percent of patients were classified as uncontrolled according to GINA and 24.8% as partially controlled at baseline visit. The median annual exacerbation frequency was 3 in the previous 12 months. At the time of baseline visit, 23.4% of all patients had regular treatment with oral corticosteroids. Furthermore, 23.9% had received any severe asthma monoclonal antibody prior to the baseline visit. There were no notable differences in baseline characteristics between patients categorized by smoking history or measurable type 2 inflammation., Conclusions: This study provides the first multi-center characterization of Austrian severe asthma patients. Patients in this cohort had better asthma control and less frequent exacerbations compared to most international registries., Competing Interests: Declaration of competing interest Andreas Renner: None. Slagjana Stoshikj: Speaker fees from AstraZeneca, all outside the submitted work. Wolfgang Pohl: Speaker fees from AstraZeneca, Chiesi, GSK, Novartis, and Sanofi, all outside the submitted work. Christina Bal: speaker fees from AstraZeneca and IVEPA, all outside the submitted work. Matthias Reisinger: None. Judith Löffler-Ragg: None. Angela Zacharasiewicz: None. Roland Buhl: Grants to Mainz University and personal fees from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi, and Teva, all outside the submitted work. Eckard Hamelmann: funded by the German Ministry of Education and Reserch (BMBF) as consortional partner in CHAMP (01GL1742D) for research in severe asthma in children. Christian Taube: None. Stephanie Korn: speaker fees from AstraZenca, GSK, Novartis, and Sanofi, all outside the submitted work. Marco Idzko: lecture fees from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Menarini, MSD, Novartis, Roche, Sanofi, and Thermofischer; and advisory board fees from Alk-Pharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Novartis, and Sanofi, all outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Olfactory dysfunction (OD) commonly accompanies coronavirus disease 2019 (COVID-19). We investigated the kinetics of OD resolution following SARS-CoV-2 infection (wild-type and alpha variant) and its impact on quality of life, physical and mental health., Methods: OD prevalence was assessed in an ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and an observational cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up). Co-occurrence of OD with other symptoms and effects on quality of life, physical and mental health were analyzed by multi-dimensional scaling, association rule mining and semi-supervised clustering., Results: Both in the ambulatory COVID-19 survey study (72%) and the observational ambulatory and hospitalized cohort (41%) self-reported OD was frequent during acute COVID-19. Recovery from self-reported OD was slow (survey: median 28 days, observational cohort: 90 days). By clustering of the survey data, we identified a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorders (median recovery: 90 days) but low frequency of post-acute fatigue, respiratory or neurocognitive symptoms. This smell and taste disorder cluster was characterized by a high rating of physical performance, mental health, and quality of life as compared with convalescents affected by prolonged fatigue or neurocognitive complaints., Conclusion: Our results underline the heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype is characterized by good clinical, physical, and mental recovery and may pose a minor challenge for public health., Study Registration: ClinicalTrials.gov: NCT04661462 (survey study), NCT04416100 (observational cohort)., (© 2023. The Author(s).)

Background: Accurate risk stratification in pulmonary arterial hypertension (PAH), a devastating cardiopulmonary disease, is essential to guide successful therapy. Machine learning may improve risk management and harness clinical variability in PAH., Methods: We conducted a long-term retrospective observational study (median follow-up: 67 months) including 183 PAH patients from three Austrian PAH expert centers. Clinical, cardiopulmonary function, laboratory, imaging, and hemodynamic parameters were assessed. Cox proportional hazard Elastic Net and partitioning around medoid clustering were applied to establish a multi-parameter PAH mortality risk signature and investigate PAH phenotypes., Results: Seven parameters identified by Elastic Net modeling, namely age, six-minute walking distance, red blood cell distribution width, cardiac index, pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide and right atrial area, constituted a highly predictive mortality risk signature (training cohort: concordance index = 0.82 [95%CI: 0.75 - 0.89], test cohort: 0.77 [0.66 - 0.88]). The Elastic Net signature demonstrated superior prognostic accuracy as compared with five established risk scores. The signature factors defined two clusters of PAH patients with distinct risk profiles. The high-risk/poor prognosis cluster was characterized by advanced age at diagnosis, poor cardiac output, increased red cell distribution width, higher pulmonary vascular resistance, and a poor six-minute walking test performance., Conclusion: Supervised and unsupervised learning algorithms such as Elastic Net regression and medoid clustering are powerful tools for automated mortality risk prediction and clinical phenotyping in PAH., (© 2023. The Author(s).)

Background: Recovery trajectories from coronavirus disease 2019 (COVID-19) call for longitudinal investigation. We aimed to characterise the kinetics and status of clinical, cardiopulmonary and mental health recovery up to 1 year following COVID-19., Methods: Clinical evaluation, lung function testing (LFT), chest computed tomography (CT) and transthoracic echocardiography were conducted at 2, 3, 6 and 12 months after disease onset. Submaximal exercise capacity, mental health status and quality of life were assessed at 12 months. Recovery kinetics and patterns were investigated by mixed-effect logistic modelling, correlation and clustering analyses. Risk of persistent symptoms and cardiopulmonary abnormalities at the 1-year follow-up were modelled by logistic regression., Findings: Out of 145 CovILD study participants, 108 (74.5%) completed the 1-year follow-up (median age 56.5 years; 59.3% male; 24% intensive care unit patients). Comorbidities were present in 75% (n=81). Key outcome measures plateaued after 180 days. At 12 months, persistent symptoms were found in 65% of participants; 33% suffered from LFT impairment; 51% showed CT abnormalities; and 63% had low-grade diastolic dysfunction. Main risk factors for cardiopulmonary impairment included pro-inflammatory and immunological biomarkers at early visits. In addition, we deciphered three recovery clusters separating almost complete recovery from patients with post-acute inflammatory profile and an enrichment in cardiopulmonary residuals from a female-dominated post-COVID-19 syndrome with reduced mental health status., Conclusion: 1 year after COVID-19, the burden of persistent symptoms, impaired lung function, radiological abnormalities remains high in our study population. Yet, three recovery trajectories are emerging, ranging from almost complete recovery to post-COVID-19 syndrome with impaired mental health., Competing Interests: Conflict of interest: P. Tymoszuk owns the Data Analytics as a Service data science enterprise and is (from May 2021 on) a freelance data scientist working in his own enterprise; he received honoraria for the statistical analysis of the CovILD study. All other authors have no conflict of interest related to this study to declare., (Copyright ©The authors 2023.)

The severity of coronavirus disease 2019 (COVID-19) is related to the presence of comorbidities including metabolic diseases. We herein present data from the longitudinal prospective CovILD trial, and investigate the recovery from COVID-19 in individuals with dysglycemia and dyslipidemia. A total of 145 COVID-19 patients were prospectively followed and a comprehensive clinical, laboratory and imaging assessment was performed at 60, 100, 180, and 360 days after the onset of COVID-19. The severity of acute COVID-19 and outcome at early post-acute follow-up were significantly related to the presence of dysglycemia and dyslipidemia. Still, at long-term follow-up, metabolic disorders were not associated with an adverse pulmonary outcome, as reflected by a good recovery of structural lung abnormalities in both, patients with and without metabolic diseases. To conclude, dyslipidemia and dysglycemia are associated with a more severe course of acute COVID-19 as well as delayed early recovery but do not impair long-term pulmonary recovery., (© 2023. The Author(s).)

Background: Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder that can manifest as lung disease. A delay between onset of symptoms and diagnosis of AATD is common and associated with worse clinical status and more advanced disease stage but the influence on survival is unclear., Objective: We aimed to investigate the impact of diagnostic delay on overall survival (OS) and transplant-free survival (TS) in AATD patients., Methods: We analysed 268 AATD patients from the prospective multi-centre Austrian Alpha-1 Lung (AAL) Registry, employing descriptive statistics, Chi-square-test as well as univariable (Kaplan-Meier plots, log-rank test) and multivariable survival analysis (Cox regression)., Results: The predominant phenotype was Pi*ZZ (82.1%). At diagnosis, 90.2% had an AAT level below 0.6 g/L. At inclusion, 28.2% had never smoked, 68.0% had quit smoking and 3.8% continued to smoke. Lung disease was diagnosed in 98.5%, thereof most patients were diagnosed with emphysema (63.8%) and/or chronic obstructive pulmonary disease (44.0%). Median diagnostic delay was 5.3 years (inter-quartile range [IQR] 2.2-11.5 years). In multivariable analysis (n = 229), a longer diagnostic delay was significantly associated with worse OS (hazard ratio [HR] 1.61; 95% CI 1.09-2.38; p = 0.016) and TS (HR 1.43; 95% CI 1.08-1.89; p = 0.011), independent from age, smoking status, body mass index (BMI), forced expiratory volume in one second (FEV 1 ) and long-term oxygen treatment. Furthermore, BMI, age and active smoking were significantly associated with worse OS as well as BMI, active smoking and FEV 1 were with worse TS., Conclusions: A delayed diagnosis was associated with significantly worse OS and TS. Screening should be improved and efforts to ensure early AATD diagnosis should be intensified., (© 2023. The Author(s).)

Introduction: COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). As the respiratory tract is the primary site of infection and host-mediated inflammatory responses, pathologies and dysfunction of the respiratory system characterize the severe disease and are typically associated with the need for oxygen supply or even ventilator support. In survivors of severe COVID-19, computed tomography follow-up frequently reveals structural lung abnormalities, and one-third of individuals who were hospitalized during acute COVID-19 demonstrate persisting lung abnormalities for at least 12 months after disease onset., Areas Covered: This review summarizes current evidence on pulmonary recovery after COVID-19, focusing on adult patients who suffered from COVID-19 pneumonia., Expert Opinion: Severe COVID-19 is associated with a high frequency of persisting lung abnormalities at follow-up. The long-term consequences of these findings remain elusive and urge further evaluation to identify individuals at risk for COVID-19 long-term consequences.

Background: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities., Methods: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities., Results: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities., Conclusions: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Determination of antibody levels against the nucleocapsid (N) and spike (S) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to estimate the humoral immune response after SARS-CoV-2 infection or vaccination. Differences in the design and specification of antibody assays challenge the interpretation of test results, and comparative studies are often limited to single time points per patient. We determined the longitudinal kinetics of antibody levels of 145 unvaccinated coronavirus disease 2019 (COVID-19) patients at four visits over 1 year upon convalescence using 8 commercial SARS-CoV-2 antibody assays (from Abbott, DiaSorin, Roche, Siemens, and Technoclone), as well as a virus neutralization test (VNT). A linear regression model was used to investigate whether antibody results obtained in the first 6 months after disease onset could predict the VNT results at 12 months. Spike protein-specific antibody tests showed good correlation to the VNT at individual time points ( r S , 0.74 to 0.92). While longitudinal assay comparison with the Roche Elecsys anti-SARS-CoV-2 S test showed almost constant antibody concentrations over 12 months, the VNT and all other tests indicated a decline in serum antibody levels (median decrease to 14% to 36% of baseline). The antibody level at 3 months was the best predictor of the VNT results at 12 months after disease onset. The current standardization to a WHO calibrator for normalization to binding antibody units (BAU) is not sufficient for the harmonization of SARS-CoV-2 antibody tests. Assay-specific differences in absolute values and trends over time need to be considered when interpreting the course of antibody levels in patients. IMPORTANCE Determination of antibodies against SARS-CoV-2 will play an important role in detecting a sufficient immune response. Although all the manufacturers expressed antibody levels in binding antibody units per milliliter, thus suggesting comparable results, we found discrepant behavior between the eight investigated assays when we followed the antibody levels in a cohort of 145 convalescent patients over 1 year. While one assay yielded constant antibody levels, the others showed decreasing antibody levels to a varying extent. Therefore, the comparability of the assays must be improved regarding the long-term kinetics of antibody levels. This is a prerequisite for establishing reliable antibody level cutoffs for sufficient individual protection against SARS-CoV-2.

Increasing evidence suggests persistent cognitive dysfunction after COVID-19. In this cross-sectional study, frontal lobe function was assessed 12 months after the acute phase of the disease, using tailored eye tracking assessments. Individuals who recovered from COVID-19 made significantly more errors in all eye tracking tasks compared to age/sex-matched healthy controls. Furthermore, patients who were treated as inpatients performed worse compared to outpatients and controls. Our results show impaired inhibitory cortical control in individuals who recovered from COVID-19. The association between disease severity and its sequelae may contribute to a better understanding of post-COVID-19 cognitive function., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Standardized exercise therapy programs in pulmonary rehabilitation have been shown to improve physical performance and lung function parameters in post-acute COVID-19 patients. However, it has not been investigated if these positive effects are equally beneficial for both sexes. The purpose of this study was to analyze outcomes of a pulmonary rehabilitation program with respect to sex differences, in order to identify sex-specific pulmonary rehabilitation requirements. Data of 233 post-acute COVID-19 patients (40.4% females) were analyzed before and after a three-week standardized pulmonary rehabilitation program. Lung function parameters were assessed using body-plethysmography and functional exercise capacity was measured by the Six-Minute Walk Test. At post-rehabilitation, females showed a significantly smaller improvement in maximal inspiration capacity and forced expiratory volume (F=5.86, ω 2= .02; p<0.05) than males. Exercise capacity improvements between men and women did not differ statistically. Females made greater progress towards reference values of exercise capacity (T(231)=-3.04; p<0.01) and forced expiratory volume in the first second (T(231)=2.83; p<0.01) than males. Sex differences in the improvement of lung function parameters seem to exist and should be considered when personalizing standardized exercise therapies in pulmonary rehabilitation., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Lung involvement is the most frequent cause of death in patients with systemic sclerosis (SSc). As lung involvement is frequently asymptomatic, the current recommendation is to carry out thoracic computed tomography (CT) in all patients newly diagnosed with SSc. There is currently disagreement on how patients with SSc for whom no lung involvement was found at the time of diagnosis, should be followed up. Based on a consensus of Austrian rheumatologists, pneumologists and radiologists it is recommended that for asymptomatic patients with a negative CT at the time of initial diagnosis, a transthoracic ultrasound examination should be carried out annually and a lung function examination every 6-12 months. In the presence of a positive lung ultrasound finding a supplementary CT for further clarification is recommended. Based on the data situation, annual CT follow-up controls are recommended for patients with a high risk as defined by appropriate risk factors., (© 2022. The Author(s).)

Background The long-term pulmonary sequelae of COVID-19 is not well known. Purpose To characterize patterns and rates of improvement of chest CT abnormalities 1 year after COVID-19 pneumonia. Materials and Methods This was a secondary analysis of a prospective, multicenter observational cohort study conducted from April 29 to August 12, 2020, to assess pulmonary abnormalities at chest CT approximately 2, 3, and 6 months and 1 year after onset of COVID-19 symptoms. Pulmonary findings were graded for each lung lobe using a qualitative CT severity score (CTSS) ranging from 0 (normal) to 25 (all lobes involved). The association of demographic and clinical factors with CT abnormalities after 1 year was assessed with logistic regression. The rate of change of the CTSS at follow-up CT was investigated by using the Friedmann test. Results Of 142 enrolled participants, 91 underwent a 1-year follow-up CT examination and were included in the analysis (mean age, 59 years ± 13 [SD]; 35 women [38%]). In 49 of 91 (54%) participants, CT abnormalities were observed: 31 of 91 (34%) participants showed subtle subpleural reticulation, ground-glass opacities, or both, and 18 of 91 (20%) participants had extensive ground-glass opacities, reticulations, bronchial dilation, microcystic changes, or a combination thereof. At multivariable analysis, age of more than 60 years (odds ratio [OR], 5.8; 95% CI: 1.7, 24; P = .009), critical COVID-19 severity (OR, 29; 95% CI: 4.8, 280; P < .001), and male sex (OR, 8.9; 95% CI: 2.6, 36; P < .001) were associated with persistent CT abnormalities at 1-year follow-up. Reduction of CTSS was observed in participants at subsequent follow-up CT ( P < .001); during the study period, 49% (69 of 142) of participants had complete resolution of CT abnormalities. Thirty-one of 49 (63%) participants with CT abnormalities showed no further improvement after 6 months. Conclusion Long-term CT abnormalities were common 1 year after COVID-19 pneumonia. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Leung in this issue.

Coronavirus disease 2019 (COVID-19) is frequently associated with iron dyshomeostasis. The latter is related to acute disease severity and COVID-19 convalescence. We herein describe iron dyshomeostasis at COVID-19 follow-up and its association with long-term pulmonary and symptomatic recovery. The prospective, multicentre, observational cohort study "Development of Interstitial Lung Disease (ILD) in Patients With Severe SARS-CoV-2 Infection (CovILD)" encompasses serial extensive clinical, laboratory, functional and imaging evaluations at 60, 100, 180 and 360 days after COVID-19 onset. We included 108 individuals with mild-to-critical acute COVID-19, whereas 75% presented with severe acute disease. At 60 days post-COVID-19 follow-up, hyperferritinaemia (35% of patients), iron deficiency (24% of the cohort) and anaemia (9% of the patients) were frequently found. Anaemia of inflammation (AI) was the predominant feature at early post-acute follow-up, whereas the anaemia phenotype shifted towards iron deficiency anaemia (IDA) and combinations of IDA and AI until the 360 days follow-up. The prevalence of anaemia significantly decreased over time, but iron dyshomeostasis remained a frequent finding throughout the study. Neither iron dyshomeostasis nor anaemia were related to persisting structural lung impairment, but both were associated with impaired stress resilience at long-term COVID-19 follow-up. To conclude, iron dyshomeostasis and anaemia are frequent findings after COVID-19 and may contribute to its long-term symptomatic outcome.

The Austrian Society of Pneumology (ASP) launched a first statement on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in May 2020, at a time when in Austria 285 people had died from this disease and vaccinations were not available. Lockdown and social distancing were the only available measures to prevent more infections and the breakdown of the health system. Meanwhile, in Austria over 13,000 patients have died in association with a SARS-CoV‑2 infection and coronavirus disease 2019 (COVID-19) was among the most common causes of death; however, SARS-CoV‑2 has been mutating all the time and currently, most patients have been affected by the delta variant where the vaccination is very effective but the omicron variant is rapidly rising and becoming predominant. Particularly in children and young adults, where the vaccination rate is low, the omicron variant is expected to spread very fast. This poses a particular threat to unvaccinated people who are at elevated risk of severe COVID-19 disease but also to people with an active vaccination. There are few publications that comprehensively addressed the special issues with SARS-CoV‑2 infection in patients with chronic lung diseases. These were the reasons for this updated statement. Pulmonologists care for many patients with an elevated risk of death in case of COVID-19 but also for patients that might be at an elevated risk of vaccination reactions or vaccination failure. In addition, lung function tests, bronchoscopy, respiratory physiotherapy and training therapy may put both patients and health professionals at an increased risk of infection. The working circles of the ASP have provided statements concerning these risks and how to avoid risks for the patients., (© 2022. The Author(s).)

The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19., (© 2022. The Author(s).)

Background: The optimal procedures to prevent, identify, monitor, and treat long-term pulmonary sequelae of COVID-19 are elusive. Here, we characterized the kinetics of respiratory and symptom recovery following COVID-19., Methods: We conducted a longitudinal, multicenter observational study in ambulatory and hospitalized COVID-19 patients recruited in early 2020 (n = 145). Pulmonary computed tomography (CT) and lung function (LF) readouts, symptom prevalence, and clinical and laboratory parameters were collected during acute COVID-19 and at 60, 100, and 180 days follow-up visits. Recovery kinetics and risk factors were investigated by logistic regression. Classification of clinical features and participants was accomplished by unsupervised and semi-supervised multiparameter clustering and machine learning., Results: At the 6-month follow-up, 49% of participants reported persistent symptoms. The frequency of structural lung CT abnormalities ranged from 18% in the mild outpatient cases to 76% in the intensive care unit (ICU) convalescents. Prevalence of impaired LF ranged from 14% in the mild outpatient cases to 50% in the ICU survivors. Incomplete radiological lung recovery was associated with increased anti-S1/S2 antibody titer, IL-6, and CRP levels at the early follow-up. We demonstrated that the risk of perturbed pulmonary recovery could be robustly estimated at early follow-up by clustering and machine learning classifiers employing solely non-CT and non-LF parameters., Conclusions: The severity of acute COVID-19 and protracted systemic inflammation is strongly linked to persistent structural and functional lung abnormality. Automated screening of multiparameter health record data may assist in the prediction of incomplete pulmonary recovery and optimize COVID-19 follow-up management., Funding: The State of Tyrol (GZ 71934), Boehringer Ingelheim/Investigator initiated study (IIS 1199-0424)., Clinical Trial Number: ClinicalTrials.gov: NCT04416100., Competing Interests: TS, SS, AB, AP, AL, CS, MN, PG, KK, SK, MA, BP, AE, GH, EW, GW, GW, IT, JL No competing interests declared, PT owns his own business, Data Analytics as a Service Tirol, for which he performs freelance data science work. Has also received an honorarium for the study data management, curation and analysis and minor manuscript work. The author has no other competing interests to declare, (© 2022, Sonnweber et al.)

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care., Competing Interests: The authors declare no competing interests. Author John F. Timms was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge., (Copyright: © 2022 Demichev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The determinants of successful humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of critical importance for the design of effective vaccines and the evaluation of the degree of protective immunity conferred by exposure to the virus. As novel variants emerge, understanding their likelihood of suppression by population antibody repertoires has become increasingly important., Methods: In this study, we analyzed the SARS-CoV-2 polyclonal antibody response in a large population of clinically well-characterized patients after mild and severe COVID-19 using a panel of microarrayed structurally folded and unfolded SARS-CoV-2 proteins, as well as sequential peptides, spanning the surface spike protein (S) and the receptor-binding domain (RBD) of the virus., Results: S- and RBD-specific antibody responses were dominated by immunoglobulin G (IgG), mainly IgG 1 , and directed against structurally folded S and RBD and three distinct peptide epitopes in S2. The virus neutralization activity of patients´ sera was highly correlated with IgG antibodies specific for conformational but not sequential RBD epitopes and their ability to prevent RBD binding to its human receptor angiotensin-converting enzyme 2 (ACE2). Twenty percent of patients selectively lacked RBD-specific IgG. Only immunization with folded, but not with unfolded RBD, induced antibodies against conformational epitopes with high virus-neutralizing activity. Conformational RBD epitopes required for protection do not seem to be altered in the currently emerging virus variants., Conclusion: These results are fundamental for estimating the protective activity of antibody responses after natural infection or vaccination and for the design of vaccines, which can induce high levels of SARS-CoV-2-neutralizing antibodies conferring sterilizing immunity., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

This guideline comprises the state of science at the time of the editorial deadline. In view of the high turnover of knowledge the guideline is designed as a living guideline. The main objective was to provide a tool for the use in primary care, being considered well suited as a first point of entry and for the provision of care. The guideline gives recommendations on the differential diagnosis of symptoms following SARS-CoV‑2 infection, on their therapeutic options, as well as for guidance and care of the patients concerned. It also offers advice concerning return to daily life and rehabilitation. Long COVID being a very variable condition, we chose an interdisciplinary approach., (© 2021. The Author(s).)

Background: Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data., Methods: The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD., Results: A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of follow-up, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of "Non-Eisenmenger PAH" patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described., Conclusions: Analyzing "real life data" from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the "Non-Eisenmenger PAH" group and to patients with complex CHD, including Fontan patients., Trial Registration: www.clinicaltrials.gov, study identifier: Clinicaltrials.gov NCT01347216., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-351). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. Dr. DH reports non-financial support from Actelion, Boehringer-Ingelheim, and Shire, outside the submitted work; Dr. DP reports personal fees from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, outside the submitted work; Dr. MD reports personal fees from Actelion, Bayer, GSK and MSD, outside the submitted work; Dr. HAG reports personal fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work; Dr. MG reports personal fees from Actelion, Bayer and GSK, outside the submitted work; Dr. MMH reports personal fees from Acceleron, Actelion, Bayer, MSD and Pfizer, outside the submitted work; Dr. CDV reports personal fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics, outside the submitted work; Dr. RE reports personal fees from Actelion, Boehringer Ingelheim, OMT, Bayer, and Berlin Chemie; grants from Actelion and Boehringer Ingelheim, outside the submitted work; Dr. MH reports grants and personal fees from Actelion, personal fees from Bayer, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen, Novartis and MSD, outside the submitted work; Dr. MH reports personal fees from Acceleron, Actelion, AstraZeneca, Bayer, BERLIN CHEMIE, GSK, MSD, Novartis and OMT, outside the submitted work; Dr. HW reports personal fees from Action, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche, outside the submitted work; Dr. DS reports personal fees from Actelion, Bayer, and GSK, outside the submitted work; Dr. LS reports personal fees from Actelion, Bayer, and MSD, outside the submitted work; Dr. SU reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, grants and personal fees from Actelion SA/Johnson & Johnson, Switzerland, and MSD Switzerland, outside the submitted work; Dr. TJL reports personal fees from Actelion, Janssen-Cilag, BMS, MSD, and OMT GmbH, outside the submitted work; Dr. LB reports personal fees from Actelion, outside the submitted work; Dr. MC reports personal fees from Boehringer Ingelheim Pharma GmbH, Roche Pharma, and Boehringer Ingelheim, outside the submitted work; Dr. HW reports personal fees from Boehringer Ingelheim, and Roche, outside the submitted work. Dr. EG reports personal fees from Actelion, Janssen, Bayer, MSD, Bial, OrPha Swiss GmbH, OMT and Medscape, outside the submitted work; Dr. SR reports personal fees from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)