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COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sahanic, Löffler-Ragg, Tymoszuk, Hilbe, Demetz, Masanetz, Theurl, Holfeld, Gollmann-Tepeköylü, Tzankov, Weiss, Giera and Tancevski.)

Background: After the 2002/2003 severe acute respiratory syndrome outbreak, 30% of survivors exhibited persisting structural pulmonary abnormalities. The long-term pulmonary sequelae of coronavirus disease 2019 (COVID-19) are yet unknown, and comprehensive clinical follow-up data are lacking., Methods: In this prospective, multicentre, observational study, we systematically evaluated the cardiopulmonary damage in subjects recovering from COVID-19 at 60 and 100 days after confirmed diagnosis. We conducted a detailed questionnaire, clinical examination, laboratory testing, lung function analysis, echocardiography and thoracic low-dose computed tomography (CT)., Results: Data from 145 COVID-19 patients were evaluated, and 41% of all subjects exhibited persistent symptoms 100 days after COVID-19 onset, with dyspnoea being most frequent (36%). Accordingly, patients still displayed an impaired lung function, with a reduced diffusing capacity in 21% of the cohort being the most prominent finding. Cardiac impairment, including a reduced left ventricular function or signs of pulmonary hypertension, was only present in a minority of subjects. CT scans unveiled persisting lung pathologies in 63% of patients, mainly consisting of bilateral ground-glass opacities and/or reticulation in the lower lung lobes, without radiological signs of pulmonary fibrosis. Sequential follow-up evaluations at 60 and 100 days after COVID-19 onset demonstrated a vast improvement of symptoms and CT abnormalities over time., Conclusion: A relevant percentage of post-COVID-19 patients presented with persisting symptoms and lung function impairment along with radiological pulmonary abnormalities >100 days after the diagnosis of COVID-19. However, our results indicate a significant improvement in symptoms and cardiopulmonary status over time., Competing Interests: Conflict of interest: T. Sonnweber has nothing to disclose. Conflict of interest: S. Sahanic has nothing to disclose. Conflict of interest: A. Pizzini has nothing to disclose. Conflict of interest: A. Luger has nothing to disclose. Conflict of interest: C. Schwabl has nothing to disclose. Conflict of interest: B. Sonnweber has nothing to disclose. Conflict of interest: K. Kurz has nothing to disclose. Conflict of interest: S. Koppelstätter has nothing to disclose. Conflict of interest: D. Haschka has nothing to disclose. Conflict of interest: V. Petzer has nothing to disclose. Conflict of interest: A. Boehm has nothing to disclose. Conflict of interest: M. Aichner has nothing to disclose. Conflict of interest: P. Tymoszuk has nothing to disclose. Conflict of interest: D. Lener has nothing to disclose. Conflict of interest: M. Theurl has nothing to disclose. Conflict of interest: A. Lorsbach-Köhler has nothing to disclose. Conflict of interest: A. Tancevski has nothing to disclose. Conflict of interest: A. Schapfl has nothing to disclose. Conflict of interest: M. Schaber has nothing to disclose. Conflict of interest: R. Hilbe has nothing to disclose. Conflict of interest: M. Nairz has nothing to disclose. Conflict of interest: B. Puchner has nothing to disclose. Conflict of interest: D. Hüttenberger has nothing to disclose. Conflict of interest: C. Tschurtschenthaler has nothing to disclose. Conflict of interest: M. Aßhoff has nothing to disclose. Conflict of interest: A. Peer has nothing to disclose. Conflict of interest: F. Hartig has nothing to disclose. Conflict of interest: R. Bellmann has nothing to disclose. Conflict of interest: M. Joannidis has nothing to disclose. Conflict of interest: C. Gollmann-Tepeköylü has nothing to disclose. Conflict of interest: J. Holfeld has nothing to disclose. Conflict of interest: G. Feuchtner has nothing to disclose. Conflict of interest: A. Egger has nothing to disclose. Conflict of interest: G. Hoermann has nothing to disclose. Conflict of interest: A. Schroll has nothing to disclose. Conflict of interest: G. Fritsche has nothing to disclose. Conflict of interest: S. Wildner has nothing to disclose. Conflict of interest: R. Bellmann-Weiler has nothing to disclose. Conflict of interest: R. Kirchmair has nothing to disclose. Conflict of interest: R. Helbok has nothing to disclose. Conflict of interest: H. Prosch has nothing to disclose. Conflict of interest: D. Rieder has nothing to disclose. Conflict of interest: Z. Trajanoski has nothing to disclose. Conflict of interest: F. Kronenberg has nothing to disclose. Conflict of interest: E. Wöll has nothing to disclose. Conflict of interest: G. Weiss has nothing to disclose. Conflict of interest: G. Widmann has nothing to disclose. Conflict of interest: J. Löffler-Ragg has nothing to disclose. Conflict of interest: I. Tancevski reports an Investigator Initiated Study (IIS) grant from Boehringer Ingelheim (IIS 1199-0424)., (Copyright ©ERS 2021.)

Objective: Sleep complaints are frequent after acute COVID-19. Aim of this study was to videopolysomnographically evaluate sleep and sleep disorders after SARS-Cov2 infection., Methods: Patients with suspected sleep disorders after acute COVID-19 underwent video-polysomnography (v-PSG) at the Sleep Disorders Clinic, Department of Neurology, Medical University Innsbruck. V-PSG was conducted 4.2 (SD = 1.3) months after diagnosis of SARS-CoV-2 infection., Results: Eleven patients [nine men, age 52.5 (SD = 11.7) years; BMI 29 (SD = 5.2) kg/m 2 ] were included. At 60 days follow-up after diagnosis, persisting breathing complaints were present in 7/11 (64%) patients. After v-PSG four patients (36%) were diagnosed with obstructive sleep apnea (OSA). Respiratory frequency during sleep was normal and no tachypnea, thoracoabdominal asynchrony, or periodic deep sighing were detected. Four patients (36%) showed REM sleep without atonia (RWA), and two additional patients showed an RWA index within the highest range of normality., Conclusion: We report videopolysomnographic findings in a series of eleven patients after acute COVID-19. A major finding of this study was the presence of isolated RWA, a recognized prodromal stage of RBD, in more than one third of the patients. Future videopolysomnographic investigations including quantification of RWA in patients after COVID-19 will give more insights into a possible acute or post-infectious CNS pathology related to the SARS-CoV-2 infection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The Coronavirus Disease 2019 (COVID-19) pandemic increases the demand for postacute care in patients after a severe disease course. Various long-term sequelae are expected and rehabilitation medicine is challenged to support physical and cognitive recovery., Aim: We aimed to explore the dysfunctions and outcome of COVID-19 survivors after early postacute rehabilitation., Design: Observational cohort study., Methods: This study evaluated the postacute sequelae of patients hospitalized for SARS-CoV-2 infection and analyzed rehabilitative outcomes of a subgroup of patients included in the prospective observational multicenter CovILD study., Results: A total of 23 subjects discharged after severe to critical COVID-19 infection underwent an individualized, multiprofessional rehabilitation. At the start of postacute rehabilitation, impairment of pulmonary function (87%), symptoms related to postintensive care syndrome, and neuropsychological dysfunction (85%) were frequently found, whereas cardiac function appeared to be largely unaffected. Of interest, multi-disciplinary rehabilitation resulted in a significant improvement in lung function, as reflected by an increase of forced vital capacity (P=0.007) and forced expiratory volume in one second (P=0.014), total lung capacity (P=0.003), and diffusion capacity for carbon monoxide (P=0.002). Accordingly, physical performance status significantly improved as reflected by a mean increase of six-minute walking distance by 176 (SD±137) meters. Contrarily, a considerable proportion of patients still had limited diffusion capacity (83%) or neurological symptoms including peripheral neuropathy at the end of rehabilitation., Conclusions: Individuals discharged after a severe course of COVID-19 frequently present with persisting physical and cognitive dysfunctions after hospital discharge. Those patients significantly benefit from multi-disciplinary inpatient rehabilitation., Clinical Rehabilitation Impact: Our data demonstrated the highly promising effects of early postacute rehabilitation in survivors of severe or critical COVID-19. This findings urge further prospective evaluations and may impact future treatment and rehabilitation strategies.

Introduction: Sarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course. There is still no reliable biomarker available, which assists in the diagnosis or prediction of the clinical course. According to a murine model, the expression level of the metabolic checkpoint kinase mechanistic target of Rapamycin complex 1 (mTORC1) in granulomas of sarcoidosis patients may be used as a clinical biomarker., Material and Methods: This is a retrospective analysis of 58 patients with histologically confirmed sarcoidosis. Immunohistochemical staining of granulomas from tissue samples was evaluated for the expression of activated mTORC1 signaling, including phosphorylated mTOR, its downstream effectors S6K1, 4EBP1 and the proliferation marker Ki-67. Patients were categorized according to different clinical phenotypes, serum biomarkers, and immunomodulatory therapy., Results: All patients showed activated mTORC1 signaling in granulomas, which correlated with its downstream effectors S6K1 and 4EBP1 but was not related to Ki-67 expression. The mTORC1 activity revealed an association neither to disease severity nor the necessity of treatment; however, p-mTOR inversely correlated with cumulative corticosteroid dosage., Conclusion: Our data confirm activation of the mTORC1 pathway in sarcoidosis, supporting the hypothesis that mTOR is a significant driver in granuloma formation. However, we could not find a relationship between the degree of mTOR activation and disease severity or the need for therapy., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Risk stratification is essential to assess mortality risk and guide treatment in patients with precapillary pulmonary hypertension (PH). We herein compared the accuracy of different currently used PH risk stratification tools and evaluated the significance of particular risk parameters., Methods: We conducted a retrospective longitudinal observational cohort study evaluating seven different risk assessment approaches according to the current PH guidelines. A comprehensive assessment including multi-parametric risk stratification was performed at baseline and 4 yearly follow-up time-points. Multi-step Cox hazard analysis was used to analyse and refine risk prediction., Results: Various available risk models effectively predicted mortality in patients with precapillary pulmonary hypertension. Right-heart catheter parameters were not essential for risk prediction. Contrary, non-invasive follow-up re-evaluations significantly improved the accuracy of risk estimations. A lack of accuracy of various risk models was found in the intermediate- and high-risk classes. For these patients, an additional evaluation step including assessment of age and right atrium area improved risk prediction significantly., Discussion: Currently used abbreviated versions of the ESC/ERS risk assessment tool, as well as the REVEAL 2.0 and REVEAL Lite 2 based risk stratification, lack accuracy to predict mortality in intermediate- and high-risk precapillary pulmonary hypertension patients. An expanded non-invasive evaluation improves mortality risk prediction in these individuals.

The novel Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a global health concern. Vitamin D (VITD) deficiency has been suggested to alter SARS-CoV-2 susceptibility and the course of disease. Thus, we aimed to investigate associations of VITD status to disease presentation within the CovILD registry. This prospective, multicenter, observational study on long-term sequelae includes patients with COVID-19 after hospitalization or outpatients with persistent symptoms. Eight weeks after PCR confirmed diagnosis, a detailed questionnaire, a clinical examination, and laboratory testing, including VITD status, were evaluated. Furthermore, available laboratory specimens close to hospital admission were used to retrospectively analyze 25-hydroxyvitamin D levels at disease onset. A total of 109 patients were included in the analysis (60% males, 40% females), aged 58 ± 14 years. Eight weeks after the onset of COVID-19, a high proportion of patients presented with impaired VITD metabolism and elevated parathyroid hormone (PTH) levels. PTH concentrations were increased in patients who needed intensive care unit (ICU) treatment, while VITD levels were not significantly different between disease severity groups. Low VITD levels at disease onset or at eight-week follow-up were not related to persistent symptom burden, lung function impairment, ongoing inflammation, or more severe CT abnormalities. VITD deficiency is frequent among COVID-19 patients but not associated with disease outcomes. However, individuals with severe disease display a disturbed parathyroid-vitamin-D axis within their recovery phase. The proposed significance of VITD supplementation in the clinical management of COVID-19 remains elusive.

Background: Current evidence suggests an increased prevalence of iron deficiency (ID) and anemia in chronic obstructive pulmonary disease (COPD). ID and subsequent anemia can be due to iron losses via bleeding resulting in absolute ID or inflammation-driven retention of iron within macrophages resulting in functional ID and anemia of inflammation. Methods: This is a retrospective analysis of 204 non-exacerbated COPD patients in outpatient care. Current definitions of absolute and functional ID were applied to determine the prevalence of ID and to analyze associations to disease severity in terms of lung function parameters and clinical symptoms. Results: The studied cohort of COPD patients demonstrated a high prevalence of ID, ranging from 30 to 40% during the observation time. At the initial presentation, absolute or functional ID was found in 9.3% to 12.3% of COPD individuals, whereas combined forms of absolute and functional ID were most prevalent (25.9% of all individuals). The prevalence of ID increased during longitudinal follow-up (37 ± 15 months), and especially combined forms of ID were significantly related to anemia. Anemia prevalence ranged between 14.2% and 20.8% during the observation period and anemia was associated with lower FEV1, DLCOc, and CRP elevation. Accordingly, ID was associated with decreased FEV1, DLCOc, and an elevation in CRP. Conclusion: ID is common in COPD patients, but a uniform definition for accurate diagnosis does not exist. Prevalence of functional ID and anemia increased during follow-up. The associations of ID and anemia with reduced functional lung capacity and elevated inflammation may reflect a more severe COPD phenotype., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The coronavirus disease 2019 (COVID-19) pandemic is currently a challenge worldwide. In Austria, a crisis within the healthcare system has so far been prevented. The treatment of patients with community-acquired pneumonia (CAP), including SARS-CoV‑2 infections, should continue to be based on evidence-based CAP guidelines during the pandemic; however, COVID-19 specific adjustments are useful. The treatment of patients with chronic lung diseases has to be adapted during the pandemic but must still be guaranteed.

Anaemia is a highly prevalent condition, which negatively impacts on patients' cardiovascular performance and quality of life. Anaemia is mainly caused by disturbances of iron homeostasis. While absolute iron deficiency mostly as a consequence of chronic blood loss or insufficient dietary iron absorption results in the emergence of iron deficiency anaemia, inflammation-driven iron retention in innate immune cells and blockade of iron absorption leads to the development of anaemia of chronic disease. Both, iron deficiency and anaemia have been linked to the clinical course of pulmonary hypertension. Various mechanistic links between iron homeostasis, anaemia, and pulmonary hypertension have been described and current treatment guidelines suggest regular iron status assessment and the implementation of iron supplementation strategies in these patients. The pathophysiology, diagnostic assessment as well as current and future treatment options concerning iron deficiency with or without anaemia in individuals suffering from pulmonary hypertension are discussed within this review.

Isolated partial anomalous pulmonary venous connection (PAPVC) is an uncommon congenital heart anomaly that is sporadically associated with pulmonary arterial hypertension in the adult population. The diagnosis and therapy for this condition are challenging. We report on three cases of patients with unexpected severe precapillary pulmonary hypertension in single PAPVC treated with an upfront pulmonary arterial hypertension-specific combination therapy. Our cases indicate that the combination of PAPVC and pulmonary comorbidities may trigger the development of severe pulmonary arterial hypertension. The initiation of pulmonary arterial hypertension-targeted combination therapy revealed to be a safe and efficacious strategy for patients with PAPVC-associated severe pulmonary arterial hypertension., (© The Author(s) 2020.)

Imbalances of iron homeostasis are associated with an adverse clinical outcome of pulmonary hypertension (PH). Herein, we aimed to analyze the impact of iron deficiency (ID) in a real-life PH patient cohort according to different currently used ID definitions. In a retrospective study including 153 precapillary PH patients followed over a mean period of five years, iron deficiency was assessed according to five clinical definitions used in previous trials. The impact of ID on clinical, hematological and hemodynamic parameters was investigated. Depending on the different cutoff levels for serum ferritin and transferrin saturation, currently used ID definitions indicated a prevalence of either true or functional ID in 11 to 75 percent of PH patients. A good diagnostic accuracy was achieved by using the sTFRF/log ferritin (sTFRF) index, which identified 33 to 42 percent of PH patients as being iron deficient. The sTFRF index had the best prediction for the association between ID and clinical outcome. Iron deficient patients with precapillary PH had a significantly higher mortality as compared to non-iron deficiency subjects, which was true for both, PH patients with and without anemia. Although levels of the iron hormone hepcidin were rather affected by ID than by inflammation, they were not associated with the clinical course or mortality of PH subjects. To conclude, ID had a significant impact on the clinical course of precapillary PH patients. The appropriate use of robust biomarkers to define ID is a prerequisite to further evaluate the role of ID and the potential benefit of iron supplementation in precapillary PH patients., Competing Interests: The authors have declared that no competing interests exist.

Aviscumine, a recombinant lectin I, has been identified as an immunomodulatory agent within a new class of ribotoxic stress-inducing anticancer substances that have demonstrated efficacy in phase I/II trials. The aim of the present study was to elucidate the presumed effect of aviscumine on enhancing human natural killer (NK) cell antitumor cytotoxicity. To measure the effect of aviscumine on human NK cell cytotoxicity, chromium-51-release assays against K-562 cells were performed with isolated NK cells from the whole blood of 34 healthy volunteers. Two effector-to-target cell ratios (12.5:1 and 25:1) were used by two independent investigators with a focus on the concentration-dependent effect (0.5 vs. 1 ng/ml aviscumine), reproducibility (first vs. second investigator) and the specificity of the effect by comparison to a heat-inactivated aliquot and interleukin 2 (IL-2) stimulation (10 ng/ml). The mediation of the effect via degranulation was demonstrated by flow cytometric analyses of CD107α expression. Statistics were performed with SPSS using Student's t-tests for normally distributed data. Aviscumine induced a significant and reproducible, concentration-dependent increase in NK cell cytotoxicity (n=22; P<0.01 for both concentrations and ratios), which was also demonstrated when administered in combination with IL-2 (n=12; 12.5:1 ratio, P<0.001; 25:1 ratio, P=0.025) and when compared with the heat-inactivated aliquots (n=12; 12.5:1, P=0.004; 25:1 ratio, P=0.007). The mediation of its effect via interferon γ degranulation was demonstrated by significantly enhanced CD107α expression (n=7; P=0.005). Taken together, the results indicate that aviscumine induced an increase in NK cell anticancer cytotoxicity. These results highlight its clinical potential as an immunostimulatory agent, particularly with regard to combined use with chemotherapeutics or immune checkpoint inhibitors. However, further studies are required.

Background/aims: Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) are over-represented in patients with chronic pancreatitis: 13-37% of pancreatitis patients are heterozygous for CFTR mutations, compared with the carrier estimate of 3.2% in the central European population. The aim of the current study was to investigate the association between clinical manifestations of pancreatitis and CFTR carrier status., Methods: A cohort of 133 pancreatitis patients was recruited in a confined geographical region (Tyrol-Western Austria) and analysed for the 30 most common CFTR gene mutations in Europe by multiplex PCR and gene sequencing. Pancreatitis was classified as acute or chronic according to the criteria of the Japan Pancreas Society (JPS) and etiological factors included in the TIGAR-O classification, namely toxic, idiopathic, genetic, autoimmune, recurrent and obstructive causes were assessed., Results: The overall frequency of CFTR mutations in the patient cohort was 11.2%. In patients classified as 'idiopathic definitive chronic pancreatitis' (JPS criteria), the frequency of mutations was 12.7%, whereas patients with 'acute pancreatitis' or 'possible chronic pancreatitis' (JPS criteria) had a frequency of CFTR mutations of 10% and 9.1%, respectively., Conclusion: The frequency of CFTR mutations is highest in patients with definitive chronic pancreatitis and may therefore be regarded as a risk factor for the development of CP. However, multiple etiological factors for pancreatitis are present in the majority of patients. Mutation analysis of the CFTR gene therefore appears to be of limited diagnostic and prognostic value in the management of chronic pancreatitis.

Background: In patients with Marfan syndrome, progressive aortic dilation implicates a still-unpredictable risk of life-threatening aortic dissection and rupture. We sought to quantify aortic wall dysfunction noninvasively, determine the diagnostic power of various aortic parameters, and establish a diagnostic model for the early detection of aortic abnormalities associated with Marfan syndrome., Methods: In 19 patients with Marfan syndrome (age, 17.7 +/- 9.5 years) and 19 age- and sex-matched healthy control subjects, computerized ascending and abdominal aortic wall contour analysis with continuous determination of aortic diameters was performed out of transthoracic M-mode echocardiographic tracings. After simultaneous oscillometric blood pressure measurement, aortic elastic properties were determined automatically., Results: The following ascending aortic elastic parameters showed statistically significant differences between the Marfan group and the control group: (1) decreased aortic distensibility ( P < .001), (2) increased wall stiffness index ( P < .01), (3) decreased systolic diameter increase ( P < .01), and (4) decreased maximum systolic area increase ( P < .001). The diagnostic power of all investigated parameters was tested by single logistic regression models. A multiple logistic regression model including solely aortic parameters yielded a sensitivity of 95% and a specificity of 100%., Conclusions: In young patients with Marfan syndrome, a computerized image-analyzing technique revealed decreased aortic elastic properties expressed by parameters showing high diagnostic power. A multiple logistic regression model including merely aortic parameters can serve as useful predictor for Marfan syndrome.