To evaluate three commercial AI software tools for pulmonary nodule detection and segmentation and to assess their impact on guideline-based management recommendations. A total of 740 CT and PET-CT studies from clinical routine were analyzed using three software tools (S1, S2, S3). We compared the total number of detected nodules and “actionable” nodules (per British Thoracic Society (BTS) definition). We further evaluated how measurement variations between tools affected hypothetical management according to Fleischner Society and BTS guidelines for incidental nodules. The tools differed significantly in the total number of detections (S1: 1336; S2: 1060; S3: 1536; p < 0.001) and wrong findings (S1: 965; S2: 720; S3: 1169; p < 0.001). However, the detection of actionable nodules was comparable across all tools (S1: 375; S2: 341; S3: 373; p = 0.73). While no statistically significant differences were found in mean diameter or volume measurements, small absolute variations led to significant differences in management. Specifically, S2 triggered significantly more 1-year follow-up recommendations than S3 under BTS guidelines (p < 0.001). No significant management differences were observed when applying Fleischner Society guidelines. While the three included AI tools show comparable performance in detecting actionable nodules, minor measurement variations significantly impact downstream management when using guidelines with narrow thresholds, such as the BTS criteria. Fleischner Society guidelines appear more robust to these inter-software variations. Question How do commercial software tools for pulmonary nodule detection perform in real-world settings and impact hypothetical management under BTS and Fleischner guidelines? Findings Detection of actionable nodules was comparable across all tools, but small absolute measurement variations triggered significantly more 1-year follow-up recommendations under BTS guidelines. Clinical relevance AI software can cause inconsistent BTS-based management due to narrow thresholds, while Fleischner criteria appear more stable. Frequent detection of benign lesions potentially poses a risk of overdiagnosis and overtreatment in standalone AI-based reporting.

Interleukin-33 (IL-33) is a promising therapeutic target in chronic obstructive pulmonary disease (COPD). However, recent clinical trial setbacks have highlighted the complexity of its biology. This review examines the functions of IL-33 in inflammation, host defense, and tissue remodeling and discusses the potential benefits and harms of targeting this pathway in patients with COPD. We synthesize data from clinical trials of anti-IL-33/ST2 agents and integrate these findings with recent molecular and cellular immunology research to elucidate IL-33’s dual functionality, induced by the reduced IL-33 and oxidized IL-33 isoforms. Additionally, we highlight the impact of modifying factors, including multimorbidity, exogenous exposures, and microbial pathogens, on the IL-33 cascade. Divergent trial outcomes in patients with COPD treated with anti-IL-33 and anti-ST2 antibodies revealed critical mechanistic insights. Inconsistent efficacy of single-pathway inhibitors likely reflect incomplete targeting of IL-33’s dual functionality. While the IL-33red/ST2 pathway drives type 2 inflammation, it is also essential for neutrophil-mediated antibacterial host defense. In contrast, IL-33ox signals through the RAGE/EGFR axis to promote steroid-resistant epithelial remodelling and mucus hypersecretion, a pathway not addressed by ST2-targeted therapies. Experimental data suggesting a potential increase in infection risk associated with anti-IL-33 therapies further underscore the clinical relevance of these mechanistic considerations. Effective IL-33-targeted therapy in COPD will require a mechanistically comprehensive strategy with precision medicine approaches that address patient heterogeneity, including infection risk and comorbidity burden, and incorporate assessment of IL-33 redox states, soluble ST2, and soluble RAGE.

The single nucleotide polymorphism rs12979860 is associated with the production of IFNλ4, a type III interferon, which offers protection from viral infection via its proinflammatory properties. We investigated if a genetically determined increase in IFNλ4 affects disease progression in SARS-CoV-2. This prospective, single-center study involved critically ill SARS-CoV-2 patients admitted to the intensive care unit. We performed genotyping for rs12979860 and analyzed daily laboratory data. Genotype frequencies were compared with an external validation cohort. Critically ill individuals with COVID-19 (n = 184; 29.3% women) were included. Median age was 63 years. The TT genotype was present in 11%, CT in 48% and CC in 41%. At baseline, CRP, ferritin, transferrin and neopterin did not differ significantly between groups. Longitudinal analysis revealed significant genotype-dependent differences in CRP, ferritin and neopterin with the highest peak in TT patients after 10-15 days. A higher need for renal replacement therapy (31.6% vs. 11.7%, p = 0.044) and mechanical ventilation (22 days vs. 15 days, p = 0.018) was observed in the TT group. The SNP rs12979860 near IFNL4 is associated with distinct inflammatory trajectories in critically ill COVID-19 patients. Genetic determinants of the immune response influence the severity of inflammation and clinical outcomes in severe COVID-19.

Aims:Cardiac shockwave therapy (SWT) improves left ventricular (LV) function in patients with ischaemic cardiomyopathy. Shockwave therapy activates Toll-like receptor 3 (TLR3), a receptor-inducing chromatin remodelling and nuclear reprogramming of cardiac cells. We hypothesized that mechanical activation of TLR3 facilitates reprogramming of fibroblasts towards endothelial cells restoring myocardial perfusion and function. Methods and results:Human cardiac fibroblasts were treated by mechanical stimulation via SWT or TLR3 agonist Poly(I:C) in the presence of endothelial induction medium. A lineage tracing experiment was performed in a transgenic mouse model of Fsp1-Cre/LacZ mice after coronary occlusion. Left ventricular function and scarring were assessed. Single-cell sequencing including RNA trajectory analysis was performed. Chromatin remodelling and epigenetic plasticity were evaluated via western blot and Assay for Transposase-Accessible Chromatin sequencing. Mechanical stimulation of human fibroblasts with SWT activated TLR3 signalling and enhanced the expression of endothelial genes in a TLR3-dependent fashion. The induced endothelial cells (ECs) resembled genuine ECs in that they produced endothelial nitric oxide and formed tube-like structures in Matrigel. In a lineage tracing experiment in Fsp1-Cre/LacZ mice, shockwave treatment increased LacZ/CD31-positive cells (indicating transdifferentiation) after coronary occlusion. Furthermore, SWT reduced myocardial scar size and improved LV function. Single-cell RNA-seq and RNA trajectory analyses revealed that SWT induced an endothelial fibroblast cluster and mechanical stimulation induced significant changes in chromatin organization, with chromatin being more accessible after both treatments in 1705 genomic regions. Conclusion:Shockwave therapy enhances DNA accessibility via TLR3 activation and facilitates the transdifferentiation of fibroblasts towards endothelial cells in ischaemic myocardium.

Objectives: Prediction of lung function deficits following pulmonary infection is challenging and suffers from inaccuracy. We sought to develop machine-learning models for prediction of post-inflammatory lung changes based on COVID-19 recovery data. Methods: In the prospective CovILD study (n = 420 longitudinal observations from n = 140 COVID-19 survivors), data on lung function testing (LFT), chest CT including severity scoring by a human radiologist and density measurement by artificial intelligence, demography, and persistent symptoms were collected. This information was used to develop models of numeric readouts and abnormalities of LFT with four machine learning algorithms (Random Forest, gradient boosted machines, neural network, and support vector machines). Results: Reduced DLCO (diffusion capacity for carbon monoxide <80% of reference) was found in 94 (22%) observations. Those observations were modeled with a cross-validated accuracy of 82–85%, AUC of 0.87–0.9, and Cohen’s κ of 0.45–0.5. No reliable models could be established for FEV1 or FVC. For DLCO as a continuous variable, three machine learning algorithms yielded meaningful models with cross-validated mean absolute errors of 11.6–12.5% and R2 of 0.26–0.34. CT-derived features such as opacity, high opacity, and CT severity score were among the most influential predictors of DLCO impairment. Conclusions: Multi-parameter machine learning trained with demographic, clinical, and artificial intelligence chest CT data reliably and reproducibly predicts LFT deficits and outperforms single markers of lung pathology and human radiologist’s assessment. It may improve diagnostic and foster personalized treatment.

Pulmonary vein stenosis is a rare but serious complication after atrial fibrillation ablation. We present a 41-year-old man with a history of paroxysmal atrial fibrillation and dilated cardiomyopathy who developed new-onset hemoptysis and ground-glass opacities on imaging, months after his ablation procedure. Differential diagnoses included vasculitis, infection, and interstitial lung disease, all of which were ruled out. A dedicated pulmonary vein protocol computed tomography scan confirmed the diagnosis of high-grade stenosis of the left upper pulmonary vein. Due to the patient's asymptomatic status posthemoptysis, conservative management was pursued. This case underscores the importance of considering pulmonary vein stenosis in patients with similar presentations and highlights the role of interdisciplinary management in select cases.

A hyperinflammatory state with highly elevated concentrations of inflammatory biomarkers such as C-reactive protein (CRP) is a characteristic feature of severe coronavirus disease 2019 (COVID-19). To examine a potential role of common genetic factors that may influence COVID-19 outcomes, we investigated whether individuals with a polygenic predisposition for a pro-inflammatory response (in the form of Polygenic Scores) are more likely to develop severe COVID-19. The innovative approach of polygenic scores to investigate genetic factors in COVID-19 severity should provide a comprehensive approach beyond single-gene studies. In our cohort of 156 patients of European ancestry, two overlapping Polygenic Scores (PGS) predicting a genetic predisposition to basal CRP concentrations were significantly different between non-severe and severe COVID-19 cases and were associated with less severe COVID-19 outcomes. Furthermore, specific single nucleotide polymorphisms (SNPs) that contribute to either of the two Polygenic Scores predicting basal CRP levels are associated with different traits that represent risk factors for COVID-19 disease initiation (ACE2 receptor, viral replication) and progression (CRP). We suggest that genetically determined enforced CRP formation may contribute to strengthening of innate immune responses and better initial pathogen control thereby reducing the risk of subsequent hyperinflammation and adverse course of COVID-19.

Background & Aims Quantification of the human S100A8/S100A9 tetrameric protein complex in stool, referred to as fecal calprotectin, is an extensively validated biomarker supporting the diagnosis and management of gastrointestinal diseases. Here, we studied the quaternary protein structures (termed configuration) of S100A8 and S100A9 and their biological function in inflammatory bowel diseases (IBD). Methods We dissected fecal S100A8 and S100A9 configurations in patients with IBD by size-exclusion chromatography coupled with tandem mass spectrometry and systematically defined human S100A8 and S100A9 homodimer functions compared with the calprotectin heterotetramer (CP) in the intestine of mice and in human epithelium and T cells. Moreover, we report a protein interaction network of fecal S100A8 and S100A9 in IBD. Results Stool from patients with active IBD contained abundant S100A8 and S100A9 dimers besides CP. Fecal S100A9 detection associated with clinical and endoscopic disease activity in IBD patients with low CP concentration. Oral exposure to human recombinant S100A8 and S100A9 homodimers, but not to CP, worsened intestinal inflammation in toxic and genetic mouse models. Functional profiling revealed that human S100A8 and S100A9 homodimers enhanced activation of cluster of differentiation 4+ and 8+ T cells, which promoted experimental colitis. In turn, genetic inactivation of S100a9 protected against experimental enteritis and colitis, and pharmacologic inhibition of S100A9 ameliorated chronic colitis. Conclusions Collectively, this study links the detection of fecal S100A9 dimers with clinical and endoscopic disease activity in IBD and identifies inflammatory actions of S100A8 and S100A9 homodimers in the intestine. Our findings pave the way for novel diagnostic and therapeutic approaches in patients with inflammatory diseases of the intestine.

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω 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-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7–9,196.6]) than for auto-Abs neutralizing IFN-ω 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-ω and/or IFN-α2.

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.

The human’s heart responds to tissue damage with persistent fibrotic scarring. Unlike humans, zebrafish exhibit the ability to repair cardiac injury and re-grow heart tissue throughout life. Here, we provide novel evidence for toll-like receptor 3 (tlr3) driving cardiac regeneration in zebrafish. Upon cardiac injury, survival is decreased in tlr3-/- fish as compared to wildtype controls. Tlr3-/- zebrafish fail to recruit innate immune cells to the injured ventricle, resulting in impaired DNA repair and transcriptional reprogramming of cardiomyocytes. Mechanistically, we uncover an evolutionary conserved mechanism of tlr3 activation in fibroblasts promoting monocyte migration towards an injured ventricular area. Our data reveal tlr3 as a novel therapeutic target to promote cardiac regeneration.

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.

We have read with interest the recent article comparing different therapies in induction and maintenance of remission in Crohn’s disease (CD). Recently, Janus kinase (JAK) inhibitors have expanded the armamentarium to treat inflammatory bowel diseases (IBD), while patienttailored precision approaches are needed to further improve treatment. Rare gainoffunction variants affecting signal transducer and activator of transcription 1 (STAT1), a transcription factor activated by JAKs, have been linked with susceptibility to infection, immunodeficiency and immune dysregulation, 5 while some cases develop IBD. A 33yearold patient was referred to our tertiary care centre in poor condition. He presented a body mass index (BMI) of 12.9 kg/m, refractory fever up to 39.5°C and abdominal pain with watery diarrhoea 15 times per day for 3 months. He reported recurrent respiratory infections since childhood, which probably caused diffuse varicose bronchiectasis with mucus plugging diagnosed at the age of 23, requiring repeated antibiotic therapy, and a clinical history that was compatible with primary immunodeficiency as further detailed in the online supplemental file. At the age of 28, he reported the first episode of severe chronic diarrhoea and abdominal pain and was diagnosed with CD, as endoscopy indicated ileitis and pancolitis. Stool and mucosal biopsies were repeatedly tested for infections, but no pathogen was detected, and no other autoinflammatory disease was diagnosed. At admission, he presented elevated inflammatory parameters in the serum (C reactive protein, CRP 19.43 mg/dL) and stool (faecal calprotectin 2221.6 μg/g) (table 1). Pseudomonas aeruginosa and Mycobacterium chimaera were cultured from sputum, despite several antiinfective therapies before referral. Immunophenotyping documented adequate vaccination responses, but low abundance of lymphocytes (table 1). Colonoscopy revealed severe large discontinuous punchedout ulcers throughout the colon and ileitis, which appeared untypical for CD (figure 1A). Histology revealed a frank ulceration and dense discontinuous lymphocyte infiltration with lymphoid aggregates (figure 1B). Trio exome sequencing identified a heterozygous de novo missense variant c.1256C>G in the STAT1 gene (NM_007315.4), which was previously associated with a gainoffunction and described in two individuals from one family. 7 Indeed, peripheral blood mononuclear cells (PBMCs) from the patient exhibited increased phosphorylation of STAT1 (figure 1C), similar to T cells in the mucosa (online supplemental figure S1A) and bloodderived granulocytes and Thelper cells (online supplemental figure S1B). Moreover, increased activation and proliferation of T cells (online supplemental figure S1C, D) and expression of IFN-γ-induced and Th17related genes (figure 1D,E) were observed. In vitro, STAT1 signalling could be reduced by stimulation with JAK inhibitors (figure 1C–E and online supplemental figure S1B–D). We diagnosed primary immunodeficiency caused by STAT1 gainoffunction (STAT1 gainoffunction disease) and offered the patient tofacitinib therapy, despite risk of serious infection. We initiated tofacitinib 10 mg two times per day with reduction to 5 mg after 8 weeks, combined with antibiotic treatment for pulmonary infection and parenteral nutrition. After 2 weeks of treatment, the patient reported clinical remission and after 12 weeks his general appearance had substantially improved. He presented a BMI of 17.9 kg/m and reported no abdominal symptoms. Colonoscopy revealed mucosal healing with few small ulcers limited to the rectum (figure 1A), which was confirmed by histology (figure 1B) and a reduction in faecal calprotectin (300.6 μg/g) (table 1). Indeed, immunophenotyping indicated a reduction of STAT1 phosphorylation Letter

ObjectiveLipomatous hypertrophy of the interatrial septum (LHIS) is a distinct section of epicardial adipose tissue. However, its association with COPD is poorly documented.MethodsPatients undergoing coronary computed tomography angiography (CTA) for clinical indications were recruited retrospectively and screened for LHIS and COPD. LHIS density and the coronary artery disease profile were quantified by CTA: stenosis severity (coronary artery disease radiological reporting system (CADRADS)), coronary artery calcium (CAC) and high-risk plaque (HRP). COPD patients with LHIS were matched for age and sex, the major cardiovascular risk factors (CVRFs), and compared to controls.ResultsThe prevalence of LHIS in all 5466 patients was 5.9%. 151 (72.6%) of 208 patients with COPD had LHIS. LHIS density in COPD patients was higher (−10.93 HUversus−21.1 HU; p<0.001), despite body mass index (BMI) (28.8versus27.01 kg·m−2; p=0.002) being lower. LHIS density was lower in obese (BMI >30 kg·m−2) patients (20.4versus13.6 HU; p=0.02). BMI was inversely correlated with LHIS density (BetaR −0.031; 95% CI: −0.054– −0.008; p=0.007). LHIS density was associated with COPD, but not with BMI on multivariate models. CAC and coronary stenosis severity (CADRADS and >50% stenosis) were not different (p=0.106, p=0.156 and p=0.350, respectively). HRPs were observed more frequently in COPD patients with severe Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages ≥2 (32.3%versus20.1%; p=0.044), but not when adding mild GOLD stages.ConclusionsThe prevalence of LHIS in COPD patients is high (72.6%), and the adipose tissue density is higher, indicating a higher brown fat component. In obese, patients LHIS density is lower and declines along with BMI. Coronary stenosis severity and calcium were not different; however HRPs were more frequent in severe COPD.

The incidence, presentation, and predisposing factors of post-acute sequelae of COVID-19 (PASC) are currently poorly understood. Lung explants may provide a rare insight into terminal SARS-CoV-2-associated lung damage and its pathophysiology. A 62-year-old man presented with progressively worsening respiratory symptoms after recovering from mild COVID-19 3 months earlier. No underlying pulmonary comorbidities were reported. A chest CT revealed bilateral extensive ground-glass and reticular opacities, suspicious of pulmonary fibrosis. Despite initial high-dose glucocorticoid therapy, the interstitial lung disease progressed, and after exhausting all viable therapeutic options, bilateral lung transplantation was successfully conducted. Histological analysis revealed extensive end-stage interstitial fibrosis with diffuse dendriform ossification and bronchiolar and transitional cell metaplasia. Signs of interstitial remodeling such as an increased interstitial collagen deposition, a pathological accumulation of CD163+/CD206+ M2-polarized macrophages with an increased expression of phosphorylated ERK, and an increased density of CD105+ newly formed capillaries were observed. qRT-PCR and immunohistochemistry for SARS-CoV-2 N-protein in the endothelium of medium-sized vessels confirmed a persistence of SARS-CoV-2. Our findings highlight a highly unusual presentation of SARS-CoV-2-associated lung fibrosis, implying that incomplete viral clearance in the vascular compartment may play a vital pathophysiological role in the development of PASC.

OBJECTIVE:Subjective illness perception (IP) can differ from physician's clinical assessment results. Herein, we explored patient's IP during coronavirus disease 2019 (COVID-19) recovery. METHODS:Participants of the prospective observation CovILD study (ClinicalTrials.gov: NCT04416100) with persistent somatic symptoms or cardiopulmonary findings one year after COVID-19 were analyzed (n = 74). Explanatory variables included demographic and comorbidity, COVID-19 course and one-year follow-up data of persistent somatic symptoms, physical performance, lung function testing, chest computed tomography and trans-thoracic echocardiography. Factors affecting IP (Brief Illness Perception Questionnaire) one year after COVID-19 were identified by regularized modeling and unsupervised clustering. RESULTS:In modeling, 33% of overall IP variance (R2) was attributed to fatigue intensity, reduced physical performance and persistent somatic symptom count. Overall IP was largely independent of lung and heart findings revealed by imaging and function testing. In clustering, persistent somatic symptom count (Kruskal-Wallis test: η2 = 0.31, p < .001), fatigue (η2 = 0.34, p < .001), diminished physical performance (χ2 test, Cramer V effect size statistic: V = 0.51, p < .001), dyspnea (V = 0.37, p = .006), hair loss (V = 0.57, p < .001) and sleep problems (V = 0.36, p = .008) were strongly associated with the concern, emotional representation, complaints, disease timeline and consequences IP dimensions. CONCLUSION:Persistent somatic symptoms rather than abnormalities in cardiopulmonary testing influence IP one year after COVID-19. Modifying IP represents a promising innovative approach to treatment of post-COVID-19 condition. Besides COVID-19 severity, individual IP should guide rehabilitation and psychological therapy decisions.

Life-threatening "breakthrough" cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab 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 Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Background:Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism. Aim:This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence. Patients and methods:Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated. Results and conclusion:Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

Anemia of inflammation (AI) is frequently present in subjects with inflammatory disorders, primarily caused by inflammation-driven iron retention in macrophages. So far, only limited data on qualitative and quantitative estimates of tissue iron retention in AI patients exist. We performed a prospective cohort study analyzing splenic, hepatic, pancreatic, and cardiac iron content with MRI-based R2*-relaxometry in AI patients, including subjects with concomitant true iron deficiency (AI+IDA) hospitalized between 05/2020-01/2022. Control groups were individuals without inflammation. Spleen R2* values in AI patients with ferritin ≤200 μg/L (AI+IDA) were comparable with those found in controls. In AI patients with ferritin >200 μg/L, spleen (47.6 s-1 vs. 19.3 s-1 , p < .001) and pancreatic R2* values (32.5 s-1 vs. 24.9 s-1 , p = .011) were significantly higher compared with controls, while liver and heart R2*-values did not differ. Higher spleen R2* values were associated with higher ferritin, hepcidin, CRP, and IL-6 concentrations. Spleen R2* values normalized in AI patients after recovery (23.6 s-1 vs. 47.6 s-1 , p = .008), while no changes were found in patients with baseline AI+IDA. This is the first study investigating tissue iron distribution in patients with inflammatory anemia and AI with concomitant true iron deficiency. The results support the findings in animal models demonstrating iron retention in macrophages, which are primarily accumulating in the spleen under inflammatory conditions. MRI-related iron measurement may help to better characterize actual iron needs and to define better biomarker thresholds in the diagnosis of true ID in patients with AI. It may qualify as a useful diagnostic method to estimate the need for iron supplementation and to guide therapy.