Phenotyping of Acute and Persistent Coronavirus Disease 2019 Features in the Outpatient Setting: Exploratory Analysis of an International Cross-sectional Online Survey.

BACKGROUND: Long COVID, defined as the presence of coronavirus disease 2019 (COVID-19) symptoms ≥28 days after clinical onset, is an emerging challenge to healthcare systems. The objective of the current study was to explore recovery phenotypes in nonhospitalized individuals with COVID-19. METHODS: A dual cohort, online survey study was conducted between September 2020 and July 2021 in the neighboring European regions Tyrol (TY; Austria, n = 1157) and South Tyrol (STY; Italy, n = 893). Data were collected on demographics, comorbid conditions, COVID-19 symptoms, and recovery in adult outpatients. Phenotypes of acute COVID-19, postacute sequelae, and risk of protracted recovery were explored using semi-supervised clustering and multiparameter least absolute shrinkage and selection operator (LASSO) modeling. RESULTS: Participants in the study cohorts were predominantly working age (median age [interquartile range], 43 [31-53] years] for TY and 45 [35-55] years] for STY) and female (65.1% in TY and 68.3% in STY). Nearly half (47.6% in TY and 49.3% in STY) reported symptom persistence beyond 28 days. Two acute COVID-19 phenotypes were discerned: the nonspecific infection phenotype and the multiorgan phenotype (MOP). Acute MOP symptoms encompassing multiple neurological, cardiopulmonary, gastrointestinal, and dermatological symptoms were linked to elevated risk of protracted recovery. The major subset of individuals with long COVID (49.3% in TY; 55.6% in STY) displayed no persistent hyposmia or hypogeusia but high counts of postacute MOP symptoms and poor self-reported physical recovery. CONCLUSIONS: The results of our 2-cohort analysis delineated phenotypic diversity of acute and postacute COVID-19 manifestations in home-isolated patients, which must be considered in predicting protracted convalescence and allocating medical resources.

Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial.

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.

Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective observational cohort study.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) is frequently associated with hyperinflammation and hyperferritinemia. The latter is related to increased mortality in COVID-19. Still, it is not clear if iron dysmetabolism is mechanistically linked to COVID-19 pathobiology. METHODS: We herein present data from the ongoing prospective, multicentre, observational CovILD cohort study (ClinicalTrials.gov number, NCT04416100), which systematically follows up patients after COVID-19. 109 participants were evaluated 60 days after onset of first COVID-19 symptoms including clinical examination, chest computed tomography and laboratory testing. RESULTS: We investigated subjects with mild to critical COVID-19, of which the majority received hospital treatment. 60 days after disease onset, 30% of subjects still presented with iron deficiency and 9% had anemia, mostly categorized as anemia of inflammation. Anemic patients had increased levels of inflammation markers such as interleukin-6 and C-reactive protein and survived a more severe course of COVID-19. Hyperferritinemia was still present in 38% of all individuals and was more frequent in subjects with preceding severe or critical COVID-19. Analysis of the mRNA expression of peripheral blood mononuclear cells demonstrated a correlation of increased ferritin and cytokine mRNA expression in these patients. Finally, persisting hyperferritinemia was significantly associated with severe lung pathologies in computed tomography scans and a decreased performance status as compared to patients without hyperferritinemia. DISCUSSION: Alterations of iron homeostasis can persist for at least two months after the onset of COVID-19 and are closely associated with non-resolving lung pathologies and impaired physical performance. Determination of serum iron parameters may thus be a easy to access measure to monitor the resolution of COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04416100.

The Significance of iron deficiency and anemia in a real-life COPD cohort.

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.

Investigating phenotypes of pulmonary COVID-19 recovery: A longitudinal observational prospective multicenter trial.

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.

COPD exacerbations are related to poor air quality in Innsbruck: A retrospective pilot study.

BACKGROUND: Triggers of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are diverse, potentially including airborne pollutants. OBJECTIVES: To analyze whether daily air pollution levels correlate with AECOPD frequency. METHODS: In this retrospective pilot-study, AECOPD frequency was recorded between 2010 and 2016 at the University Hospital of Innsbruck's emergency department and correlated with daily air quality parameters. Data was compared to pulmonary embolism (PE) frequency, a disease not directly involving the airways. RESULTS: In total, 669 AECOPD and 857 PE events were registered. Days with AECOPD revealed significantly higher concentrations of CO and SO2, whereas days with PE displayed an elevation of NO. Higher frequencies of AECOPD during winter months correlated with higher CO and SO2 levels, disclosing a seasonal trend, while no such pattern was observed for PE. CONCLUSION: Air pollution is linked to AECOPD frequency, however, prospective studies are needed to confirm this possible, underrecognized trigger of AECOPD.

High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis.

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.

Impact of Vitamin D Deficiency on COVID-19-A Prospective Analysis from the CovILD Registry.

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.