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Background: The complement system, an upstream recognition system of innate immunity, is activated upon SARS‐CoV‐2 infection. To gain a deeper understanding of the extent and duration of this activation, we investigated complement activation profiles during the acute phase of COVID‐19, its persistence post‐recovery and dynamic changes in relation to disease severity. Methods: Serial blood samples were obtained from two cohorts of hospitalized COVID‐19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3–5 and days 7–10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60‐day total mortality and pulmonary pathology after 3 months. Findings: During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID‐19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60‐day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls. Conclusion: Hospitalized COVID‐19 patients display prominent and long‐lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in‐hospital changes of complement activation products. [ABSTRACT FROM AUTHOR]

Objectives: To investigate temporal changes in the association between SARS‐CoV2 viral load (VL) and markers of inflammation during hospitalization, as well as the ability of these markers alone or in combination to predict severe outcomes. Methods: Serial oropharyngeal and blood samples were obtained from hospitalized COVID‐19 patients (n = 160). Levels of inflammatory markers and oropharyngeal VL were measured during hospitalization (admission, days 3–5, and days 7–10) and related to severe outcomes (respiratory failure/intensive care unit admission). Results: Elevated admission levels of IL (interleukin)‐6, IL‐33, IL‐8, monocyte chemoattractant protein‐1 (MCP‐1), interferon‐γ‐induced protein 10 (IP‐10), IL‐1β, and IL‐1Ra were associated with severe outcomes during hospitalization. Although no inflammatory markers correlated with VL at baseline, there was a significant correlation between VL and levels of IP‐10 and MCP‐1 at days 3–5, accompanied by IL‐8 and IL‐6 at days 7–10. Finally, there was a seemingly additive effect of IP‐10, MCP‐1, and IL‐6 in predicting severe outcomes when combined with high VL at baseline. Conclusions: An increasing number of inflammatory markers were associated with VL during the first 10 days of hospitalization, and several of these markers were associated with severe outcomes, in particular when combined with elevated VL. Future studies should assess the potential for combining antiviral and immunomodulatory treatment, preferably guided by viral and inflammatory biomarkers, for the selection of high‐risk patients. [ABSTRACT FROM AUTHOR]

Objectives: To investigate changes in chest CT between 3 and 12 months and associations with disease severity in patients hospitalized for COVID-19 during the first wave in 2020. Materials and methods: Longitudinal cohort study of patients hospitalized for COVID-19 in 2020. Chest CT was performed 3 and 12 months after admission. CT images were evaluated using a CT severity score (CSS) (0–12 scale) and recoded to an abbreviated version (0–3 scale). We analyzed determinants of the abbreviated CSS with multivariable mixed effects ordinal regression. Results: 242 patients completed CT at 3 months, and 124 (mean age 62.3±13.3, 78 men) also at 12 months. Between 3 and 12 months (n = 124) CSS (0–12 scale) for ground-glass opacities (GGO) decreased from median 3 (25th–75th percentile: 0–12) at 3 months to 0.5 (0–12) at 12 months (p<0.001), but increased for parenchymal bands (p<0.001). In multivariable analysis of GGO, the odds ratio for more severe abbreviated CSS (0–3 scale) at 12 months was 0.11 (95%CI 0.11 0.05 to 0.21, p<0.001) compared to 3 months, for WHO severity category 5–7 (high-flow oxygen/non-invasive ventilation/ventilator) versus 3 (non-oxygen use) 37.16 (1.18 to 43.47, p = 0.032), and for age ≥60 compared to <60 years 4.8 (1.33 to 17.6, p = 0.016). Mosaicism was reduced at 12 compared to 3 months, OR 0.33 (95%CI 0.16 to 0.66, p = 0.002). Conclusions: GGO and mosaicism decreased, while parenchymal bands increased from 3 to 12 months. Persistent GGO were associated with initial COVID-19 severity and age ≥60 years. [ABSTRACT FROM AUTHOR]

Background: Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID‐19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID‐19, we examined circulating levels of mediators involved in various aspects of these processes in COVID‐19 patients. Methods: Serial blood samples were obtained from two cohorts of hospitalised COVID‐19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3‐month follow‐up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60‐day total mortality and pulmonary pathology after 3‐months. We also evaluated the direct effect of inactivated SARS‐CoV‐2 on the release of the different ECM mediators in relevant cell lines. Results: Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium‐binding protein A12 and YKL‐40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3‐months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS‐CoV‐2 suggesting a direct link between these mediators and the causal agent of COVID‐19. Conclusion: Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL‐40 in the pathogenesis of severe COVID‐19. [ABSTRACT FROM AUTHOR]

COVID-19 primarily affects the respiratory system. We aimed to evaluate how pulmonary outcomes develop after COVID-19 by assessing participants from the first pandemic wave prospectively 3 and 12 months following hospital discharge. Pulmonary outcomes included self-reported dyspnoea assessed with the modified Medical Research Council dyspnoea scale, 6-min walk distance (6MWD), spirometry, diffusing capacity of the lung for carbon monoxide ( D LCO ), body plethysmography and chest computed tomography (CT). Chest CT was repeated at 12 months in participants with pathological findings at 3 months. The World Health Organization (WHO) ordinal scale for clinical improvement defined disease severity in the acute phase. Of 262 included COVID-19 patients, 245 (94%) and 222 (90%) participants attended the 3- and 12-month follow-up, respectively. Self-reported dyspnoea and 6MWD remained unchanged between the two time points, while D LCO and total lung capacity improved (0.28 mmol·min -1 ·kPa -1 , 95% CI 0.12-0.44, and 0.13 L, 95% CI 0.02-0.24, respectively). The prevalence of fibrotic-like findings on chest CT at 3 and 12 months in those with follow-up chest CT was unaltered. Those with more severe disease had worse dyspnoea, D LCO and total lung capacity values than those with mild disease. There was an overall positive development of pulmonary outcomes from 3 to 12 months after hospital discharge. The discrepancy between the unaltered prevalence of self-reported dyspnoea and the improvement in pulmonary function underscores the complexity of dyspnoea as a prominent factor of long-COVID. The lack of increase in fibrotic-like findings from 3 to 12 months suggests that SARS-CoV-2 does not induce a progressive fibrotic process in the lungs., Competing Interests: Conflict of interest: T.V. Lerum has nothing to disclose. Conflict of interest: C. Meltzer has nothing to disclose. Conflict of interest: J.R. Rodriguez has nothing to disclose. Conflict of interest: T.M. Aaløkken has nothing to disclose. Conflict of interest: E. Brønstad has nothing to disclose. Conflict of interest: B.B. Aarli reports personal fees for lectures and advisory board work from AstraZeneca, personal fees for lectures from GlaxoSmithKline, Novartis, Boehringer Ingelheim and Chiesi Pharma, outside the submitted work. Conflict of interest: K.M. Aarberg-Lund has nothing to disclose. Conflict of interest: M.T. Durheim reports grants to his institution and personal fees from Boehringer Ingelheim and Roche, and personal fees from AstraZeneca, outside the submitted work. Conflict of interest: H. Ashraf reports grants from Boehringer Ingelheim, during the conduct of the study. Conflict of interest: G. Einvik reports grants from Boehringer Ingelheim, during the conduct of the study; and personal fees for consultancy from AstraZeneca AB, outside the submitted work. Conflicts of interest: O.H. Skjønsberg has nothing to disclose. Conflict of interest: K. Stavem reports fees from UCB Pharma and MSD, outside the submitted work., (Copyright ©The authors 2023.)

Rationale: To describe cardiopulmonary function during exercise 12 months after hospital discharge for coronavirus disease 2019 (COVID-19), assess the change from 3 to 12 months, and compare the results with matched controls without COVID-19., Methods: In this prospective, longitudinal, multicentre cohort study, hospitalised COVID-19 patients were examined using a cardiopulmonary exercise test (CPET) 3 and 12 months after discharge. At 3 months, 180 performed a successful CPET, and 177 did so at 12 months (mean age 59.3 years, 85 females). The COVID-19 patients were compared with controls without COVID-19 matched for age, sex, body mass index and comorbidity. Main outcome was peak oxygen uptake ( V ' O 2  peak )., Results: Exercise intolerance ( V ' O 2  peak <80% predicted) was observed in 23% of patients at 12 months, related to circulatory (28%), ventilatory (17%) and other limitations including deconditioning and dysfunctional breathing (55%). Estimated mean difference between 3 and 12 months showed significant increases in V ' O 2  peak % pred (5.0 percentage points (pp), 95% CI 3.1-6.9 pp; p<0.001), V ' O 2  peak ·kg -1 % pred (3.4 pp, 95% CI 1.6-5.1 pp; p<0.001) and oxygen pulse % pred (4.6 pp, 95% CI 2.5-6.8 pp; p<0.001). V ' O 2  peak was 2440 mL·min -1 in COVID-19 patients compared to 2972 mL·min -1 in matched controls., Conclusions: 1 year after hospital discharge for COVID-19, the majority (77%), had normal exercise capacity. Only every fourth had exercise intolerance and in these circulatory limiting factors were more common than ventilator factors. Deconditioning was common. V ' O 2  peak and oxygen pulse improved significantly from 3 months., Competing Interests: Conflict of interest: C.B. Ingul has received lecture fees from Bayer AS, unrelated to the current study. I. Skjørten has provided lectures for doctors’ education paid by Norwegian Directorate of Health and Norwegian Medical Association. G. Einvik has received research grants from AstraZeneca to perform the current study. A. Edvardsen has received payment or honoraria for lectures, presentations or educational events from GlaxoSmithKline and Chiesi. K. Stavem has received consulting fees from UCB Pharma and MSD, unrelated to the present study. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients., Methods: Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms., Results: A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up., Conclusions: Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19., Clinical Trials Registration: NCT04321616 and NCT04381819., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown., Methods: Plasma was collected during hospital admission and after 3 months from the NOR-Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DL CO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene., Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DL CO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO 2 /fiO 2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low-grade inflammation and respiratory dysfunction after 3 months., Conclusion: Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID., (© 2022 The Association for the Publication of the Journal of Internal Medicine.)

The long-term pulmonary outcomes of coronavirus disease 2019 (COVID-19) are unknown. We aimed to describe self-reported dyspnoea, quality of life, pulmonary function and chest computed tomography (CT) findings 3 months following hospital admission for COVID-19. We hypothesised outcomes to be inferior for patients admitted to intensive care units (ICUs), compared with non-ICU patients.Discharged COVID-19 patients from six Norwegian hospitals were enrolled consecutively in a prospective cohort study. The current report describes the first 103 participants, including 15 ICU patients. The modified Medical Research Council (mMRC) dyspnoea scale, the EuroQol Group's questionnaire, spirometry, diffusing capacity of the lung for carbon monoxide ( D LCO ), 6-min walk test, pulse oximetry and low-dose CT scan were performed 3 months after discharge.mMRC score was >0 in 54% and >1 in 19% of the participants. The median (25th-75th percentile) forced vital capacity and forced expiratory volume in 1 s were 94% (76-121%) and 92% (84-106%) of predicted, respectively. D LCO was below the lower limit of normal in 24% of participants. Ground-glass opacities (GGO) with >10% distribution in at least one of four pulmonary zones were present in 25% of participants, while 19% had parenchymal bands on chest CT. ICU survivors had similar dyspnoea scores and pulmonary function as non-ICU patients, but higher prevalence of GGO (adjusted OR 4.2, 95% CI 1.1-15.6) and lower performance in usual activities.3 months after admission for COVID-19, one-fourth of the participants had chest CT opacities and reduced diffusing capacity. Admission to ICU was associated with pathological CT findings. This was not reflected in increased dyspnoea or impaired lung function., Competing Interests: Conflict of interest: T.V. Lerum has nothing to disclose. Conflict of interest: T.M. Aaløkken has nothing to disclose. Conflict of interest: E. Brønstad has nothing to disclose. Conflict of interest: B. Aarli reports personal fees for lectures and advisory board work from AstraZeneca, personal fees for lectures from GlaxoSmithKline, Novartis, Boehringer Ingelheim and Chiesi Pharma, outside the submitted work. Conflict of interest: E. Ikdahl has nothing to disclose. Conflict of interest: K.M.A. Lund has nothing to disclose. Conflict of interest: M.T. Durheim reports grants and personal fees from Boehringer Ingelheim, personal fees from Roche and AstraZeneca, outside the submitted work. Conflict of interest: J.R. Rodriguez has nothing to disclose. Conflict of interest: C. Meltzer has nothing to disclose. Conflict of interest: K. Tonby has nothing to disclose. Conflict of interest: K. Stavem has nothing to disclose. Conflict of interest: O.H. Skjønsberg has nothing to disclose. Conflict of interest: H. Ashraf reports grants from Boehringer Ingelheim, during the conduct of the study. Conflict of interest: G. Einvik reports grants from Boehringer Ingelheim, during the conduct of the study; personal fees for consultancy from AstraZeneca AB, outside the submitted work., (Copyright ©ERS 2021.)