Corrigendum: Post-COVID-19 interstitial lung disease: Insights from a machine learning radiographic model.

[This corrects the article DOI: 10.3389/fmed.2022.1083264.].

Reduced immunogenicity of the mRNA vaccine BNT162b2 in patients with idiopathic pulmonary fibrosis.

Patients with #IPF do not mount appreciable anti-spike antibody responses to two doses of #SARSCoV2 mRNA vaccine compared to the general population. National authorities should prioritise patients with IPF for booster doses. https://bit.ly/3K2KXQ0.

Post-COVID-19 interstitial lung disease: Insights from a machine learning radiographic model.

Introduction: Post-acute sequelae of COVID-19 seem to be an emerging global crisis. Machine learning radiographic models have great potential for meticulous evaluation of post-COVID-19 interstitial lung disease (ILD). Methods: In this multicenter, retrospective study, we included consecutive patients that had been evaluated 3 months following severe acute respiratory syndrome coronavirus 2 infection between 01/02/2021 and 12/5/2022. High-resolution computed tomography was evaluated through Imbio Lung Texture Analysis 2.1. Results: Two hundred thirty-two (n = 232) patients were analyzed. FVC% predicted was ≥80, between 60 and 79 and <60 in 74.2% (n = 172), 21.1% (n = 49), and 4.7% (n = 11) of the cohort, respectively. DLCO% predicted was ≥80, between 60 and 79 and <60 in 69.4% (n = 161), 15.5% (n = 36), and 15.1% (n = 35), respectively. Extent of ground glass opacities was ≥30% in 4.3% of patients (n = 10), between 5 and 29% in 48.7% of patients (n = 113) and <5% in 47.0% of patients (n = 109). The extent of reticulation was ≥30%, 5-29% and <5% in 1.3% (n = 3), 24.1% (n = 56), and 74.6% (n = 173) of the cohort, respectively. Patients (n = 13, 5.6%) with fibrotic lung disease and persistent functional impairment at the 6-month follow-up received antifibrotics and presented with an absolute change of +10.3 (p = 0.01) and +14.6 (p = 0.01) in FVC% predicted at 3 and 6 months after the initiation of antifibrotic. Conclusion: Post-COVID-19-ILD represents an emerging entity. A substantial minority of patients presents with fibrotic lung disease and might experience benefit from antifibrotic initiation at the time point that fibrotic-like changes are "immature." Machine learning radiographic models could be of major significance for accurate radiographic evaluation and subsequently for the guidance of therapeutic approaches.

Post-COVID-19 interstitial lung disease: Insights from a machine learning radiographic model

Introduction Post-acute sequelae of COVID-19 seem to be an emerging global crisis. Machine learning radiographic models have great potential for meticulous evaluation of post-COVID-19 interstitial lung disease (ILD). Methods In this multicenter, retrospective study, we included consecutive patients that had been evaluated 3 months following severe acute respiratory syndrome coronavirus 2 infection between 01/02/2021 and 12/5/2022. High-resolution computed tomography was evaluated through Imbio Lung Texture Analysis 2.1. Results Two hundred thirty-two (n = 232) patients were analyzed. FVC% predicted was ≥80, between 60 and 79 and <60 in 74.2% (n = 172), 21.1% (n = 49), and 4.7% (n = 11) of the cohort, respectively. DLCO% predicted was ≥80, between 60 and 79 and <60 in 69.4% (n = 161), 15.5% (n = 36), and 15.1% (n = 35), respectively. Extent of ground glass opacities was ≥30% in 4.3% of patients (n = 10), between 5 and 29% in 48.7% of patients (n = 113) and <5% in 47.0% of patients (n = 109). The extent of reticulation was ≥30%, 5–29% and <5% in 1.3% (n = 3), 24.1% (n = 56), and 74.6% (n = 173) of the cohort, respectively. Patients (n = 13, 5.6%) with fibrotic lung disease and persistent functional impairment at the 6-month follow-up received antifibrotics and presented with an absolute change of +10.3 (p = 0.01) and +14.6 (p = 0.01) in FVC% predicted at 3 and 6 months after the initiation of antifibrotic. Conclusion Post-COVID-19-ILD represents an emerging entity. A substantial minority of patients presents with fibrotic lung disease and might experience benefit from antifibrotic initiation at the time point that fibrotic-like changes are "immature.” Machine learning radiographic models could be of major significance for accurate radiographic evaluation and subsequently for the guidance of therapeutic approaches.

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial.

Background: The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. Methods: This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Findings: Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Interpretation: Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90. Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Corrigendum: ACTIVATE-2: A double-blind randomized trial of BCG vaccination against COVID-19 in individuals at risk.

[This corrects the article DOI: 10.3389/fimmu.2022.873067.].

Moderate COVID-19: Clinical Trajectories and Predictors of Progression and Outcomes.

BACKGROUND: Patients with COVID-19 commonly present at healthcare facilities with moderate disease, i.e., pneumonia without a need for oxygen therapy. AIM: To identify clinical/laboratory characteristics of patients with moderate COVID-19, which could predict disease progression. METHODS: 384 adult patients presented with moderate COVID-19 and admitted to two hospitals were retrospectively evaluated. In a multivariate analysis gender, age, BMI, Charlson Comorbidity Index (CCI) and National Early Weaning Score 2 were treated as co-variates. The development of hypoxemic respiratory failure, intubation rate and risk of death were considered as dependent variables. Estimated values are presented as odds-ratio (OR) with 95% confidence interval (CI). RESULTS: Most of the patients were male (63.28%) with a mean (standard deviation) age of 59 (16.04) years. Median (interquartile range) CCI was 2 (1-4). A total of 58.85% of the patients developed respiratory failure; 6.51% were intubated, and 8.85% died. The extent of pneumonia in chest X-ray (involvement of all four quartiles) [OR 3.96 (1.18-13.27), p = 0.026], respiratory rate [OR 1.17 (1.05-1.3), p = 0.004], SatO2 [OR 0.72 (0.58-0.88), p = 0.002], systolic blood pressure [OR 1.02 (1-1.04), p = 0.041] and lymphocyte count [OR 0.9993 (0.9986-0.9999), p = 0.026] at presentation were associated with the development of respiratory failure. The extent of pneumonia [OR 26.49 (1.81-387.18), p = 0.017] was associated with intubation risk. Age [OR 1.14 (1.03-1.26), p = 0.014] and the extent of pneumonia [OR 22.47 (1.59-316.97), p = 0.021] were associated with increased risk of death. CONCLUSION: Older age, the extent of pneumonia, tachypnea, lower SatO2, higher systolic blood pressure and lymphopenia are associated with dismal outcomes in patients presenting with moderate COVID-19.

ACTIVATE-2: A Double-Blind Randomized Trial of BCG Vaccination Against COVID-19 in Individuals at Risk.

In a recent study of our group with the acronym ACTIVATE, Bacillus Calmete-Guérin (BCG) vaccination reduced the occurrence of new infections compared to placebo vaccination in the elderly. Most benefit was found for respiratory infections. The ACTIVATE-2 study was launched to assess the efficacy of BCG vaccination against coronavirus disease 2019 (COVID-19). In this multicenter, double-blind trial, 301 volunteers aged 50 years or older were randomized (1:1) to be vaccinated with BCG or placebo. The trial end points were the incidence of COVID-19 and the presence of anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies, which were both evaluated through 6 months after study intervention. Results revealed 68% relative reduction of the risk to develop COVID-19, using clinical criteria or/and laboratory diagnosis, in the group of BCG vaccine recipients compared with placebo-vaccinated controls, during a 6-month follow-up (OR 0.32, 95% CI 0.13-0.79). In total, eight patients were in need of hospitalization for COVID-19: six in the placebo group and two in the BCG group. Three months after study intervention, positive anti-SARS-CoV-2 antibodies were noted in 1.3% of volunteers in the placebo group and in 4.7% of participants in BCG-vaccinated group. These data indicate that BCG vaccination confers some protection against possible COVID-19 among patients older than 50 years with comorbidities. BCG vaccination may be a promising approach against the COVID-19 pandemic.

Predictors of Mortality in Tocilizumab-Treated Severe COVID-19.

PURPOSE: Tocilizumab is associated with positive outcomes in severe COVID-19. We wanted to describe the characteristics of nonresponders to treatment. METHODS: This was a retrospective multicenter study in two respiratory departments investigating adverse outcomes at 90 days from diagnosis in subjects treated with tocilizumab (8 mg/kg intravenously single dose) for severe progressive COVID-19. RESULTS: Of 121 subjects, 62% were males, and 9% were fully vaccinated. Ninety-six (79.4%) survived, and 25 died (20.6%). Compared to survivors (S), nonsurvivors (NS) were older (median 57 versus 75 years of age), had more comorbidities (Charlson comorbidity index 2 versus 5) and had higher rates of intubation/mechanical ventilation (p < 0.05). On admission, NS had a lower PO2/FiO2 ratio, higher blood ferritin, and higher troponin, and on clinical progression (day of tocilizumab treatment), NS had a lower PO2/FiO2 ratio, decreased lymphocytes, increased neutrophil to lymphocyte ratio, increased ferritin and lactate dehydrogenase (LDH), disease located centrally on computed tomography scan, and increased late c-reactive protein. Cox proportional hazards regression analysis identified age and LDH on deterioration as predictors of death; admission PO2/FiO2 ratio and LDH as predictors of intubation; PO2/FiO2 ratios, LDH, and central lung disease on radiology as predictors of noninvasive ventilation (NIV) (a < 0.05). The log-rank test of mortality yielded the same results (p < 0.001). ROC analysis of the above predictors in a separate validation cohort yielded significant results. CONCLUSIONS: Older age and high serum LDH levels are predictors of mortality in tocilizumab-treated severe COVID-19 patients. Hypoxia levels, LDH, and central pulmonary involvement radiologically are associated with intubation and NIV.

SARS-Cov-2 Infection in Severe Asthma Patients Treated With Biologics.

BACKGROUND: At the beginning of the pandemic, there have been considerable concerns regarding coronavirus disease 2019 (COVID-19) severity and outcomes in patients with severe asthma treated with biologics. OBJECTIVE: To prospectively observe a cohort of severe asthmatics treated with biologics for the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and disease severity during the COVID-19 pandemic. METHODS: Physicians from centers treating patients with severe asthma all over Greece provided demographic and medical data regarding their patients treated with biologics. Physicians were also asked to follow up patients during the pandemic and to perform a polymerase chain reaction test in case of a suspected SARS-Cov-2 infection. RESULTS: Among the 591 severe asthmatics (63.5% female) included in the study, 219 (37.1%) were treated with omalizumab, 358 (60.6%) with mepolizumab, and 14 (2.4%) with benralizumab. In total, 26 patients (4.4%) had a confirmed SARS-CoV-2 infection, 9 (34.6%) of whom were admitted to the hospital because of severe COVID-19, and 1 required mechanical ventilation and died 19 days after admission. Of the 26 infected patients, 5 (19.2%) experienced asthma control deterioration, characterized as exacerbation that required treatment with systemic corticosteroids. The scheduled administration of the biological therapy was performed timely in all patients with the exception of 2, in whom it was postponed for 1 week according to their doctors' suggestion. CONCLUSION: Our study confirms that despite the initial concerns, SARS-CoV-2 infection is not more common in asthmatics treated with biologics compared with the general population, whereas the use of biologic treatments for severe asthma during the COVID-19 pandemic does not seem to be related to adverse outcomes from severe COVID-19.

Reduced immunogenicity of the mRNA vaccine BNT162b2 in patients with IPF

The emergence and spread of 2019 coronavirus disease (COVID-19) are causing a growing global public health crisis. Despite advances in treatment, vaccination remains the best way to contain the pandemic [1]. Vaccines are currently available by means of conditional marketing approval, full approval and emergency use authorization pathways [2]. Evidence suggest that immunocompromised individuals including solid organ transplants recipients and patients under immunosuppressive treatment may have increased mortality from SARS-CoV-2 infection despite double dose messenger RNA (mRNA) vaccine regimens [3]. This is partially attributed to blunted immune responses to vaccination since only 38–54% of kidney and liver transplant recipients developed detectable SARS-CoV-2 antibodies following the second dose of mRNA vaccines [3, 4].

Intensive-Dose Tinzaparin in Hospitalized COVID-19 Patients: The INTERACT Study.

(1) Background: It is well-established that coronavirus disease-2019 (COVID-19) is highly pro-inflammatory, leading to activation of the coagulation cascade. COVID-19-induced hypercoagulability is associated with adverse outcomes and mortality. Current guidelines recommend that hospitalized COVID-19 patients should receive pharmacological prophylaxis against venous thromboembolism (VTE). (2) INTERACT is a retrospective, phase IV, observational cohort study aiming to evaluate the overall clinical effectiveness and safety of a higher than conventionally used prophylactic dose of anticoagulation with tinzaparin administered for VTE prevention in non-critically ill COVID-19 patients with moderate disease severity. (3) Results: A total of 705 patients from 13 hospitals in Greece participated in the study (55% men, median age 62 years). Anticoagulation with tinzaparin was initiated immediately after admission. A full therapeutic dose was received by 36.3% of the participants (mean ± SD 166 ± 33 IU/Kgr/day) and the remaining patients (63.9%) received an intermediate dose (mean ± SD 114 ± 22 IU/Kgr/day). The median treatment duration was 13 days (Q1-Q3: 8-20 days). During the study (April 2020 to November 2021), 14 thrombotic events (2.0%) were diagnosed (i.e., three cases of pulmonary embolism (PE) and 11 cases of deep venous thrombosis, DVT). Four bleeding events were recorded (0.6%). In-hospital death occurred in 12 patients (1.7%). Thrombosis was associated with increasing age (median: 74.5 years, Q1-Q3: 62-79, for patients with thrombosis vs. 61.9 years, Q1-Q3: 49-72, p = 0.0149), increased D-dimer levels for all three evaluation time points (at admission: 2490, Q1-Q3: 1580-6480 vs. 700, Q1-Q3: 400-1475, p < 0.0001), one week ± two days after admission (3510, Q1-Q3: 1458-9500 vs. 619, Q1-Q3: 352-1054.5, p < 0.0001), as well as upon discharge (1618.5, Q1-Q3: 1010-2255 vs. 500, Q1-Q3: 294-918, p < 0.0001). Clinical and laboratory improvement was affirmed by decreasing D-dimer and CRP levels, increasing platelet numbers and oxygen saturation measurements, and a drop in the World Health Organization (WHO) progression scale. (4) Conclusions: The findings of our study are in favor of prophylactic anticoagulation with an intermediate to full therapeutic dose of tinzaparin among non-critically ill patients hospitalized with COVID-19.

Development and validation of SCOPE score: A clinical score to predict COVID-19 pneumonia progression to severe respiratory failure.

Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but many develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from circulating concentrations of C-reactive protein, D- dimers, interleukin-6, and ferritin among patients not receiving non-invasive or invasive mechanical ventilation during the SAVE-MORE study, offers predictive accuracy for progression to SRF or death within 14 days comparable to that of a suPAR concentration of ≥6 ng/mL (area under receiver operator characteristic curve 0.81 for both). The SCOPE score is validated in two similar independent cohorts. A SCOPE score of 6 or more is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.

Outpatient Management of COVID-19 Disease: A Holistic Patient-Centered Proposal Based on the Greek Experience.

Novel coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic and affected more than 227 countries or territories, resulting in more than 179 million cases with over 3.890.00 deaths, as of June 25, 2021. The Hellenic Thoracic Society (HTS) during the second wave of COVID-19 pandemic released a guidance document for the management of patients with COVID-19 in the community and in hospital setting. In this review, with guidance the HTS document, we are discussing the outpatient management of COVID-19 patients, including the preventive measures, the patients' isolation and quarantine criteria of close contacts, the severity and risk stratification, including the decisions for advanced hospitalization, and the disease management at home in patients with mild disease and after hospital discharge for those with more severe disease.

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.

Reduction in Hospitalizations for Respiratory Diseases during the First COVID-19 Wave in Greece.

INTRODUCTION: During the first COVID-19 wave, a considerable decline in hospital admissions was observed worldwide. AIM: This retrospective cohort study aimed to assess if there were any changes in the number of patients hospitalized for respiratory diseases in Greece during the first CO-VID-19 wave. METHODS: In the present study, we evaluated respiratory disease hospitalization rates across 9 tertiary hospitals in Greece during the study period (March-April 2020) and the corresponding period of the 2 previous years (2018-2019) that served as the control periods. Demographic data and discharge diagnosis were documented for every patient. RESULTS: Of the 1,307 patients who were hospitalized during the study period, 444 (35.5%) were males with a mean (±SD) age of 66.1 ± 16.6 years. There was a 47 and 46% reduction in all-cause respiratory morbidity compared to the corresponding periods of 2018 and 2019, respectively. The mean incidence rate for respiratory diseases during the study period was 21.4 admissions per day, and this rate was significantly lower than the rate during the same period in 2018 (40.8 admissions per day; incidence rate ratio [IRR], 0.525; 95% confidence interval [CI], 0.491-0.562; p < 0.001) or the rate during 2019 (39.9 admissions per day; IRR, 0.537; 95% CI, 0.502-0.574; p < 0.001). The greatest reductions (%) in the number of daily admissions in 2020 were observed for sleep apnoea (87% vs. 2018 and 84% vs. 2019) followed by admissions for asthma (76% vs. 2018 and 79% vs. 2019) and chronic obstructive pulmonary disease (60% vs. 2018 and 51% vs. 2019), while the lowest reductions were detected in hospitalizations for pulmonary embolism (6% vs. 2018 and 23% vs. 2019) followed by tuberculosis (25% vs. both 2018 and 2019). DISCUSSION/CONCLUSION: The significant reduction in respiratory admissions in 2020 raises the reasonable question of whether some patients may have avoided seeking medical attention during the COVID-19 pandemic and suggests an urgent need for transformation of healthcare systems during the pandemic to offer appropriate management of respiratory diseases other than COVID-19.