preVIEW: COVID-19

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MeSH Disease

Pneumonia (70)

COVID-19 (69)

Inflammation (21)

Death (16)

Coronavirus Infections (12)


HGNC Genes

interleukin 6 (70)

C-reactive protein (12)

tumor necrosis factor (8)

interleukin 6 receptor (5)

C-X-C motif chemokine ligand 8 (5)


SARS-CoV-2 proteins

NSP5 (1)


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    CERC-002, a human anti-LIGHT mAb reduces respiratory failure MESHD and death MESHD in hospitalized COVID-19 MESHD ARDS MESHD patients

    Authors: David S. Perlin; Garry A. Neil; Colleen Anderson; Inbal Zafir-Lavie; Lori Roadcap; Shane Raines; Carl Ware; Jeffrey Wilkins

    doi:10.1101/2021.04.03.21254748 Date: 2021-04-07 Source: medRxiv

    Background Severe COVID-19 MESHD infection is associated with dysregulated MESHD immune response which, in a substantial minority of patients, results in cytokine release syndrome ( CRS MESHD) and acute respiratory distress syndrome MESHD ( ARDS MESHD). Inhibition of cytokines or cytokine-associated signal transduction is a promising strategy to ameliorate ARDS MESHD associated with CRS. We and others have previously shown that serum free LIGHT ( TNFSF14 HGNC) levels are markedly elevated in patients with COVID-19 MESHD pneumonia MESHD/ARDS10,11, suggesting that LIGHT neutralization may offer therapeutic benefit to COVID-19 MESHD ARDS MESHD patients. Methods We conducted a randomized, double-blind, placebo-controlled, multi-center, proof-of-concept clinical trial of CERC-002 in adults with mild to moderate ARDS MESHD associated with COVID-19 MESHD (n=83). Enrolled patients received a single dose of CERC-002 or placebo, in addition to standard of care that included high dose corticosteroids. The primary efficacy endpoint was alive and free of respiratory failure MESHD status through Day 28. Secondary outcomes included alive status at Day 28, free of invasive ventilation through Day 28, and serum free LIGHT levels. Results In patients hospitalized with COVID-19 MESHD associated pneumonia MESHD and mild to moderate ( ARDS MESHD), CERC-002 increased the rate of alive and free of respiratory failure MESHD status through Day 28 as compared to placebo (83.9% vs 64.5%; p=0.044). Efficacy was highest in the prespecified subgroup of patients 60 years old and older (76.5% vs 47.1%; p=0.042), the population most vulnerable to severe complications and death MESHD with COVID-19 MESHD infection. Through both the initial 28-day and 60-day follow-up periods, reductions of approximately 50% in mortality were observed for CERC-002 compared to placebo (7.7% vs 14.3% at Day 28 and 10.8% vs 22.5% at Day 60). Importantly, this improvement was incremental to standard of care including high dose steroids and remdesivir 88.0% and 57.8%, respectively). In addition, serum LIGHT levels but not IL-6 HGNC levels were markedly reduced in patients treated with CERC-002. Conclusions The data presented herein demonstrate that CERC-002 markedly reduces the risk of respiratory failure MESHD and death incremental MESHD to standard of care including high dose corticosteroids and reduces LIGHT levels in patients with COVID-19 MESHD ARDS MESHD. (ClinicalTrials.gov number NCT04412057).

    Tocilizumab Effect in COVID-19 MESHD Hospitalized Patients: A Systematic Review and Meta-Analysis of Randomized Control Trials

    Authors: Waleed Tharwat Aletreby; Basheer Abdulrahman; Ahmed Fouad Mady; Alfateh Mohammed Noor; Mohammed H Lhmdi; Fahad Faqihi; Abdulrahman M Alharthy; Mohammed A Al-Odat; Dimitrios Karakitsos; Ziad Memish

    doi:10.1101/2021.03.15.21253581 Date: 2021-03-17 Source: medRxiv

    Since the emergence of the first cases of COVID-19 MESHD viral pneumonia MESHD late 2019 several studies evaluated the benefits of different treatment modalities. Early in the pandemic, the interleukin 6 HGNC (IL-6) receptor antibody Tocilizumab was considered in view of the cytokine release syndrome associated with COVID-19 MESHD infection. Several early observational studies showed beneficial effect of treatment with Tocilizumab on mortality, however, results from well-designed randomized clinical trials (RCT) were contradicting. ObjectivesTo perform a systematic literature review and meta-analysis of RCTs utilizing Tocilizumab in the treatment of COVID-19 MESHD pneumonia MESHD, with in-hospital mortality as a primary objective, while secondary objectives included composite outcome of mortality, intubation, or ICU admission, another secondary outcome was super added infection. MethodThis was a random effects model (DerSimonian and Laird) model of relative risk (RR), along with corresponding 95% confidence intervals, p values, and forest plots of both primary and secondary outcomes. A fixed effect sensitivity test was performed for the primary outcome, in addition to subgroup and meta-regression analyses with predefined criteria. ResultsThe primary outcome of mortality showed statistically insignificant reduction of mortality with Tocilizumab (RR = 0.9, 95% CI: 0.8 - 1.01; p = 0.09) although with an unmistakable apparent clinical benefit. There was a significant reduction in the RR of the secondary composite outcome (RR = 0.83, 95% CI: 0.76 - 0.9; p < 0.001), and no difference between groups in super-added infection (RR = 0.77, 95% CI: 0.51 - 1.19; p = 0.24). Treatment protocol allowing a second dose was the only significant predictor of improved mortality in the meta-regression analysis. Certainty of evidence was reduced to moderate for the primary outcome and the secondary outcome of clinical deterioration, while it was reduced to low for the secondary outcome of super-added infection. ConclusionModerate certainty of evidence suggest no statistically significant improvement of 28-30 day all-cause mortality of hospitalized COVID-19 MESHD patients treated with TCZ, although there may be clinically important value. Moderate certainty of evidence suggest lowered relative risk of a composite outcome of death MESHD or clinical deterioration, while, low grade evidence indicate no increase in the risk of super-added infection associated with TCZ treatment. A protocol allowing two doses of TCZ shows evidence of improved mortality as compared to a strictly single dose protocol.

    SARS-CoV-2 Nsp5 HGNC Protein Causes Acute Lung Inflammation MESHD: A Dynamical Mathematical Model

    Authors: José Díaz; Elena R. Álvarez-Buylla; Antonio Bensussen

    id:10.20944/preprints202012.0749.v2 Date: 2021-03-15 Source: Preprints.org

    In the present work we propose a dynamical mathematical model of the lung cells inflammation process MESHD in response to SARS-CoV-2 infection MESHD. In this scenario the main protease PROTEIN Nsp5 HGNC enhances the inflammatory process, increasing the levels of NF kB, IL-6 HGNC, Cox2 HGNC, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 HGNC also increases above the threshold value of 7 pg mL-1 s-1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6 HGNC. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation MESHD state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5 HGNC.To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 HGNC is effectively a central node underlying the severe acute lung inflammation MESHD during SARS-CoV-2 infection MESHD. The persistent production of IL-6 HGNC by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19 MESHD. Nsp5 HGNC seems to be the switch to start inflammation MESHD, the consequent overproduction of the ACE2 HGNC receptor, and an important underlying cause of the most severe cases of COVID19 MESHD.

    Clinical course and risk factors for in-hospital mortality of 205 patients with SARS-CoV-2 pneumonia MESHD in Como, Lombardy Region, Italy

    Authors: Mauro Turrini; Angelo Gardellini; Livia Beretta; Lucia Buzzi; Stefano Ferrario; Sabrina Vasile; Raffaella Clerici; Andrea Colzani; Luigi Liparulo; Giovanni Scognamiglio; Gianni Imperiali; Giovanni Corrado; Antonella Strada; Marco Galletti; Nunzio Castiglione; Claudio Zanon

    doi:10.1101/2021.02.25.20134866 Date: 2021-03-05 Source: medRxiv

    Importance: With randomized clinical trials ongoing and vaccine still a long distance away, efforts to repurpose old medications used for other diseases provide hope for treatment of COVID-19 MESHD. Objectives: To examine the risk factors for in-hospital mortality and describe the effectiveness of different treatment strategies in a real-life setting of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia MESHD. Design: Real-life single-center study during the Lombardy COVID-19 MESHD outbreak. Setting: Valduce Hospital in Como, Lombardy Region, Italy. Participants: 205 laboratory-confirmed patients presenting with SARS-Cov-2 pneumonia MESHD requiring hospitalization. Interventions: All patients received best supportive care and, based on their clinical needs and comorbidities, specific interventions that included the main drugs being tested for repurposing to treat COVID-19 MESHD, such as hydroxychloroquine, anticoagulation, antiviral drugs, steroids or interleukin-6 HGNC pathway inhibitors. Main outcomes and measures: Clinical, laboratory and treatment characteristics were analyzed with univariate and multivariate logistic regression methods to explore their impact on in-hospital mortality and compared with current literature data. Results: Univariate analyses for clinical variables showed prognostic significance for age equal or greater than 70 years (estimated 28-days survival: 21.4 vs 67.4%; p<0.0001), presence of 2 or more relevant comorbidities (35.3 vs 61.8%; p=0.0008), ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) less than 200 at presentation (21-days survival: 14.7 vs 52.4%;p<0.0001), high levels of lactate dehydrogenase (LDH) (26.4 vs 65.3%; p=0.0001), and elevated C-reactive protein HGNC (CRP) values (25.4 vs 74.9%; p=0.0001), while no statistical significance was found for all the other clinical variables tested. At univariate analysis for the different treatment scheduled, prognostic significance for survival was showed for intermediate or therapeutic-dose anticoagulation (estimated 28-days survival: 37.1 vs 23.4%; p=0.0001), hydroxychloroquine (35.7 vs 27.3%; p=0.0029), early antiviral therapy with lopinavir/ritonavir (60.1 vs 22.4%; p<0.0001), late short-course of steroids (47.9 vs 18.2%; p<0.0001) or tocilizumab therapy (69.4 vs 29.4%; p=0.0059). Multivariable regression confirmed increasing odds of in-hospital death associated with age older than 70 years (odds ratio 3.26, 95% CI 1.81 - 5.86; p<0.0001) and showed a reduction in mortality for patients treated with anticoagulant (-0.37, 0.49 - 0.95; p=0.0273), antiviral (-1.22, 0.16 - 0.54; p<0.0001), or steroids (-0.59, 0.35 - 0.87; p=0.0117) therapy.

    Compassionate use of rectal Ozone (O3) in severe COVID-19 MESHD pneumonia MESHD: a case-control study.

    Authors: Marcos Edgar Fernández-Cuadros; María Jesús Albaladejo-Florín; Sandra Alava-Rabasa; Juan Gallego-Galiana; Gerardo Fabiel Pérez-Cruz; Isabel Usandizaga-Elio; Enrique Pacios; David Torres-Garcia; Daiana Peña-Lora; Luz Casique-Bocanegra; María Jesús López-Muñoz; Javier Rodríguez-de-Cía; Olga Susana Pérez-Moro

    doi:10.21203/rs.3.rs-231696/v1 Date: 2021-02-11 Source: ResearchSquare

    Objectives: To evaluate effect of rectal Ozone in severe COVID-19 MESHD pneumonia MESHD and to compare to Standard-of-care (SOC). Material and Methods: In a case-control study, 14 patients with severe bilateral COVID-19 MESHD pneumonia MESHD (positive RT-PCR), treated with SOC and rectal Ozone, were evaluated before-and-after treatment and compared with SOC (14 patients) in a 10 day follow-up period. Ozone-protocol consisted of 8 sessions (1 session/day) of intra-rectal Ozone, (150mL volume, 35mg/ml concentration [5.25mg total dose]). The SOC-protocol included O 2- supply, antivirals (Remdesivir), corticosteroids (Dexamethasone/Metilprednisolone), monoclonal antibodies (Anakinra/Tocilizumab), antibiotics (Azytromicine), anticoagulants (Enoxaparine) and hyperimmune serum (if necessary). Primary outcome variables: a) clinical (O 2- saturation and O 2- supply); b) biochemical (Lymphocyte count, Fibrinogen HGNC, D-Dimer, Urea, Ferritin, LDH, IL-6 HGNC and CRP HGNC); c) radiological Taylor Scale. Secondary outcome variables: a) hospitalization length-of-stay, b) mortality-rate. Results: At baseline, Ozone/SOC-groups were not different on age, comorbidities, O 2 -saturation and O 2 -supply. Patients in Ozone-Group improved O 2- saturation and decrease O 2- supply. SOC maintained O 2- saturation and required more O 2- supply. Lymphocyte-count improved only in Ozone-group and with statistical difference (p<0.05). Biomarkers of inflammation MESHD ( Fibrinogen HGNC, D-Dimer, Urea, LDH, CRP HGNC and IL-6 HGNC) decreased in both groups, but only significantly in favor of Ozone-group (p<0.05). Ferritin showed a significant decrease in the Ozone-group but an increase on the SOC-Group. Radiological pneumonitis MESHD decreased on both groups but the decrease was only significant in the Ozone-Group (p<0.0001). Mortality and length-of-stay, although not significant, were inferior in Ozone-Group. Conclusion: Compassionate use of Rectal Ozone improved O 2 -saturation, reduced O 2 -supply, decreased inflammation MESHD biomarkers and improved Taylor’s radiological scale significantly when compared to SOC-Group. Mortality and length-of-stay was inferior in the Ozone-group, but this difference was not significant.

    Combination therapy of Tocilizumab and steroid for management of COVID-19 MESHD associated cytokine release syndrome: A single center experience from Pune, Western India

    Authors: Ameet Dravid; Reema Kashiva; Zafer Khan; Danish Memon; Aparna Kodre; Prashant Potdar; Milind Mane; Rakesh Borse; Vishal Pawar; Dattatraya Patil; Debashis Banerjee; Kailas Bhoite; Reshma Pharande; Suraj Kalyani; Prathamesh Raut; Madhura Bapte; Anshul Mehta; M Sateesh Reddy; Krushnadas Bhayani; S S Laxmi; P D Vishnu; Shipra Srivastava; Shubham Khandelwal; Sailee More; Rohit Shinde; Mohit Pawar; Amol Harshe; Sagar Kadam; Uma Mahajan; Gaurav Joshi; Dilip Mane

    doi:10.1101/2021.02.04.21249959 Date: 2021-02-06 Source: medRxiv

    Background: Cytokine release syndrome ( CRS MESHD) or cytokine storm is thought to be the cause of inflammatory lung damage MESHD, worsening pneumonia MESHD and death MESHD in patients with COVID-19 MESHD. Steroids (Methylprednisolone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor HGNC antagonist, are approved for the treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroids in COVID-19 MESHD associated CRS. Methods: This retrospective cohort study was conducted at a tertiary level private hospital in Pune, India between 2nd April and 2nd November 2020. All patients administered TCZ and steroids for treatment of CRS were included. The primary endpoint was the incidence of all-cause mortality. Secondary outcomes studied were the need for mechanical ventilation and incidence of infectious complications. Baseline and time-dependent risk factors significantly associated with death MESHD were identified by Relative risk estimation. Results: Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. Median age of the cohort was 57 (IQR: 46.5, 66) years. Almost 72 % patients had preexisting co-morbidities. Median time to TCZ administration since onset of symptoms was 9 days (IQR: 7, 11). 63% patients needed intensive care unit (ICU) admission. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Infectious complications like hospital acquired pneumonia MESHD, bloodstream bacterial and fungal infections MESHD were observed in 2.13 %, 2.13 % and 0.06 % patients respectively. Age [≥] 60 years (p=0.014), presence of co-morbidities like hypertension MESHD (p = 0.011), IL-6 HGNC [≥] 100 pg/ml (p = 0.002), D-dimer [≥] 1000 ng/ml (p < 0.0001), CT severity index [≥] 18 (p < 0.0001) and systemic complications like lung fibrosis MESHD (p = 0.019), cardiac arrhythmia MESHD (p < 0.0001), hypotension MESHD (p < 0.0001) and encephalopathy MESHD (p < 0.0001) were associated with increased risk of death MESHD. Conclusions: Combination therapy of TCZ and Steroids is likely to be safe and effective in the management of COVID-19 MESHD associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled clinical trials.

    Home-based management of COVID-19 MESHD by identification of low-risk features

    Authors: Fernando Cabanillas; Javier Morales; Jorge Bertran-Pasarell; Ricardo Fernandez; Jose G. Conde; Yaimara Hernandez-Silva; Idalia Liboy

    doi:10.1101/2021.01.25.21249684 Date: 2021-01-26 Source: medRxiv

    Abstract Background: Covid-19 MESHD is a triphasic disorder characterized by a viral phase lasting 7-10 days from onset of symptoms. In approximately 20% it is followed by a second stage heralded by elevation of pro-inflammatory markers such as ferritin, IL-6 HGNC, CRP, LDH and D-dimers. We hypothesized that those with few abnormalities would have a low risk for progression to respiratory insufficiency MESHD and hence could be monitored at home without treatment. Methods: Inclusion criteria included Covid infection, age >21, Oxygen saturation >90%. To be observed without treatment, patients could have no more than 1 of the following: CRP > 10 mg/dL, high LDH, ferritin > 500 ng/ml, D-dimer > 1 mg/L, IL-6 HGNC > 10 pg/ml, absolute lymphocyte count <1,000, Oxygen saturation <94%, or CT chest evidence of pneumonia MESHD. Primary endpoint was progression to respiratory failure MESHD and secondary endpoints was 28-day survival. Results: Of 208 entered, 132 were low-risk and hence were monitored without therapy. None progressed to respiratory failure MESHD or died. Conclusions: We have shown that our approach can identify cases who can safely be observed without treatment, thus avoiding expensive, potentially toxic therapies, and circumventing unnecessary, costly hospitalizations. These results support our hypothesis that applying our criteria, 64% of Covid-19 MESHD cases can be monitored as outpatients without therapy.

    Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 MESHD patients

    Authors: Jorge A. Masso-Silva PhD; Alexander Moshensky BS; Michael T. Y. Lam MD PhD; Mazen Odish MD; Arjun Patel MBBS; Le Xu PhD; Emily Hansen MS; Samantha Trescott BS; Celina Nguyen BS; Roy Kim BS; Katherine Perofsky MD; Samantha Perera N/A; Lauren Ma BS; Josephine Pham N/A; Mark Rolfsen MD; Jarod Olay MS; John Shin BS; Jennifer M. Dan MD PhD; Robert Abbott PhD; Sydney Ramirez MD PhD; Thomas H. Alexander MD MHSc; Grace Y. Lin MD; Ana Lucia Fuentes MD; Ira N. Advani BS; Deepti Gunge BS; Victor Pretorius MBChB MD; Atul Malhotra MD; Xin Sun PhD; Jason Duran MD PhD; Shane Crotty PhD; Nicole G. Coufal MD PhD; Angela Meier MD PhD; Laura E. Crotty Alexander MD

    doi:10.1101/2021.01.14.21249831 Date: 2021-01-15 Source: medRxiv

    BackgroundIncreased inflammation MESHD is a hallmark of COVID-19 MESHD, with pulmonary and systemic inflammation MESHD identified in multiple cohorts of patients. Definitive cellular and molecular pathways driving severe forms of this disease remain uncertain. Neutrophils, the most numerous leukocytes in blood circulation, can contribute to immunopathology in infections, inflammatory diseases MESHD and acute respiratory distress syndrome MESHD ( ARDS MESHD), a primary cause of morbidity and mortality in COVID-19 MESHD. Changes in multiple neutrophil functions and circulating cytokine levels over time during COVID-19 MESHD may help define disease severity and guide care and decision making. MethodsBlood was obtained serially from critically ill COVID-19 MESHD patients for 11 days. Neutrophil oxidative burst, neutrophil extracellular trap formation (NETosis), phagocytosis and cytokine levels were assessed ex vivo. Lung tissue was obtained immediately post-mortem for immunostaining. ResultsElevations in neutrophil-associated cytokines IL-8 HGNC and IL-6 HGNC, and general inflammatory cytokines IP-10 HGNC, GM-CSF HGNC, IL-1b HGNC, IL-10 and TNF MESHD, were identified in COVID-19 MESHD plasma both at the first measurement and at multiple timepoints across hospitalization (p < 0.0001). Neutrophils had exaggerated oxidative burst (p < 0.0001), NETosis (p < 0.0001) and phagocytosis (p < 0.0001) relative to controls. Increased NETosis correlated with both leukocytosis and neutrophilia MESHD. Neutrophils and NETs were identified within airways and alveoli in the lung parenchyma of 40% of SARS-CoV-2 infected lungs MESHD. While elevations in IL-8 HGNC and ANC correlated to COVID-19 MESHD disease severity, plasma IL-8 HGNC levels alone correlated with death MESHD. ConclusionsCirculating neutrophils in COVID-19 MESHD exhibit an activated phenotype with increased oxidative burst, NETosis and phagocytosis. Readily accessible and dynamic, plasma IL-8 HGNC and circulating neutrophil function may be potential COVID-19 MESHD disease biomarkers.

    Risk Factors Associated with Disease Severity and Clinical Outcomes for COVID-19 MESHD in Wuhan, China

    Authors: Yun Liu; Hao Wu; Bei Zhu; Yi Yang; Peng Cheng; Chaolin Huang; Wenjuan Wu; Weihong Zhao; Jinsong Zhang

    doi:10.21203/rs.3.rs-143695/v1 Date: 2021-01-08 Source: ResearchSquare

    Background: A new type of pneumonia MESHD caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) appeared in Wuhan, China. However, the risk factors and characteristics related to the severity of the disease and its outcomes need to be further explored.Methods: In this retrospective study, we evaluated COVID-19 MESHD patients with severe disease and those who were critically ill, as diagnosed at Jinyintan Hospital (Wuhan, China). The demographic information, clinical characteristics, complications, and laboratory results for the patients were evaluated. Multivariate logistic regression methods were used to analyze risk factors related to hospital deaths.Results: The 235 COVID-19 MESHD patients included were divided into a severe group of 183 (78%) and a critical group of 52 (22%). Of these patients, 185 (79%) were discharged, and 50 (21%) died during hospitalization. In multivariate logistic analyses, age (OR=1.07, 95% CI 1.02-1.14, P=0.009), critical disease MESHD (OR=48.23, 95% CI 10.91-323.13, P<0.001), low lymphocyte counts (OR=15.48, 95% CI 1.98-176.49, P=0.015), elevated interleukin 6 HGNC ( IL-6 HGNC) (OR=9.11, 95% CI 1.69-67.75, P=0.017), and elevated aspartate aminotransferase ( AST HGNC) (OR=8.46, 95% CI 2.16-42.60, P=0.004) were independent risk factors for adverse outcomes.Conclusions: The results show that advanced age (> 64 years), critical illness, low lymphocyte levels, and elevated IL-6 HGNC and AST HGNC were factors for the risk of death for COVID-19 MESHD patients who had severe disease and those who were critically ill.

    Prognostic and predictive biomarkers in patients with COVID-19 MESHD treated with tocilizumab in a randomised controlled trial

    Authors: Jennifer Tom; Min Bao; Larry Tsai; Aditi Qamra; David Summers; Montserrat Carrasco-Triguero; Jacqueline McBride; Carrie M Rosenberger; Celia J F Lin; William Stubbings; Kevin G Blyth; Jordi Carratala; Bruno Francois; Thomas Benfield; Derrick Haslem; Paolo Bonfanti; Cor H van der Leest; Nidhi Rohatgi; Lothar Wiese; Charles Edouard Luyt; Farrah Kheradmand; Ivan O Rosas; Fang Cai

    doi:10.1101/2020.12.23.20247379 Date: 2020-12-26 Source: medRxiv

    Background Retrospective observational studies suggest that interleukin-6 HGNC ( IL-6 HGNC), C-reactive protein HGNC ( CRP HGNC), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 MESHD pneumonia MESHD. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti- IL-6 HGNC receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 MESHD pneumonia MESHD. Methods Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Findings Modelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo. Interpretation Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

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