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BackgroundRetrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), 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 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti-IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia. MethodsCandidate 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. FindingsModelling 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. InterpretationMultiple 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. RESEARCH IN CONTEXT Evidence before this studyThe efficacy and safety of the anti-interleukin-6 receptor antibody tocilizumab in the treatment of patients hospitalised with COVID-19 pneumonia was investigated in COVACTA, a double-blind, randomised, placebo-controlled trial. The primary endpoint of improved clinical status on a seven-category ordinal scale (1, discharged/ready for discharge; 7, death) at day 28 was not met in this trial. Among the secondary endpoints, no difference in mortality at day 28 was observed, but time to hospital discharge was shorter in the tocilizumab group. Subgroup analysis suggested there might be a treatment benefit in patients grouped according to their ordinal scale category at baseline. We searched PubMed on September 14, 2020, using the terms "tocilizumab AND (COVID-19 OR coronavirus) AND biomarker" with no language or date restrictions. The search retrieved 18 articles, four of which identified laboratory measures as potential biomarkers in patients who received tocilizumab for the treatment of COVID-19 pneumonia. The biomarkers reported in these studies include interleukin-6, C-reactive protein, ferritin, fibrinogen, liver transaminases, lymphocytes, platelets, and D-dimer. However, these previous studies were single-centre, retrospective, observational studies. Larger, prospective, controlled trials are needed to investigate potential prognostic and predictive biomarkers to assess the outcomes and response to treatments for COVID-19. Added value of this studyThis exploratory analysis of data from COVACTA demonstrated interleukin-6, C-reactive protein, ferritin, neutrophils (percentage and absolute count), neutrophil-to-lymphocyte ratio, lymphocytes (percentage and absolute count), monocytes (percentage), and platelets as strong prognostic biomarkers in patients hospitalised with severe COVID-19 pneumonia. More important, ferritin showed predictive value for tocilizumab treatment effects on day 28 clinical outcomes of mortality, mechanical ventilation (among the subgroup of patients not receiving mechanical ventilation at randomisation), and clinical status compared with placebo. Implications of all the available evidenceIn patients with elevated levels of ferritin at baseline, tocilizumab decreased the probability of death, mechanical ventilation, and worsening clinical status at day 28 compared with placebo, suggesting that ferritin might be useful as a predictive biomarker of efficacy outcomes for tocilizumab in patients with severe COVID-19 pneumonia.
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While the current pandemic remains a thread to human health, the polyclonal nature of the antibody response against SARS-CoV-2 is not fully understood. Other than SARS-CoV-2, humans are susceptible to six different coronaviruses, and previous exposure to antigenically related and divergent seasonal coronaviruses is frequent. We longitudinally profiled the early humoral immune response against SARS-CoV-2 on hospitalized COVID-19 patients, and quantify levels of pre-existing immunity to OC43, HKU1 and 223E seasonal coronaviruses. A strong back-boosting effect to conserved, but not variable regions of OC43 and HKU1 betacoronaviruses spike protein was observed. All patients developed antibodies against SARS-CoV-2 spike and nucleoprotein, with peak induction at day 7 post hospitalization. However a negative correlation was found between antibody memory boost to human coronaviruses and induction of IgG and IgM against SARS-CoV-2 spike. Our findings provide evidence of immunological imprinting that determine the antibody profile to COVID-19 patients in an original antigenic sin fashion.
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Introducción: existen diferencias considerables en la duración de la estancia media de los pacientes hospitalizados por neumonía adquirida en la comunidad (NAC). La estancia media es la variable con mayor impacto en el coste económico del manejo de la NAC. El objetivo de nuestro estudio fue identificar los factores relacionados con una estancia media hospitalaria prolongada (>8 días). Métodos: estudio observacional de una cohorte prospectiva de pacientes adultos no inmunodeprimidos con NAC que precisaron hospitalización entre 1995 y 2006. Resultados: se documentaron 2.688 episodios consecutivos de NAC. Se excluyó del análisis a los pacientes que precisaron ingreso en UCI desde el servicio de urgencias (n=107), los fallecidos durante la hospitalización (n=200) o aquellos con una estancia media mayor de 30 días (n=60). La mediana de la duración del ingreso fue 8 días (intervalo, 6¿11). Los factores relacionados con una estancia media prolongada en el análisis multivariable fueron la edad avanzada (riesgo relativo [RR]=1,58; intervalo de confianza [IC] del 95%, 1,002¿2,503), el abuso de alcohol (RR=2,07; IC del 95%, 1,341¿3,199), la gravedad de la NAC (RR=1,72; IC del 95%, 1,094¿2,703), la neumonía aspirativa (RR=4,57; IC del 95%, 1,085¿19,285), el derrame pleural complicado (RR=3,73; IC del 95%, 1,978¿7,04) y el tiempo hasta la estabilidad clínica (RR=1,13; IC del 95%, 1,065¿1,196). Conclusiones: los factores identificados deberían ser considerados al evaluar la idoneidad de la duración del ingreso hospitalario en la NAC en una institución determinada, así como en el diseño de estudios que propongan nuevas estrategias para reducir la estancia media (AU)
Introduction: The length of hospital stay in patients with community-acquired pneumonia (CAP) varies considerably, even though this factor has a great impact on the cost of care for this condition. The objective of this study was to identify factors associated with prolonged hospitalization in these patients (>8 days). Methods: Observational analysis of a prospective cohort of nonimmunosuppressed adults with CAP requiring hospitalization from 1995 through 2006. Results: We documented a total of 2688 consecutive episodes of CAP. Patients who required intensive care unit admission from the emergency room (n=107), those who died during hospitalization (n=200), and patients hospitalized for more than 30 days (n=60) were excluded from the analysis. The median duration of hospital stay was 8 days (IQR, 6-11). Factors independently associated with prolonged hospital stay by stepwise multiple logistic regression analysis were advanced age (OR=1.58; 95% CI, 1.002¿2.503), alcohol abuse (OR=2.07; 95% CI, 1.341¿3.199), high-risk Pneumonia Severity Index class (OR=1.72; 95% CI, 1.094¿2.703), aspiration pneumonia (OR=4.57; 95% CI, 1.085¿19.285), pleural empyema (OR=3.73; 95% CI, 1.978¿7.04), and time to clinical stability (OR=1.13; 95% CI, 1.065¿1.196). Conclusions: Several factors that were independently associated with longer hospital stay in adult patients with CAP. These factors should be considered when evaluating the adequacy of the duration of hospitalization in a specific center and when designing future studies investigating new strategies to reduce the length of hospital stay (AU)
