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1.
BMJ Case Rep ; 14(1)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33419750

RESUMEN

As of 28 October 2020, there are over 44 000 000 confirmed COVID-19 infections and over 1 000 000 deaths worldwide, including 945 367 infections and 45 765 deaths in the UK. Acute respiratory distress syndrome occurs in 50% of patients with secondary haemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome characterised by a surge of cytokines, including interleukin 6 (IL-6). Here we describe the case of the first patient with severe COVID-19 pneumonia successfully treated with tocilizumab, a humanised monoclonal antibody against the IL-6 receptor, in the UK. Early treatment (after 7-10 days from the onset of symptoms) with tocilizumab could (1) reduce the risk of requiring non-invasive or invasive ventilation; (2) offer a chance of survival to people who are not fit for escalation or have refused to be ventilated; and (3) potentially increase the chance of survival in some patients who are already ventilated but fail to improve with supportive treatment.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Hipoxia/terapia , Anciano , /fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Hipertensión/complicaciones , Hipoxia/fisiopatología , Masculino , Terapia por Inhalación de Oxígeno , Receptores de Interleucina-6/antagonistas & inhibidores , Índice de Severidad de la Enfermedad
2.
Biomed Pharmacother ; 133: 110825, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33378989

RESUMEN

BACKGROUND: Since December 2019, COVID-19 has spread to almost every corner of the world. In theory, tocilizumab and favipiravir are considered to be reliable drugs for the treatment of COVID-19 with elevated IL-6. We aimed to assess the efficacy and safety of tocilizumab combined with favipiravir in patients with COVID-19. METHODS: This was a multicenter trial in adults with COVID-19. Patients were randomly assigned (3:1:1) to a 14-day combination of favipiravir combined with tocilizumab (combination group), favipiravir, and tocilizumab. The primary outcome was the cumulative lung lesion remission rate (lung CT examination indicated absorption of lung inflammation). RESULTS: Between Feb 2 and March 15, 2020, 26 patients were recruited; 14 were randomly assigned to the combination group, 7 were assigned to the favipiravir group and 5 were assigned to the tocilizumab group. The cumulative lung lesion remission rate at day 14 was significantly higher in combination group as compared with favipiravir group (P = 0.019, HR 2.66 95 % CI [1.08-6.53]). And there was also a significant difference between tocilizumab and favipivavir (P = 0.034, HR 3.16, 95 % CI 0.62-16.10). In addition, there was no significant difference between the combination group and the tocilizumab group (P = 0.575, HR 1.28 95 %CI 0.39-4.23). Furthermore, combined therapy can also significantly relieve clinical symptoms and help blood routine to return to normal. No serious adverse events were reported. CONCLUSION: Tocilizumab combined with or without favipiravir can effectively improve the pulmonary inflammation of COVID-19 patients and inhibit the deterioration of the disease.


Asunto(s)
Amidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Pirazinas/uso terapéutico , /efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Amidas/administración & dosificación , Amidas/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antivirales/administración & dosificación , Antivirales/efectos adversos , /patología , Quimioterapia Combinada , Femenino , Humanos , Interleucina-6/sangre , Estimación de Kaplan-Meier , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Receptores de Interleucina-6/antagonistas & inhibidores , Respiración Artificial/estadística & datos numéricos , Tamaño de la Muestra , Resultado del Tratamiento
3.
Monaldi Arch Chest Dis ; 90(4)2020 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-33372741

RESUMEN

We report the case of a man affected by cystic fibrosis who developed a severe SARS-CoV-2 related pneumonia in March 2020. In addition to lopinavir/ritonavir and hydroxychloroquine, he was treated with two doses of tocilizumab, displaying a significant clinical improvement. This is the first case described in the literature of an adult patient affected by cystic fibrosis who received tocilizumab for COVID-19, with documented total recovery, also assessed by a spirometry.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Fibrosis Quística , Hidroxicloroquina/administración & dosificación , Lopinavir/administración & dosificación , Neumonía Viral , Infecciones del Sistema Respiratorio/microbiología , Ritonavir/administración & dosificación , /aislamiento & purificación , Adulto , Antivirales/administración & dosificación , /diagnóstico , /fisiopatología , Fibrosis Quística/complicaciones , Fibrosis Quística/inmunología , Fibrosis Quística/fisiopatología , Combinación de Medicamentos , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Terapia por Inhalación de Oxígeno/métodos , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/etiología , Receptores de Interleucina-6/antagonistas & inhibidores , Pruebas de Función Respiratoria/métodos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/etiología , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento
4.
BMC Infect Dis ; 20(1): 964, 2020 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-33353546

RESUMEN

BACKGROUND: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2. METHODS: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020. RESULTS: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. Within 30 days from receiving tocilizumab, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After tocilizumab was administered, there was a slight increase in PaO2/FiO2 and an initial reduction in CRP, but this effect was not sustained beyond day 10. CONCLUSIONS: Majority of patients demonstrated clinical improvement and were successfully discharged alive from the hospital after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the early treatment of COVID-19, however larger randomized controlled studies are needed to confirm this.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptores de Interleucina-6/antagonistas & inhibidores , Insuficiencia Respiratoria/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Estudios de Cohortes , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria/virología , Estudios Retrospectivos , Resultado del Tratamiento
5.
Sci Rep ; 10(1): 16826, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033405

RESUMEN

Excessive interleukin-6 signaling is a key factor contributing to the cytokine release syndrome implicated in clinical manifestations of COVID-19. Preliminary results suggest that tocilizumab, a humanized monoclonal anti-interleukin-6 receptor antibody, may be beneficial in severely ill patients, but no data are available on earlier stages of disease. An anticipated blockade of interleukin-6 might hypothetically prevent the catastrophic consequences of the overt cytokine storm. We evaluated early-given tocilizumab in patients hospitalized with COVID-19, and identified outcome predictors. Consecutive patients with initial Sequential-Organ-Failure-Assessment (SOFA) score < 3 fulfilling pre-defined criteria were treated with tocilizumab. Serial plasma biomarkers and nasopharyngeal swabs were collected. Of 193 patients admitted with COVID-19, 64 met the inclusion criteria. After tocilizumab, 49 (76.6%) had an early favorable response. Adjusted predictors of response were gender, SOFA score, neutrophil/lymphocyte ratio, Charlson comorbidity index and systolic blood pressure. At week-4, 56.1% of responders and 30% of non-responders had cleared the SARS-CoV-2 from nasopharynx. Temporal profiles of interleukin-6, C-reactive protein, neutrophil/lymphocyte ratio, NT-ProBNP, D-dimer, and cardiac-troponin-I differed according to tocilizumab response and discriminated final in-hospital outcome. No deaths or disease recurrences were observed. Preemptive therapy with tocilizumab was safe and associated with favorable outcomes in most patients. Biological and clinical markers predicted outcomes.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Puntuaciones en la Disfunción de Órganos , Neumonía Viral/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Femenino , Estudios de Seguimiento , Humanos , Interleucina-6/sangre , Recuento de Linfocitos , Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/virología , España/epidemiología , Resultado del Tratamiento
6.
Front Immunol ; 11: 2132, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32983172

RESUMEN

In December 2019, a novel coronavirus, COVID-19, was discovered to be the causal agent of a severe respiratory infection named SARS-CoV-2, and it has since been recognized worldwide as a pandemic. There are still numerous doubts concerning its pathogenesis and particularly the underlying causes of the various clinical courses, ranging from severe manifestations to asymptomatic forms, including acute respiratory distress syndrome. The major factor responsible for acute respiratory distress syndrome is the so-called "cytokine storm," which is an aberrant response from the host immune system that induces an exaggerated release of proinflammatory cytokines/chemokines. In this review, we will discuss the role of cytokine storm in COVID-19 and potential treatments with which counteract this aberrant response, which may be valuable in the clinical translation.


Asunto(s)
Betacoronavirus/inmunología , Quimiocinas/sangre , Quimiocinas/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , /inmunología , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Glucocorticoides/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Receptores de Interleucina-6/antagonistas & inhibidores , /tratamiento farmacológico
7.
Trials ; 21(1): 794, 2020 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-32938496

RESUMEN

OBJECTIVES: In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. TRIAL DESIGN: A phase two multi-center randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h: CRP, LDH, serum ferritin, lymphopenia, or d-dimer. EXCLUSION CRITERIA: high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. MAIN OUTCOMES: Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. RANDOMIZATION: Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 1:1 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. BLINDING (MASKING): All study drugs will be administered as open label. No blinding methods will be used in this trial. NUMBERS TO BE RANDOMISED (SIMPLE SIZE): The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). TRIAL STATUS: Protocol Code: SARTRE Protocol Date: May 05th 2020. Version: 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment: August, 2020 End of recruitment: May, 2021 TRIAL REGISTRATION: Identifier: EudraCT Number: 2020-002037-15 ; Registration date: 26 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Asunto(s)
Anticuerpos Monoclonales Humanizados , Betacoronavirus , Infecciones por Coronavirus , Síndrome de Liberación de Citoquinas/prevención & control , Pandemias , Neumonía Viral , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Betacoronavirus/efectos de los fármacos , Betacoronavirus/aislamiento & purificación , Ensayos Clínicos Fase II como Asunto , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/fisiopatología , Síndrome de Liberación de Citoquinas/inmunología , Femenino , Humanos , Masculino , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/etiología , Neumonía Viral/inmunología , Neumonía Viral/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Interleucina-6/antagonistas & inhibidores , Resultado del Tratamiento
8.
J Immunother Cancer ; 8(2)2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32784217

RESUMEN

BACKGROUND: The inflammatory pathology observed in severe COVID-19 disease caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by elevated serum levels of C reactive protein (CRP) and cytokines, including interferon gamma, interleukin 8 (IL-8), and interleukin 6 (IL-6). Initial reports from the outbreak in Italy, China and the USA have provided anecdotal evidence of improved outcomes with the administration of anti-IL-6 agents, and large-scale trials evaluating these therapies are ongoing. STUDY DESCRIPTION: In this retrospective case series, clinical outcomes and correlates of response to treatment with the IL-6 receptor antagonist sarilumab are described for 15 patients with COVID-19 from a single institution in Southern Italy. Among 10 patients whose symptoms improved after sarilumab treatment, rapid decreases in CRP levels corresponded with clinical improvement. Lower levels of IL-6 at baseline as well as lower neutrophil to lymphocyte ratio as compared with patients whose COVID-19 did not improve with treatment were associated with sarilumab-responsive disease. CONCLUSIONS: This observation may reflect a possible clinical benefit regarding early intervention with IL-6-modulatory therapies for COVID-19 and that CRP could be a potential biomarker of response to treatment.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores Farmacológicos/sangre , Infecciones por Coronavirus/tratamiento farmacológico , Interleucina-6/sangre , Neumonía Viral/tratamiento farmacológico , Anciano , Antivirales/uso terapéutico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico por imagen , Femenino , Humanos , Italia , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico por imagen , Receptores de Interleucina-6/antagonistas & inhibidores , Estudios Retrospectivos , Resultado del Tratamiento
9.
Proc Natl Acad Sci U S A ; 117(36): 22351-22356, 2020 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-32826331

RESUMEN

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.


Asunto(s)
Síndrome de Liberación de Citoquinas/metabolismo , Células Endoteliales/metabolismo , Interleucina-6/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Transducción de Señal , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus , Quemaduras/metabolismo , Quemaduras/patología , Células Cultivadas , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/patología , Citocinas/sangre , Citocinas/metabolismo , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Inflamación , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Pandemias , Inhibidor 1 de Activador Plasminogénico/sangre , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/metabolismo , Neumonía Viral/patología , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/metabolismo , /patología , Sepsis/metabolismo , Sepsis/patología
10.
Paediatr Respir Rev ; 35: 81-87, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32792288

RESUMEN

The rapid spread of SARS-CoV-2 infection globally coupled with the relatively high case-fatality rate has led to immediate need for therapeutic intervention to prevent and treat COVID-19 disease. There is accumulating evidence that morbidity and mortality in COVID-19 may be exacerbated by a dysregulated host immune response resulting in significant hyperinflammation and cytokine release. The aim of this review is to describe the basis for the immune dysregulation caused by SARS-CoV-2 infection and to examine current investigations into immunomodulatory therapies aimed at targeting the excessive host immune response.


Asunto(s)
Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Factores Inmunológicos/uso terapéutico , Neumonía Viral/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Corticoesteroides/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Complejo Antígeno-Anticuerpo/inmunología , Betacoronavirus , Niño , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Síndrome de Liberación de Citoquinas/fisiopatología , Síndrome de Liberación de Citoquinas/terapia , Humanos , Inmunización Pasiva/métodos , Inmunoglobulinas Intravenosas/uso terapéutico , Inflamación/inmunología , Inflamación/fisiopatología , Inflamación/terapia , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Inhibidores de las Cinasas Janus/uso terapéutico , Pandemias , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , Receptores de Interleucina-6/antagonistas & inhibidores , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Síndrome de Respuesta Inflamatoria Sistémica/terapia
11.
Lima; Instituto Nacional de Salud; ago. 2020.
No convencional en Español | BRISA/RedTESA | ID: biblio-1122259

RESUMEN

INTRODUCCIÓN: Este documento técnico se realiza a solicitud del Seguro Integral de Salud (SIS) ­ Gerencia de Riesgo y Evaluación de Prestaciones (GREP). A. Cuadro clínico La Artritis Reumatoide (AR) es una enfermedad sistémica crónica autoinmune que se caracteriza por inflamación de articulaciones sinoviales y erosión cartilaginosa. Esta enfermedad produce limitación física, discapacidad y muerte prematura. Las complicaciones contribuyen al deterioro de las actividades sociales, la salud emocional y la calidad de vida. Por otra parte, la artritis idiopática juvenil (AIJ) se define como la presencia de artritis en una o varias articulaciones desde antes de los 16 años y que persiste por lo menos seis semanas, sin otra etiología conocida. La AIJ es la enfermedad reumática inflamatoria crónica más frecuente en la infancia. Los fármacos usados para las AR y AIJ incluyen a los analgésicos tipo AINES, corticoides, además también de los fármacos modificadores de la enfermedad (FARMEs). Existe la indicación de iniciar terapia biológica en pacientes no respondedores a la primera línea de tratamento. B. Tecnología sanitaria El Tocilizumab (TCZ) es un anticuerpo monoclonal humanizado, del grupo de los agentes biológicos con función inhibitoria del receptor de interleucina-6 (IL-6). La IL-6 promueve la activación de las células T y la diferenciación de las células B en células plasmáticas secretoras de inmunoglobulinas. Esta Interleucina proinflamatoria es producida por múltiples células, y tiene capacidad de estimular la diferenciación del osteoclasto que podría ser responsable de la destrucción articular. Esto tiene especial implicancia debido a que la actividad de la AR se correlaciona con niveles elevados de IL-6 en el líquido sinovial y en el suero. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura de TCZ para AR o AIJ con fracaso terapéutico a la primera línea de tratamiento. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de reumatología, y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se identificaron dos RS, dos ECA, cuatro GPC, seis ETS y una EE peruana. CONCLUSIONES La evidencia con respecto a TCZ en AR y ARJ es abundante. Las RS y ECAs identificados demuestran que TCZ es efectivo en AR y ARJ comparado con placebo, pero se asocia a más eventos adversos entre los más importantes se encuentran el aumento de LDH y otros factores de riesgo cardiovascular. Comparado con otros medicamentos biológicos, a través de comparaciones indirectas, no se evidencia superioridad. Las ETS y GPC seleccionadas coinciden en recomendar a TCZ como segunda línea de tratamiento y no mencionan a la tecnología por sobre otra. Una evaluación económica con perspectiva peruana de EsSalud concluye la dominancia de abatacept frente a otros medicamentos biológicos incluido TCZ en pacientes con AR moderada a severa con falla a MTX.


Asunto(s)
Humanos , Artritis Juvenil/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Perú , Evaluación de la Tecnología Biomédica , Análisis Costo-Beneficio
12.
J Autoimmun ; 114: 102511, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32713677

RESUMEN

In cases of COVID-19 acute respiratory distress syndrome, an excessive host inflammatory response has been reported, with elevated serum interleukin-6 levels. In this multicenter retrospective cohort study we included adult patients with COVID-19, need of respiratory support, and elevated C-reactive protein who received intravenous tocilizumab in addition to standard of care. Control patients not receiving tocilizumab were matched for sex, age and respiratory support. We selected survival as the primary endpoint, along with need for invasive ventilation, thrombosis, hemorrhage, and infections as secondary endpoints at 30 days. We included 64 patients with COVID-19 in the tocilizumab group and 64 matched controls. At baseline the tocilizumab group had longer symptom duration (13 ± 5 vs. 9 ± 5 days) and received hydroxychloroquine more often than controls (100% vs. 81%). The mortality rate was similar between groups (27% with tocilizumab vs. 38%) and at multivariable analysis risk of death was not significantly influenced by tocilizumab (hazard ratio 0.61, 95% confidence interval 0.33-1.15), while being associated with the use at baseline of non invasive mechanical or invasive ventilation, and the presence of comorbidities. Among secondary outcomes, tocilizumab was associated with a lower probability of requiring invasive ventilation (hazard ratio 0.36, 95% confidence interval 0.16-0.83; P = 0.017) but not with the risk of thrombosis, bleeding, or infections. The use of intravenous tocilizumab was not associated with changes in 30-day mortality in patients with COVID-19 severe respiratory impairment. Among the secondary outcomes there was less use of invasive ventilation in the tocilizumab group.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , /tratamiento farmacológico , Anciano , Betacoronavirus/inmunología , Estudios de Casos y Controles , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Infusiones Intravenosas , Interleucina-6/inmunología , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Receptores de Interleucina-6/metabolismo , /inmunología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del Tratamiento
14.
J Autoimmun ; 114: 102512, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32646770

RESUMEN

Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58-71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098-0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042-7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p < 0.001). Improvements in the six-point ordinal scale and SOFA score were observed in survivors after tocilizumab. Early receipt of tocilizumab in patients with severe COVID-19 was an independent predictor for in-hospital survival at 28 days.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Adulto , Anciano , Betacoronavirus/inmunología , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Infusiones Intravenosas , Interleucina-6/inmunología , Interleucina-6/metabolismo , Masculino , Michigan/epidemiología , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Pandemias , Neumonía Viral/sangre , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Pronóstico , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/metabolismo , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Tiempo de Tratamiento , Resultado del Tratamiento
15.
Rev Med Virol ; 30(5): e2123, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32648313

RESUMEN

The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αß and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Evasión Inmune/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Interferón Tipo I/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Progresión de la Enfermedad , Regulación de la Expresión Génica , Humanos , Evasión Inmune/genética , Evasión Inmune/inmunología , Inmunización Pasiva/métodos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/virología , Terapia Molecular Dirigida/métodos , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal
16.
J Infect ; 81(4): e11-e17, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32652164

RESUMEN

BACKGROUND: As the novel SARS-CoV-2 pandemic occurred, no specific treatment was yet available. Inflammatory response secondary to viral infection might be the driver of severe diseases. We report the safety and efficacy (in terms of overall survival and hospital discharge) of the anti-IL6 tocilizumab (TCZ) in subjects with COVID-19. METHODS: This retrospective, single-center analysis included all the patients consecutively admitted to our Hospital with severe or critical COVID-19 who started TCZ treatment from March 13th to April 03rd, 2020. A 1:2 matching to patients not treated with TCZ was performed according to age, sex, severity of disease, P/F, Charlson Comorbidity Index and length of time between symptoms onset and hospital admittance. Descriptive statistics and non-parametric tests to compare the groups were applied. Kaplan Meier probability curves and Cox regression models for survival, hospital discharge and orotracheal intubation were used. RESULTS: Seventy-four patients treated with TCZ were matched with 148 matched controls. They were mainly males (81.5%), Caucasian (82.0%) and with a median age of 59 years. The majority (69.8%) showed critical stage COVID-19 disease. TCZ use was associated with a better overall survival (HR 0.499 [95% CI 0.262-0.952], p = 0.035) compared to controls but with a longer hospital stay (HR 1.658 [95% CI 1.088-2.524], p = 0.019) mainly due to biochemical, respiratory and infectious adverse events. DISCUSSION: TCZ use resulted potentially effective on COVID-19 in terms of overall survival. Caution is warranted given the potential occurrence of adverse events. FINANCIAL SUPPORT: Some of the tocilizumab doses used in the subjects included in this analysis were provided by the "Multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia" (EudraCT Number: 2020-001110-38) supported by the Italian National Agency for Drugs (AIFA). No specific funding support was planned for study design, data collection and analysis and manuscript writing of this paper.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Anciano , Femenino , Hospitalización , Humanos , Italia , Masculino , Persona de Mediana Edad , Pandemias , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
17.
Immunotherapy ; 12(15): 1127-1132, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32664810

RESUMEN

Background: Severe pneumonia and acute respiratory distress syndrome (ARDS) due to COVID-19 is a challenge for nowadays medical practice. Although there is no clarity in the principal mechanism of lung damage and ARDS development, it has been suggested that one of the main reasons of this pathology is the hyperactivation of the immune system, better known as cytokine storm syndrome. Tocilizumab has been proposed to treat COVID-19 severe cases associated to ARDS. Results & methodology: Here we present two successful cases of tocilizumab administration in two COVID-19 patients with prior administration of antiviral therapy (hydroxychloroquine, azithromycin, lopinavir and ritonavir) with adequate response and resolution of ARDS, septic shock and severe pneumonia within the first 72 h. Discussion & conclusion: This case supports the usage of tocilizumab as an effective therapy in COVID-19 associated cytokine storm syndrome. Further studies should be done in order to assess its effectiveness and security.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , /terapia , Betacoronavirus , Infecciones por Coronavirus/patología , Enfermedad Crítica , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/terapia , Femenino , Humanos , Inmunoterapia , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , Receptores de Interleucina-6/antagonistas & inhibidores , Tiempo de Tratamiento , Resultado del Tratamiento
18.
Front Immunol ; 11: 1446, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32612617

RESUMEN

COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called "cytokine storm" induced by the virus. Excessive production of proinflammatory cytokines leads to ARDS aggravation and widespread tissue damage resulting in multi-organ failure and death. Targeting cytokines during the management of COVID-19 patients could improve survival rates and reduce mortality.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/patología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/patología , /prevención & control , Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/sangre , Humanos , Interleucina-6/antagonistas & inhibidores , Pandemias , Neumonía Viral/inmunología , Receptores de Interleucina-6/antagonistas & inhibidores , /patología
19.
J Autoimmun ; 114: 102523, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32690352

RESUMEN

OBJECTIVES: To describe the clinical characteristics and predictors of major outcomes in patients treated with tocilizumab (TCZ) for severe COVID-19 pneumonia. PATIENTS AND METHODS: Case series of all sequential patients with severe COVID-19 pneumonia treated with TCZ at an Academic Spanish hospital (March 12 - May 2, 2020). Clinical outcomes: death, length of hospital stay. An early clinical response to TCZ (48-72 h after the administration) was assessed by variations in respiratory function markers, Brescia COVID Respiratory Severity Scale (BCRSS), inflammatory parameters, and patients' and physicians' opinion. Associations were tested by multiple logistic regression. RESULTS: From a cohort of 236 patients, 77 patients treated with TCZ were included (median age 62 years (IQR 53.0-72.0), 64.9% were males), 42.9% had Charlson index ≥3; hypertension (41.6%), obesity (34.7%), and diabetes (20.8%). Median follow-up was 83.0 days (78.0-86.5), no patient was readmitted. ICU admission was required for 42 (54.5%), invasive mechanical ventilation in 38 (49.4%) and 10 patients died (12.9% global, 23.8% at ICU admitted). After multivariate adjustment, TCZ response by BCRSS (OR 0.03 (0.01-0.68), p = 0.028), and Charlson index (OR 3.54 (1.20-10.44), p = 0.022) has been identified as independent factors associated with mortality. Median of hospital stay was 16.0 days (11.0-23.0); BCRSS, physician subjective and D-dimer response were associated with shorter hospitalization stay. CONCLUSIONS: In a Mediterranean cohort, use of tocilizumab for severe COVID-19 show 12.9% of mortality. Early TCZ-response by BCRSS and low comorbidity were associated with increased survival. Early TCZ-response was related to shorter median hospital stay.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antivirales/administración & dosificación , Betacoronavirus/inmunología , Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , Respiración Artificial/estadística & datos numéricos , Adulto , Anciano , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Quimioterapia Combinada , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Estudios de Seguimiento , Mortalidad Hospitalaria , Humanos , Infusiones Intravenosas , Interleucina-6/inmunología , Interleucina-6/metabolismo , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Pronóstico , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/metabolismo , Pruebas de Función Respiratoria/estadística & datos numéricos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , España/epidemiología , Análisis de Supervivencia , Factores de Tiempo , Tiempo de Tratamiento , Resultado del Tratamiento
20.
Ann Rheum Dis ; 79(10): 1277-1285, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32620597

RESUMEN

OBJECTIVES: To assess the safety and efficacy of interleukin (IL)-6 blockade with sarilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation. METHODS: We conducted an open-label study of sarilumab in severe COVID-19 pneumonia (PaO2/FiO2 <300 mm Hg) with hyperinflammation (elevated inflammatory markers and serum IL-6 levels). Sarilumab 400 mg was administered intravenously in addition to standard of care and results were compared with contemporary matched patients treated with standard of care alone. Clinical improvement, mortality, safety and predictors of response were assessed at 28 days. RESULTS: Twenty-eight patients were treated with sarilumab and 28 contemporary patients receiving standard of care alone were used as controls. At day 28 of follow-up, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group (clinical improvement 64%, mortality 18%; p=NS). Baseline PaO2/FiO2 ratio >100 mm Hg and lung consolidation <17% at CT scan predicted clinical improvement in patients treated with sarilumab. Median time to clinical improvement in patients with lung consolidation <17% was shorter after sarilumab (10 days) than after standard treatment (24 days; p=0.01). The rate of infection and pulmonary thrombosis was similar between the two groups. CONCLUSIONS: At day 28, overall clinical improvement and mortality in patients with severe COVID-19 were not significantly different between sarilumab and standard of care. Sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Proteína C-Reactiva/inmunología , Infecciones por Coronavirus/tratamiento farmacológico , Inflamación/inmunología , Interleucina-6/inmunología , Neumonía Viral/tratamiento farmacológico , Administración Intravenosa , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Azitromicina/uso terapéutico , Bacteriemia/epidemiología , Betacoronavirus , Estudios de Cohortes , Coinfección/epidemiología , Infecciones por Coronavirus/diagnóstico por imagen , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Combinación de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Italia , Lopinavir/uso terapéutico , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Ventilación no Invasiva , Terapia por Inhalación de Oxígeno , Pandemias , Neumonía Viral/diagnóstico por imagen , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Modelos de Riesgos Proporcionales , Receptores de Interleucina-6/antagonistas & inhibidores , Ritonavir/uso terapéutico , Índice de Severidad de la Enfermedad , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
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