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1.
Influenza Other Respir Viruses ; 17(3): e13116, 2023 03.
Artículo en Inglés | MEDLINE | ID: covidwho-2249228

RESUMEN

Background: Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto-Abs) to type I IFNs were reported as a risk factor for life-threatening COVID-19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS). Methods: We evaluated the prevalence of type I IFN auto-Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo-controlled clinical trial for treatment with IFN-ß1b and lopinavir-ritonavir (MIRACLE trial). Samples were tested for type I IFN auto-Abs using a multiplex particle-based assay. Results: Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto-Abs for at least one subtype of type I IFNs. Auto-Abs positive patients were not different from auto-Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto-Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto-Abs negative patients. The effect of treatment with IFN-ß1b and lopinavir-ritonavir did not significantly differ between the two groups. Conclusion: This study demonstrates the presence of type I IFN auto-Abs in hospitalized patients with MERS.


Asunto(s)
COVID-19 , Interferón Tipo I , Humanos , Ritonavir/uso terapéutico , Lopinavir/uso terapéutico , Interferon beta-1b/uso terapéutico , Autoanticuerpos
2.
Sci Rep ; 12(1): 18186, 2022 Oct 28.
Artículo en Inglés | MEDLINE | ID: covidwho-2096799

RESUMEN

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).


Asunto(s)
Infecciones por Coronavirus , Ritonavir , Animales , Humanos , Antivirales/uso terapéutico , Citocinas/uso terapéutico , Interferones/uso terapéutico , Lopinavir/uso terapéutico , Ritonavir/uso terapéutico
3.
N Engl J Med ; 383(17): 1645-1656, 2020 10 22.
Artículo en Inglés | MEDLINE | ID: covidwho-834967

RESUMEN

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Interferon beta-1b/uso terapéutico , Lopinavir/uso terapéutico , Ritonavir/uso terapéutico , Administración Oral , Adulto , Anciano , Infecciones por Coronavirus/mortalidad , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Hospitalización , Humanos , Inyecciones Subcutáneas , Interferon beta-1b/efectos adversos , Estimación de Kaplan-Meier , Lopinavir/efectos adversos , Masculino , Persona de Mediana Edad , Ritonavir/efectos adversos , Estadísticas no Paramétricas , Tiempo de Tratamiento
4.
Clin Infect Dis ; 70(9): 1837-1844, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: covidwho-822200

RESUMEN

BACKGROUND: The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders. METHODS: This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders. RESULTS: Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-ß1a; none received rIFN-ß1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73-1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30-1.44]; P = .29). CONCLUSIONS: In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-ß1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/terapia , Interferón alfa-2/uso terapéutico , Ribavirina/uso terapéutico , Anciano , Enfermedad Crítica , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Coronavirus del Síndrome Respiratorio de Oriente Medio , Neumonía Viral/tratamiento farmacológico , ARN Viral/sangre , Estudios Retrospectivos , Arabia Saudita , Resultado del Tratamiento
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