Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial.

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.

Heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels.

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).

Efficacy of tocilizumab in patients with severe COVID-19: Survival and clinical outcomes.

BACKGROUND: SARS-CoV-2 is associated with a severe inflammatory response contributing to respiratory and systemic manifestations, morbidity, and mortality in patients with coronavirus disease 2019 (COVID-19). METHODS: Tocilizumab (TCZ) efficacy on mortality and length of hospital stay was retrospectively evaluated in patients who received TCZ and compared with that in controls with a similar severity of COVID-19. The primary endpoint was survival probability on day 28. The secondary endpoints included survival at day 14 and length of hospital stay. RESULTS: Of the 148 patients included in the study, 62 received TCZ and standard of care, whereas 86 served as a control group and received only standard of care. The two groups were similar, although TCZ-treated patients were more likely to exhibit hypertension (46.7% vs. 29.8%), chronic kidney disease (14.5% vs. 1.1%), and high Charlson score (1.18 vs. 1.00; p = 0.006) and less likely to receive corticosteroid treatment (48.5% vs. 93.0%). TCZ was associated with lower mortality on both day 28 (16.1% vs. 37.2%, p = 0.004) and day 14 (9.7% vs. 24.4%, p = 0.022). The hospital stay was longer in the TCZ-treated than in the control group (15.6 ± 7.59 vs.17.7 ± 7.8 days, p = 0.103). Ten patients (16.0%) in the TCZ-treated group developed infections. CONCLUSION: TCZ was associated with a lower likelihood of death despite resulting in higher infection rates and a non-significant longer hospital stay.

Longevity of Middle East Respiratory Syndrome Coronavirus Antibody Responses in Humans, Saudi Arabia.

Understanding the immune response to Middle East respiratory syndrome coronavirus (MERS-CoV) is crucial for disease prevention and vaccine development. We studied the antibody responses in 48 human MERS-CoV infection survivors who had variable disease severity in Saudi Arabia. MERS-CoV-specific neutralizing antibodies were detected for 6 years postinfection.

Reinfection, recurrence, or delayed presentation of COVID-19? Case series and review of the literature.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-cov-2), first described in December 2019, has now infected more than 28 million cases with almost one million deaths. Reinfection is not definitely established however disease recurrence is increasingly reported. CASES PRESENTATION: Four patients presented with a second episode of coronavirus disease 2019 (COVID-19) occurring 27-85 following their first illness. The initial episode was mild or asymptomatic while the second attack was severe requiring hospital admission. All four patients had a SARS-CoV-2 PCR test positive in the second episode. The chest-X-ray and/or computerized tomography (CT) scan showed bilateral alveolar shadows. Furthermore, the inflammatory markers were raised in the four patients. Three patients recovered following treatment with favipravir in addition tocilizumab and/or dexamethasone. CONCLUSION: Covid19 reinfection Recurrent COVID-19 is increasingly reported. However; other etiologies including superadded infection or pulmonary embolism should be ruled out, particularly if recurrence occurs less than 3 weeks.

Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

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.).

COVID-19 co-infection in a patient with brucella bacteremia.

We discuss a patient who presented with fever, chills and rigors, myalgia, sore throat, diarrhea, and abdominal pain. The total white blood cell count was normal. The lymphocyte and platelet counts were within normal limits. There was no contact with confirmed COVID-19 patient, but the disease was circulating at the time of presentation. He admitted to anosmia and hypogeusia. A nasopharyngeal swab r-RT PCR test was positive for the SARS-CoV-2 virus. His chest examination and chest x-ray were normal. The patient had contact with animals and consumed unpasteurized camel milk. Both the blood culture and brucella serology tests were positive. This case illustrates that co-infection can occur and it is important to rule out endemic diseases in patients with COVID-19. Similarly, patients presenting with febrile endemic diseases may be harboring mild SARS-COV-2 virus infections and may need to be screened when the disease is suggested by epidemiological exposure.