Kinetics of antibody response in critically ill patients with Middle East respiratory syndrome and association with mortality and viral clearance.

The objective of this study is to examine the IgG antibody response in critically ill patients with the Middle East respiratory syndrome (MERS) and to examine the association of early antibody response with mortality and viral clearance. We collected blood samples from 40 consecutive real-time reverse transcription-polymerase chain reaction (rRT-PCR) confirmed critically ill MERS patients on ICU days 1, 3, 7, 14 and 28. MERS-CoV antibodies were detected by enzyme-linked immunosorbent assay (ELISA), using wells coated with MERS-CoV S1 antigen. Patients were admitted to ICU after a median (Q1, Q3) of 9 (4, 13) days from onset of symptoms with an admission Sequential Organ Failure Assessment (SOFA) score of 11 (6.5, 12). Among the study cohort, 38 patients (95%) received invasive ventilation, 35 (88%) vasopressors, 21 (53%) renal replacement therapy and 17 (43%) corticosteroids. Median (Q1,Q3) ELISA optical density (OD) ratio significantly increased with time (p < 0.001) from 0.11 (0.07, 1.43) on day 1; to 0.69 (0.11, 2.08) on day 3, 2.72 (1.84, 3.54) on day 7, 2.51 (0.35, 3.35) on day 14 and 3.77 (3.70, 3.84) on day 28. Early antibody response (day 1-3) was observed in 13/39 patients (33%) and was associated with lower mortality (hazard ratio: 0.31, 95% CI 0.10, 0.96, p = 0.04) but was not associated with faster clearance of MERS-CoV RNA. In conclusion, among critically ill patients with MERS, early antibody response was associated with lower mortality but not with faster clearance of MERS-CoV RNA. These findings have important implications for understanding pathogenesis and potential immunotherapy.

Favipiravir and Hydroxychloroquine Combination Therapy in Patients with Moderate to Severe COVID-19 (FACCT Trial): An Open-Label, Multicenter, Randomized, Controlled Trial.

INTRODUCTION: Antiviral drugs have shown limited effectiveness in treating patients with coronavirus disease 2019 (COVID-19). We aimed to assess the effects of a favipiravir and hydroxychloroquine combination on treating moderate-to-severe COVID-19 patients. METHODS: An investigator-initiated, multicenter, open-label, randomized trial at nine hospitals. Eligible patients were adults with moderate-to-severe COVID-19 defined as oxygen saturation (SaO2) of ≤ 94% while breathing ambient air or significant clinical symptoms with chest x-ray changes requiring hospital admission. Randomization was in a 1:1 ratio to receive standard care (control group) or standard care plus favipiravir and hydroxychloroquine. The primary outcome was time to clinical improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital within 14 days. Analyses were done in an intention-to-treat population. RESULTS: From May 2020 to Jan 2021, 254 patients were enrolled; 129 were assigned to standard of care and 125 to the treatment. The mean age was 52 (± 13) years, and 103 (41%) were women. At randomization, six patients were on invasive mechanical ventilation, 229 (90.15%) were requiring supplemental oxygen only (with or without non-invasive ventilation), and 19 (7.48%) were receiving neither. The time to clinical improvement was not significantly different between the groups: median of 9 days in the treatment group and 7 days in the control group (HR: 0.845; 95% CI 0.617-1.157; p-value = 0.29). The 28-day mortality was not significantly different between the groups (7.63% treatment) vs. (10.32% control); p-value = 0.45. The most prevalent adverse events were headache, elevation in ALT, and the prolonged QTc interval in the treatment group. CONCLUSION: The combination of favipiravir and hydroxychloroquine did not result in a statistically significant clinical benefit in patients with moderate-to-severe COVID-19. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04392973).

A retrospective evaluation of the value of COVID-19 screening and testing in patients with cancer: Aiming at a moving target.

BACKGROUND: Diagnosis of COVID-19 infection in cancer patients is critical to co-manage their underlying disease and infection appropriately. Our study aimed at evaluating the sensitivity and specificity of screening patients with cancer for COVID-19 infection. METHODS: All oncology patients receiving care at Department of Oncology at King Abdulaziz Medical City in Riyadh were screened using the acute respiratory infection (ARI) survey. Nasopharyngeal and throat swap for polymerase chain reaction (PCR) testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was performed on patients who have high ARI score (i.e. ≥ 4), or any patient requiring elective/emergency hospitalization, undergoing a procedure as well as screening asymptomatic patients receiving chemotherapy between April 1st and July 30, 2020. Institutional Review Board approval was obtained. Descriptive and inferential analyses were done and sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated considering the COVID-19 PCR as the gold standard. RESULTS: During the study period, a total of 473 patients were included with a median age was 56 years (14-104), 51% were female, 73% had solid tumors, and 66% received treatment within the last 3 months. These patients underwent 688 PCR tests along with ARI survey screening. Testing was done in the outpatient, inpatient, and emergency department setting in 41%, 40% and 19% of the patients, respectively. Majority of tests were screening of asymptomatic patients and only 23% were tested for suspected infections with ARI ≥ 4. A total of 54 patients (8%) had positive PCR for COVID-19 infection. The prevalence of infection varied from month to month ranging from 1.09% in April up to 19.70% in June and correlated with the average daily and active case load at a national level. The diagnostic yield of the ARI score also correlated with infection burden nationally. The PPV and NPV of the ARI as a screening tool was 18.24% (0-31.8) and 95.6% (86.36-98.86%) with the PPN fluctuating considerably in parallel with the prevalence of COVID-19 result. Similarly, the sensitivity and specificity of the ARI were 55.77% (0-70.59) and 79.4 (69.19-92), respectively. CONCLUSION: The yield of screening asymptomatic patients with cancer varies based on the community burden of COVID-19 infection. As universal screening can cause delays to patient care, it should be tailored based on the individual patient risks and infection burden in the region.

SARS-CoV-2 infection in children, clinical characteristics, diagnostic findings and therapeutic interventions at a tertiary care center in Riyadh, Saudi Arabia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 was first identified in Wuhan, China. All ages are susceptible to SARS-CoV-2 infection. Few studies had reported milder course in children however, severe course of illness has been reported. We aimed to describe the clinical features of COVID-19 in pediatric patients including diagnostic findings and therapeutic interventions in sever disease manifestation. METHODS: We retrospectively reviewed 742 patients with SARS-CoV-2 proven infection at King Abdullah Specialist Children's Hospital, from April 2020 and July 2020. Inpatients, outpatient, including those with sever manifestation treated at the Intensive Care Unit (ICU) were included. We collected data including demographic data, comorbidities, symptoms, imaging data, laboratory findings, treatments and clinical outcomes of patients with COVID-19. RESULTS: Among of 742 patients, 71 (9.6%) were hospitalized. The median age of patients was 75 months old and 53.6 were male. A total of 461 (62.1%) had close contact with confirmed cases, 45 (6.1%) had no contact history, and 236 (31.8%) with unknown exposure risk. The most common symptoms at the onset of illness were fever (32.5%), respiratory symptoms (21%) and gastrointestinal symptoms (10.3%). Among the entire cohort, 7 patients were admitted to PICU with COVID-19 related symptoms, five patients diagnosed with MIS-C, one patient with Kawasaki, and one patient with pneumonia. All patients received supportive therapy, no antiviral treatment had been used however, in MIS-C patients IVIG had been given to all patients, five patients received Anakinra; and one patient received tocilizumab. CONCLUSIONS: In this study, children infected with SARS-CoV-2 are less likely to develop symptomatic or serious diseases. Among symptomatic children, the most common clinical features were fever and respiratory symptoms followed by gastrointestinal manifestations. The majority of infected children have reported contact with an infected individual. MIS-C associated with COVID-19 is a severe presentation of SARS-CoV-2 infection and of a major concern as an overlapping features with other diseases could happen, making the diagnosis challenging.

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.).