Impact of the COVID-19 pandemic on antiviral drug development for other community-acquired respiratory viruses' infections.

The coronavirus disease 2019 (COVID-19) pandemic indirectly resulted in missed therapeutic opportunities for many diseases. Here we focus on community-acquired respiratory viruses other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) [respiratory syncytial virus, parainfluenza and influenza A], and highlight the pandemics impact on clinical trials to develop novel therapies for other severe respiratory viral infections. We retrospectively reviewed inclusion rates within respiratory antiviral clinical trials in comparison with all other clinical trials in our clinical investigations center, before and during the COVID-19 pandemic. As opposed to the remaining clinical trials developed within our unit, respiratory antiviral trials inclusion rates did not recover after the initial recruitment decrease observed across all trials during the first pandemic wave. These results were discussed in the context of non-COVID-19 respiratory viral infection rates within our center, showing a general decline in seasonal respiratory viruses spread since the COVID-19 pandemic onset. Virus epidemiology changes upon the wide SARS-CoV-2 expansion as well as the lifestyle changes globally adopted to prevent SARS-CoV-2 transmission could have therefore contributed to the negative impact of the COVID-19 pandemic on antiviral drug development. Our study highlights the peculiarity of respiratory antiviral drug development during the COVID-19 pandemic era and describes potential explanations for such drug development halting.

Detection of SARS-CoV-2 in Saliva and Nasopharyngeal Swabs According to Viral Variants.

The genome of the Omicron variant of concern (VOC) contains more than 50 mutations, many of which have been associated with increased transmissibility, differing disease severity, and the potential to elute immune responses acquired after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination or infection with previous VOCs. Due to a better tropism for the upper respiratory tract, it was suggested that the detection of the Omicron variant could be preferred in saliva, compared to nasopharyngeal swabs (NPS). Our objective was to compare the SARS-CoV-2 levels in saliva fluid and NPS to estimated Ct values, according to the main SARS-CoV-2 variants circulating in France since the beginning of 2021. We analyzed 1,289 positive reverse transcription-polymerase chain reaction (RT-PCR) results during the three major waves: Alpha, Delta, and Omicron. NPS and saliva sampling were performed for 909 (71%) and 380 (29%) cases, respectively. The Ct values were significantly lower in the NPS samples than in the saliva samples for the three main VOCs. Still, the difference was less pronounced with the Omicron variant than for the Alpha and Delta variants. In contrast, in the saliva samples, Ct values were significantly lower for the Omicron variant than for the Delta (difference of -2.7 Ct) and the Alpha (difference of -3.0 Ct) variants, confirming a higher viral load in saliva. To conclude, the higher viral load in saliva was evidenced for the Omicron variant, compared to the Alpha and Delta variants, suggesting that established diagnostic methods might require revalidation with the emergence of novel variants. IMPORTANCE Established methods for SARS-CoV-2 diagnostics might require revalidation with the emergence of novel variants. This is important for screening strategy programs and for the investigation of the characteristics of new variants in terms of tropism modification and increased viral burden leading to its spread. SARS-CoV-2 RT-PCR screening on saliva samples reported lower but acceptable performance, compared to nasopharyngeal samples. Due to a better tropism for the upper respiratory tract, it was suggested that the detection of the Omicron variant could be preferred in saliva, compared to nasopharyngeal swabs. Our study analyzed 1,289 positive RT-PCR results during the three major waves in France: Alpha, Delta, and Omicron. Our findings also showed a higher viral load in saliva for the Omicron variant, compared to the Alpha and Delta variants.

SARS-CoV-2 Genomic Characteristics and Clinical Impact of SARS-CoV-2 Viral Diversity in Critically Ill COVID-19 Patients: A Prospective Multicenter Cohort Study.

The SARS-CoV-2 variant of concern, α, spread worldwide at the beginning of 2021. It was suggested that this variant was associated with a higher risk of mortality than other variants. We aimed to characterize the genetic diversity of SARS-CoV-2 variants isolated from patients with severe COVID-19 and unravel the relationships between specific viral mutations/mutational patterns and clinical outcomes. This is a prospective multicenter observational cohort study. Patients aged ≥18 years admitted to 11 intensive care units (ICUs) in hospitals in the Greater Paris area for SARS-CoV-2 infection and acute respiratory failure between 1 October 2020 and 30 May 2021 were included. The primary clinical endpoint was day-28 mortality. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing (Illumina COVIDSeq). In total, 413 patients were included, 183 (44.3%) were infected with pre-existing variants, 197 (47.7%) were infected with variant α, and 33 (8.0%) were infected with other variants. The patients infected with pre-existing variants were significantly older (64.9 ± 11.9 vs. 60.5 ± 11.8 years; p = 0.0005) and had more frequent COPD (11.5% vs. 4.1%; p = 0.009) and higher SOFA scores (4 [3-8] vs. 3 [2-4]; 0.0002). The day-28 mortality was no different between the patients infected with pre-existing, α, or other variants (31.1% vs. 26.2% vs. 30.3%; p = 0.550). There was no association between day-28 mortality and specific variants or the presence of specific mutations. At ICU admission, the patients infected with pre-existing variants had a different clinical presentation from those infected with variant α, but mortality did not differ between these groups. There was no association between specific variants or SARS-CoV-2 genome mutational pattern and day-28 mortality.

Impact of Fast SARS-CoV-2 Molecular Point-Of-Care Testing on Patients' Length of Stay in an Emergency Department.

The ID NOW COVID-19 system (IDNOW) is a point-of-care test (POCT) providing results within 15 min. We evaluated the impact of IDNOW use on patient length of stay (LOS) in an emergency department (ED). In the ED of Saint-Louis Hospital, Paris, France, adult patients requiring a rapid diagnosis of SARS-CoV-2 were tested with Cepheid Xpert Xpress SARS-CoV-2 or FilmArray respiratory panel RP2 in the virology laboratory between 18 October and 3 November 2020 (period 1) and with IDNOW between 4 November and 30 November 2020 (period 2). A total of 676 patients participated in the study, 337 during period 1 and 339 during period 2. The median LOS in ED was significantly higher in period 1 than in period 2 (276 versus 208 min, P < 0.0001). More patients spent less than 4 h in the ED in period 2 (61.3%) than in period 1 (38.3%) (P < 0.0001). By univariate analysis, factors associated with ED LOS were hypertension, anosmia/ageusia, number of patients per day, and ID NOW implementation in period 2. By multivariate analysis, the period of testing remained significantly associated with ED LOS. Rapid molecular SARS-CoV-2 POCT was associated with a reduced LOS for patients admitted to an ED. IMPORTANCE During COVID-19 pandemic upsurges, emergency departments had to deal with a massive flow of incoming patients. The need for COVID-19 infection status determination before medical ward admission worsened ED overcrowding. The development of molecular point-of-care testing gave new opportunities for getting faster results of SARS-CoV-2 genome detection 24 h a day. In our study, we show, with a multivariate analysis, that the use of the POCT COVID-19 IDNOW reduced the ED length of stay by 1 h. The rate of patients who waited less than 4 h in the ED increased significantly. Our study highlights the benefit of COVID-19 molecular POCT for preventing ED overcrowding and facilitating bed allocation and SARS-CoV-2-infected patient isolation.

Epidemiological and clinical insights from SARS-CoV-2 RT-PCR crossing threshold values, France, January to November 2020.

BackgroundThe COVID-19 pandemic has led to an unprecedented daily use of RT-PCR tests. These tests are interpreted qualitatively for diagnosis, and the relevance of the test result intensity, i.e. the number of quantification cycles (Cq), is debated because of strong potential biases.AimWe explored the possibility to use Cq values from SARS-CoV-2 screening tests to better understand the spread of an epidemic and to better understand the biology of the infection.MethodsWe used linear regression models to analyse a large database of 793,479 Cq values from tests performed on more than 2 million samples between 21 January and 30 November 2020, i.e. the first two pandemic waves. We performed time series analysis using autoregressive integrated moving average (ARIMA) models to estimate whether Cq data information improves short-term predictions of epidemiological dynamics.ResultsAlthough we found that the Cq values varied depending on the testing laboratory or the assay used, we detected strong significant trends associated with patient age, number of days after symptoms onset or the state of the epidemic (the temporal reproduction number) at the time of the test. Furthermore, knowing the quartiles of the Cq distribution greatly reduced the error in predicting the temporal reproduction number of the COVID-19 epidemic.ConclusionOur results suggest that Cq values of screening tests performed in the general population generate testable hypotheses and help improve short-term predictions for epidemic surveillance.

Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial.

BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation. METHODS: The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France. Participants, aged 18-45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert. Participants were randomly allocated in a 2:1 ratio to the experimental group (attendees) or to the control group (non-attendees). The allocation sequence was computer-generated by means of permuted blocks of sizes three, six, or nine, with no stratification. The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin <0·35%). This trial is registered with ClinicalTrials.gov, NCT04872075. FINDINGS: Between May 11 and 25, 2021, 18 845 individuals registered on the dedicated website, and 10 953 were randomly selected for a pre-enrolment on-site visit. Among 6968 who kept the appointment and were screened, 6678 participants were randomly assigned (4451 were assigned to be attendees and 2227 to be non-attendees; median age 28 years; 59% women); 88% (3917) of attendees and 87% (1947) of non-attendees complied with follow-up requirements. The day 7 RT-PCR was positive for eight of the 3917 attendees (observed incidence, 0·20%; 95% CI 0·09-0·40) and three of the 1947 non-attendees (0·15%; 0·03-0·45; absolute difference, 95% CI -0·26% to 0·28%), findings that met the non-inferiority criterion for the primary endpoint. INTERPRETATION: Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2-transmission risk, provided a comprehensive preventive intervention was implemented. FUNDING: French Ministry of Health. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Rapid identification of bacteria from respiratory samples of patients hospitalized in intensive care units, with FilmArray Pneumonia Panel Plus.

OBJECTIVES: This study aimed to evaluate the performance of FilmArray Pneumonia Panel Plus (FA-PP) for the detection of typical bacterial pathogens in respiratory samples from patients hospitalized in intensive care units (ICUs). METHODS: FA-PP was implemented for clinical use in the microbiology laboratory in March 2020. A retrospective analysis on a consecutive cohort of adult patients hospitalized in ICUs between March 2020 and May 2020 was undertaken. The respiratory samples included sputum, blind bronchoalveolar lavage (BBAL) and protected specimen brush (PSB). Conventional culture and FA-PP were performed in parallel. RESULTS: In total, 147 samples from 92 patients were analysed; 88% had coronavirus disease 2019 (COVID-19). At least one pathogen was detected in 46% (68/147) of samples by FA-PP and 39% (57/147) of samples by culture. The overall percentage agreement between FA-PP and culture results was 98% (93-100%). Bacteria with semi-quantitative FA-PP results ≥105 copies/mL for PSB samples, ≥106 copies/mL for BBAL samples and ≥107 copies/mL for sputum samples reached clinically significant thresholds for growth in 90%, 100% and 91% of cultures, respectively. FA-PP detected resistance markers, including mecA/C, blaCTX-M and blaVIM. The median turnaround time was significantly shorter for FA-PP than for culture. CONCLUSIONS: FA-PP may constitute a faster approach to the diagnosis of bacterial pneumonia in patients hospitalized in ICUs.

Interpretation of single target positivity among SARS-CoV-2 RT-PCR result tests.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged and is responsible for coronavirus disease 19 (COVID-19). Diagnostic tests have been developed, mainly based on reverse-transcriptase PCR (RT-PCR). Most RT-PCR assays target at least two SARS-CoV-2 genes. In some cases, only one target gene is detected; the interpretation of such cases remains unclear. Objectives: Our objective was to analyse one target positive (OPT) RT-PCR results, using two RT-PCR assays: the Xpert® Xpress SARS-CoV-2 (Cepheid diagnosis, "Cepheid") and the Cobas® 6800 SARS-CoV-2 Test (Roche Molecular Diagnostics, "Roche"). Methods: All SARS-CoV-2 RT-PCR results performed on respiratory samples with the Roche or the Cepheid tests, from 23rd March to 6th August 2020 were collected. A patient with an OPT result was classified as "probable COVID-19" if they met at least one of the three following criteria: (i) history of a two gene-positive SARS-CoV-2 RT-PCR result, (ii) anti-SARS-CoV-2 antibody (IgG) detection or (iii) compatible chest computed tomography scan (CT-scan). Results: A total of 18,630 and 1189 SARS-CoV-2 RT-PCR tests were performed with the Roche and Cepheid tests, respectively. Among the positive SARS-CoV-2 RT-PCR, 293 samples - corresponding to 264 patients - were OPT (11% of the positive samples). Of these patients, 180 (68%) had at least one of the three criteria listed above and were classified as probable COVID-19. Conclusions: Sixty-eight percent of the patients with an OPT result were classified as probable COVID-19 and are probably at a late stage of infection. Serology and imaging can be helpful to confirm diagnosis.

Surfaces and equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the emergency department at a university hospital.

OBJECTIVES: Environmental contamination by patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through respiratory droplets suggests that surfaces and equipment could be a medium of transmission. We aimed to assess the surface and equipment contamination by SARS-COV-2 of an emergency department (ED) during the coronavirus infectious disease-2019 (COVID-19) outbreak. METHODS: We performed multiple samples from different sites in ED patients care and non-patient care areas with sterile premoistened swabs and used real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect the presence of SARS-CoV-2 ribonucleic acid (RNA). We also sampled the personal protective equipment (PPE) from health care workers (HCWs). RESULTS: Among the 192 total samples, 10 (5.2%) were positive. In patient care areas, 5/46 (10.9%) of the surfaces directly in contact with COVID-19 patients revealed the presence of SARS-CoV-2 RNA, and 4/56 (7.1%) of the surfaces that were not directly in contact with COVID-19 patients were positive. SARS-CoV-2 RNA was present only in the patients' examination and monitoring rooms. Before decontamination SARS-CoV-2 RNA was present on the saturation clip, the scuff for blood pressure measurement, the stretcher, the plastic screens between patients and the floor. After decontamination, SARS-CoV-2 RNA remained on the scuff, the stretcher and the trolleys. All samples from non-patient care areas or staff working rooms were negative. Only one sample from the PPE of the HCWs was positive. CONCLUSIONS: Our findings suggest that surfaces and equipment contamination by SARS-CoV-2 RNA in an ED during the COVID-19 outbreak is low and concerns exclusively patients' examination and monitoring rooms, preserving non-patient care areas.

Evaluation of the COVID-19 IgG/IgM Rapid Test from Orient Gene Biotech.

While the coronavirus disease 2019 (COVID-19) pandemic has peaked in many countries already, the current challenge is to assess population immunity on a large scale. Many serological tests are available and require urgent independent validation. Here, we report performance characteristics of Orient Gene Biotech COVID-19 IgG/IgM Rapid Test Cassette (OG) and compare it to Abbott SARS-CoV-2 IgG immunoassay (ASIA). Patients (n = 102) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase PCR (RT-PCR) were tested. The patients were asymptomatic (n = 2) or had mild (n = 37) or severe symptoms requiring hospitalization in a medical unit (n = 35) or intensive care unit (n = 28). Specificity was evaluated for 42 patients with previous viral and parasitic diseases as well as a high level of rheumatic factor. The sensitivity of OG was 95.8% (95% confidence interval [CI95%], 89.6 to 98.8) for samples collected ≥10 days after the onset of symptoms, which was equivalent to the sensitivity of ASIA of 90.5% (CI95%, 82.8 to 95.6). OG uncovered six false-negative results of ASIA, of which two had only IgM with OG. Specificity was 100% (CI95%, 93.4 to 100) with both tests on samples, including patients infected with endemic coronavirus. Overall, OG performance characteristics indicate that the test is suitable for routine use in clinical laboratories, and its performance is equivalent to that of immunoassay. Testing OG on a larger asymptomatic population may be needed to confirm these results.