Coronavirus COVID-19 Update for April 11, 2021

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Clinical Reports

Effect of Early Treatment with Ivermectin among Patients with Covid-19
Study authors conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2–positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19.
Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission
Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterization Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).
Children and COVID-19: State Date Report
A joint report from the American Academy of Pediatrics and the Children’s Hospital Association. Summary of publicly reported data from 49 states, NYC, DC, PR, and GU Version: 5/05/22. The numbers in this report represent cumulative counts since states began reporting. The data are based on how public agencies collect, categorize and post information. All data reported by state/local health departments are preliminary and subject to change and reporting may change over time. Notably, in the summer of 2021 and winter of 2022, some states have revised cases counts previously reported, begun reporting less frequently, or dropped metrics previously reported. For example, due to several changes on their dashboards and the data currently available, AL, TX, HI, DC and MS data in this report are not current (cumulative data through 7/29/21, 8/26/21, 1/13/22, 3/3/22, and 3/10/22 respectively). Readers should consider these factors. States may have additional information on their web sites.

Antiviral Therapeutics and Vaccines

Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age
The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age was unknown. Part 1 of this ongoing phase 2–3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, study researchers randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults.
FDA Limits Use of Janssen COVID-19 Vaccine to Certain Individuals
The U.S. Food and Drug Administration has limited the authorized use of the Janssen COVID-19 Vaccine to individuals 18 years of age and older for whom other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and to individuals 18 years of age and older who elect to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine. After conducting an updated analysis, evaluation and investigation of reported cases, the FDA has determined that the risk of thrombosis with thrombocytopenia syndrome (TTS), a syndrome of rare and potentially life-threatening blood clots in combination with low levels of blood platelets with onset of symptoms approximately one to two weeks following administration of the Janssen COVID-19 Vaccine, warrants limiting the authorized use of the vaccine.
Recall of B cell memory depends on relative locations of prime and boost immunization
Immunization or microbial infection can establish long-term B cell memory not only systemically but also locally. Evidence has suggested that local B cell memory contributes to early local plasmacytic responses after secondary challenge. However, it is unclear whether locality of immunization plays any role in memory B cell participation in recall germinal centers (GCs), which is essential for updating their B cell antigen receptors (BCRs). Using single B cell culture and fate mapping, researchers have characterized BCR repertoires in recall GCs after boost immunizations at sites local or distal to the priming. Local boosts with homologous antigen recruit the progeny of primary GC B cells to recall GCs more efficiently than do distal boosts. Recall GCs elicited by local boosts contain significantly more B cells with elevated levels of immunoglobulin (Ig) mutation and higher avidity BCRs. This local preference is unaffected by blocking CD40:CD154 interaction to terminate active, GC responses. Local boosts with heterologous antigens elicit secondary GCs with B cell populations enriched for cross-reactivity to the prime and boost antigens; in contrast, cross-reactive GC B cells are rare after distal boosts. These results suggest that local B cell memory is retained in the form of memory B cells, GC B cells, and GC phenotype B cells that are independent of organized GC structures and that these persistent “primed B cells” contribute to recall GC responses at local sites. These findings indicate the importance of locality in humoral immunity and inform serial vaccination strategies for evolving viruses.
Tixagevimab/Cilgavimab for Treatment of Hospitalised COVID-19 Patients: A Randomised, Double-Blind, Phase 3 Trial
These are the results from a phase 3, blinded, randomized, placebo-controlled trial, adults hospitalized for COVID-19 at 81 sites on four continents were assigned to receive intravenous tixagevimab 300 mg/cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. 1,417 in the primary modified intention-to-treat population were infused with tixagevimab/cilgavimab (n=710) or placebo (n=707). By day 90, sustained recovery was achieved by 617 (87%) tixagevimab/cilgavimab and 595 (84%) placebo group participants in the full cohort (rate ratio 1.08; 95%CI, 0.97-1.20; p=0.21). Results were similar in the seronegative subgroup (rate ratio 1.14; 95%CI, 0.97-1.34; p=0.13). Mortality was lower in the tixagevimab/cilgavimab (61 [8.6%]) versus placebo (86 [12.2%]) group (hazard ratio 0.70; 95%CI, 0.50-0.97; p=0.03). The composite safety outcome occurred in 178 (25%) tixagevimab/cilgavimab and 212 (30%) placebo group participants (hazard ratio 0.83, 95%CI 0.68-1.01; p=0.06).

Diagnostics

Detection of SARS-CoV-2 by Canine Olfaction: A Pilot Study
In this double-blinded, case-control, validation study, sweat samples from inpatients and outpatients were obtained and tested for SARS-CoV-2 by PCR. Medical detection dogs were trained to distinguish SARS CoV-2 positive samples from SARS-CoV-2 negative samples, using reward-based reinforcement. Samples were obtained from 584 individuals (6 to 97 years of age; 24% positive SARS CoV-2 samples and 76% negative SARS CoV-2 samples). In the Testing Phase, all dogs performed with high accuracy in detecting SARS-CoV-2: overall diagnostic sensitivity was 98% and specificity was 92%. In a follow-up phase, one dog (that was Tess a 2yo Lab-we will get back to her) screened 153 patients for SARS-CoV-2 in a hospital setting with 96% diagnostic sensitivity and 100% specificity.
Screening for SARS-CoV-2 Persistence in Long COVID Patients using Sniffer Dogs and Scents from Axillary Sweats Samples
Since April 2020, the veterinarians of the National Veterinary School of Alfort (EnvA) have been training dogs to detect SARSCoV-2 virus in human sweat, by detecting Volatile Organic Compounds (VOCs) in infected patients. The VOCs exact nature, although specific to SARS-CoV-2 as compared to other viruses, is still under identification. During the acute COVID-19 phase, the first results show a detection sensitivity close to 95% and a specificity of 97% for confirmed cases (positive PCR) versus asymptomatic and negative PCR subjects. For long COVID patients, the persistence of RNA and/or viral proteins is a widely discussed hypothesis. The literature has documented the viral RNA persistence in olfactory slots, digestive tissue sections, brain and viral proteins persistence in monocytes. Therefore, it is of great scientific interest to assess whether dogs can identify SARS-CoV-2 persistence in long COVID patients, as they do in the initial phase of the disease. This study, performed in Long COVID patients, shows for the first time that dogs can detect Volatile Organic Compounds (VOCs) up to 1.5 year after the initial phase of COVID-19. These results strongly suggest that SARS-CoV-2 may persist at least in some Long COVID patients. Furthermore, they show that dogs can detect VOCs in some patients with a negative SARS-CoV-2 serology.
Diagnostic Utility of a Ferritin-to-Procalcitonin Ratio to Differentiate Patients With COVID-19 From Those With Bacterial Pneumonia: A Multicenter Study
In this study, researchers assess the role of the ferritin-to-procalcitonin (F/P) ratio to classify pneumonia cases into those due to COVID-19 vs those due to bacterial pathogens. This multicenter case–control study compared patients with COVID-19 with those with bacterial pneumonia, admitted between March 1 and May 31, 2020. Patients with COVID-19 and bacterial pneumonia co-infection were excluded. The F/P in patients with COVID-19 vs with bacterial pneumonia were compared. Receiver operating characteristic curve analysis determined the sensitivity and specificity of various cutoff F/P values for COVID-19 vs bacterial pneumonia. A total of 242 COVID-19 pneumonia cases and 34 bacterial pneumonia controls were included. Patients with COVID-19 pneumonia had a lower mean age (57.1 vs 64.4 years; P = .02) and a higher body mass index (30.74 vs 27.15 kg/m²; P = .02) compared with patients with bacterial pneumonia. Cases and controls had a similar proportion of women (47% vs 53%; P = .5), and COVID-19 patients had a higher prevalence of diabetes mellitus (32.6% vs 12%; P = .01). The median F/P was significantly higher in patients with COVID-19 (4037.5) compared with the F/P in bacterial pneumonia (802; P < .001). An F/P ≥877, used to diagnose COVID-19, resulted in a sensitivity of 85% and a specificity of 56%, with a positive predictive value of 93.2% and a likelihood ratio of 1.92. In multivariable analyses, an F/P ≥877 was associated with greater odds of identifying a COVID-19 case (odds ratio, 11.27; 95% CI, 4–31.2; P < .001). An F/P ≥877 increases the likelihood of COVID-19 pneumonia compared with bacterial pneumonia.

Epidemiology

Prevalence of Anosmia in 10.157 Pediatric COVID-19 Cases - Multicenter Study from Turkey
COVID-19-related anosmia is a remarkable and disease-specific finding. With this multicenter cohort study, researchers aimed to determine the prevalence of anosmia in pediatric cases with COVID-19 from Turkey and make an objective assessment with a smell awareness questionnaire. This multicenter prospective cohort study was conducted with pediatric infection clinics in 37 centers in 19 different cities of Turkey between October 2020 and March 2021. The symptoms of 10,157 COVID-19 cases 10–18 years old were examined. Age, gender, other accompanying symptoms, and clinical severity of the disease of cases with anosmia and ageusia included in the study were recorded. The cases were interviewed for the smell awareness questionnaire at admission and one month after the illness. Anosmia was present in 12.5% (1.266/10.157) of COVID-19 cases 10-18 years of age. The complete records of 1053 patients followed during the study period were analyzed. The most common symptoms accompanying symptoms with anosmia were ageusia in 885 (84%) cases, fatigue in 534 cases (50.7%), and cough in 466 cases (44.3%). Anosmia was recorded as the only symptom in 84 (8%) of the cases. One month later, it was determined that anosmia persisted in 88 (8.4%) cases. In the smell awareness questionnaire, the score at admission was higher than the score one month later (P< 0.001). With this study, we have provided the examination of a large case series across Turkey. Anosmia and ageusia are specific symptoms seen in cases of COVID-19. With the detection of these symptoms, it should be aimed to isolate COVID-19 cases in the early period and reduce the spread of the infection. Such studies are important because the course of COVID-19 in children differs from adults and there is limited data on the prevalence of anosmia.
COVID-19 Risk Assessment of Public Events
Researchers describe a risk assessment framework to support event planning during COVID-19 waves. The method was developed in partnership with public health officials in Austin, Texas. The framework is based on a previously published model. The inputs to our calculations include the following; the local prevalence of COVID-19, epidemiological properties of current variants, the structure of the event, including the number of attendees, types and duration of activities, density of interactions, and ventilation, COVID-related precautions for the event, including vaccine, testing, and face mask requirements, and local demographic information. The risk assessment framework uses the above inputs to estimate the following quantities: the number of attendees likely to arrive infected, the reproduction number of COVID-19 at the event, the number of attendees likely to become infected at the event, and the number of additional infections that will occur in Austin in the subsequent four weeks, stemming from infections occurring at the event.