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Objectives This article observes the mean daily dose of fentanyl required for adequate sedation in critically ill, mechanically ventilated children randomized to receive dexmedetomidine or placebo.Methods We conducted Dexmedetomidine Opioid Sparing Effect in Mechanically Ventilated Children (DOSE), a multicenter, double-blind, randomized, placebo-controlled, dose-escalating trial. We enrolled children aged 35 weeks postmenstrual to 17 years (inclusive) admitted across 13 pediatric multidisciplinary and cardiac intensive care units. Adequate sedation was based on a State Behavioral Score and Richmond Agitation-Sedation Scale of -1 or lower. Only the first two dexmedetomidine dosing cohorts opened for enrollment, due to early trial closure during the coronavirus 2019 pandemic. Thirty children were randomized over 13 months and included in the analyses.Results Demographic and baseline characteristics were not different between dexmedetomidine and placebo cohorts. Similarly, mean daily fentanyl use was not different, using an unadjusted mixed regression model that considered treatment, time, and a treatment-by-time interaction. Adverse events and safety events of special interest were not different between cohorts.Conclusion The DOSE trial revealed that dexmedetomidine added to fentanyl does not impact safety and may not spare fentanyl use in critically ill children, although the trial did not meet its recruitment goals, due to early closure during the coronavirus 2019 pandemic. More rigorous inpatient pediatric trials like DOSE that study critically ill, mechanically ventilated children are needed. Despite the many obstacles faced, the DOSE trial presents challenges from which the greater research community can learn and use to optimize future therapeutic trials in children.
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Purpose: The safety of SARS-CoV-2 mRNA vaccines in solid organ transplant recipients (SOTRs) remains unknown. We investigated adverse events in SOTRs who received these mRNA vaccines. Methods: We studied SOTRs between 12/16/2020 - 2/10/2021 who received at least one dose of a vaccine. Vaccine reactogenicity within one week following the first or second dose was self-reported via an interactive, online platform. Results: A total of 790 SOTRs received either the Pfizer/BioNTech (49%) or Moderna (51%) vaccine. Most participants have, thus far, received only one dose, but 211 (27%) received both doses. The median (IQR) age was 58 (43-68), with 57% female, 90% White, and 81% college educated. Organs transplanted include kidney (56%), liver (20%), and heart (16%), with a median (IQR) of 6 (3-13) years since transplantation. There were no reports of new COVID-19 infection, acute rejection, anaphylaxis requiring epinephrine, or new neurological conditions such as Guillain- Barré or Bell's palsy. Overall, moderate to severe local and systemic adverse reactions remained low (Figure 1). Comparison between the first and second dose showed that moderate to severe systemic adverse reactions, while uncommon, were higher after the second dose, including fatigue (22% vs 12%, p<0.001), headache (14% vs. 8%, p<0.01), chills (6% vs. 2%, p<0.01), and fever (3% vs. 1%, p<0.001)(Table 1). Conclusions: In our observational cohort, there were no reports of new COVID-19 infection, acute rejection, anaphylaxis requiring epinephrine, or new neurological conditions following SARS-CoV-2 mRNA vaccination. While uncommon, moderate to severe systemic adverse reactions were higher after the second dose. Thus far, there are no large safety concerns for SARS-CoV-2 mRNA vaccines in SOTRs.
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Purpose: Given substantial challenges with vaccine allocation and evidence for short-term vaccine efficacy after a single dose of SARS-CoV-2 mRNA vaccines in clinical trials, some have proposed prioritizing first dose administration to reduce COVID-19 morbidity, potentially resulting in delays of second dose administration, or even purposefully withholding second doses for much longer intervals than evaluated in the clinical trials. However, this evidence is largely based off of the early vaccine trials which largely excluded immunocompromised patients. To better understand the immunogenicity of the available SARS-CoV-2 vaccines in immunocompromised individuals, we quantified the humoral response to the first dose of SARS-CoV-2 vaccine in solid organ transplant recipients (SOTRs). Methods: SOTRs who underwent SARS-CoV-2 vaccination were recruited to participate in this study. Participants underwent at-home blood sampling with the TAPIITM Blood Collection Device (7SBio, Medford, MA) or venipuncture. TapIITM samples were tested on the EUROIMMUN enzyme immunoassay (EIA) which tests for IgG to SARS-CoV-2 spike protein. Venipuncture samples were tested on the Roche Elecsys® EIA which tests for antibodies against the receptor binding domain of the SARS-CoV-2 spike protein. Both tests are semi-quantitative and consistent correlates of neutralizing immunity. Results: We studied 279 SOTRs between 12/29/20-2/12/21. None had a prior COVID-19. Median (IQR) age was 51 (40-65) years, 64% were female, 87% were white, and 6% Hispanic/Latino. Median (IQR) time since transplant was 6 (3-13) years;maintenance immunosuppression included tacrolimus (96%), steroids (53%), mycophenolate (74%), azathioprine (9%), sirolimus (4%), everolimus (4%). At a median (IQR) of 20 (15-23) days after the first dose, antibody was detectable in only 16% of participants (binomial exact 95% confidence interval 12-21%). Those not on anti-metabolite maintenance immunosuppression were 5.2 times (95% CI 3.1-8.7, p <0.001) more likely to develop an antibody response. Conclusions: The vast majority of participants did not mount appreciable antibody responses. However, those not on anti-metabolite maintenance immunosuppression were more likely to develop antibody responses. These results contrast dramatically with the robust early immunogenicity observed in mRNA vaccine trials. These findings are an important reminder that any individual with potential immune compromise should not assume they have achieved an immune response to the SARS-CoV-2 vaccine after a first dose.
ABSTRACT
Purpose: The response to SARS-CoV-2 may be blunted in transplant recipients, impacting reinfection risk, treatment selection, and vaccine protocols. We quantified antibody response and durability after COVID-19 in solid organ transplant recipients (SOTRs). Methods: SOTRs with PCR-confirmed COVID-19 were recruited through the EMR August 21-October 15, 2020. Participants underwent at-home blood sampling with the TAPTM Blood Collection Device, Second Edition (7SBio, Medford, MA). Serum samples were screened using Elecsys® anti-SARS-CoV-2 immunoassay (Roche), which uses a recombinant protein representing the nucleocapsid antigen. Confirmatory testing was performed using EUROIMMUN anti-SARS-CoV-2 enzyme-linked immuosorbent assay (ELISA) for semi-quantitative detection of IgG antibodies to spike protein (anti-S1-IgG), a likely correlate of neutralizing immunity. Results: Eighteen SOTRs were studied, for whom COVID-19 occurred at a median of 6 years (IQR 2-9) post-transplant. Median age was 56 years (IQR 42-63);56% were female;33% were Black and 11% were Hispanic. Most participants (89%) had experienced COVID-19 symptoms;72% were hospitalized. Among those hospitalized, 15% were admitted to the ICU and 8% were mechanically ventilated. COVID-19 convalescent plasma (CCP) was administered to 3 kidney and 2 lung recipients. At median 98 days (IQR 55-147) after COVID-19 diagnosis, 78% had reactive screening immunoassays (Table 1). Of the four patients with non-reactive immunoassays, 2 were the lung recipients treated with CCP and 1 was the kidney recipient receiving IVIg. Of those who screened positive, anti-S1-IgG was detectable in 83%. SOTRs who received CCP and/or IVIg were less likely to develop anti-S1- IgG and had lower antibody levels. Conclusions: We found antibody levels suggestive of neutralizing immunity in the majority of participants. However, those who were administered CCP and/or IVIg were less likely to mount a durable immune response. This raises the possibility that exogenous antibody preparations may blunt durable antibody formation. We observed a significant association between more severe disease and higher antibody levels. Seropositivity might decline over time;however, we were unable to distinguish between impaired production or rapid decrement. Our findings are important for individuals with compromised immune systems, whether deliberately for conditions like organ transplantation and cancer, or naturally in the elderly, frail, and autoimmune populations.