COVID-19 Therapeutics: Use, Mechanism of Action, and Toxicity (Vaccines, Monoclonal Antibodies, and Immunotherapeutics).

SARS-CoV-2 emerged in December 2019 and led to the COVID-19 pandemic. Efforts to develop therapeutics have led to innovations such as mRNA vaccines and oral antivirals. Here we provide a narrative review of the biologic therapeutics used or proposed to treat COVID-19 during the last 3 years. This paper, along with its companion that covers xenobiotics and alternative remedies, is an update to our 2020 paper. Monoclonal antibodies prevent progression to severe disease, are not equally effective across variants, and are associated with minimal and self-limited reactions. Convalescent plasma has side effects like monoclonal antibodies, but with more infusion reactions and less efficacy. Vaccines prevent progression for a larger part of the population. DNA and mRNA vaccines are more effective than protein or inactivated virus vaccines. After mRNA vaccines, young men are more likely to have myocarditis in the subsequent 7 days. After DNA vaccines, those aged 30-50 are very slightly more likely to have thrombotic disease. To all vaccines we discuss, women are slightly more likely to have an anaphylactic reaction than men, but the absolute risk is small.

COVID-19 Therapeutics: Use, Mechanism of Action, and Toxicity (Xenobiotics).

SARS-CoV-2 emerged in 2019 and led to the COVID-19 pandemic. Efforts to develop therapeutics against SARS-Cov-2 led to both new treatments and attempts to repurpose existing medications. Here, we provide a narrative review of the xenobiotics and alternative remedies used or proposed to treat COVID-19. Most repositioned xenobiotics have had neither the feared toxicity nor the anticipated efficacy. Repurposed viral replication inhibitors are not efficacious and frequently associated with nausea, vomiting, and diarrhea. Antiviral medications designed specifically against SARS-CoV-2 may prevent progression to severe disease in at-risk individuals and appear to have a wide therapeutic index. Colloidal silver, zinc, and ivermectin have no demonstrated efficacy. Ivermectin has a wide therapeutic index but is not efficacious and acquiring it from veterinary sources poses additional danger. Chloroquine has a narrow therapeutic index and no efficacy. A companion review covers vaccines, monoclonal antibodies, and immunotherapies. Together, these two reviews form an update to our 2020 review.

Development of a Parent-Reported Outcome Measure for Febrile Infants ≤60 Days Old.

OBJECTIVE: We aimed to develop a parent-reported outcome measure for febrile infants 60 days or younger evaluated in the emergency department. METHODS: We conducted a 3-part study: (1) individual, semistructured interviews with parents of febrile infants 60 days or younger to generate potential items for the measure; (2) expert review with pediatric emergency medicine physicians and member checking with parents, who rated each item's clarity and relevance using 4-point scales; and (3) cognitive interviews with a new sample of parents, who gave feedback and rated the measure's ease of use on a 4-point scale. The measure was iteratively revised during each part of the development process. RESULTS: In part 1, we interviewed 24 parents of 21 infants. Interviews revealed several themes: parents' experiences with medical care, communication, and decision making; parents' emotions, particularly worry, fear, and stress; the infant's outcomes valued by parents; and the impact of the infant's illness on the family. From these themes, we identified 22 potential items for inclusion in the measure. In part 2, 10 items were revised for clarity based on feedback from physicians and parents, primarily under the domains of parents' emotions and the infant's outcomes. In part 3, we further revised the measure for clarity and added an item. The final measure included 23 items and was rated as excellent in its ease of use. CONCLUSIONS: The 23-item parent-reported outcome measure includes the experiences and outcomes important to parents. Further studies are needed to evaluate the measure's psychometric properties.

Generation of bispecific antibodies by structure-guided redesign of IgG constant regions.

Bispecific antibodies (BsAbs) form an exciting class of bio-therapeutics owing to their multispecificity. Although numerous formats have been developed, generation of hetero-tetrameric IgG1-like BsAbs having acceptable safety and pharmacokinetics profiles from a single cell culture system remains challenging due to the heterogeneous pairing between the four chains. Herein, we employed a structure-guided approach to engineer mutations in the constant domain interfaces (CH1-CL and CH3-CH3) of heavy and κ light chains to prevent heavy-light mispairing in the antigen binding fragment (Fab) region and heavy-heavy homodimerization in the Fc region. Transient co-transfection of mammalian cells with heavy and light chains of pre-existing antibodies carrying the engineered constant domains generates BsAbs with percentage purity ranging from 78% to 85%. The engineered BsAbs demonstrate simultaneous binding of both antigens, while retaining the thermal stability, Fc-mediated effector properties and FcRn binding properties of the parental antibodies. Importantly, since the variable domains were not modified, the mutations may enable BsAb formation from antibodies belonging to different germline origins and isotypes. The rationally designed mutations reported in this work could serve as a starting point for generating optimized solutions required for large scale production.

Development of an App to Facilitate Communication and Shared Decision-making With Parents of Febrile Infants ≤ 60 Days Old.

OBJECTIVES: We aimed to develop and test a tool to engage parents of febrile infants ≤ 60 days of age evaluated in the emergency department (ED). The tool was designed to improve communication for all parents and to support shared decision-making (SDM) about whether to perform a lumbar puncture (LP) for infants 29 to 60 days of age. METHODS: We conducted a multiphase development and testing process: 1) individual, semistructured interviews with parents and clinicians (pediatric and general emergency medicine [EM] physicians and pediatric EM nurses) to learn their preferences for a communication and SDM tool; 2) design of a "storyboard" of the tool with design impression testing; 3) development of a software application (i.e., app) prototype, called e-Care; and 4) usability testing of e-Care, using qualitative assessment and the system usability scale (SUS). RESULTS: We interviewed 27 parents and 23 clinicians. Interviews revealed several themes, including that a communication tool should augment but not replace verbal communication; a Web-based format was preferred; and information about infections and testing, including the rationales for specific tests, would be valuable. We then developed separate versions of e-Care for infants ≤ 28 days and 29 to 60 days of age, in both English and Spanish. The e-Care app includes four sections: 1) homepage; 2) why testing is done; 3) what tests are done; and 4) what happens after testing, including a table for parents of infants 29 to 60 days of age to compare the risks/benefits of LP in preparation for an SDM conversation. Parents and clinicians reported that e-Care was understandable and helpful. The mean SUS score was 90.3 (95% confidence interval = 84 to 96.6), representing "excellent" usability. CONCLUSIONS: The e-Care app is a useable and understandable tool to support communication and SDM with parents of febrile infants ≤ 60 days of age in the ED.

Rapid Diagnostic Tests for Meningitis and Encephalitis-BioFire.

Meningitis and encephalitis (ME) are important causes of morbidity and mortality worldwide. Patients suspected of having ME are often hospitalized and started on empiric antimicrobial treatment, because of the potential adverse consequences of delaying the diagnosis or treatment. Multiplexed polymerase chain reaction panels are one of several rapid diagnostic technologies that have the potential to overcome some of the limitations of conventional diagnostic methods for ME. The BioFire FilmArray Meningitis/Encephalitis Panel was the first Food and Drug Administration-cleared multiplex polymerase chain reaction for the evaluation of cerebrospinal fluid samples, able to identify 14 organisms in a single test reaction. This newer rapid diagnostic tool has an overall high sensitivity and specificity for the diagnosis of ME with a fast turnaround time and has the potential to improve resource utilization for patients presenting with suspicion of ME. However, further research is needed to determine its optimal use in the evaluation of patients with suspected ME.

Cerebrospinal Fluid Profiles of Infants ≤60 Days of Age With Bacterial Meningitis.

OBJECTIVES: We aimed to describe the cerebrospinal fluid (CSF) profiles of infants ≤60 days old with bacterial meningitis and the characteristics of infants with bacterial meningitis who did not have CSF abnormalities. METHODS: We included infants ≤60 days old with culture-positive bacterial meningitis who were evaluated in the emergency departments of 11 children's hospitals between July 1, 2011, and June 30, 2016. From medical records, we abstracted clinical and laboratory data. For infants with traumatic lumbar punctures (CSF red blood cell count of ≥10 000 cells per mm3), we used a red blood cell count/white blood cell (WBC) count correction factor of 1000:1 to determine the corrected CSF WBC count. We calculated the sensitivity for bacterial meningitis of a CSF Gram-stain and corrected CSF pleocytosis (≥16 WBCs per mm3 for infants ≤28 days old and ≥10 WBCs per mm3 for infants 29-60 days old). RESULTS: Among 66 infants with bacterial meningitis, the sensitivity of a CSF Gram-stain was 71.9% (95% confidence interval [CI]: 59.2-82.4), and the sensitivity of corrected CSF pleocytosis was 80.3% (95% CI: 68.7-89.1). The sensitivity of combining positive Gram-stain results with corrected CSF pleocytosis was 86.4% (95% CI: 75.7-93.6). Of 9 infants with meningitis who had a negative Gram-stain result and no corrected CSF pleocytosis, 8 (88.9%) had either an abnormal peripheral WBC count (>15 000 or <5000 cells per µL) or bandemia >10%. CONCLUSIONS: Most infants ≤60 days old with bacterial meningitis have CSF pleocytosis or a positive Gram-stain result. Infants with no CSF pleocytosis and a negative Gram-stain result are unlikely to have bacterial meningitis in the absence of other laboratory abnormalities.