Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Three doses of COVID-19 mRNA vaccine induce class-switched antibody responses in inflammatory arthritis patients on immunomodulatory therapies.

Patients with inflammatory arthritis (IA) are at increased risk of severe COVID-19 due to medication-induced immunosuppression that impairs host defenses. The aim of this study was to assess antibody and B cell responses to COVID-19 mRNA vaccination in IA patients receiving immunomodulatory therapies. Adults with IA were enrolled through the Johns Hopkins Arthritis Center and compared with healthy controls (HC). Paired plasma and peripheral blood mononuclear cell (PBMC) samples were collected prior to and 30 days or 6 months following the first two doses of mRNA vaccines (D2; HC=77 and IA=31 patients), or 30 days following a third dose of mRNA vaccines (D3; HC=11 and IA=96 patients). Neutralizing antibody titers, total binding antibody titers, and B cell responses to vaccine and Omicron variants were analyzed. Anti-Spike (S) IgG and S-specific B cells developed appropriately in most IA patients following D3, with reduced responses to Omicron variants, and negligible effects of medication type or drug withholding. Neutralizing antibody responses were lower compared to healthy controls after both D2 and D3, with a small number of individuals demonstrating persistently undetectable neutralizing antibody levels. Most IA patients respond as well to mRNA COVID-19 vaccines as immunocompetent individuals by the third dose, with no evidence of improved responses following medication withholding. These data suggest that IA-associated immune impairment may not hinder immunity to COVID-19 mRNA vaccines in most individuals.

Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUND: The COVID-19 convalescent plasma (CCP) viral specific antibody levels that translate into recipient post-transfusion antibody levels sufficient to prevent disease progression is not defined. METHODS: This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low post-transfusion antibody levels was established by two methods: 1) analyzing virus neutralization-equivalent anti-S-RBD IgG responses in donors or 2) receiver operating characteristic (ROC) analysis. RESULTS: SARS-CoV-2 anti-S-RBD IgG antibody was diluted by a factor of 21.3 into post-transfusion seronegative recipients from matched donor units. Viral specific antibody delivered approximated 1.2 mg. The high antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP recipient analysis for antibody thresholds correlated to reduced hospitalizations found a significant association with Fisher's exact test between early and high antibodies versus all other CCP recipients (or control plasma) with antibody cutoffs established by both methods-donor virus neutralization-based cutoff: (0/85; 0% versus 15/276; 5.6%) p=0.03 or ROC based cutoff: (0/94; 0% versus 15/267; 5.4%) p=0.01. CONCLUSION: In unvaccinated, seronegative CCP recipients, early transfusion of plasma units corresponding to the upper 30% of all study donors reduced outpatient hospitalizations. These high antibody level plasma units, given early, should be reserved for therapeutic use.Trial registration: NCT04373460. FUNDING: Defense Health Agency and others.

Association of Frailty, Age, and Biological Sex With Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine-Induced Immunity in Older Adults.

BACKGROUND: Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized. METHODS: Plasma samples were collected from older adults (aged 75-98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18-74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs). RESULTS: Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females. CONCLUSIONS: Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

Pharmacokinetics of high-titer anti-SARS-CoV-2 human convalescent plasma in high-risk children.

BACKGROUNDWhile most children who contract COVID-19 experience mild disease, high-risk children with underlying conditions may develop severe disease, requiring interventions. Kinetics of antibodies transferred via COVID-19 convalescent plasma early in disease have not been characterized.METHODSIn this study, high-risk children were prospectively enrolled to receive high-titer COVID-19 convalescent plasma (>1:320 anti-spike IgG; Euroimmun). Passive transfer of antibodies and endogenous antibody production were serially evaluated for up to 2 months after transfusion. Commercial and research ELISA assays, virus neutralization assays, high-throughput phage-display assay utilizing a coronavirus epitope library, and pharmacokinetic analyses were performed.RESULTSFourteen high-risk children (median age, 7.5 years) received high-titer COVID-19 convalescent plasma, 9 children within 5 days (range, 2-7 days) of symptom onset and 5 children within 4 days (range, 3-5 days) after exposure to SARS-CoV-2. There were no serious adverse events related to transfusion. Antibodies against SARS-CoV-2 were transferred from the donor to the recipient, but antibody titers declined by 14-21 days, with a 15.1-day half-life for spike protein IgG. Donor plasma had significant neutralization capacity, which was transferred to the recipient. However, as early as 30 minutes after transfusion, recipient plasma neutralization titers were 6.2% (range, 5.9%-6.7%) of donor titers.CONCLUSIONConvalescent plasma transfused to high-risk children appears to be safe, with expected antibody kinetics, regardless of weight or age. However, current use of convalescent plasma in high-risk children achieves neutralizing capacity, which may protect against severe disease but is unlikely to provide lasting protection.Trial registrationClinicalTrials.gov NCT04377672.FundingThe state of Maryland, Bloomberg Philanthropies, and the NIH (grants R01-AI153349, R01-AI145435-A1, K08-AI139371-A1, and T32-AI052071).

Malaria frontline project: pre-intervention Malaria baseline assessment in Kano and Zamfara States, August 2016.

Introduction: In 2016, the Centers for Disease Control and Prevention and the Government of Nigeria initiated the Malaria Frontline Project in Kano and Zamfara States. The project goal is to improve the quality and coverages of malaria interventions adapting polio program strategy. We conducted a baseline assessment of malaria interventions. Methods: Twenty-four primary health centers per State were selected using probability sampling. Health workers (HW) were purposively sampled to assess their knowledge of national malaria control guidelines. Clients were selected for exit interview to assess health workers´ adherence to the national guidelines. WHO cluster methodology was used to survey heads of household and women of reproductive age on knowledge of malaria prevention, Long Lasting Insecticidal Net (LLIN) ownership and use. Results: Of the 158 HW interviewed, 94.3% knew the correct criteria for malaria diagnosis, 86.1% reported using artemisinin-based therapy to treat uncomplicated malaria. About 45% of HW reported prescribing artemisinin-based combination therapy (ACT) for uncomplicated malaria in first trimester of pregnancy and 39% prescribed quinine. Only 73.9% of fever cases were referred to laboratory as recommended by the national guideline. Households with one LLIN per 2 persons (Kano: 27.1%; Zamfara: 30.0%), LLIN use (Kano: 70.8%; Zamfara: 81.6%) and IPTp1 (Kano: 38.6%; Zamfara: 33.3%). Conclusion: most clinicians have knowledge of national guidelines, but fewer adhere to guidelines in practice. Population LLIN ownership, LLIN use among pregnant women and IPTp are lower than the national targets of 58%, 83% and 75% respectively for 2016. We recommend improving health workers´ technical capacity and adherence to national malaria guidelines.

The ulnar collateral ligament responds to stress in professional pitchers.

BACKGROUND: Our purpose with this study was to determine the response of the ulnar collateral ligament (UCL) in professional pitchers after exposure to a season of pitching and to rest during an off-season. METHODS: In a prospective study supported by Major League Baseball, all pitchers within a single professional baseball club were enrolled. An ultrasound of the ligament was then performed by a single fellowship-trained ultrasonographer at the beginning of the season (T1), the end of the season (T2), and the beginning of the following season (T3). We measured the UCL thickness and ulnotrochlear joint opening at 30° of flexion with and without stress. Two ultrasound images were saved. Inter- and intra-rater reliability were determined. A multivariable analysis was conducted. RESULTS: A total of185 total pitchers were included: 94 pitchers at T1, 83 at T2, and 118 at T3. These pitchers had 12 [7, 15] (median [interquartile range]) years of pitching experience and had a peak velocity of 95 [93, 97] miles/hour. Intra- and inter-rater reliability were excellent. The baseline UCL thickness was associated with peak velocity (P = .031) and prior UCL reconstruction (P = .024). After accounting for pitching experience, peak velocity, and prior UCL reconstruction, thickness increased during the season (P = .002) and decreased during the off-season (P = .001). After accounting for these same variables, valgus laxity at 30° increased during the season (P = .002) and decreased during the off-season (P = .029). CONCLUSION: The UCL responds to stress in professional pitchers by becoming thicker and more lax, and responds to rest by becoming thinner and less lax.

Cervical radiculopathy.

With regards to spinal disorders, neck pain is one of the most common presenting symptoms, only second to low back pain. When pain radiates down the arm and is associated with sensory and motor disturbances, cervical radiculopathy is suspected.

Length of stay in rehabilitation is associated with admission neurologic deficit and discharge destination.

OBJECTIVE: This study explores the link between neurologic deficit as measured by the National Institutes of Health Stroke Scale (NIHSS), and its relationship to length of stay (LOS) and discharge destination. DESIGN: A retrospective chart review was completed of 54 patients admitted for rehabilitation after experiencing a cerebrovascular accident. SETTING: The study was completed in an acute inpatient rehabilitation stroke unit in a large urban tertiary care medical center. PARTICIPANTS: Patients were included in this analysis if their record contained an NIHSS score on both admission and discharge, if they had neuroimaging documentation of an acute hemorrhagic or ischemic stroke, and if they were not transferred away from the rehabilitation unit during their stay. Of 54 cases reviewed, 47 were ultimately included. MAIN OUTCOME MEASUREMENTS: Independent variables included were NIHSS admission and discharge scores, change in score from admission to discharge, discharge destination, age, gender, type of stroke, and use of tissue plasminogen activator. These were examined against the dependent variable, LOS. RESULTS: Greater admission NIHSS scores predicted longer hospital stays. Mean admission and discharge scores were significantly greater for patients discharged to subacute facilities, and LOS was also longer for these patients compared with those discharged to the community. Surprisingly, age was inversely related to LOS, admission score, and discharge score. CONCLUSION: Stroke remains one of the most common reasons for admission to acute care hospitals. The authors know of no studies that have examined the rehabilitation aspect of care incorporating the NIHSS in this manner. This study draws a connection between neurologic impairment by using the NIHSS and LOS and discharge destination in an acute inpatient rehabilitation stroke unit. In the future, multidisciplinary rehabilitation teams may consider using this measure to predict LOS and disposition at discharge from inpatient rehabilitation.