Senefeld, Jonathon W.

This case study, longitudinal analysis of freestyle swimming performances before and after 2 yr of feminizing gender-affirming hormone therapy of an elite transgender woman (male sex, female gender identity), demonstrates superior performance relative to rank-matched female swimmers and a lower performance gap than previously observed between elite male and female swimmers.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15–20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Abstract Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.

ImportancePatients who are immunocompromised have increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19) because they less frequently mount antibody responses to vaccines. Although neutralizing anti-spike monoclonal-antibody treatment has been widely used to treat COVID-19, evolutions of SARS-CoV-2 have been associated with monoclonal antibody-resistant SARS-CoV-2 variants and greater virulence and transmissibility of SARS-CoV-2. Thus, the therapeutic use of COVID-19 convalescent plasma has increased on the presumption that such plasma contains potentially therapeutic antibodies to SARS-CoV-2 that can be passively transferred to the plasma recipient.ObjectiveTo assess the growing number of reports of clinical experiences of patients with COVID-19 who are immunocompromised and treated with specific neutralizing antibodies via COVID-19 convalescent plasma transfusion.Data SourcesOn August 12, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma use in patients who are immunocompromised.Study SelectionRandomized clinical trials, matched cohort studies, and case report or series on COVID-19 convalescent plasma use in patients who are immunocompromised were included. The electronic search yielded 462 unique records, of which 199 were considered for full-text screening.Data Extraction and SynthesisThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 3 independent reviewers in duplicate and pooled.Main Outcomes and MeauresThe prespecified end point was all-cause mortality after COVID-19 convalescent plasma transfusion; exploratory subgroup analyses were performed based on putative factors associated with the potential mortality benefit of convalescent plasma.ResultsThis systematic review and meta-analysis included 3 randomized clinical trials enrolling 1487 participants and 5 controlled studies. Additionally, 125 case series or reports enrolling 265 participants and 13 uncontrolled large case series enrolling 358 participants were included. Separate meta-analyses, using models both stratified and pooled by study type (ie, randomized clinical trials and matched cohort studies), demonstrated that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for the amalgam of both randomized clinical trials and matched cohort studies (risk ratio [RR], 0.63 [95% CI, 0.50-0.79]).Conclusions and RelevanceThese findings suggest that transfusion of COVID-19 convalescent plasma is associated with mortality benefit for patients who are immunocompromised and have COVID-19.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Abstract The anti-spike T-cell and antibody responses to SARS-CoV-2 mRNA vaccines in patients with B-cell malignancies were examined in a real-world setting. A next-generation sequencing (NGS)–based molecular assay was used to assess SARS-CoV-2–specific T-cell responses. After the second dose, 58% (166/284) of seropositive and 45% (99/221) of seronegative patients display anti-spike T cells. The percentage of patients who displayed T-cell response was higher among patients receiving mRNA-1273 vaccines compared with those receiving BNT162b2 vaccines. After the third vaccination, 40% (137/342) of patients seroconverted, although only 22% displayed sufficient antibody levels associated with the production of neutralizing antibodies. 97% (717/738) of patients who were seropositive before the third dose had markedly elevated anti-spike antibody levels. Anti-spike antibody levels, but not T-cell responses, were depressed by B cell–directed therapies. Vaccinated patients with B-cell malignancies with a poor response to SARS-CoV-2 vaccines may remain vulnerable to COVID-19 infections. Significance: This study represents the first investigation of SARS-CoV-2–specific immune responses to vaccination in a patient registry using an NGS-based method for T-cell receptor repertoire–based analysis combined with anti-spike antibody assessments. Vaccinated patients with B cell–derived hematologic malignancies are likely at higher risk of infection or severe COVID-19. This article is highlighted in the In This Issue feature, p. 476