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Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are "noncanonical" immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function., Competing Interests: Competing interests statement:R.E.S. is on the scientific advisory of Miromatrix, Inc. and Lime Therapeutics and is a consultant for Alnylam, Inc. D.C.W. is on the scientific advisory boards of Pano Therapeutics, Inc., and Medical Excellent Capital.

Background: Understanding the risk of chikungunya virus (CHIKV) infection and rheumatic sequelae across populations, including travelers and the military, is critical. We leveraged healthcare delivery data of over 9 million U.S. Military Health System (MHS) beneficiaries to identify cases, and sampled controls, to estimate the risk of post-CHIKV rheumatic sequelae., Methodology/principal Findings: MHS beneficiary CHIKV infections diagnosed 2014-2018 were identified from the Disease Reporting System internet, TRICARE Encounter Data Non-Institutional, and Comprehensive Ambulatory/Professional Encounter Record systems. Non-CHIKV controls were matched (1:4) by age, gender, beneficiary status, and encounter date. The frequency of comorbidities and incident rheumatic diagnoses through December 2018 were derived from International Classification of Diseases codes and compared between cases and controls. Poisson regression models estimated the association of CHIKV infection with rheumatic sequelae. We further performed a nested case-control study to estimate risk factors for post-CHIKV sequelae in those with prior CHIKV. 195 CHIKV cases were diagnosed between July 2014 and December 2018. The median age was 42 years, and 43.6% were active duty. 63/195 (32.3%) of CHIKV cases had an incident rheumatic diagnosis, including arthralgia, polyarthritis, polymyalgia rheumatica, and/or rheumatoid arthritis, compared to 156/780 (20.0%) of controls (p < 0.001). CHIKV infection remained associated with rheumatic sequelae (aRR = 1.579, p = 0.008) after adjusting for prior rheumatic disease and demography. Those with rheumatic CHIKV sequelae had a median 7 healthcare encounters (IQR 3-15). Among CHIKV infections, we found no association between post-CHIKV rheumatic sequelae and demography, service characteristics, or comorbidities., Conclusions/significance: CHIKV infection is uncommon but associated with rheumatic sequelae among MHS beneficiaries, with substantial healthcare requirements in a proportion of cases with such sequelae. No demographic, clinical, or occupational variables were associated with post-CHIKV rheumatic sequelae, suggesting that prediction of these complications is challenging in MHS beneficiaries. These findings are important context for future CHIKV vaccine decision making in this and other populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Financial, operational, and clinical workflow impacts of deploying an automated dispensing cabinet (ADC) in long-term care (LTC) facilities based on actual observations have not been documented in peer-reviewed literature., Objectives: To evaluate the impact of a closed-door pharmacy (CDP) implementing an ADC with unique secure, removable, and transportable locked pockets in an unstudied setting (LTC facilities) for management of first and emergency dose medications., Practice Description: This study was conducted in 1 CDP and 2 LTC facilities., Practice Innovation: Enhancing emergency medication management and inventory tracking in an unstudied setting through implementation of an ADC system featuring unique electronically encoded medication storage pockets that can be prepared in the CDP, locked and securely transported to the LTC, and when inserted into ADC it informs staff of its presence, position, and contents., Evaluation Methods: Mixed methods, pre- and poststudy to assess the impact of replacing manual emergency medication kits with an ADC. Outcomes were evaluated using rapid ethnography with workflow modeling; inventory and delivery reports; a nursing perception survey; and transactional data from the ADC during postimplementation phase., Results: Pharmacy technician preparation time and pharmacist checking time decreased by 59% and 80%, respectively, and standing inventory was reduced by more than $10,000 combined for the CDP and 2 LTCs by replacing emergency medication kits with the ADC. In the LTCs, this change led to a 71% reduction in emergency medication retrieval time, an increase in emergency medication utilization, and a 96% reduction in the cost of unscheduled deliveries. Over 70% of the nurses surveyed favored replacement of the emergency medication kits with the ADC system., Conclusion: Replacing manual emergency medication kit with the described ADC system improved workflow efficiency in the CDP and LTC. It also significantly reduced unscheduled (STAT) deliveries and standing inventory and increased the availability of medications commonly used., Competing Interests: Disclosure D.D., M.J. and J.L. are employees and shareholders of BD. During the duration of the study, S.F. was an employee of BD and DT was an employee and is a shareholder of BD. All other authors declare no potential conflicts of interest or financial disclosures., (Copyright © 2024 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Chronic neuropsychological sequelae following SARS-CoV-2 infection, including depression, anxiety, fatigue, and general cognitive difficulties, are a major public health concern. Given the potential impact of long-term neuropsychological impairment, it is important to characterize the frequency and predictors of this post-infection phenotype., Methods: The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study is a longitudinal study assessing the impact of SARS-CoV-2 infection in U.S. Military Healthcare System (MHS) beneficiaries, i.e. those eligible for care in the MHS including active duty servicemembers, dependents, and retirees. Four broad areas of neuropsychological symptoms were assessed cross-sectionally among subjects 1-6 months post-infection/enrollment, including: depression (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), fatigue (PROMIS® Fatigue 7a), and cognitive function (PROMIS® Cognitive Function 8a and PROMIS® Cognitive Function abilities 8a). Multivariable Poisson regression models compared participants with and without SARS-CoV-2 infection history on these measures, adjusting for sex, ethnicity, active-duty status, age, and months post-first positive or enrollment of questionnaire completion (MPFP/E); models for fatigue and cognitive function were also adjusted for depression and anxiety scores., Results: The study population included 2383 participants who completed all five instruments within six MPFP/E, of whom 687 (28.8%) had at least one positive SARS-CoV-2 test. Compared to those who had never tested positive for SARS-CoV-2, the positive group was more likely to meet instrument-based criteria for depression (15.4% vs 10.3%, p<0.001), fatigue (20.1% vs 8.0%, p<0.001), impaired cognitive function (15.7% vs 8.6%, p<0.001), and impaired cognitive function abilities (24.3% vs 16.3%, p<0.001). In multivariable models, SARS-CoV-2 positive participants, assessed at an average of 2.7 months after infection, had increased risk of moderate to severe depression (RR: 1.44, 95% CI 1.12-1.84), fatigue (RR: 2.07, 95% CI 1.62-2.65), impaired cognitive function (RR: 1.64, 95% CI 1.27-2.11), and impaired cognitive function abilities (RR: 1.41, 95% CI 1.15-1.71); MPFP/E was not significant., Conclusions: Participants with a history of SARS-CoV-2 infection were up to twice as likely to report cognitive impairment and fatigue as the group without prior SARS-CoV-2 infection. These findings underscore the continued importance of preventing SARS-CoV-2 infection and while time since infection/enrollment was not significant through 6 months of follow-up, this highlights the need for additional research into the long-term impacts of COVID-19 to mitigate and reverse these neuropsychological outcomes., Competing Interests: Potential conflicts of interest. S. D. P., T. H. B., J.S.R., and M.P.S. report that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the Henry M. Jackson Foundation (HJF) were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US Government COVID-19 response. Neither is related to the work presented here. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Introduction: Natural killer (NK) cells can both amplify and regulate immune responses to vaccination. Studies in humans and animals have observed NK cell activation within days after mRNA vaccination. In this study, we sought to determine if baseline NK cell frequencies, phenotype, or function correlate with antibody responses or inflammatory side effects induced by the Pfizer-BioNTech COVID-19 vaccine (BNT162b2)., Methods: We analyzed serum and peripheral blood mononuclear cells (PBMCs) from 188 participants in the Prospective Assessment of SARS-CoV-2 Seroconversion study, an observational study evaluating immune responses in healthcare workers. Baseline serum samples and PBMCs were collected from all participants prior to any SARS-CoV-2 infection or vaccination. Spike-specific IgG antibodies were quantified at one and six months post-vaccination by microsphere-based multiplex immunoassay. NK cell frequencies and phenotypes were assessed on pre-vaccination PBMCs from all participants by multi-color flow cytometry, and on a subset of participants at time points after the 1 st and 2 nd doses of BNT162b2. Inflammatory side effects were assessed by structured symptom questionnaires, and baseline NK cell functionality was quantified by an in vitro killing assay on participants that reported high or low post-vaccination symptom scores., Results: Key observations include: 1) circulating NK cells exhibit evidence of activation in the week following vaccination, 2) individuals with high symptom scores after 1 st vaccination had higher pre-vaccination NK cytotoxicity indices, 3) high pre-vaccination NK cell numbers were associated with lower spike-specific IgG levels six months after two BNT162b2 doses, and 4) expression of the inhibitory marker NKG2A on immature NK cells was associated with higher antibody responses 1 and 6 months post-vaccination., Discussion: These results suggest that NK cell activation by BNT162b2 vaccination may contribute to vaccine-induced inflammatory symptoms and reduce durability of vaccine-induced antibody responses., Competing Interests: SP, TB, and DT report that the Uniformed Services University USU Infectious Disease Clinical Research Program IDCRP, a US Department of Defense institution, and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. HJF were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both trials were part of the US Government COVID-19 response. Neither is related to the work presented here. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Graydon, Conner, Dunham, Olsen, Goguet, Coggins, Rekedal, Samuels, Jackson-Thompson, Moser, Lindrose, Hollis-Perry, Wang, Maiolatesi, Alcorta, Reyes, Wong, Ramsey, Davies, Parmelee, Ortega, Sanchez, Moller, Inglefield, Tribble, Burgess, O’Connell, Malloy, Pollett, Broder, Laing, Anderson and Mitre.)

Background: Comparison of humoral responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees, those with SARS-CoV-2 infection, or combinations of vaccine/ infection ("hybrid immunity") may clarify predictors of vaccine immunogenicity., Methods: We studied 2660 US Military Health System beneficiaries with a history of SARS-CoV-2 infection-alone (n = 705), vaccination-alone (n = 932), vaccine-after-infection (n = 869), and vaccine-breakthrough-infection (n = 154). Peak anti-spike-immunoglobulin G (IgG) responses through 183 days were compared, with adjustment for vaccine product, demography, and comorbidities. We excluded those with evidence of clinical or subclinical SARS-CoV-2 reinfection from all groups., Results: Multivariable regression results indicated that vaccine-after-infection anti-spike-IgG responses were higher than infection-alone (P < .01), regardless of prior infection severity. An increased time between infection and vaccination was associated with greater post-vaccination IgG response (P < .01). Vaccination-alone elicited a greater IgG response but more rapid waning of IgG (P < .01) compared with infection-alone (P < .01). BNT162b2 and mRNA-1273 vaccine-receipt was associated with greater IgG responses compared with JNJ-78436735 vaccine-receipt (P < .01), regardless of infection history. Those with vaccine-after-infection or vaccine-breakthrough-infection had a more durable anti-spike-IgG response compared to infection-alone (P < .01)., Conclusions: Vaccine-receipt elicited higher anti-spike-IgG responses than infection-alone, although IgG levels waned faster in those vaccinated (compared to infection-alone). Vaccine-after-infection elicits a greater humoral response compared with vaccine or infection alone; and the timing, but not disease severity, of prior infection predicted these post-vaccination IgG responses. While differences between groups were small in magnitude, these results offer insights into vaccine immunogenicity variations that may help inform vaccination timing strategies., Competing Interests: Conflicts of interest. S. D. P., T. H. B., D. T., and M. P. S. report that the Uniformed Services University (USU) IDCRP, a US Department of Defense institution, and the Henry M. Jackson Foundation were funded under a cooperative research and development agreement to conduct an unrelated phase 3 COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The Henry M. Jackson Foundation, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US government COVID-19 response. Neither is related to the work presented here. C. M. B. reports a leadership or fiduciary role on the Infectious Diseases Society of America Clinical Affairs Committee. R. C. M. reports grants or contracts to his institution and unrelated to this work from AiCuris, Sound Pharmaceutical, and AstraZeneca; consulting fees and honorarium for advisory panel membership from the Society of Critical Care Medicine; honorarium for a lecture from the California Thoracic Society; travel support from the American Thoracic Society, American College of Chest Physicians, and Society of Critical Care Medicine; a US patent for investigational dengue vaccine candidate (no payments made or current commercial development planned); data and safety monitoring board membership (funds to author) for Trauma Insights, LLC; member of The Society of Critical Care Medicine (SCCM) Congress Program Committee (travel support for official meetings [pre-March 2020]), chair of the American College of Chest Physicians (CHEST) COVID-19 Task Force and Disaster/Global Health Section (travel support for official meetings), and member of the CHEST Scientific Program Committee (travel support for official meetings). All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The associations between clinical phenotypes of coronavirus disease 2019 (COVID-19) and the host inflammatory response during the transition from peak illness to convalescence are not yet well understood. Blood plasma samples were collected from 129 adult SARS-CoV-2 positive inpatient and outpatient participants between April 2020 and January 2021, in a multi-center prospective cohort study at 8 military hospitals across the United States. Plasma inflammatory protein biomarkers were measured in samples from 15 to 28 days post symptom onset. Topological Data Analysis (TDA) was used to identify patterns of inflammation, and associations with peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated using logistic regression. The study population (n = 129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct inflammatory biomarker clusters were identified and were associated with significant differences in peak disease severity (p < 0.001), age (p < 0.001), BMI (p < 0.001), and CCI (p = 0.001). Host-biomarker profiles stratified a heterogeneous population of COVID-19 patients during the transition from peak illness to convalescence, and these distinct inflammatory patterns were associated with comorbid disease and severe illness due to COVID-19., (© 2022. The Author(s).)

Background: There is limited information on the functional consequences of coronavirus disease 2019 (COVID-19) vaccine side effects. To support patient counseling and public health messaging, we describe the risk and correlates of COVID-19 vaccine side effects sufficient to prevent work or usual activities and/or lead to medical care ("severe" side effects)., Methods: The EPICC study is a longitudinal cohort study of Military Healthcare System beneficiaries including active duty service members, dependents, and retirees. We studied 2789 adults who were vaccinated between December 2020 and December 2021., Results: Severe side effects were most common with the Ad26.COV2.S (Janssen/Johnson and Johnson) vaccine, followed by mRNA-1273 (Moderna) then BNT162b2 (Pfizer/BioNTech). Severe side effects were more common after the second than first dose (11% vs 4%; P  < .001). First (but not second) dose side effects were more common in those with vs without prior severe acute respiratory syndrome coronavirus 2 infection (9% vs 2%; adjusted odds ratio [aOR], 5.84; 95% CI, 3.8-9.1), particularly if the prior illness was severe or critical (13% vs 2%; aOR, 10.57; 95% CI, 5.5-20.1) or resulted in inpatient care (17% vs 2%; aOR, 19.3; 95% CI, 5.1-72.5). Side effects were more common in women than men but not otherwise related to demographic factors., Conclusions: Vaccine side effects sufficient to prevent usual activities were more common after the second than first dose and varied by vaccine type. First dose side effects were more likely in those with a history of COVID-19-particularly if that prior illness was severe or associated with inpatient care. These findings may assist clinicians and patients by providing a real-world evaluation of the likelihood of experiencing impactful postvaccine symptoms., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Little is known about severe acute respiratory syndrome coronavirus 2 "vaccine-breakthrough" infections (VBIs). Here we characterize 24 VBIs in predominantly young healthy persons. While none required hospitalization, a proportion endorsed severe symptoms and shed live virus as high as 4.13 × 103 plaque-forming units/mL. Infecting genotypes included both variant-of-concern (VOC) and non-VOC strains., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)