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Background Methods Acknowledgments Correspondence Critical COVID-19 disease explained by type I interferon autoantibodies found in patients within the Military Health System. Maria Leondaridis1, Debra Yee1, Marana Tso2, Elana Shaw3, Lindsey B. Rosen3, Emily Samuels2, Paul Bastard4,5,6, Jean-Laurent Casanova4,5,6, Steven M. Holland3, Helen C. Su3, Stephanie Richard7,8, Katrin Mende7,8,9, Tahaniyat Lalani7,8,10, David Lindholm9, Catherine M. Berjohn11, Ryan C. Maves11, Rhonda E. Colombo7,8,12, Christopher J Colombo12, Derek T. Larson13, Evan C. Ewers13, Anuradha Ganesan7,8,14, Nikhil Huprikar14, Rupal M. Mody15, Milissa U. Jones16, Mark P Simons7, David Tribble7, Eric D. Laing2, Brian Agan7,8, Simon Pollett7,8, Timothy H Burgess7, Andrew L. Snow1 & the EPICC Study Group. This work was supported by awards from the Defense Health Program (HU00012020067) and the National Institute of Allergy and Infectious Disease (HU00011920111). The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded in part by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, under an interagency agreement (Y1-AI-5072). The authors declare no conflicts of interest. Results Results Neutralizing auto-antibodies (auto-Abs) that target type I interferons (IFN), a group of cytokines that induce innate immune responses upon viral infection, are found within approximately 10-20% of patients with critical COVID-19. We sought to determine if neutralizing type I IFN auto- Abs contribute to severe COVID-19 in patients within the Military Health System (MHS). The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potent, RITM0037391, Neutralizing auto-antibodies (auto-Abs) that target type I interferons (IFN), a group of cytokines that induce innate immune responses upon viral infection, are found within approximately 10-20% of patients with critical COVID-19. We sought to determine if neutralizing type I IFN auto- Abs contribute to severe COVID-19 in patients within the Military Health System (MHS). The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) cohort collected demographic data, clinical data and sera from SARS-CoV-2 infected patients enrolled across 10 U.S. military treatment facilities. We screened sera collected <21 days post-symptom onset from 249 COVID-19 inpatients and 312 COVID-19 outpatients for IFN auto-Ab positivity and neutralizing activity using Luminex and intracellular flow cytometry, respectively. Similar to previous reports, we detected neutralizing auto-Abs against IFN-? and/or IFN-? in a significantly higher frequency of inpatients (10 total, 4%) versus outpatients (1, 0.32%) (p=0.009). Remarkably, IFN auto- Abs persisted 6-12 months post-infection in most inpatients, including several with a history of autoimmune disease. Among inpatients, multivariate logistic regression analyses demonstrated that type I IFN auto-Abs were associated with a greater risk of severe and critical COVID-19 (adjusted odds ratio (aOR) = 3.99 and 4.69, respectively) after adjusting for age, sex and comorbidity burden. Our results confirm a robust association between critical COVID-19 and the presence of type I IFN auto-Abs, which may predispose to other severe respiratory viral infections that cause substantial morbidity and mortality in the MHS.

Disclaimer: The contents of this publication are the sole responsibility of the author (s) and do not necessarily reflect the views, opinions, or policies of Uniformed Services University of the Health Sciences (USU); the Department of Defense (DoD); the Departments of the Army, Navy, or Air Force; the Defense Health Agency, Brooke Army Medical Center; Walter Reed National Military Medical Center; Naval Medical Center San Diego; Madigan Army Medical Center; United States Air Force School of Aerospace Medicine; Fort Belvoir Community Hospital; William Beaumont Army Medical Center; Tripler Army Medical Center; Naval Medical Center Portsmouth; the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc.; the National Institutes of Health. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46. Funding: This work was supported by awards from the Defense Health Program (HU00012020067) and the National Institute of Allergy and Infectious Disease (HU00011920111). The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USU) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded in part by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, under an interagency agreement (Y1-AI-5072). Age-associated variations in anti-spike antibody responses in mild COVID-19 disease Figure 2: Early anti-spike IgG response differed significantly by age group in contrast to late responses in those who are unvaccinated with mild disease. 2A. IgG magnitude (median fluorescence intensity, MFI) at 0-30 days post first positive (dpfp) SARS-CoV-2, RITM0036951, Background: SARS-CoV-2 most severely affects older age groups, while children experience minimal disease. We measured elements of adaptive immunity in children and adults with SARS-CoV-2 to define the age-dependent viral and host response. Methods: Participants were enrolled in the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) study. Eligibility required that individuals present with COVID-19-like symptoms between March 2020 to March 2022. Magnitude of viral RNA was determined by quantitative PCR. SARS-CoV-2-specific antibodies were measured from blood with multiplex microsphere immunoassays. Results: Serologic responses against the spike protein were measured at early and convalescent time points and compared by age, predominant infecting SARS-CoV-2 variant, and vaccination status. In those with mild (outpatient) disease, the seropositivity rates did not differ based on age. The magnitude of the anti-spike IgG response differed by age at early time points. Only the oldest age group differed at convalescent time points. Conclusions: The serologic response to SAR-CoV-2 differs with age, implicating host immunity in pathogenesis. Improved understanding of the host immune response has the potential to optimize vaccine design.

Disclaimer: The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF), Uniformed Services University of the Health Sciences (USU), Departments of the Navy, Army, or Air Force, the Department of Defense, Defense Health Agency, nor the U.S. Government. Source of support: This work was supported by the Coronavirus Aid, Relief, and Economic Security (CARES) Act and conducted by the DoD’s JPEO-CBRND in collaboration with the Defense Health Agency. The EPICC study was supported by the Defense Health Program (HU00012020067) and the NIAID (HU00011920111). Human subject research protections: The investigators have adhered to the policies for protection of human subjects as prescribed in 45 CFR 46. Copyright statement: Some authors are military service members and employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that “Copyright protection under this title is not available for any work of the United States Government”. Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. EVALUATION OF THE PERFORMANCE OF RAPID ANTIGEN TESTS TO DETECT EMERGING SARS-COV-2 VARIANTS AND CORRELATION WITH VIRAL CULTURE POSITIVITY Heather Poeck-Goux1, Jennetta Green1, Andrew Wilson1, Shanmuga Sozhamannan2,3, Mark Simons4, David Tribble4, Brian Agan4,5, Timothy Burgess4, Stephanie A. Richard4,5, Anthony Fries6, Simon D. Pollett, MBBS4,5, Jason Cox7, Robert Deans7, Joseph Walish7, Darci R. Smith1 1Microbiology and Immunology Department, Biological Defense Research Directorate, Naval Medical Research Command, Ft. Detrick, MD, USA, 2Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), Joint Project Lead for CBRND, RITM0040473, Diagnostic testing has been critical to identify SARS-CoV-2 infected individuals, reducing transmission, and informing public health infection control measures. Antigen-based rapid diagnostic tests (ag-RDTs) provide timely results, are simple to use, and are less expensive than molecular assays such as reverse transcriptase polymerase chain reaction (RT-PCR). It is unclear how new variants of SARS-CoV-2 may impact the performance of ag-RDTs. Furthermore, recent studies suggest that antigen-based testing may align better with virus culture-based results (a proxy of contagiousness) compared to RT-PCR. In this study, we (1) assessed the performance of antibodies and ag-RDTs to detect a range of SARS-CoV-2 variants, including the Omicron variant and (2) determined if ag-RDTs results correlate with culture positivity. We found that the ag-RDTs demonstrated minor differences in sensitivity for all SARS-CoV-2 variants. Moderate to high sensitivity of ag-RDTs was observed when compared to swab PCR positivity and all assays were positive for at least one swab per variant. Ag-RDT sensitivity against PCR appeared to be inversely correlated with detection of viable virus whereas the Abbott BinaxNOW COVID-19 ag-RDT results correlated most strongly with culture positivity, while it was found to detect the lowest percent of PCR-positive swabs among the three ag-RDTs evaluated. Furthermore, we noted N mutations did not affect antigen binding kinetics in a further set of diagnostic antibodies used for other ag-RDT internal development. Collectively, our results demonstrate that commercially available ag-RDTs may offer ongoing sensitivity to detect emerging variants and offer the prospect of predicting case transmissibility risk. However, future studies are needed to define the agreement between ag-RDTs positivity, swab culture positivity, and transmissibility risk.

When SARS-CoV-2 Omicron emerged in 2021, S gene target failure enabled differentiation between Omicron and the dominant Delta variant. In England, where S gene target surveillance (SGTS) was already established, this led to rapid identification (within ca 3 days of sample collection) of possible Omicron cases, alongside real-time surveillance and modelling of Omicron growth. SGTS was key to public health action (including case identification and incident management), and we share applied insights on how and when to use SGTS.

Background Correspondence SARS-CoV-2 infection is associated with post-acute self-reported neurocognitive symptoms Liana R. Andronescu, PhD, MPH1,2, Stephanie A. Richard, PhD, MHS 1,2, Ann I. Scher, PhD3, David A. Lindholm, MD4,5, Katrin Mende, PhD1,2,5, Anuradha Ganesan, MBBS, MPH1,2,6, Nikhil Huprikar MD6, Tahaniyat Lalani, MBBS, MHS1,2,7, Alfred Smith MD7, Rupal M. Mody, MD8, Milissa U. Jones, MD9, Samantha E. Bazan, DNP, MS10, Rhonda E. Colombo, MD, MHS1,2,4,11, Christopher J. Colombo, MD4,11, Evan Ewers12, Derek T. Larson, DO12,13, Ryan C. Maves, MD1,13, Catherine M. Berjohn, MD, MPH1,4,13, Carlos J Maldonado, PhD14, Caroline English1,2, Margaret Sanchez Edwards, MS1,2, Julia S. Rozman, BS1,2, Jennifer Rusiecki, PhD3, Celia Byrne, PhD3, Mark P. Simons, PhD1, David Tribble, MD, DrPH1, Timothy H Burgess, MD, MPH1, Simon D. Pollett, MBBS1,2, Brian K. Agan, MD1,2 Objectives 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 neurocognitive impairment on active-duty service members and other Military Health System (MHS) beneficiaries, it is important to characterize this post-infection phenotype and assess potential risk factors for poor neurocognitive outcomes. Email: landronescu@idcrp.org; liana.andronescu.ctr@usuhs.edu USU Infectious Disease Clinical Research Program (IDCRP), Department of Preventive Medicine and Biostatistics Henry M. Jackson Foundation for the Advancement of Military Medicine • Describe the prevalence of self-reported neurocognitive symptoms among SARS-CoV-2 positive vs negative subjects • Identify risk factors for self-reported neurocognitive symptoms among SARS-CoV-2 positive subjects Results 1Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 2Henry M. Jackso, RITM0027659, 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 neurocognitive impairment on active-duty service members and other Military Health System (MHS) beneficiaries, it is important to characterize this post-infection phenotype and assess potential risk factors for poor neurocognitive outcomes.

Background EPICC COVID-19 Chronic Impairment with Pulmonary Symptoms (ChIPS) S. Michael Goertzen, Capt, USAF, MC1; David A. Lindholm, Maj, USAF, MC2; Robert J. Walter, LTC, MC, USA1; Nikhil Huprikar MAJ, MC, USA3, Anuradha Ganesan, MBBS, MPH4,5,6, Katrin Mende PhD4,5, Julia Rozman4,5, CDR Travis E. Harrell, MD6, LTC P. Gabriel Peterson MD6, Christina Murillo, RRT1,5, Mark Simons PhD4, David Tribble MD4, Brian Agan MD4,5, CAPT Timothy H. Burgess MD4, Simon Pollett, MBBS4,5, Michael J. Morris, COL (Ret), MC, USA1 Objectives Chronic impairment following SARS-CoV-2 infection including persistent fatigue, dyspnea and chest pain remain a major health concern. This study sought to better characterize those who suffer from ongoing cardiopulmonary symptoms at least 3 months after initial COVID-19 • Describe the radiological (pulmonary HRCT) changes in those with persistent respiratory symptoms after COVID-19. • Describe the physiological changes (six-minute walk test, pulmonary function testing, and impulse oscillometry) after COVID-19. • Describe how radiological and lung function investigation findings correlate with self-reported symptoms in this cohort Results 1 Pulmonary/Critical Care Service, Brooke Army Medical Center, Fort Sam Houston, TX; 2 Infectious Disease Service, Brooke Army Medical Center, Fort Sam Houston, TX; 3 Pulmonary/Critical Care Service, Walter Reed National Military Medical Center, Bethesda, MD; 4Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD; 5Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD; 6Walter Reed National Military Medical Center, Bethesda, MD Disclaimer This work was supported by awards from the Defense Health Program (HU00012020067) and the National Institute of Allergy and Infectious Disease (HU00011920111) The contents of this publication are the sole responsibility of the author (s, RITM0028332, Chronic impairment following SARS-CoV-2 infection including persistent fatigue, dyspnea and chest pain remain a major health concern. This study sought to better characterize those who suffer from ongoing cardiopulmonary symptoms at least 3 months after initial COVID-19

(1) Background: Nowadays, the use of microsurgical free flaps is a standard operative procedure in reconstructive surgery. Still, thrombosis of the microanastomosis is one of the most fatal postoperative complications. Clinical evaluation, different technical devices and laboratory markers are used to monitor critical flap perfusion. Macrophage migration inhibitory factor (MIF), a structurally unique cytokine with chemokine-like characteristics, could play a role in predicting vascular problems and the failure of flap perfusion. (2) Methods: In this prospective observational study, 26 subjects that underwent microsurgical reconstruction were observed. Besides clinical data, the number of blood leukocytes, CRP and MIF were monitored. (3) Results: Blood levels of MIF, C-reactive protein (CRP) and leukocytes increased directly after surgery. Subjects that needed surgical revision due to thrombosis of the microanastomosis showed significantly higher blood levels of MIF than subjects without revision. (4) Conclusion: We conclude that MIF is a potential and innovative indicator for thrombosis of the microanastomosis after free flap surgery. Since it is easy to obtain diagnostically, MIF could be an additional tool to monitor flap perfusion besides clinical and technical assessments.