Acute #Protein Responses Control #SARS-CoV-2-specific #Neurocognitive and General Post-Viral #Sequelae

 

Abstract

Post-acute infection syndromes (PAIS) follow viral syndromes including post-acute sequelae of COVID19 (PASC) which complicates 10-25% of SARS-CoV-2 infections. These syndromes lack precise explanatory mechanisms. We studied 173 human saliva proteomes during respiratory viral syndromes, seeking associations between 44 clinically-relevant protein expression patterns and subsequent sequelae counts. Exploratory models adjusted by extensive clinical annotations found interactions between 23 acutely-responsive proteins and SARS-CoV-2 infection that inversely predicted subsequent neurocognitive sequelae. An overlapping 19 acutely-responsive proteins during any acute respiratory viral syndrome inversely predicted general fatigue-related sequelae. Altogether, 29 proteins, derived from interferon stimulated genes (ISG), were uniformly beneficial, including 13 predictive of both neurocognitive and general sequelae. The proteins suggested both shared early pathobiology and virus-specific protective responses that shaped resolution of acute disease and different PAIS. Acutely elevated protective ISG proteins associated with reduced post-viral symptoms identify investigational starting points for novel mechanisms, diagnostics and therapeutics for PASC and PAIS.

Competing Interest Statement

Theodore G. Liou, Judy L Jensen and Kristyn A Packer received research funding from Anagram, Aridis, BioMX, Calithera, Clarametyx, Gilead, Insmed, Laurent, Novartis, the US Cystic Fibrosis Foundation′s Therapeutic Development Network and Vertex for performance of clinical studies during the study period. Bricelyn H Strauch maintains the copyright for Figure 3. Theodore Liou and Frederick Adler, through the University of Utah, are named as inventors on the following patent applications related to the proteins identified in this manuscript: (1) a provisional patent application titled ″DIAGNOSTICS AND TREATMENTS FOR ACUTE AND POST-VIRAL DISEASE BASED ON INNATE IMMUNE RESPONSES TO SARS-COV-2 INFECTION,″ serial number 63/792,687, filed 4/22/2025; (2) a provisional patent application titled ″ADDITIONAL INNATE IMMUNE RESPONSES WITH DIAGNOSTIC AND TREATMENT POTENTIAL FOR POST-ACUTE SEQUELAE OF COVID19 SYNDROME AND FOR POST-ACUTE INFECTION SYNDROME,″ serial number 63/979,883, filed 2/10/2026; (3) a Patent Cooperation Treaty (PCT) application titled ″METHODS FOR PREDICTING POST-ACUTE SEQUELAE OF VIRAL INFECTIONS USING INTERFERON STIMULATED GENE PROTEINS,″ serial number PCT/US2026/024520, filed 4/21/2026, which incorporates subject matter from (1) and (2); and (4) a provisional patent application titled ″ADDITIONAL ACUTELY EXPRESSED PROTEINS PROTECTIVE AGAINST NEUROCOGNITIVE AND GENERAL POST-VIRAL SEQUELAE,″ serial number 64/102,461, filed 6/30/2026. The applicant on all applications is the University of Utah.

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.08.27.26361488v1

____

#LongCOVID associated with #SARS-CoV-2 #reinfection among #children and adolescents in the #omicron era (RECOVER-EHR): a retrospective cohort study

 

Summary

Background

Post-acute sequelae of SARS-CoV-2 infection (PASC) remain a major public health challenge. Although previous studies have focused on characterising PASC in children and adolescents after an initial infection, the risks of PASC after reinfection with the omicron variant remain unclear. We aimed to assess the risk of PASC diagnosis (U09.9) and symptoms and conditions potentially related to PASC in children and adolescents after a SARS-CoV-2 reinfection during the omicron period.

Methods

This retrospective cohort study used data from 40 children's hospitals and health institutions in the USA participating in the Researching COVID to Enhance Recovery (RECOVER) Initiative. We included patients younger than 21 years at the time of cohort entry; with documented SARS-CoV-2 infection after Jan 1, 2022; and who had at least one health-care visit within 24 months to 7 days before the first infection. The second SARS-CoV-2 infection was confirmed by positive PCR, antigen tests, or a diagnosis of COVID-19 that occurred at least 60 days after the first infection. The primary endpoint was a clinician-documented diagnosis of PASC (U09.9). Secondary endpoints were 24 symptoms and conditions previously identified as being potentially related to PASC. We used the modified Poisson regression model to estimate the relative risk (RR) between the second and first infection episodes, adjusted for demographic, clinical, and health-care utilisation factors using exact and propensity-score matching.

Findings

We identified 407 300 (87·5%) of 465 717 eligible children and adolescents with a first infection episode and 58 417 (12·5%) with a second infection episode from Jan 1, 2022, to Oct 13, 2023, in the RECOVER database. 233 842 (50·2%) patients were male and 231 875 (49·8%) were female. The mean age was 8·17 years (SD 6·58). The incident rate of PASC diagnosis (U09.9) per million people per 6 months was 903·7 (95% CI 780·9–1026·5) in the first infection group and 1883·7 (1565·1–2202·3) in the second infection group. Reinfection was associated with a significantly increased risk of an overall PASC diagnosis (U09.9) (RR 2·08 [1·68–2·59]) and a range of symptoms and conditions potentially related to PASC (RR range 1·15–3·60), including myocarditis, changes in taste and smell, thrombophlebitis and thromboembolism, heart disease, acute kidney injury, fluid and electrolyte disturbance, generalised pain, arrhythmias, abnormal liver enzymes, chest pain, fatigue and malaise, headache, musculoskeletal pain, abdominal pain, mental ill health, POTS or dysautonomia, cognitive impairment, skin conditions, fever and chills, respiratory signs and symptoms, and cardiovascular signs and symptoms.

Interpretation

Children and adolescents face a significantly higher risk of various PASC outcomes after reinfection with SARS-CoV-2. These findings add to previous evidence linking paediatric long COVID to multisystem effects and highlight the need to promote vaccination in younger populations and support ongoing research to better understand PASC, identify high-risk subgroups, and improve prevention and care strategies.

Funding

National Institutes of Health.

Source: The Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00476-1/fulltext?rss=yes

____