Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Investigative Medicine

First Advisor

Iwasaki, Akiko

Abstract

Since its emergence in late 2019, SARS-CoV-2 has infected over 15 million people—and the number continues to rise. The global impact of this novel coronavirus has been profound, reshaping not only public health infrastructure but also our understanding of human biology. The full extent of the virus’s effects on the immune system remains incompletely understood and will likely take years to fully unravel. What is already evident, however, is that SARS-CoV-2 uniquely modulates both innate and adaptive immunity, with consequences that span the developmental spectrum—from fetal and pediatric stages through adulthood. While many individuals recover without overt clinical sequelae, an increasing subset experience persistent symptoms and immune dysregulation. This thesis aims to investigate these enduring consequences, with a focus on individuals demonstrating long-term impact. Through a combination of epidemiologic analysis and immunological profiling, this work seeks to deepen our understanding of the biological underpinnings of this complex and emerging clinical entity. This thesis explores the evolving clinical entity of Long COVID within the broader framework of Post-Acute Infection Syndromes (PAIS)—a poorly understood area of medicine in which certain individuals experience prolonged signs and symptoms following acute infection. While Long COVID is often regarded as a novel condition, there is a longstanding historical precedent for post-acute syndromes following both viral and bacterial infections, particularly in the aftermath of epidemics. The first chapter provides a conceptual foundation for PAIS, emphasizing the urgent need for further investigation and clinical characterization of these syndromes. Chapter two presents a scoping review of all U.S.-based studies on pediatric Long COVID, summarizing current knowledge on its epidemiology. Across studies, adolescent females were disproportionately affected. Fatigue, headache, and chest pain emerged as the most commonly reported symptoms. Estimated prevalence varied widely—from less than 1% to 27%—with identified risk factors including older age, female sex, asthma, obesity, and severity of acute infection. Most studies suffered from methodological limitations, including inconsistent case definitions and limited follow-up. Chapter three focuses on saliva as a promising exploratory biospecimen. While blood remains the gold standard for immunologic assessment, saliva offers distinct advantages, particularly its non-invasive collection, feasibility for serial sampling, and accessibility in pediatric and hard-to-reach populations. These features make it especially valuable for studying syndromes requiring longitudinal observation. The final chapter details our own study leveraging saliva to investigate immunologic differences in individuals with Long COVID compared to controls. We found that participants with Long COVID exhibited significantly lower levels of SARS-CoV-2-specific IgG and IgA in saliva, suggesting potential mucosal immune dysregulation in this population. In sum, this thesis contributes to both the epidemiologic and immunologic understanding of Long COVID, situating it within the wider landscape of post-acute infection syndromes. SARS-CoV-2 presents a rare and important opportunity to examine the long-term consequences of a well-characterized acute viral infection, offering critical insights into the mechanisms underlying persistent illness following infection.

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