Overview and Pathophysiology of Long COVID

Long COVID is a heterogeneous, multi-system condition affecting over 400 million people worldwide, with pathology ranging from subclinical to fatal. This digest summarizes current evidence on its epidemiology, definitions, and pathophysiological mechanisms across major organ systems.

Elisa Perego· COVID· 2026· DOI 10.3390/covid6030053

The core problem

Long COVID is a disease entity triggered and potentially driven by SARS-CoV-2 infection. It is characterized by dozens of different symptoms, signs, and sequelae that can affect all organs and body systems and evolve over the disease course. Clinical manifestations vary widely between individuals and across populations. Pathology ranges from asymptomatic and subclinical manifestations to fatal outcomes. With over 400 million people worldwide estimated to suffer or have suffered from Long COVID, it represents one of the greatest public health challenges of the 21st century. This article provides an updated overview of epidemiology, definitions, main concepts, and terminology, and summarizes key evidence of pathology and disease mechanisms in major organs and body systems.

This work is a narrative review synthesizing current evidence on Long COVID. The author compiled and analyzed published literature on epidemiology, case definitions, terminology, and pathophysiological mechanisms across multiple organ systems. The review focuses on the immune system, cardiovascular system, endothelium, heart, lungs, central nervous system, peripheral nervous system, gastrointestinal system, hepatobiliary system, pancreas, and kidney. No primary data collection or meta-analysis was performed; the methodology relies on expert interpretation of existing studies to provide an updated overview and identify research gaps.

Introduction

Long COVID is a disease entity triggered and potentially driven by SARS-CoV-2 infection. It is characterized by dozens of different symptoms, signs, and sequelae that can affect all organs and body systems and evolve over the disease course. Clinical manifestations vary widely between individuals and across populations. Pathology ranges from asymptomatic and subclinical manifestations to fatal outcomes. With over 400 million people worldwide estimated to suffer or have suffered from Long COVID, it represents one of the greatest public health challenges of the 21st century. This article provides an updated overview of epidemiology, definitions, main concepts, and terminology, and summarizes key evidence of pathology and disease mechanisms in major organs and body systems.

The heterogeneity in manifestations, potential risk of death, and degree of disability in several disease subsets call for timely diagnosis of each Long COVID type and a fuller understanding of their pathophysiological underpinnings. The multi-organ nature of the condition necessitates a systems-level approach to diagnosis and management. Current evidence suggests that Long COVID is not a single disease but a collection of overlapping syndromes with distinct pathobiological mechanisms. Further research is recommended to better understand pathobiology, develop effective clinical trials, and identify treatments and scalable biomarkers. The scale of the public health challenge underscores the urgency of these efforts.

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