Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism

Abstract

Purpose: Apart from the global disease burden of acute COVID-19 disease, the health complications arising after recovery have been recognized as a long-COVID or post-COVID-19 syndrome. Evidences of long-COVID symptoms involving various organ systems are rapidly growing in literature. The objective was to perform a rapid review and evidence mapping of systemic complications and symptoms of long-COVID and underlying pathophysiological mechanisms.

Methods: Publications reporting clinical trials, observational cohort studies, case-control studies, case-series, meta-analysis, and systematic reviews, focusing on the squeal of the disease, consequences of COVID-19 treatment/hospitalization, long-COVID, chronic COVID syndrome, and post acute COVID-19 were reviewed in detail for the narrative synthesis of frequency, duration, risk factors, and pathophysiology.

Results: The review highlights that pulmonary, neuro-psychological, and cardiovascular complications are major findings in most epidemiological studies. However, dysfunctional gastrointestinal, endocrine, and metabolic health are recent findings for which underlying pathophysiological mechanisms are poorly understood. Analysis of the clinical trial landscape suggests that more than 50% of the industry-sponsored trials are focused on pulmonary symptoms. In contrast to the epidemiological trends and academic trials, cardiovascular complications are not a focus of industry-sponsored trials, suggestive of the gaps in the research efforts.

Conclusion: The gap in epidemiological trends and academic trials, particularly concerning cardiovascular complications not being a focus of industry-sponsored trials is suggestive of the gaps in research efforts and longer follow-up durations would help identify other long-COVID-related health issues such as reproductive health and fertility.

Keywords: Clinical trials; Long-COVID; Pathophysiology; Post-COVID syndrome; Post-acute COVID syndrome.

Fig. 1

Flowchart for scouting long-COVID-related studies from the clinical trial registry

Fig. 2

Pathophysiological mechanisms in long-COVID or post-COVID syndrome. Based on the current knowledge, mechanisms that are involved in long COVID are complex and interrelated. Three major categories of the pathophysiological changes are: (1) Direct cellular/tissue injury caused due to cytotoxicity or by hijacking host metabolic machinery such as mitochondrial functioning or methyl group transfer; (2) Immune activation and inflammation, this can either target the host cells through antigen cross-reactivity or induce cell damage due to inflammatory changes including cytokines/chemokines and cellular infiltrations; (3) Counter physiological response corresponds to altered hormonal changes or responsive intracellular signaling pathways. The combination of the above mechanisms (upper panel, purple boxes) and depending on the viral tissue-tropism and microenvironment organ-specific pathophysiological changes are responsible for the respective clinical symptoms (lower panel, in blue shaded boxes). Abbreviations: C-Reactive Protein (CRP); Interferon gamma (IFN-γ); Tumor necrosis factor-α (TNF-α); Interleukin-1β (IL-1β); Interleukin-1 (IL-1); Interleukin-6 (IL-6); Interleukin-8 (IL-8); Matrix metalloproteinase-7 (MMP-7); Hepatocyte growth factor (HGF); GPCR—G-protein coupled receptors; von Willebrand factor (vWF);); Thyroid stimulating hormone (TSH); Triiodothyronine (T3); Adrenocorticotropic hormone (ACTH); Hypoxia-inducible factor 1α (HIF-1α); Reactive oxygen species (ROS); Chemokine (C-X-C motif) Ligand (CXLC-2, CXCL-8 etc.)

Fig. 3

Overview of clinical trial activities related to the post-COVID syndrome. a Landscape of long-COVID clinical trials stratified by observational and interventional, followed by academic vs. industry sponsorship of the trials. b Organ system focus on clinical trials stacked by academic or industry sponsorship