Long COVID, chronic fatigue syndrome, and chronic lyme disease as Post-acute Infection Syndromes (PAIS): a translational synthesis
Sewell, Patrick E.; Reddy, Rohan
Background
Post-acute infection syndromes (PAIS) comprise a heterogeneous group of chronic, multisystem conditions characterized by persistent or relapsing symptoms following resolution of an acute infectious illness, in the absence of ongoing pathogen replication detectable by standard diagnostics. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID, post-treatment Lyme disease syndrome, and related entities are increasingly recognized as part of a shared post-infectious disease spectrum. The COVID-19 pandemic has markedly expanded the global burden of PAIS and intensified investigation into their biological underpinnings.
Main body
This narrative translational review integrates clinical, epidemiologic, genetic, immunologic, metabolic, and neurovascular evidence to propose a unified framework for PAIS pathophysiology and management. We anchor the review in clinical phenomenology before turning to mechanism, then provide depth treatment of three core mechanism areas—cellular immune dysfunction with T-cell exhaustion and immunometabolic reprogramming, viral and antigen persistence with herpesvirus reactivation, and the genetic architecture revealed by the DecodeME 2025 GWAS and complementary studies.
Convergent mechanisms across PAIS include T-cell exhaustion phenotypes, NK cell cytotoxicity defects, immunometabolic reprogramming with mitochondrial bioenergetic inefficiency, autonomic and endothelial dysfunction, neuroinflammation, altered tryptophan–kynurenine–NAD+ metabolism, viral or antigen persistence, autoantibody formation, and gut microbiome dysbiosis.
Recent genome-wide association studies support heritable susceptibility involving immune regulation, mitochondrial maintenance, and neuroinflammatory pathways. Diagnostic paradigms remain primarily clinical, though emerging multi-omic and cellular biomarkers show translational promise. Tiered diagnostic and evaluation strategies are discussed to guide clinicians while minimizing harm, particularly post-exertional malaise.
Conclusions
PAIS represent biologically grounded, systems-level disorders with shared mechanisms and heterogeneous clinical expression. Integrating molecular insights with pragmatic clinical frameworks may accelerate development of precision-oriented diagnostic and therapeutic strategies to address the growing global impact of post-infectious chronic illness.
Web | DOI | PDF | Journal of Translational Medicine | Open Access
Sewell, Patrick E.; Reddy, Rohan
Background
Post-acute infection syndromes (PAIS) comprise a heterogeneous group of chronic, multisystem conditions characterized by persistent or relapsing symptoms following resolution of an acute infectious illness, in the absence of ongoing pathogen replication detectable by standard diagnostics. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID, post-treatment Lyme disease syndrome, and related entities are increasingly recognized as part of a shared post-infectious disease spectrum. The COVID-19 pandemic has markedly expanded the global burden of PAIS and intensified investigation into their biological underpinnings.
Main body
This narrative translational review integrates clinical, epidemiologic, genetic, immunologic, metabolic, and neurovascular evidence to propose a unified framework for PAIS pathophysiology and management. We anchor the review in clinical phenomenology before turning to mechanism, then provide depth treatment of three core mechanism areas—cellular immune dysfunction with T-cell exhaustion and immunometabolic reprogramming, viral and antigen persistence with herpesvirus reactivation, and the genetic architecture revealed by the DecodeME 2025 GWAS and complementary studies.
Convergent mechanisms across PAIS include T-cell exhaustion phenotypes, NK cell cytotoxicity defects, immunometabolic reprogramming with mitochondrial bioenergetic inefficiency, autonomic and endothelial dysfunction, neuroinflammation, altered tryptophan–kynurenine–NAD+ metabolism, viral or antigen persistence, autoantibody formation, and gut microbiome dysbiosis.
Recent genome-wide association studies support heritable susceptibility involving immune regulation, mitochondrial maintenance, and neuroinflammatory pathways. Diagnostic paradigms remain primarily clinical, though emerging multi-omic and cellular biomarkers show translational promise. Tiered diagnostic and evaluation strategies are discussed to guide clinicians while minimizing harm, particularly post-exertional malaise.
Conclusions
PAIS represent biologically grounded, systems-level disorders with shared mechanisms and heterogeneous clinical expression. Integrating molecular insights with pragmatic clinical frameworks may accelerate development of precision-oriented diagnostic and therapeutic strategies to address the growing global impact of post-infectious chronic illness.
Web | DOI | PDF | Journal of Translational Medicine | Open Access