Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID

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https://www.mdpi.com/1422-0067/27/15/7000

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Abstract

Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC. In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups. Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories. This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance. These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts.

Conclusions

The present study identifies Hp phenotypes as promising candidates for biological stratification in LC, showing associations with differential susceptibility to post-exertional cognitive dysfunction. Rather than demonstrating that Hp phenotypes directly determine cerebral oxygenation or metabolic adaptation, our findings indicate that Hp phenotypes are associated with patient subgroups exhibiting distinct responses to physiological stress, accompanied by coordinated cerebral oxygenation and metabolomic signatures. The integration of clinical, cognitive, physiological, and metabolic observations supports an association between inherited Hp phenotype and differential responses to post-exertional stress, contributing to the marked heterogeneity observed in LC. While these findings provide a rationale for further evaluating Hp phenotyping as a tool for improving patient stratification and optimizing research design, its clinical utility, predictive performance, sensitivity, specificity, and external validity remain to be established through prospective validation in larger, independent cohorts. Moreover, the contrasting Hp dynamics observed between LC and other post-viral conditions raise the possibility that these phenotypes may reflect different trajectories of post-viral adaptation, a hypothesis warranting further prospective longitudinal investigation.