{"doi":"10.1113/ep092958","title":"From fatigue to physiology: Submaximal 2‐day cardiopulmonary exercise test and emerging standards in long COVID","abstract":"Persistent fatigue and activity intolerance in post-acute sequelae of COVID-19 (PASC) presents one of the most elusive diagnostic and therapeutic challenges in contemporary medicine. Post-exertional symptom exacerbation (PESE), a worsening of symptoms following minimal exertion, mirrors the hallmark post-exertional malaise (PEM) long described in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which may share post-infectious origins (Blomberg et al., 2018). While widely recognized by patients, PESE remains physiologically under-defined. The recent analysis of PESE in PASC patients in this issue of Experimental Physiology by Thomas et al. provides critical progress toward resolving this gap (Thomas et al., 2025). Thomas and colleagues utilized a 2-day submaximal stepwise incremental cardiopulmonary exercise test (CPET) protocol in 68 individuals with PASC, where Day 2 was intended to identify physiological changes elicited by Day 1 exertion. The authors observed significant declines in key physiological parameters at the first ventilatory threshold (VT₁), with no notable differences at peak-level exercise. They noted a decrease of 6.8% in oxygen consumption ( V ̇ O 2 ${\\dot V_{{{\\mathrm{O}}_{\\mathrm{2}}}}}$ ) over a 24-h period. Similarly, O₂ pulse declined by 8.5%, and P ETC O 2 ${P_{{\\mathrm{ETC}}{{\\mathrm{O}}_{\\mathrm{2}}}}}$ decreased by 2.6%. These changes were accompanied by a lower workload, a modest reduction in minute ventilation (V̇E), and a small decline in carbon dioxide production ( V ̇ C O 2 ${\\dot V_{{\\mathrm{C}}{{\\mathrm{O}}_{\\mathrm{2}}}}}$ ). While each of these changes is modest in isolation, the consistent decline across multiple physiological domains may, however, reflect impaired submaximal exercise tolerance, or effort limitation on Day 2. Given the substantial inter-individual variability that ranged from ∼± 9% for end-tidal carbon dioxide pressure ( P ETC O 2 ${P_{{\\mathrm{ETC}}{{\\mathrm{O}}_{\\mathrm{2}}}}}$ ) to over ±22% for O₂ pulse and V ̇ O 2 ${\\dot V_{{{\\mathrm{O}}_{\\mathrm{2}}}}}$ , these findings may fall within the range of potential measurement noise. This raises an important question: what degree of change in cardiopulmonary exercise parameters performed over a 24-h interval constitutes true physiological deterioration versus normal biological or even technical fluctuation? In the absence of standardized reproducibility thresholds or normative datasets for 2-day CPET protocols, particularly in symptomatic long COVID populations, interpretation of small absolute changes remains challenging and context dependent. The authors concluded that this profile of impairment at VT1 identifies diminished O2 uptake and delivery without overt ventilatory or chronotropic limitation, suggesting impairments in central and peripheral O2 transport. While Thomas et al. employed non-invasive measures, the findings align well with the pathophysiology identified by invasive CPET (iCPET) studies (Risbano et al., 2023). Our work evaluating long COVID subjects with iCPET (Risbano et al., 2023) has identified distinct physiological endotypes including preload failure and impaired systemic O2 extraction. Preload failure consists of low biventricular filling pressures with reduced cardiac output in the upright position (with normal left ventricular function) at peak exercise and at submaximal effort (Fakhri et al., 2025; Oldham et al., 2016). This phenotype is mechanistically linked to impaired stroke volume augmentation and can overlap with inadequate peripheral O₂ utilization. Although not derived from iCPET, the findings reported by Thomas et al. (2025) may be consistent with this physiological framework. Oxygen pulse, which serves as a rough surrogate for stroke volume and peripheral oxygen extraction efficiency, and P ETC O 2 ${P_{{\\mathrm{ETC}}{{\\mathrm{O}}_{\\mathrm{2}}}}}$ , a complex measure reflecting the combined effects of pulmonary perfusion, alveolar ventilation and cardiac output, both declined","journal":"Experimental Physiology","year":2025,"id":533924,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9692,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":339994,"name":"Michael G. Risbano","orcid":"0000-0003-3334-7046","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:51:43.451278Z","pmid":"40532111","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}