Why a Patient Made the Two-Day CPET

And What It Means to ME/CFS Research

In exercise physiology, the cardiopulmonary exercise test (CPET) is one of the field’s most trusted tools. It is designed to measure integrated cardiovascular, pulmonary, and metabolic performance. We consider it to be so reliable that repeating it often doesn’t make any sense from a testing perspective. This is often little more than a formality to make sure the equipment works and people know how to use it.

In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), however, repeating the CPET became something else entirely. It is one of the first and still few objective measures indicative of post-exertional malaise (PEM); a disruptive and ultimately foundational discovery.

Two-day CPET did not emerge from some large federally funded clinical center or a national research initiative or a complicated machine learning deep dive of a massive data set. It began as a small experiment to understand PEM conducted by a scientist living with ME/CFS. And it’s maybe the first and best example of patient-led science in the field.

Here is the background story of why a patient made two-day CPET.

A Scientific Breakthrough From Lived Experience

The origins of the two-day CPET trace back to Staci Stevens, MA. Staci is a person living with ME/CFS. She came down with mononucleosis, subsequently diagnosed as ME/CFS, and never recovered. PEM compromised her ability to function and exercise only made it worse. Gentle walking around the block landed her in bed for days. Recovery was impaired, delayed, and dysfunctional. She began to wonder, as an athlete before she became ill, if she had overtrained.

Ten years after she first became ill, a clinical trial was using a single CPET as an outcome measure. After talking to patients who all experienced PEM from the testing, she realized the researchers were not measuring the right way. Measurements taken in one single point in time were missing the most important part of the illness: PEM. They were missing the impairment. The symptoms that hit 24 hours and beyond and build in intensity. The symptoms that make no sense and are not believed. PEM is the defining feature of ME/CFS, and yet no one was objectively characterizing it.

She knew she could.

Staci’s central scientific question did not arise from theory or textbooks, but from lived experience. This means, from the very beginning, the two-day CPET line of research was not imposed on patients. It originated from a patient using the scientific process and the tools of her discipline to understand her own reality, which science and medicine still have largely failed to adequately explain.

CPET Should be a Reliable Stand-by

CPET is prized for its high test-retest reliability in healthy people and across disease states. When a someone performs a maximal CPET and repeats it a day or two later, the expectations are straightforward. Oxygen consumption should be reproducible. Anaerobic or ventilatory threshold should remain stable. Maximal workload, cardiovascular, and ventilatory responses should closely overlap. Sure, there is a little variability between tests, but the measurements should be very dependable.

Because this reproducibility is assumed, repeat CPETs are used as baseline laboratory validation just to verify equipment calibration, train personnel, and the consistency of a protocol. These ‘practice runs’ exist behind the scenes as simple confirmation that the lab can get the equipment to work. It is mainly ‘throwaway data’ or something that gets cited only briefly in the paper as mundane preparation for the main event.

However, Staci’s thinking was different in a crucial way. Single CPET was making a physiological change that was not measured in the post-exertional state. If there was something different about the post-exertional state, she hypothesized that people with ME/CFS would not be able to reproduce CPET measurements on a second test in the post-exertional state. This meant what we normally think of as throwaway data should be the main analysis.

The Unexpected Finding

At the Pacific Fatigue Laboratory (PFL), the team began observing what should not have been possible under accepted physiological assumptions. On a second CPET performed 24 hours later, people with ME/CFS showed a whole host of unusual findings that deconditioned people did not. These included reduced volume of oxygen consumed, earlier onset of anaerobic threshold, and lower workloads at submaximal levels of exertion. All this evidence began to point to an aerobic energy system that broke down following the first CPET.

These deficits appeared despite objective evidence of maximal physiological effort on both test days. For the first time, the team showed what patients have known for years. Under rigorous testing conditions, PEM is not a failure of motivation, fear, or deconditioning. Instead, it is a failure of metabolic recovery.

“Well, You Don’t Know How to Use the Equipment”

Like anything new in science, the early response from the scientific community was frequently dismissive and hostile. Critics claimed the findings must reflect user error, improper calibration, misapplication of protocols, or misunderstanding of CPET interpretation.

It was too much to accept that a foundational belief might be wrong. And, in certain circles, that acceptance is still difficult, even in the face of abundant research evidence.

What these critiques have ignored and continue to ignore is the data itself. CPET test-retest reliability should be among the most stable principles in the field. If ME/CFS patients uniquely fail to reproduce performance, the issue is the biology and not the test.

Two-day CPET faced (and arguably continues to face) entrenched resistance within the scientific and medical communities. It is still surprising how much resistance this objective evidence of PEM has received and continues to receive both in the research and clinical community even though there is still no definitive diagnostic test for ME/CFS.

However, despite skepticism and institutional pushback, findings from two-day CPET have endured. Carefully done replication studies largely have confirmed the pattern. Independent analyses have demonstrated the same deterioration at submaximal exertion. In a disease marked by noise, this signal has been robust over time.

Two-Day CPET and the Role for Exertional Testing

Even studies that do not perform a second CPET now routinely employ a single CPET or standardized exertional challenge, followed by post-exertional measurement of symptoms, autonomic changes, metabolic disruption, immune markers, or cognitive impairment. In effect, post-exertional assessment is now standard in ME/CFS research. There is a recognition that cross-sectional measurements involving patients only at rest is no longer sufficient. This shift toward understanding what exertion does to the body traces directly back to the two-day CPET paradigm.

With the emergence of Long COVID, CPET has assumed a new importance. Clinicians and researchers began to encounter the familiar pattern of PEM. Many people living with Long COVID show exertion intolerance, a delayed onset of worsening of severe symptoms and signs, and functional collapse that can not be explained by cardiopulmonary disease or deconditioning alone. For this reason, both single-day and two-day CPET protocols are now used in Long COVID research and clinical practice. While not all people with Long COVID show identical findings, the conceptual framework developed in ME/CFS has profoundly shaped how post-exertional disability is now studied more broadly.

Real-World Impact: Supporting Determination of Disability

Beyond the lab and clinic, CPET has had tangible, life-altering implications. Objective CPET findings, particularly from two-day testing, have helped countless people with ME/CFS and ME-like illnesses secure recognition and validation. This has led to disability benefits, workplace accommodations, and legal recognition of functional impairment for many. In systems that routinely discount subjective symptoms, CPET documents physiological limits, demonstrates loss of capacity rather than lack of effort, and proves disability caused by exertion itself. For many patients, these objective data have meant the difference between being believed and being dismissed.

The Future of Exertional Testing

CPET, in part, is a test of physiological limits. We are also now beginning to explore the earliest physiological signatures of PEM and how soon they appear. The answers to these questions may hold the key for more accessible exertional testing with less payback for the patient.

This new line of research does not mean simplistic “submaximal” testing. In fact, poorly characterized low-intensity or prolonged exertional tasks may be more harmful than a brief, controlled maximal CPET. Despite the public perception, maximal CPET is relatively brief, tightly monitored, and well understood. Light or moderate activity, if misapplied, can impose a greater cumulative physiological load while seeming to be biologically innocuous.

This new frontier of exertional testing focuses on detecting metabolic, autonomic, immune, and neurological changes at the very onset of physiological changes associated with exertion. This work to identify the physiological tipping point at the edges of the energy envelope is happening right now. Two-day CPET has made this new work possible and continues to be the gold standard against which new methodologies must be validated.

More on this in future articles.

The ‘Throwaway Data’ That Began to Uncover the Disease

Reliability testing was never designed to validate ME/CFS. It was designed to answer a mundane laboratory question: “if we test someone twice, do we get the same result?” This question is necessary to answer so we can ensure the equipment is working and we can use it correctly.

But for people with ME/CFS, the answer was consistently “no.” In that failure of reproducibility, an important pattern of the disease emerged. The defining pathology of ME/CFS is not fatigue, but a physiological inability to recover from exertion. That insight now underpins ME/CFS research, informs Long COVID science, supports disability justice.

And this insight continues to shape the field, decades after an exercise scientist living with ME/CFS quietly began to answer a question no one else thought to ask.