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Three studies on post-exertional malaise in chronic fatigue syndrome (ME/CFS) and one on ME/CFS and long COVID have recently popped up. In this blog, we cover them all.

The Distinctive Symptom – PEM (Not Fatigue)

Exercise intolerance

Exercise Intolerance; i.e. post-exertional malaise – the key symptom in ME/CFS.

That “fatigue” in “chronic fatigue syndrome (ME/CFS)” – boy, has that ever muddied the waters.  Just about everyone, whether healthy or not, experiences fatigue – and regularly. The symptom is so universal that the use of it to describe ME/CFS allowed – and still allows – people to treat it like it’s nothing.

People who have it, though, know that fatigue was never it. While the fatigue in ME/CFS is simply enormous, what makes the disease so different is in the inability to exert oneself, even in a mild way, without negative consequences. Symptoms – including fatigue – worsen, and new symptoms pop up. Get into a nice strong PEM state, and things really go haywire – people retreat to dark spaces, isolate themselves, their ability to process information takes a hike, gut problems can get worse, and of course, they feel more fatigue and often more pain.

Since PEM is the distinguishing symptom of ME/CFS, we really should be able to know it, describe it, and make it distinguishable. Drug companies, after all, need to have confidence that they have an ME/CFS patient, and not some other type of patient, in their trials. If they have to use symptoms to do that, they’re going to have good measures of the distinguishing symptom in ME/CFS – PEM.

Some work has been done on that by (who else?) Lenny Jason. Lenny Jason’s DePaul Questionnaire contained a PEM subscale which contained 5 symptoms that participants rated according to how severe they were and how frequently they occurred:

  • A dead, heavy feeling after exercise
  • Muscle weakness even after resting
  • Next day soreness after everyday activities
  • Mentally tired after the slightest effort
  • Physically drained after mild activity.

In 2018, Jason and company added four additional questions that addressed how long the symptoms lasted, and one which asked if the person had reduced their activity levels to avoid PEM. Jason then used the PEM subscale to see if it could differentiate people with ME/CFS from people with two other highly fatiguing diseases: multiple sclerosis and post-polio syndrome (PPS). (Note that both of these diseases could be considered post-infectious diseases.)

In, “A Brief Questionnaire to Assess Post-Exertional Malaise”, the Jason group reported that the subscale was able to correctly identify 80% of the ME/CFS, MS, and PPS patients.

In the present study, Workwell Foundation researchers took their slant at the problem. Who better to assess PEM than Workwell? They regularly, after all, employ the greatest stressor of all – exercise – in their 2-day exercise tests in research studies and for disability. A past exercise study found that assessing four symptom categories (fatigue, pain, immune, and sleep-related) accurately classified 92% of ME/CFS 164 patients and 88% of healthy controls.

That was a good step forward, but Workwell wanted more. They wanted to be able to come up with a questionnaire a doctor could very quickly use in their office to determine whether a person experiences PEM, and therefore, likely has ME/CFS.

Workwell - cardiopulmonary exercise test

Workwell used two cardiopulmonary exercise tests to assess PEM in ME/CFS.

A Simple Diagnostic for PEM?

The study which, included 49 people with ME/CFS and 10 sedentary but healthy controls, assessed their symptoms for up to a week after the exercise.

  • Cardiopulmonary symptoms
  • Cognitive dysfunction
  • Cold limbs
  • Decrease in function
  • Fatigue
  • Flu-like symptoms
  • Gastrointestinal disturbance
  • Headache
  • Increase in sensitivity
  • Light-headedness
  • Mood disturbance
  • Muscle/joint pain
  • Neurologic symptoms
  • Pain
  • Positive feelings mood
  • Sleep disturbances
  • Temperature control
  • Tingling
  • Weakness.

While the study was small, the results were fascinating in what they may tell us about ME/CFS and the effects of exertion.

First Exercise Test and the Next Day

Cognition was impaired in about 30% of ME/CFS patients but not in any healthy controls. Twenty-four hours later, PEM was clearly creeping in as 40% of ME/CFS patients experienced cognitive dysfunction while no healthy controls did. Fatigue was very common (@80%) in the ME/CFS patients but was much less frequent in the healthy controls (37-20%), despite their general lack of physical activity.

Muscle and joint pain was interesting, as it charted with the “burn” healthy people can experience after exercise. It was almost nil directly after exercise in the healthy controls, climbed for the next couple of days, and then disappeared completely by the end of the week. It was present in ME/CFS (38%), climbed the second day (57%), then stayed at about 40%.

Second Exercise Test and the Next Day

For the first time, a decrease in function was seen. Thirty-five percent of patients report decreased functioning 24 hours later, but no healthy controls do. Fatigue is actually heading downwards in both the healthy controls and, surprisingly enough, in the ME/CFS patients. Both groups experienced higher rates of fatigue 24 hours after the first exercise test (@ 80% for ME/CFS; 27% for HCs) than the second (63%, 9%). (I don’t know if these are statistically significant).

Twenty-four hours after the second exercise test, it appears that some adaptation has occurred, at least in some patients, as “only” 63% of ME/CFS patients report fatigue. Still, while most of the ME/CFS patients report fatigue, only 9% of the HCs now do – they are almost all over it. The same was true of weakness; over time, weakness actually declined in ME/CFS from 37% after the first test to 21% after the second test, but weakness is not present at all in the HCs 24 hours after exercise.

For the first time, sleep disturbances pop up (37% in ME/CFS vs 0% in HCs). Cognition gets whacked – not in everyone or even in most people with ME/CFS (33%) – but not at all in the healthy controls (0%).

Seven Days Later 

Workwell does not measure the “second-day effect”, where some people report symptoms really ramp up, but they do assess symptoms after 7 days. Things are, in general, getting better. Fatigue continues to lower a bit – now 59% of ME/CFS patients are experiencing it, but get this – zero healthy controls are reporting experiencing fatigue. Muscle/joint pain and pain overall have remained pretty stable in the ME/CFS patients (39%, 33%) but have also completely disappeared in the healthy controls (0%).

Overall Symptom Reports

Looking at whether a symptom has been reported by a person at some point, it was clear that the symptoms in people with ME/CFS popped in and out over time as the percentage of symptoms reported at least once typically far exceeded those reported during any one of the exercise days.

Ninety-six percent of ME/CFS patients (vs 55% of HCs) reported increased fatigue by the end of the study. Muscle/joint pain showed a similar pattern (86 vs 36%), but the key findings are still to come. What Workwell wants are discriminating factors, though, and that’s what is next.

Discriminating Factors

Discriminating symptoms

Symptoms like reduced functioning, cognitive problems, sleep issues, lack of positive affect and headaches after exercise made the ME/CFS patients stand out.

Workwell was primarily after symptoms that could discriminate the PEM ME/CFS patients’ experience from the healthy controls; i.e. symptoms that were common in PEM but almost rarely produced by exercise in healthy but sedentary controls. Fatigue and muscle/joint pain wouldn’t do it – they occur too frequently after exercise in everyone.

Some healthy controls may still feel some fatigue or muscle pain, but they never experienced problems with functioning. Not one HC has reported a drop in functioning, yet 61% of ME/CFS patients reported they did. The pattern is similar – far more people with ME/CFS experience headaches (57 vs 9%), pain (53 vs 9%), sleep disturbance (57 vs 9%), lightheadedness (50-18%), weakness (55-18%), and far fewer experience positive feelings/positive mood. Remarkably, while only 18% of people with ME/CFS reported experiencing positive feelings at some point, 73% of healthy controls do. 

The researchers were able to track how discriminating the symptoms were as the exercise test proceeded. The more the ME/CFS patients exercised, and the longer Workwell tracked symptoms, the easier it was to differentiate people with ME/CFS vs the healthy controls.

First Exercise Test

First, the researchers found experiencing any two of the following symptoms 24 hours after the first exercise test was highly discriminating (AUC – 898; Specificity – .818; Sensitivity – .878).

  • Cognitive Dysfunction
  • Fatigue
  • Headache
  • Pain
  • Absence of Positive Feelings/Positive Mood.

Twenty-four hours after the 2nd exercise test, any two of this larger set of symptoms more highly discriminated ME/CFS. (AUC -.927, Specificity – 992, Sensitivity – .861)

  • Cognitive Dysfunction
  • Decrease in Function
  • Fatigue
  • Headache
  • Pain
  • Absence of Positive Feelings/Positive Mood • Sleep Disturbances.

Finally, symptoms found a week after the exercise stressor produced a veritable lock on an ME/CFS diagnosis. With the healthy controls fully recovered, but with many of the ME/CFS patients still suffering from PEM, presence of any one of the following symptoms produced the highest degree of certainty yet that a person with ME/CFS was present. (AUC-949, Specificity – 1.000, Sensitivity – .895). I don’t know if you can get a much better example of the long-lasting effects of PEM after exercise.

  • Cognitive Dysfunction
  • Decrease in Function
  • Fatigue
  • Muscle/Joint Pain
  • Pain
  • Sleep Disturbances.

Reduced Functioning and Lack of Positive Feelings After Exercise

Mood exercise and chronic fatigue syndrome

Exercise tended to improve the healthy, sedentary controls’ moods. Not so in ME/CFS, where few reported positive feelings and almost 30% reported a mood disturbance.

Functioning, or the lack of it, is the key problem in ME/CFS.  Komaroff’s stunning 1996 study found that functioning was significantly worse in ME/CFS than in serious diseases like heart failure, diabetes, and multiple sclerosis. A 2019 survey found that “reduced stamina and functional ability” was the most common consequence (99.4%!) of ME/CFS, yet the authors pointed out that functioning as a criterion has never received its due either in the research or the medical realm.

Reduced functioning only explicitly showed up in ME/CFS criteria after 2017 and sixty to 98% of medical records of ME/CFS patients fail to even mention problems with functioning. Doctors tend to underestimate the extent of a patient’s disability by two-thirds. Most clearly still don’t get it about functioning and ME/CFS.

A couple of exercise studies that have assessed how exercise affects functioning show declines in the number of steps, decreased activity, increased number of naps, and reduced cognitive abilities.

It was notable, given the well-known emotional benefits of exercise (i.e., the “runner’s high”) and its ability to increase energy levels and feelings of well-being – even in people with depression – that few people with ME/CFS experienced that. The healthy controls did – 73% of them reported feeling more positive, but only 18% of ME/CFS patients did. Meanwhile, 29% reported feeling symptoms associated with a mood disturbance while none of the healthy controls did.

A Personal Experience

One wonders what would have shown up if the survey had been extended one more day in order to get in the day two hit after exercise. I kept an eye on my symptoms after a double-espresso-powered day that required an extraordinary amount of walking (11,600 steps!) and some substantial driving. The range of symptoms I went through was remarkable.

  • Day 1- I felt little pain but felt fatigued and weak, and so I rested. The most interesting symptom was that I could not take in or enjoy nature.
  • Day 2 – The next day, I had lots of burning muscle pain, and felt edgy, but my mind felt sharp. I was able to enjoy nature again – it was like it suddenly clicked back into focus. Still fatigued, I walked a little and was a little fluey by the end of the day.
  • Day 3 – Despite resting for two days, day 3 was in some ways my worst day. My burning muscle pain was worse, I had heart palpitations during the day, and my mental sharpness was gone, I had difficulty concentrating, some dizziness, and the fluey feeling kicked in during the afternoon again.

A Simple Diagnostic For PEM Indeed…

In the end, the authors proposed that if a doctor asked someone if they experienced increased fatigue, cognitive dysfunction, lack of positive feelings/mood, or a decrease in function after exercise, and the person answered yes to two of those symptoms, the doctor could safely assume that they have ME/CFS.

Well, you might say maybe those are just the background symptoms of ME/CFS. Maybe after a week, people with ME/CFS are back to baseline? The next Workwell study answered that question.

The Recovery from Exercise Study

Recovery after exercise chronic fatigue syndrome

Recovery was rapid in the healthy controls and most recovered within a day. It took two weeks for the average ME/CFS patient to recover.

Besides Jared and Staci Stevens from Workwell, “Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)” also included Maureen Hanson, John Chia, and Susan Levine.

Involving 80 people with ME/CFS and 64 healthy but not physically active controls, this 2-day cardiopulmonary exercise test study assessed how long it took to recover from these short, but intense, bicycle exercise tests. It’s a good question. These studies are almost never done unless you are in a research study or are attempting to get disability. It’s good to know if you’re going to have to sacrifice your body either for science or to get some financial security.

This study simply followed the participants until their symptoms returned to baseline; i.e. to the same level that was present prior to the exercise tests. They used something called the Specific Symptom Questionnaire and asked for free text inputs as well.

The study showed that most of the sedentary controls not only recovered in two days but many reported they recovered in one day, and some even stated they recovered that day

Not so with the ME/CFS patients. It took them, on average, about two weeks to recover from the 2-day CPET.  Around 7–8% of people had a prolonged recovery of 1–2 months, and one person, who was not included in the study because he was such an outlier, reported that he felt he had not recovered a year later. Interestingly, he had been in the low-symptom group. Workwell says their data shows them that a very small percentage of ME subjects feel that they never recover.

The answer, then, to the question, “Am I going to sacrifice my body to science (if you’re in a research study) or in order to help secure my financial future”, is no. You’re going to take a hit, but unless you’re a very rare patient, you will get back to baseline.

The authors called the “decay rate of fatigue and PEM symptoms” in ME/CFS extremely prolonged, and suggested that they responded to the exercise as if they were already “overtrained”; i.e. had already exhausted their reserves.

This helps explain why graded exercise doesn’t work – patients are asked to exercise again while they are still recovering. “Small wonder”, the authors wrote, “that graded exercise therapy has fallen into disfavor in the ME/CFS community.”

Indeed, the symptom surveys sent out before they got to the exercise facility indicated that 2/3rds of the ME/CFS participants were already considered to be in the high-symptom group. They proposed that even while at rest at home, people with ME/CFS “constantly live in the long tail of the recovery response”; i.e. they suffer from “constant and persistent PEM”.

Most interestingly, the time to recovery was not associated with symptom severity; i.e. the patients with more severe symptoms did not necessarily take longer to recover. The authors noted the concerns regarding recovery from these quite short, but intense, exercise stressors but stated their surveys suggest that most people recover within 2 weeks,

Both the post-exertional malaise (PEM) studies noted the potential applicability of their findings to long COVID – and what do you know – up popped a long-COVID/ME/CFS PEM study.

Post-exertional Malaise – A Key Symptom in ME/CFS and Long COVID? 

PEM in long COVID and ME/CFS

With few exceptions, the PEM in long COVID looked just like the PEM found in ME/CFS.

The “Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)” study was a collaboration between the Bateman Horne Center (BHC) in Salt Lake City (Suzanne Vernon, Lucinda Bateman) and Derya Unutmaz’s research group at the Jackson Labs. Given that PEM is the defining characteristic of ME/CFS – the term was actually created by the ME/CFS community – it’s obviously quite important to determine how present it is in long COVID. This is the first study I know of that’s looked at this crucial aspect of long COVID in detail.

The study assessed the responses to an online questionnaire given to long-COVID and ME/CFS patients at the Bateman Horne Center. (The fact that 80 long-COVID responses (out of potentially several hundred) were received indicates that the BHC has seen many long-COVID patients.)

The Gist

  • It’s the existence of post-exertional malaise – an eruption of symptoms after mild exertion – that makes ME/CFS so different from other diseases.  Within the morass of other common systems (fatigue, pain, cognitive problems, sleep problems) found in it, it’s PEM that provides clarity.
  • Both the most distinctive (who else talks about PEM?) and most fundamental of symptoms in ME/CFS, PEM needs to be carefully distinguished, measured, and associated with biological findings – and ultimately used in clinical trials.
  • It’s the presence of PEM, after all, that hampers functionality – the key problem in ME/CFS. The devastating impact this disease has on functioning was made clear in a 1996 study that found that functionality was significantly lower in ME/CFS than in heart failure, multiple sclerosis, and diabetes. 
  • Most doctor reports, though, don’t even mention functionality and most doctors dramatically underestimate (by 2/3rds) how impaired their ME/CFS patients are.
  • Three studies recently took a closer look at PEM in ME/CFS, and one did in long COVID. The first indicated that two short but intense physical exercise stressors (exercise tests) provoke a standard suite of symptoms across ME/CFS compared to healthy but sedentary controls.
  • While it appears that some symptoms (cardiovascular, neurological, temperature issues, etc.) are not particularly provoked by exercise, all the major symptoms of ME/CFS (fatigue, reduced functioning, gut problems, sleep issues, muscle/joint pain) are.
  • A distinctive enough symptom set was found that if a doctor asked someone if they experienced increased fatigue, cognitive dysfunction, lack of positive feelings/mood, or a decrease in function after exercise, and that person answered yes to two of those symptoms, the doctor could safely assume that they’re experiencing PEM – and therefore have ME/CFS.
  • The recovery after exercise study indicated that ME/CFS patients, on average, took two weeks to recover. A small portion (7-8%) took up to two months to recover, and one patient reported he was not recovered after a year. Workwell, which has done hundreds of these tests, reports these “never-recover” patients are “exceptionally rare”. The healthy but sedentary controls, on the other hand, recovered within two days and many reported they’d recovered within one day.
  • The authors called the “decay rate of fatigue and PEM symptoms” in ME/CFS extremely prolonged and suggested that people with ME/CFS responded to the exercise as if they were already “overtrained”; i.e. had already exhausted their energy reserves. Interestingly, people with more severe symptoms did not tend to take longer to recover. 
  • Finally, the incidence and symptoms associated with post-exertional malaise (PEM) in long-COVID patients appear to be nearly identical to those found in ME/CFS, with the proviso that PEM symptoms appear to be more severe in long COVID. That may be because long-COVID patients have not learned how to handle their PEM as well as people with ME/CFS.
  • Documenting that PEM is a key symptom in long COVID is vitally important as PEM was little known outside the ME/CFS community prior to long COVID, and needs more study.  The ubiquitousness of PEM found in long COVID should pave the way for more study of this unusual yet fundamental symptom. 
The mystery regarding the incidence of PEM in long COVID was quickly solved: all but one person stated they experienced PEM i.e.; they almost all agreed that they “experienced an unusual worsening of symptoms after minimal physical or mental exertion, which can persist for 24 hours or more after the exertion”. When asked how long the symptoms lasted,, the answers were the same for the ME/CFS and long-COVID patients (several days).

The PEM the long-COVID patients experienced, however, was worse than that experienced by the ME/CFS patients. The authors suggested that this was because people with ME/CFS had learned over time how to avoid it better.

When it came to the specific symptoms the participants experienced, both groups reported that fatigue, muscle and joint pain, infection and immune reaction, neurologic and gastrointestinal symptoms, and orthostatic intolerance all worsened. The long-COVID group, though, reported significantly more sleepiness, respiratory issues, depression and anxiety, irregular body temperature, and excessive thirst.

Conclusions

Post-exertional malaise (PEM) is finally starting to get the recognition it deserves. It’s ME/CFS’s ability to inhibit functioning, after all, that makes it so particularly devastating, and post-exertional malaise – the uproar of symptoms that occurs after even mild exertion – has, thus far, only been documented in it – and now long COVID. It’s the existence of PEM that makes ME/CFS so different from other diseases. Within the morass of other common systems (fatigue, pain, cognitive problems, sleep problems) found in ME/CFS, it’s PEM that provides clarity about this disease.

Three studies recently took a closer look at PEM in ME/CFS, and one did in long COVID. They indicate that two short, but intense, physical exercise stressors (exercise tests) provoke a standard suite of symptoms across ME/CFS compared to healthy but sedentary controls.

While it appears that some symptoms (cardiovascular, neurological, temperature issues, etc.) are not particularly provoked by exercise, all the major symptoms of ME/CFS (fatigue, reduced functioning, gut problems, sleep issues, muscle/joint pain) are.

A distinctive enough symptom set was found that if a doctor asked someone if they experienced increased fatigue, cognitive dysfunction, lack of positive feelings/mood, or a decrease in function after exercise, and that person answered yes to two of those symptoms – the doctor could safely assume that they’re experiencing PEM – and therefore have ME/CFS.

The recovery after exercise study indicated that ME/CFS patients, on average, took two weeks to recover. A small portion (7-8%) took up to two months to recover and one patient reported he was not recovered after a year. Workwell, which has done hundreds of these tests, reports these “never-recover” patients are “exceptionally rare”. The healthy but sedentary controls, on the other hand, recovered within two days, and many reported they’d recovered within one day.

The authors called the “decay rate of fatigue and PEM symptoms” in ME/CFS extremely prolonged and suggested that people with ME/CFS responded to the exercise as if they were already “overtrained”; i.e. had already exhausted their energy reserves. Interestingly, people with more severe symptoms did not tend to take longer to recover.

Finally, the incidence and symptoms associated with post-exertional malaise (PEM) in long-COVID patients appear to be nearly identical to those found in ME/CFS patients, with the proviso that PEM symptoms appear to be more severe in long COVID. That may be because long-COVID patients have not learned how to handle their PEM as well as people with ME/CFS.

Documenting that PEM is a key signature in long COVID is vitally important as PEM was little known outside the ME/CFS community prior to long COVID, and it hasn’t received the study it needs. High rates of PEM in long COVID will hopefully pave the way for more recognition and study of this unusual yet fundamental symptom – and that should benefit everyone.

 
 

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