Long Covid research- persistent dyspnea and exercise intolerance

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I noticed that Dr. David Systrom published a paper that resonates a lot with what I have been experiencing.

Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.
https://journal.chestnet.org/article/S0012-3692(21)03635-7/fulltext

They concluded that

Post-COVID-19 patients without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit along with an exaggerated hyper-ventilatory response during exercise.

In my case, my Covid infection was on April/2020. I developed several symptoms by the end of May/2020. The most impacting ones were all POTS-like symptoms. I had some dyspnea at rest, but it went away in a couple of weeks.

Fast forward to Summer/2021, some symptoms resolved, while others stagnated. I was not great, but I could work from home. Also, I no longer had any fatigue at this point.

I decided to take my Pfizer shots, and around ~3 weeks later I noticed a stronger dyspnea creeping back in. It would affect me at rest, and not only while exercising. It made me uncomfortable to speak. I felt that I had to gasp for air. In some cases, I had my arms tingling (which possibly indicates hyperventilation).

I told that to my doctor, who ordered the following exams:
  1. Spirometry Pre and Post: They stated "Normal spirometry with no clear evidence of airflow obstruction or pulmonary restriction. However, although subtle, there is suspicion of reactive airway disease and airflow obstruction given the improvement postbronchodilator in the visual curve.". I felt it was weird because I do not feel any better by taking postbronchodilators;
  2. CT SCAN: Completely normal;
  3. CPET: to be taken next month (exams may take a while in Canada);
My doctor prescribed a steroid inhaler, called Breo Ellipta. Has anyone heard about it? I took it for around one week, and decided to give it up. Not only because I was seeing no improvement, but I felt worse on it. It gave me back pain and sore throat as side effects. Not sure if I should have waited longer.

As mentioned, bronchodilator (Salbutamol) also has no effect.

I also tried diaphragm breathing exercises. They have a Covid-19 recovery program called Stasis (https://stasisperformance.com/), which I tried in the past. I have been doing it for about 3 weeks now, but I do not think it helps that much. I have been wondering if similar programs may work better, like Wim Hof or Buteyko.

Along with the breathing exercises, I tried swimming. I can do some comfortable 15min-20min without triggering any side effect. In fact, I do not feel breathless and discomfort while swimming. Similar to the diaphragm breathing, I feel it does help to some extent, but it does not feel like persisting gains, and that I am continuously improving.

Some other things that have been tried without noticeable effect on the dyspnea: NAC, LDN (2 months), Nebulized gluthatione, vagal nerve stimulation.

I am really at a loss here, and looking for anything to at least give me some relief. I did notice a few things that may be relevant:
  1. Dyspnea feels worse with heat, like I really need the AC on. I guess this could point out to dysautonomia being at play. Although I must say that I had worse POTS symptoms in the beginning of my disease without the dyspnea. Nowadays my POTS is not that bad;
  2. Oxygen saturation is within normal ranges.

I heard about similar things happening in other conditions, like Post-Lyme. I did a search here on other threads regarding persistent dyspnea, but I do not think I saw a consensus, they felt a bit dispersed. That is why I decided to create this one. I wanted to know if there is a certain guide on how to deal with this.

Could this be related to auto-immunity? That is a strong suspicion, given the worsening after the Pfizer shot. I do have autoantibodies detected against the alpha-1 adrenergic receptor (through the CellTrend panel).
I have been considering plasmapheresis.
 

Pyrrhus

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Persistent Exertional Intolerance after COVID-19: Insights from Invasive Cardiopulmonary Exercise Testing.
https://journal.chestnet.org/article/S0012-3692(21)03635-7/fulltext
Thanks for sharing that article, very interesting.

I am really at a loss here, and looking for anything to at least give me some relief.
I don't know, but you might find this discussion interesting:

Treatment for shortness of breath?
https://forums.phoenixrising.me/threads/treatment-for-shortness-of-breath.81325/
 

Pyrrhus

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The authors of this paper include the following "Take-home points":
Study Question: What is the pathophysiologic mechanism of exercise intolerance that underlies post-COVID-19 long-haul syndrome in patients with COVID-19 without cardiopulmonary disease?

Results: Patients who have recovered from COVID-19 demonstrate reduced peak exercise aerobic capacity with impaired systemic oxygen extraction and abnormal ventilatory efficiency slope.

Interpretation: Patients without cardiopulmonary disease who have recovered from COVID-19 demonstrate a marked reduction in peak oxygen consumption from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.

And here's the full abstract:

Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing (Singh et al., 2021)
Background
Some patients with COVID-19 who have recovered from the acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that often is unexplained by conventional investigative studies.

Research Question
What is the pathophysiologic mechanism of exercise intolerance that underlies the post-COVID-19 long-haul syndrome after COVID-19 in patients without cardiopulmonary disease?

Study Design and Methods
This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19.

Results
The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation.

Interpretation
Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.
 

Pyrrhus

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A couple of thoughts on this paper:


On patient selection:
  • The study did not include any Long Covid patients who had any measurable heart or lung problems. Nine of the 10 patients had experienced mild COVID, while one patient had been hospitalized for 2 days. The average length of time that the patients had suffered with Long Covid was 11 months.
  • The study subjects consisted of only 10 Long Covid patients, and they were enrolled prospectively: "We consecutively enrolled all patients who had recovered from COVID-19 and were referred to [our clinics] between February and June 2021 for unexplained exercise intolerance."
  • This patient selection procedure contrasts with what the authors did for their ME study. In their ME study, they retrospectively selected patients based on existing medical records and pre-existing iCPET data. The authors explained that it would be unethical to prospectively enroll ME patients in an exercise study.

On study results:
  • Just as seen with ME patients, the Long Covid patients had a lower peak oxygen consumption (peak VO2) during exercise.
  • Just as seen with ME patients, the Long Covid patients had lower blood pressure in the veins transporting blood back to the heart (lower Right Atrial Pressure RAP). However, this finding was not statistically significant at the 95% level. (3 mmHg vs 6 mmHg; p=0.08)
  • Just as with ME patients, the authors note that the observations are not due to deconditioning.
  • Unlike in their ME study, the authors mention that Long Covid patients demonstrated a hyperventilatory response during exercise. As the authors describe it: "patients who had recovered from COVID-19 exhibited a greater degree of ventilatory inefficiency compared with control participants (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 vs 27; p=0.01)"

On the implications:
  • The lower peak oxygen consumption found in both Long Covid and ME patients means that the patients can not perform aerobic exercise efficiently, as their bodies do not extract oxygen from the blood fast enough to keep up with the exercise.
  • The lower blood pressure in the veins transporting blood back to the heart (lower Right Atrial Pressure RAP) in both Long Covid and ME patients suggests that the veins are failing to constrict during exercise, which is a form of dysautonomia. The result is impaired blood flow from the muscles.
  • The authors interpret the hyperventilatory response seen in Long Covid patients by saying "the abnormal ventilatory efficiency [...] can be attributed to enhanced peripheral [autonomic reflex] sensitivity," referring to the autonomic nervous system reflex that leads from muscle tissue to the brainstem, which controls the breathing rate.
 

Pyrrhus

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Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing (Singh et al., 2021)
The lower blood pressure in the veins transporting blood back to the heart (lower Right Atrial Pressure RAP) in both Long Covid and ME patients suggests that the veins are failing to constrict during exercise, which is a form of dysautonomia. The result is impaired blood flow from the muscles.

And now David Systrom and colleagues might be putting two and two together.

In the above paper, they suggested that exercise intolerance in Long Covid is associated with impaired blood flow to muscles.

In the following paper, a similar set of authors suggest that orthostatic intolerance in Long Covid is associated with impaired blood flow to the brain.

However, it should be noted that the following paper is more of an exploratory analysis than a full study. (Only 9 Long Covid patients were assessed, 3 with POTS and 6 apparently with regular orthostatic intolerance.)

Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC) (Novak et al., 2021)
https://doi.org/10.1002/ana.26286
Methods
This retrospective study evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with PASC. Controls included postural tachycardia syndrome patients (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in middle cerebral artery), respiratory (capnography monitoring) and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.

Results
Nine PASC patients were evaluated 0.7±0.3 years after a mild COVID-19 infection, treated as home observations. Autonomic, pain, brain fog, fatigue and dyspnea surveys were abnormal in PASC and POTS (n=10), compared to controls (n=15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic [cerebral blood flow velocity (CBFv)] declined in [Long Covid/PASC] (-20.0±13.4%) and POTS (-20.3±15.1%), compared to controls (-3.0±7.5%,p=0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n=6) and with (n=3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p=0.013). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs. 60%) but not in inflammatory markers (67% vs. 70%). Supine and orthostatic hypocapnia was observed in PASC.
(emphasis added)
 
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Any results from the CardioPulmonary Exercise Test (CPET) that you'd like to share, as a Long Covid patient?

Is your shortness of breath (dyspnea) still bad?
Hello Pyrrhus,

I did not go for a CPET in the end. I did however book a consultation with Dr Systrom. He recommended me an ICPET, along with a biopsy to rule out SFN. I am currently checking if I can get these tests in Canada, which is several years behind US in modern medicine, so I doubt these are easily available here. They are helping me to figure this out.

It will be a while before I get these tests. In the meantime, however, I was recommended to go for Mestinon. I tried it months ago, without noticing much difference, but he said the dose needs to be higher.

I also asked him about the GPCR-AAb results I had. He could not tell me if they were clinically relevant though. It does not seem to be his specialty.

I would say my SOB is doing better these days, but it is because I am speaking much less (and it is also winter). I can sense that the underlying problem is still there somewhere. When I visited Dr Systrom, his little exercise test was able to capture the hyperventilation response.
 

Pyrrhus

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It will be a while before I get these tests. In the meantime, however, I was recommended to go for Mestinon. I tried it months ago, without noticing much difference, but he said the dose needs to be higher.
That's interesting. You might be interested in @Rebeccare's experience from this thread:
https://forums.phoenixrising.me/threads/for-those-who-got-worse-with-mestinon.78121/
I'm a patient of Dr. Systrom, and I didn't do well with Mestinon--I got terrible chills, constipation, and was extremely short of breath (for me, the drug seemed to do the opposite of what was expected!). I started off on 30 mg 3x/day and then worked up to 60 mg 3x/day, then I took the extended release pill which is 180 mg once a day. I was able to stay on it for a few months, but then the side effects got so bad that I gave up. I felt like a bad patient for failing on a drug which was supposed to help!

After a few months I decided to try Midodrine (which was an alternative he suggested), and it's helped a little but there has not been a dramatic improvement in my day-to-day functioning. However, the results of my exercise tests have improved quite a bit: my peak V02 went from 78% of predicted to 93% of predicted, and my VE/VCO2 slope went from severely abnormal to borderline abnormal.

Florinef was the other drug he suggested.

When I visited Dr Systrom, his little exercise test was able to capture the hyperventilation response.
That's very interesting. I wonder why Systrom sees a hyperventilation response in Long Covid patients, but not (so far) in ME patients.

To me, the fact that some people get tachycardia during exercise (POTS?) and the fact that some people get hyperventilation during exercise (Long Covid?) demonstrate very interesting types of dysautonomia...