There have been case reports and social media posts on survivors of SARS COVID 2 infections that have persistent symptoms even though they have been labeled as “recovered.” These individuals may have many symptoms similar to post viral syndromes seen from some people “recovered” from influenza. We will be looking at a few studies regarding these SARS COVID-2 survivors that have persistent symptoms. This is the first of a two part series discussing the two main organs involved; the lungs and the heart. We will focus today on shortness breath and the lungs.
In this first part of our discussion we will look at a research letter published in the JAMA Network about these persistent symptoms in patients after acute covid-19 that came from Rome, Italy. In Rome the Italians set up a post infection clinic to look after these patients and they summarized their symptoms in an electronic medical record and the results were published. There were three criteria to be included in the study: Number one no fever for three days, Number two is improvement in symptoms and number three is two negative tests twenty-four hours apart. They asked each participant to rate a number of symptoms on a scale of 0 to 100, 0 being the worst they could possibly imagine and 100 being the best they can possibly imagine reflecting on when they initially had the virus a few weeks before and now at present after their recovery and being following up in the clinic. They enrolled one hundred and seventy-nine people but ended up testing only 143 because some dropped out either because they refused to engage in the study or they were still testing positive. The mean age of these people was 56 years of age and 63% of them were men. 73% of them got pneumonia and the average length of stay was 2 weeks and the average BMI was 26. When they asked these people to look back and write down when the length of time they actually had most of their symptoms, the average amount of time written on the questionnaire was two months. They were then asked for a number of different types of symptoms; these symptoms were pretty consistent with covid-19 symptoms like chest pain, shortness of breath, and fatigue, among other symptoms. They were grouped based on how many had zero symptoms now, how many still had one or two symptoms, and how many still had three or more symptoms. Only 13% said they had no more symptoms after 2 months, 32% still had at least one to two symptoms and 55% of those questioned still had three or more symptoms even two months after the initial symptoms and infection. So the majority of the people who recovered from covid-19 even after 2 months still had three or more of the symptoms that they had at the very beginning. These people with post viral or delayed recoveries were definitely not the minority. At 2 months out, they looked at their quality of life and they asked the participants “Has your quality of life gotten better or worse since” having the infection over 2 months ago and 44% stated their quality of life had gotten worse. The graph from the publication shows percent of patients that actually have the listed symptom. In the dark color we see the percentage of those that had the acute symptoms and on the other side we see the numbers for those that still have some of these symptoms even after two months. In the acute phase the symptoms of fatigue, dyspnea, cough, lack of appetite , myalgia seem to go away after 2 months but the things that tend to continue are listed at the top part of the graph including fatigue, dyspnea, joint pain, and chest pain. Even cough may still remain months after the initial infection (see charts and diagrams in the video).
Case studies have reported patients complaining of a chest heaviness , a fatigue with shortness of breath predominantly in the morning but gets better towards the afternoon; some patients have depression while others have clotting problems. I have mentioned previously that increased clots may be formed with increased formation of megakaryocytes and platelets. There appears to be first insult with the infection and here some patients seem to get better if they can clear the virus but then a second insult can occur especially if the oxidative stress cannot be handled and an inflammatory response is triggered which can lead to “cytokine storm” in some individuals. The initial symptoms may be chest heaviness, fatigue, shortness of breath, fever, nausea, and diarrhea but there are other less common longer-term symptoms as well. There also has been a hair loss associated with stress where the hair doesn’t grow grows back in for weeks to months which has been seen in other stress conditions.
Of interest is that in some of these case reports, patients that took supplements, specifically n-acetyl-cysteine or NAC seemed to cope better with their symptoms. NAC is a mucolytic, which means it can break down mucous but it is involved in many other processes. I’ve discussed elsewhere about how NAC not only recharges the body’s glutathione peroxidase, one of the body’s major antioxidant system. It also has thiol groups that allows it to break disulfide bonds such as the bonds that cross link together in the presence of Von Willebrand factor released by endothelial damage and toxidative stress. This forms the clot. This is the connection between NAC and blood clots and therefore NAC is a potential treatment for some of the platelet-rich clots from both the arterial and the venous systems. People who have died from COVID are known to have endothelial damage leading to the activation of Von Willebrand’s factor and have been shown to have 9 times as many clots in the lung arterioles or small lung blood vessels on autopsies compared to autopsies from ordinary influenza, other viral infections, and organ transplant autopsies. These reports were published in the New England Journal of Medicine.
Therefore, people with post viral syndrome may be having shortness of breath as a result of clots being formed and possibly those people taking N-acetyl cysteine may be breaking those up or at least accelerating their dissolution more quickly. We don’t know for certain at this time how NAC works in this way. A randomized double blinded placebo controlled trial to see whether or not NAC might help these post viral syndrome patients would be worth doing.
Let’s next consider the people that have had COVID-19, no longer have a fever but have continued shortness of breath or fatigue. What might be happening to them? There is a research letter published by the European Respiratory Journal who looked at patient’s respiratory function who were discharged from the hospital after treatment for COVID-19 infection. The authors acknowledge that persistent impairment of pulmonary function and exercise capacity have been known to last for months or even years in patients who have had Severe Acute Respiratory Syndrome (SARS ) or Middle Eastern Respiratory Syndrome (MERS) which are cousins of COVID in the same family. They looked at their pulmonary function test after the acute infection. In the paper, they looked at 24 patients with mild illness, 67 with mild pneumonia , 19 with severe pneumonia and then they looked at a comparison of these groups ( p-value ) to see if there was detectable differences. Examining and going down the chart we can see the first big difference is the duration of their hospitalization and presumably the more severe cases are going to be in the hospital for much longer. It would be expected that they would have more severe dysfunction. The major differences between these groups in their pulmonary function tests was the diffusion capacity. The diffusion capacity represents how much of the surface area of your lung is available for use. An example is if you think of a tennis court which is roughly equivalent to the surface area of the lung and if you have less diffusion capacity then you have don’t have access to all areas of the court. You can see in the mild illness group there was 87% available surface area and this progressively goes down to 79%, and then 64.79% in the severe pneumonia group (see diagrams and chart in the video). This is consistent with the fact that there was interstitial lung damage from inflammation of the small blood vessels and scarring which results in the loss of surface area; like damaged areas on the tennis court that is quartered off so there are areas you cannot have access to.
In conclusion, they found that in the discharged survivors with COVID-19, the impairment of diffusion capacity is the most common abnormality of lung function followed by restrictive ventilatory defect, which are both associated with the severity of the disease.
Pulmonary function test (not only spirometry, but also diffusion capacity) should be considered and performed in routine clinical follow-up for certain recovered survivors, especially in severe cases. Subsequent pulmonary rehabilitation might be considered as an optional strategy.
These diffusion capacity deficits are normally seen in pulmonary vascular problems such as a pulmonary embolism or a clot that blocks a blood vessel from exchanging oxygen in a branch of the lung. Pulmonary arterial hypertension can have this picture as well. There are case reports as I mentioned elsewhere, where N acetyl cysteine have been reported to be helpful in some of these post viral syndrome patients. N acetyl cysteine is a mucolytic breaking up mucous but as we’ve been discussing it also plays a role regenerating the antioxidant glutathione, supports the endothelium or blood vessel lining and plays a role in correcting clotting dysfunction by breaking apart clots. Our discussion continues next week with shortness of breath post COVID arising from changes in the heart.
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