Disclaimer: This article is far from a definitive guide to post COVID-19 patient care. The situation associated with those who have recovered from COVID-19 is dynamic and we are learning more by the day about its mechanisms of action, the broader impact on physiology and the long-term effects to those who survive infection. This commentary is a snapshot in time; it lays out a portion of what we know at this point and merely suggests that we continue to monitor the data and keep a holistic point of view when dealing with patients who have overcome infection and who may have residual effects. I think it is important, too, that we attempt to “see around corners” on behalf of our patients and provide them with complete, thorough assessments and proactively test the organs and systems that the data suggests could be involved but may not be presenting with obvious symptomatology.
At the time of this writing, more than 220,000 Americans have died and more than 8 million Americans are infected. Like everyone else my heart, prayers and thoughts go out to all of those who have been affected directly and indirectly by this devastating virus.
As we begin to see more and more of those roughly 5 million who have recovered from the infection in our practices (whether in person or virtually), I think it is critically important to consider the potential long-term negative effects that this virus can have and keep that at the forefront of our minds when developing their treatment plans.
Many of the lingering complications are associated with the organs rich with Angiotensin I Converting Enzyme 2 (ACE2). And drawing from previous experience relative to the organs affected by SARS-CoV-1 from the early 2000s we can begin to piece together the areas to hone in on when treating post COVID-19 patients. We will see, though, ACE2 receptors are not always the lynchpin as they are not as abundant in certain areas, such as the nervous system, however, we are still seeing a significant rise in neurological (mental/emotional) issues in patients who have recovered from COVID-19. Nevertheless, let’s begin by looking at where the ACE2 receptors are found and tie that to potential for longer term complications.
ACE2 Receptor Distribution
Mapping out ACE2 receptor distribution throughout the body is not something that has been done as a result of COVID-19. In fact, in 2004 The Journal of Pathology outlined the distribution of ACE2 receptors as it related to SARS-CoV because of a similar mode of action and affinity for these receptors.1
As a result of that article, as well as the recently published data on the impact of COVID-19, the primary areas that this article will focus on are the respiratory system, digestive system, neurological system as well as the pancreas and kidney.
Not surprisingly, the highest concentration of receptors was found in the alveolar tissue of the lungs. An early study out of China published in June 2020 found out of 55 recovered COVID-19 patients assessed, 39 had residual radiographic abnormalities three months post infection. Spirometry and pulmonary diffusion capacity test was also conducted and included forced vital capacity (FVC), forced expiratory capacity at the first second of exhalation (FEV1), total lung capacity (TLC), and diffusion capacity of the lung for carbon monoxide (DLCO) measured by means of the single-breath test. And despite most of the participants experiencing no respiratory symptoms, 25 percent showed decreased functionality.2 Another note from the discussion of this particular study was the structural differences between SARS-CoV-1 and SARS-CoV-2, the novel coronavirus that causes COVID-19 which results in a heightened ability to spread and more potential for long-term damage to lung tissue.
Also noted in the Journal of Pathology’s ACE2 receptor distribution map was the presence of ACE2 receptors in the nasal and oral mucosa and the nasopharynx. This easy access and the structural advantages SARS-CoV-2 sets up a mechanism for easier access and binding to the host receptor proteins.
There were ACE2 receptors found throughout the digestive system, which is to be expected, however, they were found not only in the smooth muscle and endothelium of the stomach, small intestine and colon but also the muscularis mucosae, which aids in the epithelium’s ability to move and fold (adapt to digestive processes) as well as muscularis propria, which are the muscle bundles of the detrusor muscle associated with the bladder. It was also noted, “Remarkably, ACE2 was abundantly present in the enterocytes of all parts of the small intestine including the duodenum, jejunum and ileum, but not in enterocytes of the colon.”1 This immediately triggers a thought process around intestinal permeability and associated disorders. One study out of Stanford, again early on in this pandemic, found 39 percent of those they looked at experienced digestive disorders while actively infected with COVID-19. Incidentally, 40 percent of those patients had elevated liver enzymes and those with the highest numbers required longer hospital stays.3 The curiosity there is the liver cells, Kupffer cells, hepatocytes and the endothelium in were negative for ACE2 receptors.1
In the brain, ACE2 receptors are found only in the endothelium and smooth muscle cells. This is not to say that there is no negative impact to the brain; we’ve seen considerable evidence to the contrary. In fact, in the Journal of Neurological Science a novel syndrome has been identified as Post COVID-19 Neurological Syndrome. The article cites, “Neutrophils, effector T cells, monocytes and macrophages (key cells of the innate immune system) accumulate at the entry points of the SARS-CoV-2 virus resulting in the generation of additional cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α). Viral downregulation of ACE2 receptors leads to endothelial dysfunction with associated hyperinflammation promoting further endothelial dysfunction culminating in endotheliitis not only at the entry points but also at the neuro-vascular units in the brain…” and goes on to say, “On-going hyperinflammation and endotheliitis contribute to the disruption of the blood-brain barrier, allowing entry of innate immune cells into the brain and further pro-inflammatory cytokine cascades.”4
Pancreas & Kidney
The two other areas that have consistently presented in studies about organ involvement either during an active infection or post infection are the pancreas and the kidney. Pancreatitis is not always synonymous with pancreas injury from an infection. There can be residual injury without overt symptoms. The complication here is that the pancreas has proven to offer an abundance of ACE2 receptors and, according to a 2010 Diabetes article the ACE2 receptor population and the integrity of the receptors themselves are key to insulin secretion and damage to or deficiency of ACE2 receptors could be a contributing factor to diabetes.5
In terms of kidney involvement, according to C. John Sperati, MD, MHS in his hopkinsmedicine.com discussion, reports of up to 30 percent of those hospitalized in China and New York developed moderate to severe kidney damage, which can carry over post infection and manifest into ongoing renal issues. Keeping this possible side effect of COVID-19 in mind and monitoring for dysfunction via blood and urine, even in the absence of symptoms, could prove to be an important piece to a post COVID-19 treatment plan.
Functional Tests to Consider for Post-COVID-19 Patients
Regardless of the mechanism responsible for the neurological involvement, attention being paid to peripheral blood markers for inflammation, such as C-reactive protein, neutrophil/lymphocyte ratio, D-dimer and ferritin levels could be helpful in the treatment of these cases.
When it comes to monitoring kidney function, blood tests such as BUN, creatinine, BUN/creatine ratio, GFR should be adequate and urine, looking for elevated protein levels and at the albumin to creatinine ratio.
One test to consider is Genova’s Metabolomix+ test. This is being aimed at allowing practitioners to provide patients with customized nutritional therapies. And while this is great for enabling practitioners to provide a higher level of personalized medicine, the areas of focus for this test relate directly to what one might look at for a patient who has recovered from a COVID-19 infection. It includes an organic acid test, which measures malabsorption and dysbiosis, cellular energy and mitochondrial function; then it looks at essentially and metabolic fatty acids, including omega-3 and omega-6 levels, which are key for inflammation as well as lending to a cardiovascular risk assessment. Its view into amino acids can provide insight into liver detoxification and whether your body is getting what it needs for adequate glutathione synthesis.
Nutrients to Consider for Post-COVID-19 Patients
Again, this is far from a comprehensive list and, quite frankly, I imagine I’m not listing anything here that you haven’t already thought of. There have recently been a number of interesting articles directly tied to COVID-19 and potentially beneficial nutrients. Respiratory
Glutathione: The master antioxidant was discussed in Antioxidants (Basel) in July 2020 as a method for preventing COVID and subduing its severity but can also be applied ongoing for respiratory, and multi-system support. An interesting case study was also published in Respiratory Medicine Case Report in April 2020 which demonstrated GSH’s ability to relieve two patients’ dyspnea within one hour of administration.
NAC: Potential mechanisms were outlined in Future Microbiology in June of 2020, relative to NAC and COVID-19. With NAC’s role as a GSH precursor, ongoing application post infection may make sense.
Probiotics: npj Sci Food in October of 2020 discusses the potential application of probiotics and prebiotics for the prevention and treatment of COVID-19 and delves into the gut-lung axis. Many strains are listed including L. acidophilus, L. rhamnosus and L. casei and prebiotics included resistant starch and galactomannan and arabinogalactan.
Omega-3 Fatty Acids: Free Radical Biology & Medicine in August of 2020 discusses the various mechanisms by which omega-3 fatty acid therapy could provide key benefits to COVID patients and could potentially ameliorate the need for some patients’ need for intensive care admission. Curcumin: “Curcumin: a Wonder Drug as a Preventive Measure for COVID19 Management” was published in the Indian Journal of Clinical Biochemistry in July of 2020 and laid out nicely the ways in which curcumin can lend targeted support to the brain in COVID-19 patients.
Ongoing Immune Support
EGCG: In Phytomedicine, July 2020, “Antiviral activity of green tea and black tea polyphenols in prophylaxis and treatment of COVID-19: A review” was published and making the case for EGCG to be applied clinically in COVID-19 cases.
Resveratrol: Indian Journal of Clinical Practice in September of 2020 examines the potential role as an adjunct therapy in COVID-19 cases due to its potent antiviral properties.
And obviously vitamins A and D, zinc, vitamin C, quercetin, elderberry and garlic are all strong candidates to provide immune support when it comes to active COVID-19 and post infection. When it comes to the pancreas and kidney, there is no clear data on the application of natural compounds in COVID-19 or post COVID-19 cases, however, when taking into consideration the inflammatory involvement and potential for the cytokine storm to have a negative impact on these organs, one could make the case that omega-3 fatty acids and possibly curcumin might be beneficial.
Everyone talks about our “new normal” in life which, inevitably, extends into clinical practice. And while we as health care providers stay educated and are aware of the information included in this article and the potential for ongoing complications post COVID-19, our patients may not be. Our “new normal” is undoubtedly going include more specific assessments with patients who have been infected and have come out the other side and, as always, being the best, most supportive, most informative resource possible for them.
1 Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637. doi:10.1002/path.1570.
2 Yu-miao Zhao, et al. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine July 2020.
3 George Cholankeril, et al. High Prevalence of Concurrent Gastrointestinal Manifestations in Patients With Severe Acute Respiratory Syndrome Coronavirus 2: Early Experience From California. Gastroenterology. Volume 159, Issue 2, AUGUST 01, 2020.
4 Tissa Wijeratne, Sheila Crewther. Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community. Journal of Neurological Sciences. Volume 419, 2020.
5 Daniel Batlle. ACE2 and Diabetes: ACE of ACEs? Diabetes 2010 Dec; 59(12): 2994-2996.
Dr. Adam Killpartrick is a chiropractor, specializing in upper cervical chiropractic and cranial work and a certified nutrition specialist. While in private practice, Dr. Killpartrick began working as a clinical consultant and medical educator in the nutritional supplement industry, and then moved on to a director of product development role. Currently, he is the chief science officer for FoodScience Corporation, makers of DaVinci Labs and VetriScience products, overseeing research and development for both the human products as well as pet product lines.