By Lyn Patrick, ND, and Anne Marie Fine, NMD, FAAEM

The current COVID-19 pandemic has been described exclusively in terms of virology, with the toxicological contributions almost entirely excluded from the discussion. The research body of evidence linking the major role of the exposome as a whole, and toxicants in particular, to chronic disease continues to grow. Data from COVID-19-related deaths show that we can no longer overlook the contributions of chemical body burden to the symptoms from this disease.

In any discussion of health, the integrity of the immune system is crucial for proper defense against infectious organisms. In this current pandemic, there has been an absolute blackout of information about how environmental stressors negatively impact immunity, or how lifestyle choices can enhance it.

There is a significant relationship between toxins and immune function; toxins dysregulate the immune system making it less capable of vigilant responses against invaders and more likely to respond inappropriately to a toxic exposure or a viral challenge. Therefore, toxic load must be addressed in order to achieve optimal immune function.

Two relevant examples of this arise from air pollution and wildfire smoke studies, both of which illustrate the connection between pollutants in the air, including particulate matter (PM 2.5), and risks of COVID-19 infection severity and mortality.

In the case of air pollution, a recent study indicated that a 1 ug/m³ long-term average PM 2.5 exposure was associated with an 11% increase in COVID-19 death rates in the United States.¹ To better imagine the significance of this, PM 2.5 can vary from double digits to triple digits (PM 2.5 readings ranged from 35 to over 500 in Northern California during 2020).  

In the case of wildfire smoke, which produces high levels of PM 2.5, an excess of COVID-19 cases and mortality has been noted in relation to the 2020 wildfires on the west coast of the United States.² A recent analysis by Harvard T H Chan School of Public Health indicated that there is strong evidence that wildfires have amplified the effect of PM 2.5 on COVID-19 cases and deaths.

The contributions of toxicant impact are also being noted in the post-acute covid syndrome. Post-acute covid syndrome (PACS) is a clinical entity that is gaining attention as more and more previously recovered COVID-19 patients are reporting chronic symptoms four weeks or more after their recovery. PACS patients complain of fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia, diffuse myalgia, hair loss, depressive symptoms, non-restorative sleep, migraine-like headaches, and late-onset headaches.³

The key mechanisms leading to long-term sequelae of COVID-19 remain to be elucidated, although in this paper we present the clinical hallmarks, particularly as they relate to environmental factors, both as contributors and as relevant to treatment.

Chronic inflammation – the Hallmark of PACS: Post-infection cellular damage, an innate immune response leading to chronically elevated cytokine production, endothelial damage, microvascular injury, and a pro-coagulant state are all thought to contribute to the sequelae of an acute SARS-CoV-2 infection.

Chronic lung inflammation, characterized by elevated TGF-β, TNF-a, and IL-6 along with depressed intracellular glutathione can lead to chronic systemic inflammation in PACS.^4,5

Loss of glutathione (GSH) during COVID-19 infection occurs due to both oxidative stress and suppressed GSH production. An inability to produce GSH can occur because the cytokine TGFβ1 is one of the main repressors of glutamate-cysteine ligase (GCL) and glutathione synthase (GS)—both crucial enzymes needed for GSH production.⁶ Long-term and more severe manifestation of COVID-19 infection correlates to loss of GSH.⁷

TGFβ1 increases as viral load increases, driving the disease process.⁸ The same phenomenon occurs in mold exposure where TGFβ1 elevation leads to GSH loss.

Some of the co-morbid conditions that increase risk for severe COVID-19 infection are themselves associated with low GSH levels: diabetes, obesity, coronary artery disease, cognitive decline, COPD and of course, aging.⁹

Obesity appears to be a major risk factor for both severe COVID-19, and post-acute covid syndrome.¹⁰ Obesity is a condition being driven by environmental chemicals termed “obesogens” and no longer assumed to be simply a function of increased calorie intake and lack of exercise.¹¹

Many of these obesogens are found in everyday consumer and personal care products and our patients are completely unaware of their presence. Obesogens include the ubiquitous bisphenols A, S, F, and AF, pesticides/herbicides, plastic ingredients, per- and polyfluoralkyl substances (PFAS), parabens, and flame retardants that can be tested for, assessed, and addressed in our patient population.

Addressing the growing epidemic of obesity and other metabolic derangements in our population and their relation to body burden should be considered.

Lung inflammation is due to antioxidant depletion. The fibrotic changes in the lungs seen in ARDS (acute respiratory distress syndrome) and in pulmonary fibrosis occur in those with acute COVID-19 and PACS and are associated with decreased glutathione. Multiple studies show that COPD and pulmonary fibrosis respond to NAC treatment, which replenishes GSH in the lungs.¹²  The lung epithelial lining fluid is rich in glutathione and other antioxidants (superoxide dismutase, vit. E, etc.)  to protect the lining from inhaled toxicants and pathogens.

The fibrotic state in PACS may be provoked by interleukin-6 (IL-6) and TGF-β, which have been implicated in the development of pulmonary fibrosis and may also predispose to bacterial and fungal colonization (Aspergillosis) and subsequent infection.^13-15

Exposure to PM 2.5 (particulate air pollution) is one of the toxicants capable of causing lung inflammation via potent IL-1β secretion, which activates the NLRP3 inflammasome.¹⁶

The Lombardy and the Emilia Romagna regions of Northern Italy recorded the highest levels of virus lethality in the world during the COVID-19 outbreak in 2020 and are among Europe’s most polluted regions with regard to chronically high PM 2.5 levels. PM 2.5 levels in this area of Northern Italy were highly correlated with COVID deaths.¹⁷

Endothelial Damage Leading to Oxidative Stress, Thrombosis and Cardiovascular Risk – The Role of NAC: The endothelial damage in both acute and post-acute COVID is the result of altered ACE2 activity resulting in higher levels of angiotensin II and lower levels of its metabolite, angiotensin 1,7.¹⁸ Lower levels of angiotensin 1,7 in the bloodstream lead to an increase in oxygen radicals and the subsequent release of von Willebrand factor from the endothelium of the blood vessel, increasing risk for platelet activation and thrombus formation.¹⁹

Interestingly, this is where NAC has a significant role to play. In addition to increasing GSH levels and reducing risk for a multitude of upper respiratory conditions, colds, and flu, NAC also has an anticoagulant effect via von Willebrand factor. Multiple clinical studies demonstrate a role for NAC in prolonging prothrombin times in surgery, and decreasing coagulation factor II, VII, VIII, X. NAC also reverses cerebral injury in type 2 diabetics through its antithrombotic effect, enhances platelet levels of GSH to prevent coagulation, prevents endothelial damage and release of von Willebrand factor and promotes lysis of platelet thrombi.^20-25

The above mechanisms of action for NAC, including its role as an antioxidant and precursor to GSH, anti-inflammatory, mucolytic, and anti-thrombotic effect, lends itself to further consideration for use in treatment of COVID-19 and PACS.

The Gut-Lung Axis. The microbiome has a reciprocal relationship with COVID-19 infection. COVID-19 acute infection has the ability to increase risk for opportunistic infectious organisms in the gut as well as depleting beneficial bacteria. The GI tract involvement with COVID-19 is gaining recognition and study.

Specifically, in COVID-19, decreased levels of Faecalibacterium prausnitzii, a butyrate-producing anaerobe typically associated with good health, has been inversely correlated with disease severity.²⁶ Furthermore, the changes in the gut microbiome persisted beyond 30 days past infection resolution, and more severe disease was associated with greater changes to the microbiome and elevated concentrations of inflammatory cytokines.

Interesting, in one pilot study of hospitalized COVID-19 patients, disturbances of the gut fungal microbiome, or mycobiome were observed with increases in the genera Candida and Aspergillus.²⁷

While it is known that the lung microbiome is associated with many respiratory diseases, including viral diseases, what is less well known is that there is crosstalk between the respiratory and the GI tract, which is known as the gut-lung axis.  The gut-lung axis permits the bidirectional flow of microbial metabolites, endotoxins, cytokines, and chemokines through their release into the bloodstream. In this way, changes in the gut microbiome can influence immune responses in the lungs, and lung inflammation can produce similar changes to the gut microbiome.²⁸

Studies are currently evaluating the long-term consequences of COVID-19 on post-infectious irritable bowel syndrome and dyspepsia. ²⁹ On the other hand, the ability of the gut microbiome to influence the course of respiratory disease is just now being acknowledged.  The crucial role the gut-lung axis plays in COVID-19 is currently a focus of mainstream research.
Conclusion

The contributions of toxicants to the current viral pandemic cannot be overlooked for a deeper understanding of how we arrived here.

PACS is an inflammatory pro-thrombotic state that can be addressed if one understands the immunology, exacerbating agents and appropriate use of anti-inflammatory interventions.

Barb, their pictures are in the email.

Lyn Patrick, ND, and Anne Marie Fine, NMD, FAAEM are the medical directors of Environmental Medicine Education International, LLC., a one-year, post-graduate training program in environmental medicine for health care providers.  For more information, visit www.emeiglobal.com.
  
For more information about the research in this post, see our EMEI Faculty, Dr. Tim Guilford’s article:
Guloyan V, Oganesian B, Baghdasaryan N, Yeh C, Singh M, Guilford F, Ting YS, Venketaraman V. Glutathione Supplementation as an Adjunctive Therapy in COVID-19. Antioxidants (Basel). 2020 Sep 25;9(10):914. doi: 10.3390/antiox9100914. PMID: 32992775;

For more information about NAC, ACE2  and oxidative stress:
Watch the excellent MEDCRAM video by pulmonologist and critical care specialist Roger Seheult MD: https://youtu.be/gzx8LH4Fjic
 

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