Throughout the time of COVID-19, the disease caused by the virus SARS-CoV-2, there has been more and more research coming out about the nature of this virus and its disease. However, despite the presence of nuanced findings in various health-related fields, the dominant narrative still adheres firmly to the Germ Theory of disease. This theory, which has been one of the most powerful theories of disease in the past 150 years, states that sickness and disease are caused primarily by infections due to microorganisms, such as viruses, bacteria, fungi, and the like. Of course, the rise of chronic conditions in modern times has begun to offer alternative theories of disease, but in the case of SARS-CoV-2, Germ Theory is assumed to apply.
This essay is not arguing for or against Germ Theory, but hopes to present evidence for the multifactorial nature of COVID-19, bringing in factors beyond the virus itself that are likely influencing the symptoms and course of the disease. Historically, this is known as the Terrain Theory of disease, and posits that when an individual encounters an infectious organism, the terrain (referring to the inner and outer environments) of that person is a significant – if not deciding – factor in whether a particular individual will become sick or die. This essay will discuss some of these terrain elements that are influencing the course of this disease.
Much of the following information has been shared at length by other medical experts, particularly Dr. Zach Bush in various interviews over the past few months. To gain a deeper understanding of a different context for this disease, you can watch them on his website, https://zachbushmd.com/video/.
A Different Perspective on Viruses
What is a virus? Let’s start with the common understanding as found in the Merriam-Webster dictionary. A virus is defined as:
“Any of a large group of submicroscopic infectious agents that are usually regarded as nonliving extremely complex molecules, that typically contain a protein coat surrounding an RNA or DNA core of genetic material but no semipermeable membrane, that are capable of growth and multiplication only in living cells, and that cause various important diseases in humans, animals, and plants.”
Most of us know viruses as tiny little things that act mostly like parasites, getting into our bodies and hijacking our cellular machinery in order to reproduce themselves. According to this understanding, our immune system functions as a defender against this constant viral assault on our body, destroying viruses as they seek to enter and subvert our biology.
Evolution with Viruses
There is an alternative to the above perspective. What if viruses were viewed more as genetic messengers, existing symbiotically with more complex life forms as a way to facilitate adaptation and survival? Viruses have played a crucial role in the evolution of life on earth, no matter what specific theory [Viral evolution] of viral origin you may choose [What Does Virus Evolution Tell Us about Virus Origins?]. A few fascinating elements highlight our symbiotic relationship with viruses.
One very simple fact is that viruses are both ubiquitous and extraordinarily numerous. A recent study found that billions of viral particles per square meter rain down from the sky every day [Trillions Upon Trillions of Viruses Fall From the Sky Each Day]. We are surrounded by viruses, bathed in them, inundated by them. We would never be able to fight off all these viruses if they were constantly attacking us. We are also discovering an ever-growing list of viral species that live within us, now called the virome [Human virome]. Just as our microbiome is necessary to insure a balanced ecosystem within us, so too is our community of viruses.
It’s well known that 8% of human DNA comes from retroviruses [Endogenous retroviruses in the human genome sequence], but it’s possible that 50% or more of our DNA is actually viral in origin. A large portion of our DNA is made up of little snippets called Transposable Elements (TE). Instead of staying in one place within our strands of DNA, they can detach and move around. This is very similar to how viruses behave, and has led some scientists to postulate that these bits of DNA also came originally from viruses [Transposable elements and viruses as factors in adaptation and evolution: an expansion and strengthening of the TE-Thrust hypothesis].
Virus or Exosome?
Another hint that viruses may be more integrated into our biology than we think is the similarities between viruses and exosomes. Exosome are these little tiny sacs [Q&A: What are exosomes, exactly?] that are released from our cells that contain various substances, such as proteins, enzymes, and genetic material. The current understanding is that they are used primarily for cell-to-cell communication in the body, which includes the transfer of DNA or RNA between cells. Though cells secrete exosomes all the time, the rate increases in response to stress or pathologic conditions [Pathologic Function and Therapeutic Potential of Exosomes in Cardiovascular Disease].
Viruses, though we think of them as separate from us, are in fact incredibly similar to these exosomes. They are typically similar in size; they also bud out of cells in the body; they deliver various substances, such as proteins and DNA; and, they are very difficult to distinguish from each other [Extracellular vesicles and viruses: Are they close relatives?].
Viruses as Genetic Updates
With viruses playing such a significant role in the evolution of our DNA, their potentially outsized presence in our genome, and their similarity to one of our innate cellular communication mechanisms, viruses may not be the enemy we’ve thought they were. It’s quite likely they function more as genetic updates to alert us of stressful conditions in our environment, such as changes in climate, the presence of pollution, population overcrowding, and other shifts that we need to adapt to. As vectors of genetic information, and with high rates of mutation, viruses speed up evolution and help us adapt to the changing conditions of the world.
If viruses are more like messengers than invaders, infectious viral diseases need to be reinterpreted. Illness results primarily from the body’s response to the virus, and the degree of balance within the body’s terrain determines the severity of this response. Thus, if someone is healthy and in balance with their external environment, the disease is likely to be mild or asymptomatic. A healthy person, in balance with their environment, is resilient, and will be able to flexibly adapt to the new information brought in by the virus. However, if someone is out of balance, already under stress, living in a toxic environment, then the push to adapt and respond to the virus will produce comparatively more severe symptoms. If the person has lost the capacity to adapt, then they may die.
An analogy can be made to receiving some terrible news. Perhaps someone has lost a family member, or close friend. If this person has strong community relationships, is able to take time off work in order to process their grief, and has friends for emotional support, this loss will likely be weathered well. If they have none of these, and in addition are stressed from a toxic work environment, or an abusive relationship, the death of their loved one will likely leave a much deeper, more difficult to heal, wound. Perhaps it will be so deep the person takes their own life.
Without a virus, the illness would not have happened. Yet, the outcome is also highly dependent on the individual. For COVID-19, what is the environment, the terrain, that determines whether the disease causes either no symptoms, or death?
COVID and Chronic Disease
It is now well-known that COVID is more severe in people with comorbid conditions. Data from New York shows that 90% of people who died from COVID had at least one comorbid condition, and the top conditions in COVID deaths, in order, are [NYSDOH COVID-19 Tracker]
- Hypertension (high blood pressure)
- Diabetes
- Hyperlipidemia (high cholesterol)
- Dementia
- CAD (coronary artery disease)
- Renal Disease
- COPD (chronic obstructive pulmonary disorder)
- Atrial fibrillation
- Cancer
- Stroke
Looking at the commonalities between these conditions should help create some context for the terrain of this disease.
Chronic Inflammation
It is now common knowledge that chronic inflammation and oxidative stress are key factors in the development of chronic disease [Chronic Inflammation and Oxidative Stress as a Major Cause of Age-Related Diseases and Cancer]. Chronic inflammation has been shown to decrease the immune response to acute infection [Chronic inflammation and the immune response to acute challenges], and oxidative stress can also reduce this response [Oxidative Stress, Viral Infection, and Mitochondrial Function—Are Your Mitochondria “Tough Enough?”]. The presence of inflammation in these patients is supported by laboratory tests showing high BNP (Brain Natriuretic Peptide), C-reactive protein, ferritin, lactate dehydrogenase, and d-dimer, all of which are correlated with inflammation.
In contrast, even though many patients reported having symptoms of a viral infection in the days prior to hospitalization, by the time they got there findings typically associated with infection were absent. Only about 30% of patients had a temperature above 38 ℃, and white blood cell counts were normal, suggesting the body was not producing more WBCs to fight infection [Clinical Characteristics, Comorbidities, and Outcomes Among Patients With COVID-19 Hospitalized in the NYC Area]. Though many of the above markers of inflammation can also be elevated during a viral infection, the lack of fever and normal WBCs suggests the inflammation present is due to something in addition to, or instead of, the virus.
Medication Use
Another commonality in a number of these comorbidities is medication use. Two out of the top three most prescribed medications are atorvastatin and lisinopril, a statin and an ACE inhibitor [10 Most Popular Prescriptions]; one or both of these drugs are commonly prescribed for hypertension, diabetes, hyperlipidemia, coronary artery disease, and renal disease. The importance of these two drugs is that they both increase levels of ACE2 [Can angiotensin receptor-blocking drugs perhaps be harmful… : Journal of Hypertension, Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System, COVID-19, ACE2, and the Cardiovascular Consequences].
Angiotensin converting enzyme 2 (ACE2) is known as the receptor that is used by the SARS-CoV-2 virus to enter the cell [Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target]. Incidentally, the original SARS virus also used this same receptor [Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus]. Though more recent evidence appears to suggest the ACE inhibitors like lisinopril are actually protective in COVID, initial data showed that patients with hypertension that were taking an ACE inhibitor were 6% more likely to die than those not taking an ACE inhibitor [Clinical Characteristics…COVID-19 Hospitalized in the NYC Area].
Other medications that have been shown to increase ACE2 expression are Ibuprofen [Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?] and proton-pump inhibitors (PPIs) such as Prilosec [Increased Risk of COVID-19 Among Users of Proton Pump Inhibitors]. This study showed that heavier users of PPIs have an up to four times increased risk of testing positive for COVID.
Regardless of the severity of the disease, increasing ACE2 will provide more receptors for the virus to bind to and will result in more viral particles entering cells. This is an important element considering the influence of another factor: air pollution.
COVID and Air Pollution
The link between exposure to air pollution and death from COVID has been known for months. An analysis done at the Harvard Chan School of Public Health found that for every 1 microgram increase in PM2.5 (particulate matter that is 2.5 microns in size or less) per cubic meter of air, mortality from COVID goes up 8% [COVID-19 PM2.5]. This number was calculated by looking at average levels of air pollution, and the authors adjusted for things like age, population density, and lifestyle factors such as smoking. This is a fairly robust finding, and indicates there is likely a correlation between the severity of COVID symptoms and air quality.
One way in which pollution and viruses interact is by binding to each other. A study examining pollution in Northern Italy found RNA from SARS-Cov-2 attached to particulate matter in the air [SARS-Cov-2RNA found on particulate matter of Bergamo in Northern Italy: First evidence]. Other studies have shown a variety of microbes binding to particles of pollution in the air as well [Longitudinal survey of microbiome associated with particulate matter in a megacity]. The British Medical Journal also published an article on March 30, 2020, arguing for the role of airborne particulate matter in spreading this virus [Is there a Plausible Role for Particulate Matter in the spreading of COVID-19 in Northern Italy?]. Given that viral particles already fall from the sky all the time, it’s not a stretch to say that air pollution could bind to these viruses and increase both their spread and their deposition rate.
Hypoxic Injury
Many medical professionals have discussed COVID’s strange presentation, such as the extraordinarily low oxygen levels of patients presenting to the hospital and the systemic blood clots on autopsies. Many patients only come to the hospital after they’ve been sick for days with mild cold-like symptoms, when they suddenly begin having more severe breathing issues. As mentioned above, lab findings upon admission to the hospital don’t appear to show signs of infection, but 30% of patients were given supplemental oxygen during triage [Clinical Characteristics…COVID-19 Hospitalized in the NYC Area]. There have also been numerous reports of long-term effects of this disease, such as intense fatigue, shortness of breath, joint pain, chest pain, and other neurological and cardiovascular impacts [Persistent Symptoms in Patients After Acute COVID-19].
This picture fits more with something that is depriving these patients of oxygen. Perhaps that is the direct interference with hemoglobin (the iron-containing protein that carries oxygen in our red blood cells) by the virus, as one Italian scientist believes [Italian scientist says she discovered main mechanism behind COVID-19]. Another possibility, which could be complementary, is that this interference with red blood cells and oxygen carrying capacity is coming from air pollution.
We know a good amount about this type of hypoxic injury as the same symptoms often occur with high-altitude sickness. Initially people experience fatigue and shortness of breath [High-Altitude Cardiopulmonary Diseases]; the resulting tissue damage from lack of oxygen causes inflammation, which in the lungs can result in pulmonary edema: the lungs begin to fill with fluid [Altitude Illness – Pulmonary Syndromes Clinical Presentation]. People may begin to turn blue and develop wet coughs. This can lead to a secondary bacterial pneumonia as microorganisms proliferate in the fluid-filled lungs. This sequence of events matches the anecdotes coming out of hospitals, as patients who initially present with low oxygen then go on to develop pneumonia and lung failure [COVID-19 Patients Need to Be Tested for Bacteria and Fungi, Not Just the Coronavirus].
One other clue to this hypoxia is that many people don’t appear to be in serious distress, even though their oxygen levels are alarmingly low [The mystery of the pandemic’s ‘happy hypoxia’]. They don’t have shortness of breath because the body is still able to release carbon dioxide just fine, and CO2 in the blood is what tells the body that it needs to breathe faster. This shows us that something is happening to our oxygen carrying capacity, but not impacting the inner surface of the lungs, because gas exchange is still occurring without much problem.
Cyanide Poisoning
Dr. Zach Bush, in his various interviews, has suggested that the hypoxic injury is coming from being poisoned by cyanide in air pollution. Cyanide is released into the air from petroleum refineries, and can be released in the body via metabolic breakdown of other nitrogen-containing chemicals that are widely used in industrial processes. The EPA doesn’t appear to track or regulate hydrogen cyanide levels in air pollution, even though they are aware of its presence and its toxicity [EPA Must Protect Communities from Hydrogen Cyanide Exposure]. Similar to carbon monoxide, cyanide binds to hemoglobin in red blood cells and prevents the transport of oxygen, leading to a host of symptoms in numerous body systems.
With acute exposure, cyanide can cause symptoms such as weakness, headache, vertigo, inebriation, confusion, seizures, abdominal pain, nausea, vomiting, shortness of breath, and chest pain [Cyanide Toxicity Clinical Presentation: History, Physical Examination]. Though long-term neurologic symptoms after altitude sickness are rare, they are more common with cyanide poisoning. An article in Medscape writes, “Consider CN toxicity in all patients with smoke inhalation who have CNS or cardiovascular findings.” These findings include neurological and cardiovascular issues such as seizures, extrapyramidal syndromes (movement disorders, tremors, etc.), muscle jerking, twitching, or cramping, and coma [What are the possible neurological sequelae of cyanide toxicity from smoke inhalation?].
Since cyanide from industrial processes is usually emitted as hydrogen cyanide, which is a gas, I looked into how it might get amplified due to other types of particulate pollution. It turns out that it can adsorb onto airborne particles, which will allow it to travel further and keep it from breaking down [Formation of Metal-Cyanide Complexes…in Urban Environments]. And if it is bound to particles of air pollution (PM2.5) then it could be connected to viral spread as well.
Other Environmental Toxins
Our environment is admittedly full of many thousands of different chemicals, most of which we know little to nothing about in terms of their long-term impact on our health. However, one particular chemical has been getting more attention recently, and it is also one of the most common and widely used. This is glyphosate, the active ingredient in RoundUp.
Glyphosate is now present everywhere. A review from 2019 showed glyphosate residues have been found in dust, on food, in water, and in people [The evidence of human exposure to glyphosate: a review]. Many people know RoundUp as an herbicide, but it is also a potent antimicrobial for many different types of life. Any organism that uses the Shikimate pathway to synthesize aromatic amino acids is potentially vulnerable to glyphosate; this includes bacteria, fungi, and plants. Glyphosate use in the environment has been correlated with multiple chronic diseases, including hypertension, stroke, diabetes, and kidney failure; these diseases rose in conjunction with increased use of glyphosate in the mid 1990’s [Genetically engineered crops, glyphosate and the deterioration of health in the United States of America].
In addition to interfering with amino acid synthesis in bacteria, fungi, and plants, glyphosate may have impacts on humans as well. One research team suggests that glyphosate can substitute for glycine in proteins; this would interfere with the function of glutathione, one of our major antioxidant compounds [Glyphosate’s Synergistic Toxicity in Combination with Other Factors as a Cause of Chronic Kidney Disease of Unknown Origin]. This is important because low levels of glutathione may be a significant factor in increased symptom severity and death in COVID patients [Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients].
The Whole Picture
The various terrain elements discussed here need to be taken into consideration when trying to understand the nature of this disease. Diseases are almost never caused by only a single factor; even highly infectious microorganisms do not infect every person that comes in contact with them, and with COVID, a full 40% of people (according to the best estimate by the CDC) are completely asymptomatic [COVID-19 Pandemic Planning Scenarios]. What happens when we put some of these factors together?
First, since the virus is likely bound to particles of air pollution, in areas of higher air pollution more of these particles are entering the cells of the body, particularly in the lung. This will be increased even more for people with upregulated ACE2 due to medications. The pollution is also carrying molecules of cyanide with it, and over the course of several days this causes a slow decrease in the blood’s capacity to carry oxygen. Initially, people have symptoms of a viral illness, but by the time they get to the hospital their systems have cleared the virus, and what remains is the low oxygen from cyanide poisoning.
Second, markers of inflammation are high, whereas evidence of infection is low, which highlights the importance of inflammation in this disease when it becomes severe. This ties in with the issues around glyphosate, and doubtless other toxic chemicals in our environment that reduce our antioxidant capacity, and thus our ability to counter inflammation. Injury from hypoxia causes the body to respond with inflammation, but the lowered antioxidant capacity has trouble keeping the inflammation from causing excessive tissue damage. This makes the symptoms more severe.
Granted, this picture is speculative, and there are always other explanations. However, the various terrain elements that lead to this integrated result are very likely to play a role, even if different from the one painted here. And there are other terrain elements not discussed here, such as diet and nutrition, the impact of stress, the microbiome of the lung, and many more. It is time to stop focusing exclusively on the virus, and time to start examining the environment both around and within us.
