COVID-19: A Pandemic Within a Pandemic

“The race is on throughout the world to develop Covid-19 vaccines and therapeutics and end a pandemic that threatens to infect a substantial portion of the planet’s population, and perhaps kill millions of people, especially older adults. As billions of dollars flow into research and development efforts aimed at controlling the virus, the pandemic response remains hamstrung by our limited understanding of how to generate effective immunity, particularly in the elderly.”[1]

COVID-19 officially became a pandemic on March 11, 2020. The World Health Organization (WHO) had been closely monitoring this novel coronavirus since early January, when a cluster of pneumonia cases in Wuhan, Hubei Province, China was reported. Past experiences with infectious respiratory viruses such as SARS and MERS informed decision-making in the weeks that preceded the declaration of a public health emergency. Two factors were of high concern: spread and severity. These concerns proved to be more than justified.

As of June 17, 2020, more than 8,000,000 cases of COVID-19 infection have been confirmed globally, and at least 440,000 deaths have been reported. COVID-19 has provided us with the opportunity to examine emerging data in real time. By tracking the history of the infection, it quickly became clear that there are significant differences among people in terms of both risk to infection and — if infected — severity of disease.

The Lancet, a highly respected professional journal, published the first international medical report about COVID-19 infection in Wuhan, China on February 15, 2020, and this article indicated that the infection was associated with acute respiratory symptoms and many other complex medical problems.[2] A March 2020 follow-up study, also in Lancet, discussed the clinical course of the infection and risk factors associated with mortality.[3] Specifically, they looked at how comorbidities (preexisting health conditions) might increase the risk for COVID-19 complications. The researchers noted that older age, hypertension, obesity, and diabetes were all associated with increased disease severity. As the virus spread, so too did support for this finding. From Seattle to New York, patients with COVID-19 did worse when comorbidities were present.[4],[5]

Thankfully, there is some positive news. Among people with COVID-19, it appears that less than 20% become seriously ill, and for those who do experience severe symptoms, the majority seem to fully recover. Outliers — patients who follow no established trend — have also been noted. The wide range of possible outcomes has created anxiety for both the public and the medical community alike. Why do some people fare so poorly while others have only mild symptoms? The answer may be tied to the functional status of an individual’s immune system.

Certain chronic conditions, including the comorbidities mentioned above, result in altered immune system function, which can include unhealthy forms of inflammation. We have also come to understand that the COVID-19 virus can impact the function of many critical organ systems. So what’s the link? Respiratory, cardiovascular, neurological, gastrointestinal, renal, and hepatic performance are all associated with alteration in immune system function. Inflammation is a hallmark of immune system dysfunction and is also strongly associated with COVID-19 infection. We know this because of a term that has recently entered the public dialogue: cytokine storm. A cytokine storm results when there is a breakdown in control of the immune system. An overwhelming inflammatory response takes place in the body, similar to a septic shock event.[6] The title of an opinion piece published online in Lancet Rheumatology on May 29, 2020 perfectly captures the situation: “Coronavirus is the Trigger, but the Immune Response is Deadly.”[7]

This means we have to think very carefully about how our immune systems can become dysfunctional. Are there early signals that might tell us when things are going wrong? As it turns out, there is a condition called metabolic syndrome which is characterized by altered immune function. In fact, it overlaps with the comorbidities that contribute to COVID-19 severity, and has been steadily rising in frequency over the last several decades. What happens when the world’s most prevalent non-communicable health condition and a highly infectious viral disease collide? We find ourselves in our new reality: a COVID-19 pandemic within a pandemic of metabolic syndrome.

Running the Numbers

Among 5700 patients hospitalized with COVID-19 in and around New York City, most had a comorbidity associated with metabolic syndrome. These included hypertension (56%), obesity (42%), and diabetes (34%).[8] Another report, this one published in the Journal of the American Medical Association (JAMA), analyzed COVID-19-related data for the five boroughs of New York City. In this review, they found that, compared to other boroughs, the Bronx and Queens had the highest rates of hospitalizations and deaths per 100,000 residents. Notably, people in these two boroughs also had the highest prevalence of comorbidities.[9]

Clearly, there’s an important connection here. In fact, researchers around the world have been examining this link from multiple angles and many hypotheses are being offered for consideration. Angela Saini, a noted science journalist, published an article in the May 23, 2020 issue of Lancet that cautioned against associating comorbidities with genetic susceptibility based on race: “Such speculation runs the risk of forgetting that the demographic categories we recognise socially do not in fact have very much biological meaning and betrays a wider problem in medicine when it comes to race.”[10] There has been a global effort to determine specific genetic linkages to infection with COVID-19, but to date no strong genetic determinants have been found. Social determinants and lifestyle have emerged as the major factors determining risk to serious disease associated with COVID-19 infection.[11]

My study of metabolic syndrome and inflammation — an undertaking that now spans more than 30 years — leads me down a different path of thinking. I believe these comorbidities result from the complex interaction of individual genetics, lifestyle, environment, diet, and the social determinants of disease.

In a number of ways, the pandemic of metabolic syndrome had already been on the radar of public health groups, as well as clinical care providers and planners. Morbidity and mortality related to non-communicable disease (NCD) was identified as a global concern in recent years. The World Health Organization had been tracking a constellation of NCDs for some time and was well aware that they had overtaken infectious disease as the most significant global cause of illness and premature death. An article published in the May 30, 2020 issue of Lancet addressed the fact that COVID-19 provided a new layer of urgency to the prevention and control of NCDs. The authors, who are affiliated with the WHO Regional Office for Europe write: “The COVID-19 response and continued and strengthened focus on NCD prevention and management are key and interlinked aspects of public health at the present time.”[12]

As noted above, all of the comorbidities linked to both metabolic syndrome and COVID-19 severity are associated with altered immune function and a chronic state of inflammation.[13] “Inflammaging” is a term that has come to be used as a descriptor for chronic inflammation related to aging or chronic non-communicable conditions such as hypertension, insulin resistance, and obesity.[14] Right now, the attention of the world is clearly focused on threats like COVID-19 and the potential for additional outbreaks. With this in mind, certain important questions must be prioritized. When did this state of altered immune function begin to be a global health issue? What is the cause of chronic inflammation that is impacting populations in so many countries? What can be done to rectify this situation?

Working the Problem

To answer these questions, we need to take a close look at the last 50 years. In the late 1970s, comorbidities started to become more prevalent in industrialized countries like the United States. Within a few short decades, the trend had reached developing nations. In April 2011, Margaret Chan, OBE, JP, FRCP (at that time was Director-General of the WHO), said the following: “The rise of chronic noncommunicable diseases presents an enormous challenge. For some countries, it is no exaggeration to describe the situation as an impending disaster; a disaster for health, for society, and most of all for national economies.”[15] COVID-19 is the impending disaster that Dr. Chan predicted nine years ago.

David Stuckler, MPH, PhD, is currently a Professor of Political Economy and Sociology at the University of Oxford. In 2011 — the same year that Dr. Chan spoke about the WHO’s concerns about non-communicable diseases — Dr. Stuckler edited a textbook called Sick Societies: Responding to the Global Challenge of Chronic Disease. The arc of data that Dr. Stuckler has been tracking for more than a decade is compelling. In a 2008 article titled “Population Causes and Consequences: A Comparative Analysis of Prevailing Explanations,” he utilized four decades of male mortality rates to demonstrate that the division between infectious diseases and non-communicable diseases is shrinking and becoming increasingly problematic for health policy makers and health economists.[16]

In 2006, British physician and global health analyst Luke Allen penned an article that was titled “Are We Facing a Noncommunicable Disease Pandemic?” The article abstract conveys a powerful message: “The global boom in premature mortality and morbidity from noncommunicable diseases (NCDs) shares many similarities with pandemics of infectious diseases, yet public health professionals have resisted the adoption of this label. It is increasingly apparent that NCDs are actually communicable conditions, and although the vectors of disease are nontraditional, the pandemic label is apt.” Dr. Allen proposed that the response to the global pandemic of chronic noncommunicable disease should be modeled after the WHO viral pandemic response plan because of shared features and impact on both population health and the global economy.[17]

Let’s use Japan as a case study to examine this issue of the rising prevalence of comorbidities more closely. Japan historically had a very low incidence of obesity, hypertension, prediabetes, and diabetes. This started to shift in the 1980s. From 1988 through 2012, the rapid increase in these conditions was resembled the exponential growth of an infectious disease epidemic. In this case, there was no infectious agent. Rather, the population of Japan experienced dramatic changes in lifestyle, environment, diet, and stress.[18]

Unfortunately, what happened in Japan was anything but an isolated event. Instead, it reflected a trend that was spreading across the world: a global epidemic of metabolic syndrome.[19] Metabolic syndrome, as I’ve already stated, is defined as a state of chronic inflammation. It is also characterized by an imbalance of immune system function, and people with this condition typically have elevated blood pressure, blood triglycerides, and body mass index, as well as reduced levels of HDL cholesterol and impaired insulin sensitivity. Today, more than 30% of the adult population in the United States has metabolic syndrome.

Technically, metabolic syndrome is not a disease. It is probably better described as a state of lowered resilience to disease, as is evidenced by the number of associated comorbidities. People with metabolic syndrome are at increased risk to both non-communicable and infectious diseases such as COVID-19. In a May 2020 publication titled “Diabetes and Metabolic Syndrome as Risk Factors for COVID-19,” a group of authors affiliated with the University of Maribor in Slovenia point out that the disturbances associated with metabolic syndrome not only result in increased susceptibility to COVID-19 infection, but also reflect alterations in the immune system that sets the stage for more serious outcomes.[20]

Connecting the Dots

COVID-19 is a new virus within the coronavirus family. As we all know now, it has a very high infection rate. Additionally, COVID-19 has some unusual infectivity features: it can be transmitted by asymptomatic individuals, plus the severity and clinical manifestations of the infection can vary widely (from mild to life-threatening). Seemingly, all body systems can be impacted by a COVID-19 infection; serious cases of respiratory, cardiovascular, immunological, kidney and liver, gastrointestinal, and neurological crises have all been reported.[21] In the organ systems affected by COVID-19, cells have been found to express the angiotensin-converting enzyme 2 (ACE2) receptor. The ACE2 receptor is thought to represent a target for the virus which allows it to bind to and enter our cells.[22] Recent studies show that the virus binds to the ACE2 receptor more easily in the presence of inflammation.[23]

The COVID-19 virus has spike-like proteins on its surface. These give the virus the unique ability to bind tightly to the ACE2 receptors. The spike-like proteins are also what differentiate the COVID-19 virus from other coronaviruses. These spikes have what are called high affinity furin binding sites (furin is an enzyme in human blood that activates specific proteins).[24] Researchers believe a slight change in the genetic architecture of the virus resulted in a modification at the furin binding site in the spike proteins. This is what makes COVID-19 such a formidable foe. How? It enables the virus to hijack furin, which allows it to attach to the ACE2 receptors on tissues more readily and facilitate penetration into cells. Given that so many tissues express the ACE2 receptor, this mutation and sequence of events makes COVID-19 uniquely more infective than other coronaviruses.[25]

Regulation of furin levels in the blood is influenced, in part, by the immune system and inflammation. When cholesterol in the blood is elevated, furin is more vulnerable to being hijacked by the virus, and there is a greater opportunity for COVID-19 to convert to its more infective form. It is speculated that this can contribute to the comorbidity-related priming of COVID-19 in people with elevated cholesterol who are at risk to cardiovascular problems.[26] The ability of this virus to impact furin and increase infectivity is unique to COVID-19 (SARS-COV-2); it does not occur (to the same extent) with other coronaviruses, including SARS-COV-1.

Furin belongs to a family of nine proteins that are called proprotein convertases (PCSKs). The function of these proteins is to regulate various biochemical processes, both in times of good health and when a disease state is present. Furin is produced by a number of different cell types, including some within immune cells.[27] In people who have comorbidities that are associated with metabolic syndrome (hypertension, obesity, elevated triglycerides, impaired insulin sensitivity, and inflammation), furin levels have been found to be abnormal.[28],[29] Interestingly, David Harrison, MD, who leads a research team at Vanderbilt University School of Medicine, published work in 2015 indicating that hypertension is related to inflammation derived from an activated immune system.[30]

In 2018, researchers at the Department of Clinical Sciences at Lund University in Sweden and the School of Pharmacology at Helsinki University in Finland collaboratively reported the results of a study involving 4678 individuals with metabolic syndrome and diabetes that revealed elevated levels of furin in the blood.[31] Prior to that, a group representing several clinical and academic institutions in Japan had reported that certain variations in the genes that control furin production were related to metabolic syndrome.[32] This work suggests that the influence of furin on the comorbidities associated with COVID-19 may have a genetic connection. Finally, it’s well established that furin levels are elevated in people with inflammatory autoimmune disorders.[33] In sum, this research shows furin may be a key link between metabolic syndrome, inflammation, and COVID-19 complications.

Let’s now draw a straight line between the non-infectious pandemic of metabolic syndrome pandemic and the infectious pandemic of COVID-19. Metabolic syndrome dramatically increases our risk of developing comorbidities like hypertension and diabetes. These in turn predispose us to contracting COVID-19 and for developing more severe systems after infection. This is likely due to the chronic inflammatory state (altered immunity) associated with metabolic syndrome. Furthermore, the comorbidities associated with metabolic syndrome may compromise our immune function through increased levels of furin in the blood. Let’s put this together. When an individual with metabolic syndrome is exposed to COVID-19, the virus gets the benefit of a compromised immune system and extra furin to facilitate binding to our cells. This is a mechanistic explanation of the situation that the world now finds itself in: a pandemic (COVID-19) within a pandemic (metabolic syndrome).

Mapping a Strategy

We know quite a lot about COVID-19. Its genetic profile has been sequenced, and we understand the unique composition of its spike proteins. Within the body, we know that infectivity depends upon the action of the virus binding to ACE2 receptors, which are expressed on many tissues. We know that COVID-19 has the ability to hijack an enzyme in our blood — furin — and when this happens the spike protein architecture is remodeled, making the virus even more active and pathogenic. We know that the comorbidities associated with COVID-19 infection and its severity are all associated with a dysfunction in our first line of immune defense, which is called our innate immunity. Innate immunity is known to be heavily involved in chronic inflammation.[34]

How can this information inform our actions, not only in terms of mitigating the spread of the present pandemic, but also in preparing for future pandemic events? The best and most logical step is to reduce the prevalence of metabolic syndrome. Many lifestyle, environmental, and dietary factors are associated with abnormal immune function related to chronic inflammation and metabolic syndrome.[35] Studies of the COVID-19 pandemic are being published every day, and some researchers are already positing that diet and metabolic syndrome could be partially responsible for the high variability that has been noted in infection and death rates.[36] The Mediterranean diet — which is plentiful in fresh vegetables, fruits, whole grains, virgin olive oil, nuts, seeds, and fish that are high in omega-3 fats, while also low in sugar and processed foods — has been extensively studied for its positive influence on the comorbidities associated with metabolic syndrome and its ability to reduce chronic inflammation.[37] Food as medicine? A recent article suggests that it’s a valid concept to consider for the prevention of coronavirus disease.[38] Emerging evidence even shows that dietary intervention could potentially reduce the probability of infection with COVID-19 or the severity of symptoms in infected individuals.[39] Recently, a multinational research consortium published work indicating that a diet associated with lowering the incidence of metabolic syndrome both improves immune system function and reduces inflammation, which — as already noted — are important considerations in minimizing the severity of COVID-19.[40]

Why diet? Vegetables and fruits contain a class of nutrients called phytochemicals that play important dietary roles in reducing the comorbidities associated with metabolic syndrome.[41] Certain phytochemicals, such as the flavonoids quercetin and luteolin, have been found to bind to the ACE2 receptor on COVID-19, which can potentially help to protect against infection.[42],[43] A recent study evaluated how quercetin and vitamin D may contribute to the mitigation of COVID-19 through their impact on immune system function and the reduction of chronic inflammation.[44] It is clear that improvement in the lifestyle, environmental, and dietary factors associated with the comorbidities that are linked to both metabolic syndrome and COVID-19 can have a positive impact on enhancing immunity.[45] Studies have shown that improved physical fitness, reduction in obesity, and increased quality of sleep can all positively influence immunity and reduce the severity of viral infections like COVID-19.[46],[47],[48]

In a sense, COVID-19 represents an alarm bell — “a tocsin to our aging and unfit society,” to paraphrase one author’s recent work; I would add “immune compromised” to that description.[49] In 2008, Scott M. Grundy, MD, PhD, a researcher I greatly admire who is Director of the Center for Human Nutrition, Chairman of the Department of Clinical Nutrition at UT Southwestern Medical Center, published a seminal article titled “Metabolic Syndrome Pandemic.”[50] Today, twelve years later, that pandemic swirls around an infectious threat called COVID-19. The good news is we know how to manage the pandemic of metabolic syndrome. Doing so, however, will require significant changes in how health care is structured and funded, as well as a shift in the cultural context of disease.[51] Successful implementation of new thinking and new strategies has become critically important in this new era of pandemic awareness.

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