Great article which explains why Covid-19 beyond the virus pandemic is actually acting as an indicator of a much deeper social disease: Metabolic syndrome which is in fact the real pandemic which has been raging over the last 30 years all over the world.
by Jeffrey Bland, PhD
“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.