Commentary
Journal of the Royal Society of Medicine; 2020, Vol. 113(9) 346–349
Is ‘inflammaging’ fuelling severe COVID-19 disease?
Lary A Robinson1 and Christine M Pierce2
1
Division of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
2
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA
Corresponding author: Lary A Robinson. Email: lary.robinson@moffitt.org
The question
One of the most pervasive questions in the COVID-
19 pandemic is ‘differential susceptibility’: Why do
some become so ill? We know who is at greatest
risk – those with co-morbidities and advanced age –
but as yet the ‘why’ is not clear.
The spectrum of disease severity with the COVID-
19 infection ranges from the 80% who have a mild to
moderate illness and barely notice the infection to the
20% who are quite ill with severe disease, of which
one-fourth progress to critical respiratory failure,
requiring intubation and ventilator support. Also,
60%–80% of ventilator patients eventually die. The
public’s greatest fear is not just becoming ill with cor-
onavirus, but that they may become deathly ill.
According to the Centers for Disease Control
(CDC), over three-quarters of people with severe dis-
ease have significant co-morbidities and/or age over
65 years.1 Surprisingly, in the United States, about
one-fourth of younger people under the age of 65
years with no apparent co-morbidities have life-threa-
tening disease.
Pathophysiology
Although coronavirus victims may develop cardiac or
kidney failure later in their clinical course, the hall-
mark of severe disease is respiratory insufficiency
with confluent areas of pneumonia. Patients report
they feel like they are drowning and rapidly progress
to respiratory failure, acute respiratory distress syn-
drome (ARDS) and requisite ventilator support. This
deadly clinical picture of ARDS apparently results
from the virus triggering intense inflammation result-
ing in damage to the walls of the alveoli with capillary
leakage of protein-containing fluid that fills up the
alveoli. The result is severe respiratory failure, rapidly
progressing to death in 60%–80%.2 When the virus
infects the lung cells in some patients, it elicits an
intense, immune over-reaction sending in leukocytes
that release pro-inflammatory cytokines, especially
IL-6. The resultant runaway hyper-inflammation
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DOI: 10.1177/0141076820945269
termed ‘cytokine storm’ unfortunately damages the
normal lung cells more than the virus it targets.
Cytokine storm causing ARDS is the common
denominator for respiratory failure and death not
only in COVID-192 but also in Middle East respira-
tory syndrome (MERS), severe acute respiratory syn-
drome (SARS) and H1N1 influenza.
Cytokines are a diverse, large group of proteins
released by various immune system cells that regulate
inflammation and immune function. Some cytokines
cause inflammation and others calm it down. Chronic
inflammation3 is a common theme in a number of age-
related disease states such as hypertension, coronary
artery disease, chronic lung disease, liver and kidney
disease, obesity, diabetes, autoimmune and immuno-
compromised disorders, cancer and advanced age – all
of which are the common co-morbidities that increase
the risk of severe COVID-19 respiratory disease. The
newly created COVID-19-Associated Hospitalization
Surveillance Network just reported that nearly 90%
of the hospitalised patients (with severe disease) in
March 2020 had some type of underlying condition.
Obesity was the condition most often seen in the
younger age groups: 49% of those aged 50–64 years
and 59% in those aged 18–49 years.4 The Office of
National Statistics in the United Kingdom just
reported that 90% of COVID-19 patients dying have
an underlying co-morbidity.5
Since hyperinflammation may be the key patho-
physiologic pathway leading to severe COVID-19
pneumonia, then corticosteroids that vigorously
suppress IL-6 and multiple other cytokines should
provide great therapeutic benefit. Despite concerns
that corticosteroids may delay viral clearance and
be detrimental,6 the recently completed randomised,
multicentre RECOVERY Trial randomised study
of 6425 patients demonstrated that the use of the
common corticosteroid dexamethasone significantly
reduced the 28-day mortality in hospitalised
COVID-19 patients requiring respiratory support.7
Theoretically, more targeted anti-cytokine IL-6
blocking agents may provide greater benefit in this
Robinson and Pierce
hyperinflammatory state with cytokine storm pneu-
monia, but clinical trials of this therapeutic strategy
are still ongoing.8
Potential explanation
The term ‘inflammaging’ (inflammation with aging)
was coined in 20063 to describe the chronic, sterile
pro-inflammatory process occurring in age-related
diseases associated with the decline in the effective-
ness of the immune system termed immunosenes-
cence. Along with the chronic inflammatory state in
these degenerative diseases, pro-inflammatory
Figure 1. Pathway to severe COVID-19 disease.
347
cytokines are significantly elevated, especially the
cytokine IL-6. Current smokers and obese individuals
also have marked chronic inflammation and elevated
cytokines. Even just a sedentary lifestyle in younger
people results in a chronic pro-inflammatory state,
which is aggravated further by a poor diet that is
deficient in fruits, vegetables and whole grains,
and is filled with refined sugars and high amounts
of saturated fats, meat and processed foods (pro-
inflammatory diet).9
Recent statistics show that minorities, especially
African Americans, have a disproportionate higher
mortality from the virus, amounting to 42% of all
348
deaths where the demographic data are known.10
This disparity has been immediately attributed to
inequality in healthcare, air pollution, poverty and/
or depressed economic opportunity. Perhaps there is
another factor at work? France’s chief epidemiologist
Jean-François Delfraissy stated that he was worried
about Americans ‘where they will have the most
problems because of obesity’.11 According to the
CDC, 42% of Americans are obese but that
number rises to 50% in African Americans.
Diabetes, hypertension and kidney disease are com-
plications that commonly accompany obesity: all of
these problems cause chronic inflammation and ele-
vated cytokine levels. The culturally preferred, pro-
inflammatory high saturated fat/high salt//high
refined sugar diet and pronounced physical inactivity
may predispose urban African Americans living in
areas of high population density to a more severe
disease course with COVID-19.
Although many scientists are desperately searching
for the genetic polymorphisms that predispose
COVID-19 victims to a poor outcome, perhaps
there is an alternative, plausible explanation for this
so-called ‘differential susceptibility’ that causes some
individuals to progress to severe respiratory disease.
The common thread that runs through all of the co-
morbidities (including obesity and advanced age3)
that is associated with severe disease is the presence
of a turned-on, overactive immune system with
chronic inflammation and elevated cytokine levels.
Therefore, it is logical that where there is ongoing
chronic inflammation that adding an acute viral infec-
tion/inflammation such as COVID-19 (or MERS,
SARS or H1N1 influenza) is essentially pouring gas-
oline on the already-burning fire, resulting in hyperin-
flammation and severe disease. Figure 1 is a graphic
summary of the proposed pathway to severe COVID-
19 disease.
Short-term measures
If chronic inflammation from its various causes is the
key to severe disease, are there any short-term meas-
ures that these high-risk individuals can do to lessen
their possibility of adverse effects if infected with the
virus? Fortunately, lifestyles changes can rapidly
decrease chronic inflammation and high cytokine
levels, independent of co-morbidities. Aerobic exercise
provides the fastest results, but coupled with diet modi-
fications inflammatory markers drop rapidly.12–14
In light of the current COVID-19 pandemic with
the necessity of following shelter-at-home orders,
many people worldwide are practising an unsustain-
able lifestyle including a poor diet of high fat, high
sugar ‘comfort foods’ and minimal exercise that
Journal of the Royal Society of Medicine 113(9)
promotes even more whole-body inflammation as
they sit working from home and/or watching
television.
Even if certain genes or families of genes are even-
tually discovered that predispose to more severe
COVID-19 disease in some people, this does not
mean that individual is doomed if they develop the
infection. Studies have demonstrated that ‘DNA is
not your destiny’.15 Genes are only functional if
they are activated by their ‘off-on switches’, the epi-
genes. Lifestyle and environmental factors (such as
diet, exercise, smoking, etc.) control the epigenes16
which in turn control silencing or activation of
genes, including the detrimental ones that might pre-
dispose to severe COVID-19 disease.
Limitations
Even though this hypothesis of systemic chronic
inflammation predisposing to severe disease logically
may fit the reported demographics, it still may not be
an important feature of the pathophysiology of the
disease since Nature does not always follow human
logic. Hopefully in the future, careful epidemiological
studies of the pre-illness lifestyle of victims of severe
COVID-19 disease will help prove or disprove this
hypothesis. However, in the meantime, would it not
be prudent for people to dramatically change their
lifestyle to a healthy diet, daily exercise and no
tobacco? It definitely will result in less degenerative
diseases in the long term, and in the short term it may
save their life.
Declarations
Competing Interests: None declared.
Funding: None declared.
Ethics approval: Not applicable.
Guarantor: LAR.
Contributorship: All authors had access to the data and a role in
writing the manuscript.
Acknowledgements: None.
Provenance: Not commissioned; peer-reviewed by Kieran
Fernando.
ORCID iD: Lary A Robinson https://orcid.org/0000-0003-
4579-0141
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