Immune Responses and the Clinical Spectrum of COVID-19

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Introduction

When the pandemic hit in the early part of 2020, the world was dealing with an unknown virus. As of today, 56,236 peer-reviewed research papers have been published on COVID-19. We know so much more.

In this piece, we briefly review normal immune responses, abnormal immune responses, and the opportunity lifestyle medicine offers all of us to improve immune resilience. Why is this important now?

Top-down epidemiolgiocal modelling of the virus has its place for public policy, as long as it uses approriate assumptions. Bottom-up understanding of how our biology responds to the virus is vital from a personal wellbeing perspective. Education is king.

Coronavirus disease 2019 (COVID-19) is a disease caused by SARS-CoV-2. What follows is an overview of how the body becomes infected, our immune response to SARS-CoV-2 in both healthy and abnormal situations, and the lifestyle implications this brings.

SARS-CoV-2

SARS-CoV-2 belongs to the family of Coronaviruses. Coronavirus includes several species capable of infecting various animals, and some of which also affect humans.

SARS-CoV and MERS-CoV had a low level of transmission, but a high level of lethality. SARS-CoV-2 is easier to spread compared to former coronaviruses, but it is not as lethal. A September 2020 systematic review estimated worldwide infection death rate of 0.68%. However, this number will change over time as data collection improves. Death rate appears to be primarily dependent on age and underlying health status.

Research suggests that nearly 80% of all infections remain undocumented because patients are either asymptomatic or present with very mild symptoms. 

SARS-CoV-2 incubates for an average of 5.8 days. Incubation represents the time in days from the point of COVID-19 exposure to the onset of symptoms.

Upon entry into cells, viral RNA from SARS-CoV-2 gets released into the cytosol, and the virus exploits the cell machinery to replicate. The rapid viral replication causes cell damage, the release of pro-inflammatory cytokines, and the recruitment of inflammatory cells.

How Novel Is This Coronavirus?

Early in the pandemic, public health officials were unsure how the immune system would respond to SARS-CoV-2, and if a level of immunity was even possible after infection. This concern may have formed one of the assumptions behind initial lockdown strategies. We now understand a lot more about the virus, and the body’s response to infection. Two takeaways are essential here:

First, research shows that the immune system does identify SARS-CoV-2.

Second, it appears we also have a level of pre-existing immunity. At least six studies have reported T cell reactivity against SARS-CoV-2 with no known exposure to the virus.

A paper published in the prestigious journal Nature found SARS-CoV-2-reactive T cells in at least 35% of unexposed healthy individuals. The authors of this study concluded by saying:

Our study reveals pre-existing cellular SARS-CoV-2-cross-reactivity in a substantial proportion of SARS-CoV-2 seronegative healthy donors. This finding might have significant epidemiological implications regarding herd immunity thresholds and projections for the COVID-19 pandemic.

SARS-CoV-2 may be novel, but our immune system does an excellent job of recognising it.

A Healthy Immune Response to SARS-CoV-2

First Line of Defence: Innate Immunity

The first line of defence against SARS-CoV-2 is the innate immune system. Mucosal immunity refers to the production of mucus, designed to trap viral particles, be swallowed and eliminated via the gastrointestinal tract. If this barrier gets breached, there is another line of defence involving pattern recognition receptors (PRRs).

PRRs are like reconnaissance soldiers. They look for “stranger and danger” recognising different molecular structures characteristic to SARS-CoV-2. PRRs identify known viruses, bacteria and other types of pathogens that humans have had over many millennia.

PRRs recognise the SARS-CoV-2 virus and begin the inflammatory response via signalling pathways, such as NF-kB. The result is the activation of various cytokines, such as IL-6, TNF-a and IL-1b.

You can think of these cytokines as the troops. They attack and kill the virus. They are also crucial in communicating with the adaptive immune system so that we develop appropriate antibodies, and with it, the potential prevention of reinfection to SARS-CoV-2 in the future.

Second Line of Defence: Adaptive Immunity

The adaptive immune system helps to build memory and future immunity against the virus. T cells are hugely crucial in long-term immune resilience to SARS-CoV-2:

– CD4+ T cells stimulate B cells to produce SARS-CoV-2-specific antibodies

– CD8+ T cells target virus-infected cells and kill them with cytotoxic molecules, such as granzyme A

80% of the infiltrating cells in COVID-19 are CD8+ T cells.

It is worth noting that current estimations of community immunity cited by many in the medical community refer only to B cell SARS-CoV-2-specific antibodies. However, this approach ignores the role of sIgA and T cells in generating a level of immunity and protection against the virus. 

For example, a study into the original SARs-CoV virus found that six years after the virus, there were no SARs-CoV-specific B cells detectible in 91% of patients. However, there were SARs-CoV-specific memory T cells present in 61% of the SARS survivors studied.

In the image below you can see the difference between normal and abnormal responses to COVID-19:

An Unhealthy Immune Response to SARS-CoV-2

Given the capacity of the immune system to target, kill, clear and remember SARS-CoV-2 for future protection, what happens in the immune system to cause poorer outcomes with COVID-19? Let’s look at the innate and adaptive immune system in this situation.

Abnormal Innate Immune Response

First, suppose the innate immune system is not functioning correctly due to chronic illnesses, such as obesity, type II diabetes and cardiovascular disease. In that case, patients can experience the well-known “cytokine storm”.

A “cytokine storm” results from a sudden acute increase in circulating levels of different pro-inflammatory cytokines including TNF-a, IL-6, and IL-1b. Think of it as meta-inflammation in action, and way too many marines going to the site of infection causing huge collateral damage. The cytokine storm can cause lung injury, viral sepsis, pneumonitis, ARDS, respiratory failure, shock, and organ failure.

Abnormal Adaptive Immunity

Second, in response to the cytokine storm, the adaptive immune system can also go awry. Lower numbers of T cells, such as CD4 and CD8 T cells, have been found in detected in patients infected with SARS-CoV-2 with worse outcomes. The number of T regulatory (Treg) cells are also significantly decreased in severely ill patients. Regulatory T cells are vital in the maintenance of immune homeostasis: a balanced and effective immune response.

Lifestyle Medicine Implications

Understanding healthy and abnormal immune responses to COVID-19 is important. It enables us to stand back from the noise and establish our risk factors, and take control of certain lifestyle variables accordingly. 

For most, poorer outcomes with COVID-19 occur in those individuals who are already experiencing high levels of inflammation. COVID-19 and the cytokine storm is a meta-inflammation process. When you look for a common theme linking obesity, cardiovascular disease, COPD and other groups of people with poorer outcomes with COVID-19, it is the preexistence of chronic inflammation.

For example, CRP (a common generalised inflammatory marker that shows up on any blood test with your GP/doctor) quite literally predicts COVID-19 outcomes. The odds ratio of someone with high CRP being admitted to ICU in the hospital is 7.09. This is not something to be scared of: it is something to take action on. 

Preventative lifestyle measures have never been more critical in helping our immune system manage COVID-19 infection. Given that the virus is now endemic in society and here to stay, proactive wellness takes on new levels of importance.   

Diet, exercise, and other anti-inflammatory lifestyle changes can have a transformational effect on risk factors with COVID-19. This insight should be celebrated and shared, especially given the existing mental health crises caused by fear and a perceived lack of control. 

Gut HealthResearch shows that the higher the levels of a circulating pro-inflammatory cytokine called IL-6, the worse the outcomes for COVID patients. Lifestyle-induced imbalances in the gut are triggers for IL-6. Excess stress, a high-fat diet and too much alcohol can trigger dysbiosis and increase circulating IL-6. 

Probiotics may be an important weapon in helping individuals to successfully adapt to SARS-CoV-2 infection. This can be seen below from a recent paper addressing the potential effect of Lactobacillus rhamnosus CRL1505:

Diet: It well established that a whole food nutrient-dense diet reduces chronic low-grade inflammatory markers across the board. Working from home provides each of us with the opportunity to eat more wholesome foods to look after our immune resilience. 

If you are interested in learning about potential strategies to improve your nutrition to support immune resilience during this time, this is a useful research paper.

Exercise: Research also shows that exercise helps to reduce chronic inflammatory markers, such as CRP, thereby improving the chances of a positive outcome after SARS-CoV-2 infection.

Justin Buckthorp

Justin Buckthorp is Founder and CEO of 360 Health & Performance International. He has 20 years of experience healthcare, elite sport and performance coaching, and is passionate about helping others unlock their potential.

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The Importance of Gut Health in the Treatment of COVID-19

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360 is dedicated to using evidence-based medicine to proactively inform decision-making in our health. Now, more than ever, it is important we utilise peer-reviewed literature to help us navigate the pandemic on a personal level.

We live at a time of great uncertainty. Rules and regulations that affect our daily lives are changing frequently. The future is unsure. There is currently no clear finishing line to many of the challenges we face at home, at work and in society. However, whilst we cannot control all these factors in the outside world, we can take charge of factors impacting our inner world. Personal wellbeing is central here.

Nutrition is one of the many pillars we can address through small impactful lifestyle changes to look after our wellbeing. It is also an emerging area of interest in the successful management of COVID-19.

More specifically, research suggests that improving the health and diversity of the gut microbiome through a diet lower in saturated fat, higher in fibre and including probiotics may be of value in the pandemic because of the impact the gut microbiota in regulating immune tolerance and the lung microbiota.

As the authors of this paper put it:

Gut microbiota diversity and the presence of beneficial microorganisms in the gut may play an important role in determining the course of this disease. Elderly, immune-compromised patients and patients with other co-morbidities like type-2 diabetes, cardiovascular disorders fare poorly in combating Covid-19. It is interesting to note that a general imbalance of gut microbiota called “dysbiosis” is implicated in such patients and the elderly

A recent Research Review looked at the potential impact of the gut microbiome in determining outcomes of COVID-19 infection. The gut microbiota refers to the trillions of microorganisms that live inside the gastrointestinal tract, and collectively it plays a central role in regulating immune and brain function. For a deep review of the topic, this is a very good research paper by leaders in the field.

The current paper, entitled “Potential contribution of beneficial microbes to face the COVID-19 pandemic“, addressed biological mechanisms by which a healthy and diverse gut microbiota appears to be central in successfully regulating our immune responses to COVID-19 and helping to prevent the hyper-inflammatory “cytokine storm”.

The “cytokine storm” has been shown to be a key determinant of outcomes with COVID-19. Therefore, if there are proactive lifestyle medicine tools that can be used to reduce the risk of negative outcomes, it is worthy of note. This research review in question builds on the weight of research from evidence-based medicine and postulates that dysbiosis (an imbalance in the gut microbiota) is a risk factor in COVID-19 outcomes.

Simply put, an unhealthy and imbalanced gut appears to put an individual at greater risk of a “cytokine storm” and pathology within the lungs after infection by SARS-CoV-2. This risk is chiefly caused by the fact that dysbiosis promotes a release of pro-inflammatory cytokines in the gut which impairs the integrity of the lining of the gut, thereby increasing the chances of a cytokine storm within the lungs. The image below illustrates these mechanisms at play:

As you can see in the image there is a gut microbiota and a lung microbiota. An imbalance in the gut microbiota caused by poor diet sets up a chain of pro-inflammatory events in the body that affect the lung microbiota and can contribute to the cytokine storm.

As the authors of the paper postulate:

Dysbiosis in the microbiome may create an inflammatory environment that the coronavirus can exploit. Gut-related inflammatory proteins, cytokines, are amplified by more cytokines when coronavirus hits. The combined inflammation may ignite a “cytokine storm”—a runaway immune reaction that can cause more damage than the virus itself, including multiorgan injury.”

At 360, we have a distinct philosophy in all of our work which is to be proactive and treat the cause, not the symptom. We focus on positively impacting the first domino rather than reactively chasing the fifth.

In this instance, it is important that hospitals use various anti-inflammatory medications to manage the cytokine storm once it hits, but from a preventative medicine standpoint, our interest is in helping people ahead of time prevent the cytokine storm in the first place if they become infected with SARS-CoV-2. The gut is one key piece of the immune resilience matrix in this respect. This is summarised well in a new research paper which concluded:

The gut microbiome can play a crucial role in modulating the immune responses of COVID-19 infected individual, and prevent the damage of vital organs, including lungs. Therefore, re-formulating the gut microbiota may emerge as a new therapeutic target in the disease management of COVID-19 patients employing nutritional therapy, probiotics or fecal microbiota transplantation (using standard guidelines).

As we approach winter, make gut health central to your wellness programme and that of your employees.

Justin Buckthorp

Justin Buckthorp is Founder and CEO of 360 Health & Performance International. He has 20 years of experience healthcare, elite sport and performance coaching, and is passionate about helping others unlock their potential.

Measure Resilience | Surface Insight | Empower Teams

To learn how 360 can help you improve the health, resilience and productivity of your employees, get in touch today.

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Using 360 Through COVID-19

Introduction

In this post, we want to show you how you can use 360 to help you look after your health through the COVID-19 pandemic. The cumulative effect of stress, uncertainty and exposure to the virus is having a significant impact on the population. Even with a successful vaccine, there will be a need to look after our immune resilience and take proactive steps to look after personal wellbeing. With 360, you have the unique ability to measure, learn and improve your health. This post will outline how to do so in the context of COVID-19.

360 Markers & COVID-19

360 measures your subjective and objective wellbeing. Both can be valuable in supporting you through the pandemic and into the future. Let’s have a look at each in turn.

Subjective Wellness Markers

As you are about to learn, the physiological measurements that you get from 360 can be powerful in successfully navigating COVID-19, but so too can your subjective data. Each day you have the opportunity to self-rate your sleep, energy, diet, exercise and happiness. You also have the chance to add tags each day, pinpointing specific lifestyle factors that are involved in the regulation of your health.

The subjective trends screen can be very helpful in managing your health. The bar graph shows your daily score (white line) compared to your average score over time (green bar). It is worth taking ten seconds to look at your strengths and gaps here to see what area you might want to prioritise to look after your immune resilience.

For example, nutrition is central to optimising immune function. Our innate and adaptive immune system needs sufficient nutrients to function correctly and in a balanced way. Diet also has a significant effect on the integrity of the gastrointestinal lining, which is where up to roughly 75% of immune-sensing cells reside. If we disrupt the lining of the gut through too much saturated fat, processed foods and alcohol, we are more at risk of immune dysfunction, and with it the effects of COVID-19.

How does this relate to 360? Well, the science of immune regulation is complicated, but the application for us is easy. If on the subjective wellness trends screen, you notice that diet is scoring low compared to other areas of your wellbeing, make it a priority and proactively support your immunity. 

Tags can also be powerful in helping you look after your lifestyle and support immune resilience. For example, if you notice on the subjective trends screen that “stress” is your top-rated tag, treat it as useful feedback. 

Chronic low-grade stress is has a pro-inflammatory effect on the body. It depletes the ability of the immune system to mount a balanced, robust and effective response to bacteria and viruses. 

A recent review looked at the links between mental and emotional resilience and immunity. The researchers authoring the paper found a bi-directional relationship. In other words, there was a top-down influence of the brain impacting immunity and a bottoms-up impact of immunity impacting the brain.

The researchers went on to explain that “exposure to recent and chronic stressful life events has repeatedly been shown to increase an individual’s risk of developing clinical illness following inoculation with the challenge virus.”

In the case of COVID-19, constant mental and emotional stress, therefore, makes us more vulnerable from an immune perspective, should we become infected. That is, unless, we take proactive control. 

This is why 360 is valuable. It helps because by becoming aware of the dominant factors in your lifestyle, you can take control of them. You cannot change what you are not aware of. 360 surfaces these habits and behaviours so you can nudge them in the right direction.

In the case of stress, you might find new approaches to manage your mental and emotional stress. This approach might include tools from CBT, using fitness training to look after your mental health, practicing mindfulness, journalling gratitude, connecting with others, or honouring your body’s need for downtime. 

In summary, use the subjective data to be proactive in your self-care. Everything we have built for you in 360 is there to surface insight quickly and easily. 

Objective Wellness Markers

The physiological markers in 360 are remarkably sensitive to immune challenges. You can use this to your advantage with COVID-19, and take early steps to mitigate its effects or protect others.

You tend to see three objective wellness changes if you experience coronavirus infection.

First, you will likely see a sudden and sharp rise in resting heart rate upon waking up and checking-in. This is a normal response to heightened activation of innate immunity, the release of inflammatory cytokines going to the site of infection, and the corresponding ramp of the sympathetic nervous system which helps in all of this. In such a scenario, you would expect your resting heart rate to jump up by at least 20%.

Second, you will likely see a sudden and sharp drop in levels of parasympathetic activity, as indexed by your morning objective wellness score. This too is a normal response to infection. Whilst the body is dealing with immediate needs driven by immune and inflammatory activity, long-term cellular renewal and regenerative processes are naturally inhibited and therefore parasympathetic tone decreases significantly.

Third, you will see your PNS fluctuation percentage increase. This is simply a result of sudden large changes in your objective wellness.

Often, these changes in your scores can happen prior to any major symptoms.

This is a sign that your first lines of immune defence have been mobilised, and are getting to work to kill the virus. Now, this might not be COVID-19 but another type of virus, but either way it is helpful. You are getting an early warning indicator which you will want to follow up on.

– Reach out to the relevant healthcare channels to ensure you get the support you need

– If you were meant to go to work, this would be a good day to stay at home to protect others

– Even if you do not have symptoms, avoid heavy exercise in such a scenario to ensure you do not compromise immunity

– Make sure you hydrate and eat a nutrient-dense, whole food diet that day to support immune resilience

– Optimise vitamin D status. Whilst there are many supplements that can help, vitamin D appears to be a clear winner based on the current incoming clinical research.

If you get a diagnosis of COVID-19, please use the SARS-CoV-2 tag in the Journal to note the day it happened. Just tag it once and on that day. This will help you keep a record of events and track your recovery afterwards. 360 will be a powerful partner in your journey back to full health by giving you insight and helping you understand when you are adapting well and can push, and when you are driving systems too hard and need to prioritise regeneration. Enjoy!

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Vitamin D in the Treatment of COVID-19

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Justin Buckthorp

Justin Buckthorp is Founder and CEO of 360 Health & Performance International. He has 20 years of experience healthcare, elite sport and performance coaching, and is passionate about helping others unlock their potential.

In recent months, a significant amount of research has been published on risk factors, medical treatments, and lifestyle medicine tools to help in the management of SARS-CoV-2. 

There is a matrix of solutions in this respect, and one of those solutions to mitigate risk and effect is nutrition. A new study from August 2020 looked at the potential role of Vitamin D in the treatment of patients hospitalised with COVID-19.

Entitled “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”, this paper is worthy of mention.

Vitamin D is an inexpensive supplement with few contraindications at the appropriate dose, and with winter coming, the results have important implications in protecting our health.

Design Set-Up

There were 76 participants in the trial; all hospitalised with COVID-19. The average age of patients was 53, and at the start of the study, there were no significant differences in the number of subjects with at least one risk health factor.

Results

Of the 50 patients treated with Vitamin D, only one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%).

Of the patients treated with Vitamin D, none died, and all were discharged, without complications. Of the 13 patients admitted to the ICU who were not given Vitamin D, two died.

Implications

This trial into the therapeutic effect of Vitamin D is the first study of its kind. More well-controlled RCTs are currently taking place, and they are needed to add confidence to the data. But the results of this study are very encouraging.

Mechanisms of Success

From a biological perspective, why might Vitamin D help patients recover from COVID-19?

Research suggests the Vitamin D works through multiple mechanisms. These include:

1) Decreasing the cytokine and chemokine storm 

2) Regulating the renin-angiotensin system 

3) Maintaining the integrity of the epithelial barrier in the lungs

4) Stimulating the repair of the epithelial barrier in the lungs

5) Modulating neutrophil (immune) activity 

The image above provides a visualisation of these potential mechanisms. As the study concluded,

“Coronavirus infection is a serious health problem awaiting an effective vaccine and/or antiviral treatment. The major complication of SARS-Covid-19 pneumonitis is ARDs (Acute Respiratory Distress syndrome) mediated by a variety of mechanisms that may be aggravated by vitamin D deficiency and tapered down by activation of the vitamin D receptor.

We would add that even in the presence of a vaccine, the virus is endemic and not all parts of the population are going to receive or take up the opportunity of a vaccine. As such, it is important to get ahead of the curve and find ways to protect our health ahead of time. Vitamin D status is one of the multiple avenues to help optimise immune resilience.

As we approach winter, ensure you optimise vitamin D for yourself and your employees.

Measure Resilience | Surface Insight | Empower Teams

To learn how 360 can help you improve the health, resilience and productivity of your employees, get in touch today.

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