Can exercise protect against respiratory infections?

Can exercise protect against respiratory infections?

Microbiologiste et infectiologue. Institut de Cardiologie de Montréal22 June 2020

OVERVIEW

  • Participants in more than 14 studies were randomly separated into two groups: one group who did not exercise and one who exercised regularly and under supervision.
  • Exercise did not reduce the incidence of acute respiratory infections.
  • Exercise appears to reduce the severity of symptoms associated with episodes of acute respiratory infections.
  • According to several other studies, exercise can improve the immune response to viruses, bacteria and other antigens. Regular physical activity and frequent exercise may reduce or delay the aging of the immune system.

COVID-19 caused by infection with the SARS-CoV-2 virus particularly affects people who have certain risk factors (advanced age, male) or a comorbidity such as chronic respiratory disease, obesity, cardiovascular disease, diabetes, hypertension and cancer (see this article). A healthy lifestyle, including eating well, not smoking, consuming alcohol in moderation, and exercising regularly, is the best way to prevent many diseases such as diabetes, cancer and cardiovascular disease. Also, certain conditions are associated with a decrease in immune activity, for example, stress, diabetes and the deficiency of certain dietary compounds like vitamin D and zinc. By its action on these conditions, exercise is likely to influence our resistance to infections.

Can exercise prevent acute respiratory infections, including COVID-19? Researchers at the Cochrane Library recently updated a systematic review of the effect of exercise on the occurrence, severity and duration of acute respiratory infections.  The systematic review included 14 studies of 1377 healthy individuals aged 18 to 85 who were followed for a median period of 12 weeks. The participants were randomly separated into two groups: one who did not exercise and one who exercised regularly. In most cases, the exercise was supervised and was performed at least three times per week. The exercise sessions lasted 30 to 45 minutes and consisted of moderate intensity exercise such as walking, cycling, treadmill or a combination of these exercises. Exercise did not have a significant effect on biochemical parameters, quality of life or number of injuries.

Exercise did not decrease the number of acute respiratory infections (ARI) episodes, nor the proportion of participants who had at least one episode of ARI during the study, or the number of days with symptoms during each of these episodes. On the other hand, exercise was associated with a decrease in symptom severity in two studies and in the number of days with symptoms during the total study duration (4 studies). The study authors indicate that certainty about the data is low and that data from ongoing or future studies may impact their conclusions.

Exercise and the immune system
The immune system is very responsive to exercise, depending on both the duration and the intensity of effort (see this review article). Exercise causes multiple micro-injuries to the muscles, triggering a local and systemic inflammation reaction. During a moderate to high intensity exercise session lasting less than 60 minutes, the number of leukocytes (white blood cells) and several cytokines (proteins produced by the immune system to stimulate the proliferation of defence cells) increases rapidly in the bloodstream. The increase in the number of neutrophils (a type of white blood cell) often lasts for up to 6 hours after the end of the exercise session. This physiological response to stress caused by exercise is followed, during the recovery period, by a drop in the number of leukocytes in the bloodstream to a level below that measured at the start of the exercise session.

Although exercise transiently increases markers of inflammation, including several cytokines (interleukins, chemokines, interferons, and others), at rest, people who exercise regularly have lower blood levels of these pro-inflammatory proteins than people who exercise little or not at all or who are obese. Regular exercise therefore appears to moderate the inflammatory response and promote an anti-inflammatory environment in the body. The persistent increase in markers of inflammation (chronic inflammation) is linked to several conditions and diseases, including obesity, osteoarthritis, atherosclerosis and cardiovascular disease, chronic kidney disease, liver disease, metabolic syndrome, insulin resistance, type 2 diabetes, chronic obstructive pulmonary disease, dementia, depression, and various types of cancers. In short, exercise reduces the negative effects on the immune system of a recognized factor that is diabetes and the associated insulin resistance.

It is known that in severe forms of COVID-19 an exaggerated inflammatory reaction called “cytokine storm” destroys the cells of the pulmonary endothelium that allow oxygenation of the blood and body. Could regular exercise that provides a less inflammatory environment protect us in the event of a SARS-CoV-2 virus infection? This has not been demonstrated, but it is certainly a hypothesis that will need to be examined. Moreover, it seems that in the elderly, immune aging (also called “immunosenescence”) is associated with a decline in the cells that regulate the immune response. It is because of this decline that we observe an increase in immune disorders such as autoimmune diseases and an increase in cancers. However, the cytokine storm would be secondary to the lack of control by these cells. A healthy immune system would be less likely to lack these “regulatory” cells.

Suppression of immunity in athletes: Myth or reality?
In recent decades, an idea has taken root in the scientific literature according to which aerobic exercise, particularly if it is vigorous and of long duration, can interfere with immunocompetence, i.e. the body’s ability to produce a normal immune response in response to exposure to an antigen. This idea is now increasingly questioned and has even been called a myth by some researchers. This hypothesis dates from the early 20th century, when fatigue was believed to contribute to infections that caused pneumonia, but it was not until the 1980s–1990s that studies verified this assertion with professional and amateur athletes. In general, it is increasingly certain that it is “psychological” stress rather than physical stress that is immunosuppressive. For example, a study in the 1980s among medical students showed that immune capacity collapsed within 24 to 48 hours of exams. The “mental” stress on the eve of competitions could be the comparison. Exercise is a great stress reliever for most people.

One of the studies indicated that one third of the 150 runners participating in the 1982 Two Oceans ultramarathon (56 km) in South Africa reported symptoms of upper respiratory tract infection (runny nose, sore throat, sneezing) within two weeks of the race. The control group reported half as many symptoms of upper respiratory tract infection than runners. Similar results were obtained from athletes who participated in the Los Angeles Marathon (42 km) in 1987. Among the 2311 participants who completed the race and who had not reported symptoms of infection in the week before the race, 12.9% reported symptoms of infection in the week following the race. Only 2.2% of participants who dropped out of the race (for reasons other than health reasons) reported symptoms of infection in the week after the race. Another study conducted at the same time did not find an association between aerobic exercise and the risk of upper respiratory tract infection for runs over shorter distances, namely 5 km, 10 km, and 21 km (half marathon). This suggested that the risk of infections increases only after exercising for a very long period of time.

The major problem with these studies is that they are questionnaire-based and none of the infections reported by athletes were confirmed in the laboratory. In a 2007 study, researchers took swabs and tested athletes who reported symptoms of upper respiratory tract infection over a period of 5 months. Only 30% of the cases reported by the participants were associated with the presence of viruses, bacteria, or mycoplasmas. These results suggest that the symptoms experienced by athletes in previous studies may not have been caused by infection, but rather by other causes, including allergies, asthma, inflammation of the mucous membranes, or trauma to the epithelial cells of the airways caused by increased breathing or exposure to cold air.

The decrease in leukocytes in the bloodstream that is observed after exercise has led to the so-called “open window” hypothesis that intense exercise causes transient immunosuppression during the recovery period. During this “open window”, athletes would be more susceptible to viral and bacterial infections. Another hypothesis would be that of the recruitment of white blood cells to repair small damage to the muscles. Indeed, tissue damage, whether mechanical or infectious, causes the release of cytokines, which “call” the defences to “see what happens.” Yet, contrary to the studies cited above, recent studies indicate that exercise is rather associated with a reduction in the incidence of infections. There are as many epidemiological studies that show that regular exercise is associated with a reduction in infections as there are that show that regular exercise is associated with an increase in infections, but the former are less taken into account than the latter in the literature on exercise immunology.

For example, a Swedish study of 1509 men and women aged 20 to 60 found that high levels of physical activity are associated with a reduced incidence of upper respiratory tract infections. Studies of ultramarathon runners, one of the most taxing sports, have shown that these people report fewer days of absence from school or work due to illness compared to the general population. For example, the average number of sick days reported annually was 1.5 days in a study of 1212 ultramarathon runners and 2.8 days in another study of 489 161-km ultramarathon runners, while that year the number of sick days reported in the American population was 4.4 days. An often overlooked aspect of outdoor exercise is its vitamin D intake with exposure to the sun. The longer the routes, the greater the exposure and endogenous skin production of vitamin D. Vitamin D intake would be beneficial for the regulatory cells of the immune system.

In summary, contrary to the immunosuppression (“open window”) hypothesis, regular exercise can be beneficial for the immune system, or at least not harmful. Exercise does not increase the risk of diagnosed opportunistic infections. Exercise can improve the immune response to viruses, bacteria, and other antigens. Regular physical activity and frequent exercise may reduce or delay the aging of the immune system.

The social environment, essential for mental and physical health

The social environment, essential for mental and physical health

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.15 June 2020

OVERVIEW

  • A large number of studies have established a strong association between an inadequate social network and an increased risk of developing a variety of diseases and dying prematurely.
  • One of the major challenges in the fight against infectious diseases such as COVID-19 is therefore to find a balance between the measures necessary to prevent viral transmission while maintaining a sufficient level of social interaction for the mental and physical well-being of the population.

The containment of the population in response to the COVID-19 pandemic has made it possible to substantially reduce the number of people infected with the SARS-CoV-2 coronavirus. According to recent estimates, the measures implemented to contain the epidemic have prevented around 530 million infections worldwide, including 285 million in China and 60 million in the United States. However, these measures mean that less than 4% of the population seems to have been infected with the virus, which means that the fight is far from won and that we must remain vigilant if we want to avoid further waves of infection.

One of the main challenges in the fight against COVID-19 is to find a balance between the measures necessary to prevent viral transmission while maintaining a sufficient level of social interaction for the well-being of the population. Humans are social animals and much has been said, and rightly so, about the deleterious effects of confinement on mental health. This is confirmed by the results of a survey recently published in the Journal of the American Medical Association (JAMA). Using a questionnaire developed to assess the presence of mental disorders (Kessler 6 Psychological Distress Scale), researchers noted that in April 2020, during the COVID-19 epidemic, 14% of American adults exhibited serious symptoms of psychological distress compared to 4% in 2018. These symptoms were particularly common in young adults aged 18 to 29 (24%), as well as among low-income households (less than $35,000 per year).

Physical harm
It should also be remembered that the social environment has a huge influence on physical health in general. It has long been known that certain parameters of our social life, in particular the level of social integration, socioeconomic status and negative experiences at an early age, are among the main predictors of the state of health of individuals and their life expectancy. Disruptions to life in society, such as those caused by a large-scale epidemic, can therefore have negative consequences on the health of the population in the medium and long term.

A large number of studies have established a very clear association between social adversity (negative experiences of life in society) and an increased risk of developing a variety of diseases and dying prematurely (Figure 1). Three main aspects were studied:

Social integration. Studies show that the level of social integration (positive interactions with family, friends and/or colleagues, emotional and physical support from those around them) increases people’s life expectancy by 30 to 80% (Fig. 1B). Conversely, poor social integration (also called social isolation) is associated with an increased risk of several diseases, in particular cardiovascular disease (Fig. 1E), and an increase of about 50% of overall mortality, a risk similar to that associated with well-known risk factors such as obesity, hypertension or sedentary lifestyle (see also our article on this subject). This impact of the level of social integration on health appears to be biologically “programmed”, as similar effects have been observed in a large number of social animals, including primates, rodents, whales and horses. On the scale of the evolution of life on Earth, the link between the degree of social integration and life expectancy has therefore existed for several million years and can consequently be considered as a fundamental characteristic of the life of several species, including ours.

Socioeconomic status. Another consequence of social distancing measures is to disrupt economic activity and, at the same time, cause a drop in or even a loss of income for many people. It has long been known that there is a close correlation between socioeconomic inequalities (generally measured by household income) and the health of the population. For example,  as early as the 1930s, it was observed in the United Kingdom that the risk of death from cardiovascular disease was twice as high among men of lower social class compared to those of the upper classes. Studies since that time have shown that these income differences are associated with an increased prevalence of a large number of diseases (Fig. 1D) and a significant decrease in life expectancy (Figure 1A). In the United States, a comparison of the poorest 1% of the population to the richest 1% of the population indicates that the difference in longevity is of the order of 15 years for men and 10 years for women. This difference may be less pronounced in countries with a better social safety net than Americans (such as Canada), but nevertheless remains significant. In Montreal, for example, the life expectancy of residents of Hochelaga-Maisonneuve was 74.2 years in 2006–2008, compared to 85.0 years for residents of Saint-Laurent, a gap of almost 11 years.

Negative experiences of childhood. The first years of life represent a period of extreme vulnerability to the external environment, both physical and social. One of the dangers associated with periods of prolonged confinement is exposing some children living in precarious conditions to an increased risk of injuries. Unfortunately, this appears to be the case with the COVID-19 epidemic, as U.S. pediatricians recently reported an abnormal rise in children admitted to hospital with severe physical trauma.

This is an extremely worrying situation, as it has been clearly shown that social adversity at an early age is associated with an increased risk of several diseases, including cardiovascular disease, stroke, respiratory disease and cancer (Fig. 1F), as well as a greater susceptibility to viral infections and premature mortality (Fig. 1C). These negative impacts that occur during childhood appear to form a lasting imprint that persists throughout life, even when there is an improvement in living conditions. For example, a study of American doctors reported that subjects who had lived in early childhood in a family with low socioeconomic status had a twice as high risk of premature cardiovascular disease (before age 50), even if they had achieved high socioeconomic status in adulthood.

Figure 1. Association between social adversity and the risk of disease and premature death. (A) Life expectancy at age 40 for American men and women by annual income. (B) Proportion of subjects alive after 9 years of follow-up according to the social network index (quantity and quality of social relations) (n = 6298 people). (C) Average age at death based on the number of adverse childhood experiences (ACEs) (n = 17,337 people). (D) Prevalence of various diseases among American adults as a function of their annual income (n = 242,501 people). (E) Risk of disease by level of social integration among American adults (n = 18,716 people). (F) Risk of disease based on the number of adverse childhood experiences (ACEs) (n = 9,508 people). From Snyder-Mackler et al. (2020).

Role of chronic stress
Several studies indicate that stress plays an important role in the association between social adversity and the increased risk of disease and premature death. All forms of social adversity, whether it is social isolation, insufficient income to meet children’s needs or childhood trauma, are perceived by the body as a form of aggression and therefore cause activation of physiological mechanisms involved in the stress response, such as the secretion of cortisol and adrenaline. For example, exposure to some form of social adversity has been shown to be associated with epigenetic changes (DNA methylation) that alter the expression of certain inflammatory genes involved in the stress response. Studies also show that individuals who are socially isolated tend to adopt behaviours that are more harmful to health (smoking, sedentary lifestyle, excessive drinking, etc.), which obviously contributes to reducing life expectancy.

To prevent cardiovascular disease, medication should not be a substitute for improved lifestyle

To prevent cardiovascular disease, medication should not be a substitute for improved lifestyle

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.28 May 2020

OVERVIEW

  • Cardiovascular disease dramatically increases the risk of developing serious complications from COVID-19, again highlighting the importance of preventing these diseases in order to live long and healthy lives.
  • And it is possible! Numerous studies clearly show that more than 80% of cardiovascular diseases can be prevented by simply adopting 5 lifestyle habits (not smoking, maintaining a normal weight, eating a lot of vegetables, exercising regularly, and drinking alcohol moderately).

The current COVID-19 pandemic has exposed two major vulnerabilities in our society. The first is, of course, the fragility of our health care system, in particular everything related to the care of the elderly with a loss of autonomy. The pandemic has highlighted serious deficiencies in the way this care is delivered in several facilities, which has directly contributed to the high number of elderly people who have died from the disease. Hopefully, this deplorable situation will have a positive impact on the ways of treating this population in the future.

A second vulnerability highlighted by the pandemic, but much less talked about, is that COVID-19 preferentially affects people who present pre-existing conditions at the time of infection, in particular cardiovascular disease, obesity and type 2 diabetes. These comorbidities have a devastating impact on the course of the disease, with increases in the death rate of 5 to 10 times compared to people without pre-existing conditions. In other words, not only does poor metabolic health have a disastrous impact on healthy life expectancy, it is also a significant risk factor for complications from infectious diseases such as COVID-19. We are therefore not as helpless as we might think in the face of infectious agents such as the SARS-CoV-2 coronavirus: by adopting a healthy lifestyle that prevents the development of chronic diseases and their complications, we simultaneously greatly improve the probability of effectively fighting infection with this type of virus.

Preventing cardiovascular disease
Cardiovascular disease is one of the main comorbidities associated with severe forms of COVID-19, so prevention of these diseases can therefore greatly reduce the impact of this infectious disease on mortality. It is now well established that high blood pressure and high blood cholesterol are two important risk factors for cardiovascular disease. As a result, the standard medical approach to preventing these diseases is usually to lower blood pressure and blood cholesterol levels with the help of drugs, such as antihypertensive drugs and cholesterol-lowering drugs (statins). These medications are particularly important in secondary prevention, i.e. to reduce the risk of heart attack in patients with a history of cardiovascular disease, but they are also very frequently used in primary prevention, to reduce the risk of cardiovascular events in the general population.

The drugs actually manage to normalize cholesterol and blood pressure in the majority of patients, which can lead people to believe that the situation is under control and that they no longer need to “pay attention” to what they eat or be physically active on a regular basis. This false sense of security associated with taking medication is well illustrated by the results of a recent study, conducted among 41,225 Finns aged 40 and over. By examining the lifestyle of this cohort, the researchers observed that people who started medication with statins or antihypertensive drugs gained more weight over the next 13 years, an excess weight associated with an 82% increased risk of obesity compared to people who did not take medication. At the same time, people on medication reported a slight decrease in their level of daily physical activity, with an increased risk of physical inactivity of 8%.

These findings are consistent with previous studies showing that statin users eat more calories, have a higher body mass index than those who do not take this class of drugs, and do less physical activity (possibly due to the negative impact of statins on muscles in some people). My personal clinical experience points in the same direction; I have lost count of the occasions when patients tell me that they no longer have to worry about what they eat or exercise regularly because their levels of LDL cholesterol have become normal since they began taking a statin. These patients somehow feel “protected” by the medication and mistakenly believe that they are no longer at risk of developing cardiovascular disease. This is unfortunately not the case: maintaining normal cholesterol levels is, of course, important, but other factors such as smoking, being overweight, sedentary lifestyle, and family history also play a role in the risk of cardiovascular disease. Several studies have shown that between one third and one half of heart attacks occur in people with LDL-cholesterol levels considered normal. The same goes for hypertension as patients treated with antihypertensive drugs are still 2.5 times more likely to have a heart attack than people who are naturally normotensive (whose blood pressure is normal without any pharmacological treatment) and who have the same blood pressure.

In other words, although antihypertensive and cholesterol-lowering drugs are very useful, especially for patients at high risk of cardiovascular events, one must be aware of their limitations and avoid seeing them as the only way to reduce the risk of cardiovascular events.

Superiority of lifestyle
In terms of prevention, much more can be done by addressing the root causes of cardiovascular disease, which in the vast majority of cases are directly linked to lifestyle. Indeed, a very large number of studies have clearly shown that making only five lifestyle changes can very significantly reduce the risk of developing these diseases (see Table below).

The effectiveness of these lifestyle habits in preventing myocardial infarction is quite remarkable, with an absolute risk drop to around 85% (Figure 1). This protection is seen both in people with adequate cholesterol levels and normal blood pressure and in those who are at higher risk for cardiovascular disease due to high cholesterol and hypertension.

Figure 1. Decreased incidence of myocardial infarction in men combining one or more protective factors related to lifestyle. The comparison of the incidences of infarction was carried out in men who did not have cholesterol or blood pressure abnormalities (upper figure, in blue) and in men with high cholesterol levels and hypertension (lower figure, in orange). Note the drastic drop in the incidence of heart attacks in men who adopted all 5 protective lifestyle factors, even in those who were hypertensive and hypercholesterolemic. Adapted from Åkesson (2014).

Even people who have had a heart attack in the past and are being treated with medication can benefit from a healthy lifestyle. For example, a study conducted by Canadian cardiologist Salim Yusuf’s group showed that patients who modify their diet and adhere to a regular physical activity program after a heart attack have their risk of heart attack, stroke and mortality reduced by half compared to those who do not change their habits (Figure 2). Since all of these patients were treated with all of the usual medications (beta blockers, statins, aspirin, etc.), these results illustrate how lifestyle can influence the risk of recurrence.

Figure 2. Effect of diet and exercise on the risk of heart attack, stroke, and death in patients with previous coronary artery disease. Adapted from Chow et al. (2010).

In short, more than three quarters of cardiovascular diseases can be prevented by adopting a healthy lifestyle, a protection that far exceeds that provided by drugs. These medications must therefore be seen as supplements and not substitutes for lifestyle. The development of atherosclerosis is a phenomenon of great complexity, which involves a large number of distinct phenomena (especially chronic inflammation), and no drug, however effective, will ever offer protection comparable to that provided by a healthy diet, regular physical activity, and maintenance of a normal body weight.

COVID-19 is a disease that also affects blood vessels

COVID-19 is a disease that also affects blood vessels

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.27 May 2020

OVERVIEW

  • A high proportion of patients with COVID-19 have clotting disorders that clinically manifest as venous thrombosis and pulmonary embolisms.
  • These disorders are believed to be caused, at least in part, by a direct attack of the coronavirus on the endothelial cells that line the inside of blood vessels, causing abnormal formation of blood clots.
  • The presence of these clots is particularly important in patients who develop severe complications from COVID-19 and contributes to the increased risk of mortality observed in this population.

As the COVID-19 pandemic progresses, it is becoming increasingly clear that the coronavirus responsible for this disease is a respiratory virus like no other. The lungs are, of course, the main organs affected by this virus, and most patients who develop severe complications or die from COVID-19 have serious lung damage. However, a large number of studies have reported several very specific clinical cases, which had so far never (or very rarely) been described for this type of viral infection, in particular severe damage to the heart, digestive system, kidneys, and brain.

Coagulation disorders
Data collected so far indicates that abnormal blood clot formation (thrombosis) is another unusual manifestation of COVID-19 that may play a very important role in the severity of the disease. Since the beginning of the pandemic, several physicians have reported an abnormally high incidence of phenomena linked to a decrease in blood circulation, such as a bluish tint to the lower limbs (e.g. toes) as well as deep vein thrombosis (phlebitis). The presence of these blood clots in the veins is extremely dangerous, as they can migrate into the bloodstream, reach the right ventricle of the heart, and subsequently block the pulmonary arteries to cause embolisms. In this sense, it should be noted that studies carried out in the Netherlands and France indicate that approximately 20–30% of patients with severe forms of COVID-19 are affected by these venous thrombosis and that pulmonary embolisms represent the most common complication of these coagulation disorders. This was confirmed by an autopsy study of 12 patients who died from COVID-19: of these patients, 7 presented with deep thrombosis, and 4 of them died of pulmonary embolism.

These pulmonary embolisms really seem to represent a “signature” of the coronavirus responsible for COVID-19. For example, a study reported the presence of pulmonary embolisms in 17% of patients with severe respiratory syndrome caused by COVID-19, while these embolisms are present in only 2% of patients also suffering from a severe respiratory syndrome, but not related to COVID-19. The contribution of these clots to the severity of COVID-19 is well illustrated by studies showing that high blood levels of d-dimers, a marker of thrombosis, were associated with a very large increase (18 times) in the risk of mortality from COVID-19. In addition, 71% of patients who died from this disease were reported to have multiple blood clots scattered throughout their blood vessel network (disseminated intravascular coagulation), a phenomenon observed in only 0.6% of patients who survived the disease.

The coagulation disorders caused by the coronavirus are not limited to the veins, but also seem to affect the arteries. For example, one of the most surprising complications of COVID-19 is the observation of large-vessel strokes  in young adults (under 50) living in New York. Studies in China have also documented the presence of these strokes in about 5% of patients; however, they were older than those affecting young New Yorkers. Taken together, these observations clearly show that bleeding disorders are a common consequence of infection with the SARS-CoV-2 coronavirus and contribute greatly to the development of serious complications of the disease.

Endothelial cells are targeted
One of the factors involved in this disruption of the normal coagulation process appears to be the direct action of the virus on the cells that line the blood vessels, called the endothelium. Under normal conditions, one of the main functions of this endothelium is to ensure good blood circulation, in particular by preventing the formation of blood clots. On the other hand, when these endothelial cells are damaged by physical (cut, wound) or biochemical (inflammation, pathogenic agents) aggressors, the rupture of the endothelial barrier allows the factors involved in coagulation to come into contact with the blood and form fibrin clots to restore the integrity of the endothelium.

In patients who develop severe forms of COVID-19, an exaggerated inflammatory response, often referred to as a “cytokine storm” (hypercytokinemia), is frequently observed. This high intensity inflammation makes the blood vessels very permeable and is therefore perceived by the body as an injury, which causes the activation of coagulation and the formation of clots. This process may be amplified by the presence of antiphospholipid antibodies, an autoimmune disorder also associated with an increased risk of thrombosis. It is also now known that the receptor that allows the entry of the coronavirus SARS-CoV-2 into cells is present in significant quantities on the surface of endothelial cells, so that the virus can directly attack the endothelium and cause damage that will trigger the activation of coagulation. This phenomenon was observed during an autopsy study recently published in the New England Journal of Medicine: by examining lung samples from patients who died of COVID-19, the researchers noted the presence of multiple viral particles in the blood vessels, as well as heavy damage to the structure of endothelial cells. This endothelial damage was accompanied by the presence of a large number of small clots obstructing blood flow in the pulmonary blood microvessels. These phenomena seem specific to COVID-19, because the parallel examination of the lungs of patients who died of influenza (H1N1) did not reveal any infection of the endothelial cells by the virus and showed a much lower incidence (9 times) of blood clots in the pulmonary vessels. This could explain why the mechanical ventilation of patients with severe forms of COVID-19 is often powerless to increase blood oxygen levels: not only is breathing compromised by the presence of fluid or pus in the pulmonary alveoli, but in addition, the damage inflicted on the endothelial cells and the presence of multiple clots obstructing the vessels prevent the blood from circulating and being oxygenated.

The impacts of these phenomena are obviously not exclusive to the lungs: every organ in the body is supplied with blood vessels, so that infection of the endothelium by the virus, combined with an increased formation of blood clots, can greatly contribute to the devastating effects of the virus on the functioning of several organs.

Hydroxychloroquine and COVID-19: A potentially harmful effect on the heart

Hydroxychloroquine and COVID-19: A potentially harmful effect on the heart

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.19 May 2020

Updated June 8, 2020

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 coronavirus strain that primarily, but not exclusively, affects the respiratory system. While in the majority of infected people the symptoms of the disease are relatively mild or moderate (cough, fever, dyspnea or difficulty breathing, digestive disorders, temporary loss of taste and smell, hives, vascular lesions on the fingertips and toes), they may worsen in some people who have one or more risk factors (diabetes, hypertension, obesity, cardiovascular disease, advanced age) into acute respiratory distress syndrome that requires hospitalization in an intensive care unit and can lead to death.

There is no vaccine or effective drug available to reduce the mortality associated with COVID-19. The use of an antiviral drug, remdesivir, which was urgently approved by the FDA on May 1, 2020, reduces the number of days in hospital in people with COVID-19, but does not significantly reduce mortality. As of May 15, 2020, more than 1,500 studies on various aspects of COVID-19 have been registered on ClinicalTrials.gov, including more than 885 intervention studies and randomized controlled studies, with 176 on the use of hydroxychloroquine.

Hydroxychloroquine
One of the first candidates tested for treating COVID-19 was hydroxychloroquine, a drug used for its anti-inflammatory properties in the treatment of rheumatoid arthritis and systemic lupus erythematosus. Prior to the current COVID-19 pandemic, it was already known that chloroquine and its derivatives, including hydroxychloroquine, have non-specific antiviral activity against several types of enveloped viruses (HIV, hepatitis C, dengue, influenza, Ebola, SARS, MERS) in vitro. Two recent studies (see here and here) have shown that hydroxychloroquine also inhibits infection with the SARS-CoV-2 virus in vitro, i.e. in cultured epithelial cells. Hydroxychloroquine, which has a better safety profile than chloroquine, has been shown to be a more potent SARS-CoV-2 inhibitor in vitro.

The results obtained in vitro do not necessarily imply that chloroquine and its derivatives have antiviral activity in humans. Indeed, studies have shown that in vivo chloroquine and/or hydroxychloroquine have no effect on viral replication or increase viral replication and the severity of illness caused by infection by influenza, dengue, Simliki forest virus, encephalomyocarditis virus, Nipah and Hendra viruses, Chikungunya virus, and Ebola virus (references here).

Initial results from studies on the use of hydroxychloroquine to treat COVID-19 are unclear. Chinese researchers have reported treating over 100 patients with beneficial effects, but have not released any data. French microbiologist Didier Raoult and his collaborators published two articles (see here and here) on the use of hydroxychloroquine (in combination with the antibiotic azithromycin) for the treatment of COVID-19, in which they concluded that this drug lowers viral load in nasal swabs. However, these studies were not randomized and they do not report essential clinical data, such as the number of deaths among participants. In addition, two other French groups (see here and here) report having found no evidence of antiviral activity of hydroxychloroquine/azithromycin or of clinical benefit in hospitalized patients with a severe form of COVID-19.

In an observational study conducted in New York City hospitals, hydroxychloroquine was administered to 811 patients out of a total of 1376 patients, with a follow-up lasting an average of 22.5 days after admission to the hospital. Analysis of the results indicates that among this large number of patients admitted to hospital with a severe form of COVID-19, the risk of having to be intubated or dying was not significantly higher or lower in patients who received hydroxychloroquine than in those who did not. The authors conclude that the results obtained do not support the use of hydroxychloroquine in the current context, except in randomized controlled trials, which remain the best way to establish the efficacy of a therapeutic intervention.

Cardiovascular risk: Prolongation of the QT interval
Although hydroxychloroquine and azithromycin are well-tolerated drugs, both can cause prolongation of the QT segment on the electrocardiogram (figure below). For this reason, cardiologists are concerned about the use of these two drugs in a growing number of clinical trials for the treatment of COVID-19 (see here, here, here and here). It should be noted that the prolongation of the corrected QT interval (QTc) is a recognized marker of an increased risk of fatal arrhythmias.

Figure. Normal and abnormal (long) QT interval on the electrocardiogram.

Hospital researchers in the United States assessed the risk of QTc prolongation in 90 patients who received hydroxychloroquine, 53 of whom were concomitantly given the antibiotic azithromycin. The most common comorbidities among these patients were hypertension (53%) and type 2 diabetes (29%). The use of hydroxychloroquine alone or in combination with azithromycin was associated with QTc prolongation. Patients who received the two drugs in combination had significantly greater QTc prolongation than those who received hydroxychloroquine alone. Seven patients (19%) who received hydroxychloroquine monotherapy saw their QTc increase to 500 milliseconds (ms) or more, and three patients (8%) saw their QTc increase by 60 ms or more. Among the patients who received hydroxychloroquine and azithromycin in combination, 11 (21%) saw their QTc increase to 500 milliseconds (ms) or more, and 7 (13%) saw their QTc increase by 60 ms or more. Treatment with hydroxychloroquine had to be stopped promptly in 10 patients, due to iatrogenic drug events (adverse reactions), including nausea, hypoglycemia and 1 case of torsades de pointes. The authors conclude that physicians treating their patients with COVID-19 should carefully weigh the risks and benefits of treatment with hydroxychloroquine and azithromycin, and monitor QTc closely if patients are receiving these drugs.

French doctors have also published the results of a study on the effects of hydroxychloroquine treatment on the QT interval in 40 patients with COVID-19. Eighteen patients were treated with hydroxychloroquine (HCQ) and 22 received hydroxychloroquine in combination with the antibiotic azithromycin (AZM). An increase in the QTc interval was observed in 37 patients (93%) after treatment with antiviral therapy (HCQ alone or HCQ + AZM). QTc prolongation was observed in 14 patients (36%), including 7 with a QTc ≥ 500 milliseconds, 2 to 5 days after the start of antiviral therapy. Of these 7 patients, 6 had been treated with HCQ + AZM and one patient with hydroxychloroquine only, a significant difference. The authors conclude that treatment with hydroxychloroquine, particularly in combination with azithromycin, is of concern and should not be generalized when patients with COVID-19 cannot be adequately monitored (continuous monitoring of the QTc interval, daily electrocardiogram, laboratory tests).

Update June 8, 2020
A randomized, placebo-controlled study suggests that hydroxychloroquine is not effective in preventing the development of COVID-19 in people who have been exposed to the SARS-CoV-2 virus. The study, conducted in the United States and Canada, was published in the New England Journal of Medicine. Of 821 participants, 107 developed COVID-19 during the 14-day follow-up. Among people who received hydroxychloroquine less than four days after being exposed, 11.8% developed the disease compared to 14.3% in the group who received the placebo, a non-significant difference (P = 0.35). Side effects (nausea, abdominal discomfort) were more common in participants who received hydroxychloroquine than in those who received a placebo (40% vs. 17%), but no serious side effects, including cardiac arrhythmia, were reported. Clinical trials are underway to verify whether hydroxychloroquine can be effective in pre-exposure prophylaxis.

Hydroxychloroquine and COVID-19: A potentially harmful effect on the heart

COVID-19 and cardiovascular disease

Cardiologue et Directeur de la prévention, Institut de Cardiologie de Montréal. Professeur titulaire de clinique, Faculté de médecine de l'Université de Montréal. / Cardiologist and Director of Prevention, Montreal Heart Institute. Clinical Professor, Faculty of Medicine, University of Montreal.9 April 2020

OVERVIEW

  • People with cardiovascular disease are more likely to develop the more severe forms of COVID-19, which significantly increases the mortality rate of this disease.
  • In addition to being an important risk factor for COVID-19, cardiovascular disease can also be a consequence of SARS-CoV-2 coronavirus infection.
  • Patients with severe COVID-19 frequently have heart damage, which increases the severity of the infection and is life threatening.

COVID-19 is a respiratory disease caused by a new virus, the SARS-CoV-2 coronavirus. The COVID-19 epidemic began in December 2019 in Wuhan, Hubei Province, China, and has spread rapidly worldwide with more than 1,360,000 people affected and 75,973 deaths as of April 7, 2020. Although most patients infected with the virus do not have major symptoms, about 15% of them develop a much more severe form of the disease, including severe acute respiratory syndrome that requires mechanical ventilation. This severe form of COVID-19 is particularly dangerous for the elderly: while the mortality rate is around 1% among those aged 50 and under, it rises to 3.6% in those aged 60, to 8% for those aged 70 and up, and to 14.8% for those 80 years and older.

An aggravating factor: Chronic diseases
Data from previous outbreaks caused by coronaviruses similar to SARS-CoV-2 have shown that a large proportion of infected patients are affected by underlying chronic conditions. For example, during the 2002 severe acute respiratory syndrome (SARS) epidemic, the prevalence of type 2 diabetes and preexisting cardiovascular disease was 11 and 8%, respectively, and the presence of either of these chronic conditions was associated with a very large increase (almost 10 times) in the mortality rate. Similarly, in patients infected with Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 and presenting with severe symptoms, 50% suffered from hypertension and diabetes and up to 30% from heart disease.

The presence of these comorbidities (coexistence in the same patient of two or more diseases) is also observed during the current COVID-19 epidemic. In all the studies carried out to date, a significant proportion of patients were affected by a preexisting chronic condition, the most common being hypertension, type 2 diabetes and cardiovascular disease (Table 1).

PopulationComorbiditiesSource
99 infected patients
(Wuhan, China)
Cardiovascular disease (40 %)
Diabetes (12 %)
Chen et al. (2020)
191 infected patients
(Wuhan, China)
Hypertension (30 %)
Diabetes (19 %)
Cardiovascular disease (8 %)		Zhou et al. (2020)
138 infected patients
(Wuhan, China)
Hypertension (31 %)
Diabetes (10 %)
Cardiovascular disease (15 %)
Wang et al. (2020)
1099 infected patients
(China)
Hypertension (15 %)
Diabetes (7.4 %)
Cardiovascular disease (2.5 %)
Guan et al. (2020)
46,248 infected patients
(China, meta-analysis)
Hypertension (17 %)
Diabetes (8 %)
Cardiovascular disease (5 %)
Yang et al. (2020)
355 deceased patients
(Italy)
Hypertension (76 %)
Diabetes (36%)
Cardiovascular disease (33 %)
Atrial fibrillation (25 %)
Cancer (20 %)
Instituto Superiore di Sanita (2020)

In all cases, these chronic conditions are more frequently observed in patients with the more severe forms of COVID-19. For example, a study carried out in Wuhan showed that the proportion of patients with hypertension, type diabetes 2 and cardiovascular disease is almost twice as high in those who have developed a severe form of COVID-19. This contribution of chronic diseases to the burden imposed by COVID-19 seems particularly important in Italy, one of the countries hardest hit by COVID-19: data collected by the country’s health authorities show that 99% of people who have died from the disease had at least one chronic condition such as hypertension (76%), type 2 diabetes (36%), coronary heart disease (33%), atrial fibrillation (25%) or cancer (20%).

The impact of these chronic diseases is considerable, with the mortality rate of COVID-19 increasing by 5 to 10 times compared to people who do not have preexisting conditions (Figure 1).

Figure 1. Influence of preexisting chronic conditions on the COVID-19 mortality rate. From: The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (2020).

People with a chronic condition, including cardiovascular disease, are therefore at much higher risk of developing a severe form of COVID-19, especially if they are older. Consequently, this population must be extra vigilant and avoid interacting with people who may have been in contact with the virus.

Heart damage
In addition to being an important risk factor for COVID-19, cardiovascular disease can also be a consequence of SARS-CoV-2 coronavirus infection. Studies carried out at the beginning of the pandemic observed clinical signs of cardiac injury (elevated blood level of cardiac Troponin I , abnormalities of electrocardiograms or cardiac ultrasounds) in 7.2% of infected patients, a proportion that reaches 22% in those affected by severe forms of COVID-19 and who required hospitalization in intensive care. In another study of 138 patients with COVID-19 in Wuhan, 36 patients with severe symptoms treated in intensive care units had significantly higher levels of myocardial injury markers than those not treated in intensive care units. Severe cases of COVID-19 therefore often present complications involving an acute myocardial injury, which seriously complicates the treatment of these patients. It is very likely that these cardiac injuries contribute to the mortality caused by COVID-19, since a study observed hs-cTnI values higher than the 99th percentile (which indicates a myocardial injury) in 46% of patients who had died from the disease, compared to only 1% of survivors. In addition, two recent studies (here and here) have found that the death rate of patients with cardiac injury is much higher than among those without, an increase that can be as high as 10 times in people with a history of cardiovascular disease (Figure 2).


Figure 2. Differences in mortality of patients with COVID-19 depending on the presence of preexisting cardiovascular disease and/or cardiac injury caused by infection. From Guo et al. (2020).

The mechanisms responsible for these heart lesions are very complex and involve several phenomena. On the one hand, poor functioning of the lungs can cause oxygen levels to become insufficient to keep the heart muscle working. This oxygen deficiency is all the more dangerous because the fever caused by the infection increases the body’s metabolism, which increases the workload of the heart. This imbalance between oxygen supply and demand therefore increases the risk of arrhythmia and heart damage.

Another factor involved in heart damage caused by respiratory viruses is what is known as a “cytokine storm”, a phenomenon characterized by an exaggerated inflammatory response following viral infection. The immune system goes berserk and indiscriminately attacks everything in the vicinity, including our own cells, which damages organ function and can increase susceptibility to bacterial infections. The heart is particularly sensitive to this uncontrolled inflammation given its close interaction with the lungs; the oxygenated blood from the lungs reaching the heart has been in direct contact with the foci of infection and therefore necessarily contains a greater concentration of the molecules produced by excess inflammation. When this blood is expelled from the left ventricle to the aorta, a portion of this oxygenated blood is immediately passed to the myocardium to feed the heart cells, with the result that these cells are exposed to abnormally high amounts of inflammatory molecules. An excess of inflammatory molecules can also cause thrombosis (clot formation), which blocks the flow of blood to the heart and causes a heart attack. Indeed, a recent study has shown that high levels of D-dimers, a marker of thrombosis, were associated with a very large increase (18 times) in the risk of mortality from COVID-19.

A clinical study led by Dr. Jean-Claude Tardif, Director of the MHI Research Center, has just been launched to determine whether a reduction in inflammation from viral infection with colchicine, an inexpensive and generally well tolerated anti-inflammatory medication, can prevent the excessive immune response and improve the course of the disease.

It should also be mentioned that in some rare cases, it seems that the heart is the first target of the SARS-CoV-2 virus and that cardiovascular symptoms are the first signs of infection. For example, although the first clinical signs of COVID-19 are usually fever and cough, the National Health Commission of China (NHC) reported that some patients first sought medical attention for heart palpitations and chest tightness rather than respiratory symptoms, but were subsequentlydiagnosed with COVID-19. Recent cases of acute myocarditis caused by COVID-19 in patients with no history of cardiovascular disease have also been recently reported, a phenomenon that had previously been observed for other coronaviruses, including MERS-CoV. A common feature of these viruses is to enter human cells by interacting with the surface protein ACE2 (angiotensin-converting enzyme 2), which is present in large quantities in the lungs, heart and cells of blood vessels. It is therefore possible that the virus uses this receptor to penetrate directly into the cells of the myocardium and cause heart damage. In line with this, it should be noted that analysis of heart tissue from patients who died during the 2002 SARS epidemic revealed the presence of viral genetic material in 35% of the samples. SARS-CoV-2 is very similar (75% identical) to this virus, so it is possible that a similar mechanism is at work.

COVID-19 and hypertension
The interaction of SARS-CoV-2, the virus that causes COVID-19, with the angiotensin-converting enzyme (ACE2) is intriguing, as this enzyme plays a key role in the development of hypertension, and it is precisely hypertensive people who present a more severe form of the infection. Since commonly prescribed antihypertensive drugs cause an increase in the amount of ACE2 on the surface of cells, there have been several texts on social media claiming that these drugs can increase the risk and severity of SARS-CoV-2 infection and should therefore be discontinued. It is important to mention that this hypothesis has no solid scientific basis and that all of the cardiology associations in the world still recommend hypertensive patients continue taking their drugs, whether they are inhibitors of ACE2 (captopril, enalapril, etc.) or angiotensin receptor antagonists (losartan, valsartan, telmisartan, etc.). On the contrary, preclinical studies seem rather to show that antihypertensive drugs could protect against pulmonary complications in patients infected with coronaviruses.