COVID-19 from Bench to Bedside

Why deep understanding of human physiology may help doctors deter the virus?

Robert Skalik, Consultant Cardiologist, Exercise Physiologist Senior Lecturer in Human Physiology, Wroclaw Medical University

The novel coronavirus (COVID-19) causing Acute Respiratory Distress Syndrome was considered responsible for the huge number of respiratory tract infections leading to severe respiratory failure in many cases. The COVID-19–induced failure of central mechanisms controlling breathing and circulation may explain the mismatch between the clinical symptoms and the objective physiologic life parameters in many patients. A better understanding of the complex physiologic and pathophysiologic mechanisms implicated in the detrimental COVID-19 impact on the various human body systems should facilitate decision-makers to work out brand-new therapies. Moreover, a profound investigation of the human immune system and coronavirus interactions may help scientists build an effective and safe vaccine that seems to be one of the few reasonable options to prevent future coronavirus pandemics.

The novel coronavirus (COVID-19) causing Severe Acute Respiratory Syndrome (SARSCoV-2) was considered responsible forthe huge number of respiratory tract infections leading to severe respiratory and systemic complications in many cases all over the world. Much to the surprise of many physicians, the effectiveness of conventional intensive care therapies (e.g. mechanical ventilation) is below expectation in the respectable number of COVID-19 patients suffering from acute respiratory failure. Doctors and decision-makers have realised that Extracorporeal Membrane Oxygenation (ECMO), emergency lung transplantation or other non-conventional therapies might be the last resort for some critically ill patients. The basic science, laboratory and experimental studies on the interactions between the virus and human systems supported by new IT technologies may contribute to the containment of the disease and its detrimental clinical consequences like never before. The implementation of human physiology knowledge and its rules may help doctors and scientists find more efficient diagnostic and treatment tools in COVID-19 patients.

To date, it is known that the COVID-19 infection may range from asymptomatic or poorly symptomatic course to an almost bizarre deterioration of life parameters (asymptomatic hypoxemia) through to severely ill patients with multiple organ failure including lungs, heart, kidneys, nervous system, and other organs. The virus binds and enters through Angiotensin-Converting Enzyme 2 receptor (ACE2) widely expressed in numerous human organs including heart, lungs, vessels, and the brain, which can result in the systemic inflammation, multi-organ dysfunction and cardiovascular complications (myocarditis, acute myocardial infarction, heart failure, brain stroke and venous thromboembolic events). The pathophysiology of COVID-19-related failure of various human organs and systems, and the proclivity of the virus to attack more ferociously some populations in the world or regions in the particular countries (evidently higher mortality and number of infected people in USA, France, Great Britain, and Spain as compared with Middle Eastern or South Eastern European countries such as Poland, Czech Republic, Hungary, Greece) are obviously a complex and multifactorial issue. This is a result of some ethnic or territorial variations in the immune response, the virus potential to mutate, the responsiveness of physiologic regulatory mechanisms, the prevalence of particular co-morbidities (e.g. chronic heart failure, COPD and other chronic lung diseases, immune system defects, diabetes, nicotine addiction, obesity), age of affected population, population-based genetic conditions and the effectiveness of quarantine and sanitary measures.

The latest analyses presented in September 2020 by British Medical Journal show that the efficacy of the majority of applied pharmacological therapies against COVID-19 might be limited. Antiviral drugs, including Remdesivir) or hydroxychloroquine, may not reduce the risk of death. The problem with the clinical effectiveness of many applied therapeutic tools in severe COVID-19 patients may result from pathophysiology and timing of the coronavirus attack and its dynamics. According to the latest scientific reports, the time between the contact of the virus with the upper respiratory tract cells (pre-symptomatic/asymptomatic phase) and the virus entry into the epithelial lung cells (symptomatic) is only 24 hours and it takes the virus 7 to 10 days to develop the full-fledged severe clinical condition (hospital admission time). It can be assumed on this ground that it is too late for many symptomatic or severe patients to obtain the appropriate therapy before the virus enters the cells and continues its cell disruptive attack potentiated by the subsequent huge host immune response. However, there is a still good space for immunological treatments (plasmapheresis, monoclonal antibodies, immunosuppressive drugs) that may deter self-destructive response to the virus from the human immune system.

The creation of effective therapeutic models against the present coronavirus outbreak and the containment of future pandemics should be based on the following investigational routes:

  1. A profound understanding of the complexity of physiologic or pathophysiologic mechanisms of bizarre or unusual symptoms of the disease observed in many patients and their relevance for the selection of the therapeutic strategy and prognostication
  2. Artificial intelligence (AI)-based designing of symptoms and laboratory immune tests results configuration models (e.g. blood concentration of pro- and antiinflammatory interleukins such as IL-6, TNF, IL-4 and others) predicting the course of the disease and the effectiveness of various therapies in particular patients or groups of patients (“immunological response profiling”)
  3. The new application of commonly used drugs (repurposed therapies) in combination with modern immunological treatments and sophisticated intensive care tools (ECMO)
  4. Development of brand-new therapeutic technologies and options based on the IT-assisted analysis of immunology, physiology and pathophysiology mechanisms involved in COVID-19 infection, i.e. the in-depth analysis of the virus-immune system interactions with special focus on the detailed investigation of mechanisms of the coronavirus entry into the cells
  5. Preparation of ‘intelligent’ or ‘smart’ vaccine.

There are more and more physiologic and pathophysiologic evidences that some of the strange symptoms (smell and taste sensations or lack of dyspnoea in patients with relevant hypoxemia) in some COVID-19 positive patients might be caused by damage to the Central Nervous System (CNS). The coronavirus causes smell and taste dysfunction that probably stems from some local injury in the brain and peripheral nervous system receptors. In addition, the virus may damage ‘breathlessness sensations’ centre in the brain insular cortex, central and peripheral chemoreceptors as it does taste and smell receptors. The lung ventilation is controlled by the brain, peripheral arterial vessels’ chemoreceptors and the lung stretch receptors. The coronavirus may disturb the flow of the electrical signals between the lungs, chemoreceptors, autonomic controls of breathing and circulation and other brain centres. For  this reason, the severely ill COVID-19 patients may not feel dyspnoea. Some coronaviruses have been reported to spread to the breath and circulation  controlling centre in the brain stem from the stretch receptors and chemoreceptors in the lungs.

As recently reported by the prestigious New England Journal of Medicine COVID-19 may attack brain causing clinical symptoms. Moreover, the brain structures can be affected in few asymptomatic COVID–19 patients. Around 40-60 per cent of hospitalised COVID-19 patients experience neurological complications including nerve damage and stroke in USA. For this reason, CT scanning (or/and functional MRI) of brain should become an adjunct tool to forecast the risk of clinical status deterioration, plan further treatment procedures or prognosticate death, mental or physical disability in symptomatic COVID-19 positive patients admitted to hospitals (especially those presenting symptoms that originate from the nervous system).

The acute respiratory failure in COVID-19 patients can be a result of damage to the lung gas exchange membrane and the concomitant impairment of central cardiorespiratory controls in the brain. Severely ill COVID -19 patients may suffer from respiratory failure that is augmented or coincided by acute heart failure. The severe lung damage, cardiac failure and focal brain damage in the COVID-19 patients can be related to the direct viral intrusion into the cells, an excessive immediate host immune response to the virus (cytokine storm), arterial blood hypoxemia and acidosis in the wake of the alveolar-capillary membrane damage, the impairment of brain cardiorespiratory controls and the lung-heart interaction during the acute inflammation.

The enormous host immune response to COVID-19 attack called cytokine storm decreases the interferon response that may contribute to the mismatch between the onset of viral intrusion and the severe clinical manifestation. It can be hypothesised that the early blood sample evaluation for the pro-inflammatory cytokine profile (high TNF and interleukin 6 with lowered interferon) might facilitate emergency physicians to predict the sudden deterioration of clinical status in the in-hospital symptomatic COVID-19 positive patients. The scientists and doctors from the renowned National Research Institute in Paris INSERM have just demonstrated that the severe clinical course in COVID-19 patients is most probably related to the poor interferon response and high load
of pro-inflammatory cytokines. This immunological configuration, i.e. ‘unique phenotype’ (low Interferon, high interleukin 6 and TNF), is to be a hallmark of critically ill COVID-19 patients. The reduction of interferon level in blood, i.e. a relevant component of signalling system between the pathogen and host immune system, may be the way the coronavirus utilises to ‘lead astray’ our immunological system and take more severe course. These observations may indicate that the mitigation of pro-inflammatory cytokine storm (e.g. application of antiinterleukin monoclonal antibodies, plasmapheresis, immunosuppressive drugs) plus interferon supplementation in the very early phase of the disease might be one of ways to save lives of at least some COVID-19 patients in ICU.

FDA has approved the emergency use of plasmapheresis for the severe COVID-19 patients to reduce pro-inflammatory cytokine burden. The mitigation of excessive host immune response as mediated by interleukin 6 and other pro-inflammatory cytokines and the application of ECMO might deter or reduce the risk of enormous and irreversible damage to the alveolarcapillary membrane in the lungs and respiratory failure-related deaths in COVID-19 patients. According to the previous reports, plasmapheresis has turned out to be an effective treatment method in diseases with the hyperactive response of the immunological system, i.e autoimmune diseases, myasthenia gravis or multiple sclerosis. There are also reports on the application of plasmapheresis in Ebola viral infection. The combination of plasmapheresis with ECMO may reduce the pro-inflammatory load on the gas exchange alveolar-capillary membrane and facilitate the lung recovery that is not guaranteed with use of ventilators in many cases.

It has been recently reported that dexamethasone (a commonly used steroid drug) can cause breakthrough in the treatment of the most severe COVID-19 patients demanding mechanical ventilation. Scientists from Wroclaw Medical University in Poland previously demonstrated that dexamethasone can protect cardiac muscle from acute ischaemia–induced damage. The acute inflammatory process causes release of natural steroids from adrenal glands in the early stage of inflammation, which is supposed to weaken the adverse effects of pro-inflammatory cytokines on various human systems in the experimental conditions. Dexamethasone as a strong immunosupressive drug can be most beneficial for COVID-19 severe patients with cytokine storm. Subsequently, this medicine has potential to reduce pulmonary and cardiovascular complications in some hospitalised COVID-19 patients. Glucocorticoids probably reduce mortality, mechanical ventilation and duration of hospitalisation (the RECOVERY trial ).

One of the hypothetical ways to stop the COVID-19 pandemic is to apply drugs and therapeutic methods that have potential to prevent the intrusion of the coronavirus into the cells of various human systems and tissues. Protein kinase 2 inhibitors (Imatinib and Saracatinib) were proposed by scientists from Iran, Italy, United Kingdom, Romania, and Poland as a new treatment tool. These inhibitors have power to block the effective binding of the virus to its ACE2 receptor and further penetration into the human cells.

The anti-inflammatory cytokineinterleukin 4 and its role to mitigate viral attack might be also an interesting target for investigation in the context of COVID-19 hostimmune system interaction. In the brand-new article by Yang et al., the array of immune mechanisms of the coronavirus infestation has been profoundly presented. COVID-19 causes the enormous increase in the pro-inflammatory interleukins levels. Of note, the increase in the anti-inflammatory interleukin 4 is not so remarkable as compared with pro-inflammatory interleukins. As demonstrated by de Lang et al., interleukin 4 can block SARS-CoV intrusion into the cells through modulation of ACE2 cell receptor. The interleukin 4-virus interaction takes place in the early stage of infection, therefore experimental efforts to treat SARS-CoV with this cytokine after infection failed. However, after pre-treatment of the cells with interleukin 4 and subsequent infection, excretion of SARS-CoV from the treated cells decreased. Vaccination strategies utilising inactivated SARSCoV may reinforce interleukin 4 production upon restimulation (COVID-19 attack).

Further research on the safe and efficacious vaccine (‘smart’ vaccine) should be focused not only on boosting humoral and cellular immune response, but also the profound investigation of the immune mechanisms that might block the virus entry into the cells and ways to enhance the virus entry blocking capabilities of human body. Hence, the application of experimental models assisted with IT technologies such as AI and complicated computer algorithms, nanotechnology may help pharmaceutical companies predict the pro- and anti-inflammatory interleukins’ response to the various attenuated coronavirus antigens, the potential deleterious interactions between the host immune system and the virus antigens used for vaccine formulation and build an intelligent and safe for patients vaccine.

To conclude, the future research models on the effective treatment of patients with the severe course of COVID-19 infection should include all stages of the viral infestation, pathophysiologic pathways through which the coronavirus interacts with the human body (virus entry into the cells, interferon-mediated signalling between the virus and host immune response, cellular and humoral response to the coronavirus – ‘cytokine storm’), human genetics, the ethnic specificity- related modulation of the host immune response to the viral infection, the analysis of various pharmacological treatment models using multiple combinations and configurations of the accessible drugs with convetional therapies (mechanical ventilation or ECMO) and formulation of the appropriate immunological diagnostic kits based on the blood measurements of the pre-selected set of interleukins (e.g.IL-6,TNF,IL-4) for prognostication or tailoring the suitable treatment for the individual patients’ needs or modification of the applied therapies. In fact, no matter how hard intensivists and other clinicians try to contain the pandemic, the ultimate victory over the virus will be probably made or marred by basic science.

--Issue 50--

Author Bio

Robert Skalik

Robert Skalik is a consultant cardiologist and exercise physiologist, a senior lecturer in human physiology in Wroclaw Medical University, Poland, consultant cardiologist in Specialist Hospital „Ventriculus”, Leszno, Poland.From 1998 to 2007, he worked as a physician and consultant cardiologist in Department of Cardiac Surgery and Cardiology, Wroclaw Medical University. He is an Elected Fellow of Royal Society of Medicine in London, Great Britain and Invited Member of VBHC- Centre Europe, the Netherlands. He is an author and co-author of numerous scientific reports on cardiology and human physiology and one monograph on exercise physiology. He has special interest in general cardiology, cardiovascular imaging, exercise and cardiovascular physiology, cardiac rehabilitation and sports cardiology.

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