Dr. YK Amdekar writes at length about medicine, clinical decision making and a state of uncertainty looming during the COVID-19 pandemic.

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Despite tremendous advances in medical science, uncertainty of outcome and ignorance of knowledge continue to persist. In fact, ignorance is common to every science but more so with medicine because medicine is a dynamic science, ever changing. Ignorance is not just lack of knowledge but also lack of awareness of a fact that we don’t know.

'Errors in scientific truth are recognised few years later.' –wrote Marcel Proust a century ago. It is ironical that we realise our ignorance only when we have tried to understand the subject in depth. Till then we feel we know enough. Scientists of repute realised limitations of science very early. Aristotle said- 'The more you know, the more you don’t know.' and Albert Einstein said- 'The more I learn, the more I realise how much I don’t know.' This is a learning paradox.

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Introspection of current medical progress

Medical science has rapidly progressed especially over the last two decades. Immunology, molecular biology, genetics, imaging modalities, stem cell and organ transplants and newer therapies including surgical techniques have revolutionised the entire outlook in medical practice. But unfortunately, it has not been necessarily translated into the cure of diseases and improving quality of life in general.

Vaccine-preventable diseases and treatable bacterial and few viral infections provide evidence of success. Even this success is thwarted by development of antibiotic resistance, thanks to our own misdeeds.Besides, antibiotics may kill bacteria but the host may mount abnormal immune response that may be lead to poor outcome.

There remain many more diseases such as other viral infections and non-infective illnesses such as inflammatory, degenerative or metabolic disorders for which we can do very little. This is because progress has helped to define microanatomy, pathology, and pathogenesis more accurately but control and modification of pathogenetic factors have remained largely elusive. In short, there is improved understanding of what is going wrong but we don’t know how to set it right. It is true that the first step is to know what is wrong but what decides its utility is the final outcome that is often elusive.

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Medicine a science of uncertainty and art of probability

The very fact that uncertainty exists in medical science, is cause for debate as to whether medicine is science or art. There is no doubt that as compared to the science of physics or mathematics that possess ability of accurate prediction, medicine as a science falls short of expected certainty. This is true despite unprecedented progress especially in the last two decades.

In order to counteract uncertainty and ignorance, medical science must be combined with the art of probability to make decisions. Thus, medicine is both science and art. The art of probability has no guidelines to follow and is not based on just a statistical data of probability but mainly on individual experience. The problem with experience is over-confidence. Experience is aptly defined as the ability to make same mistakes repeatedly but with increasing confidence. This is how doctors legitimately differ in their opinions. But is it not funny that judges differ in their opinion in spite of rules formulated by themselves? Nature is erratic and there are no rules about diseases.

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Why is medicine a science of uncertainty?

Occurrence of disease is multifactorial involving host factors such as genetic predisposition, immune response, nutrition and growth especially in the formative years, environment that may alter host response or enhance risk of disease and known or at times unknown infecting agents and other triggers. Thus, symptoms and signs of any disease are a result of tripartite interaction. Not only are each of these factors present in various permutations and combinations, they are also not constant, varying at different times even in the same host. Most of these factors can’t be assessed accurately; nutrition and growth can be, and to an extent genetic predisposition based on family history (though negative family history does not rule out genetic disease).

Immune response can be totally unpredictable even in an immune-competent host and it is impossible at present to know how an individual would produce immune response to react against disease. Environmental triggers are not easy to identify either. Hence, there is no standard way a particular disease presents in all persons. Textbooks describe a disease presuming ideal host and favorable environment with known trigger factor. But in real life, it is not so clear in many situations. It poses a great challenge to doctors and so decision is often based on probability.

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Host immune response the most decisive factor

Immune response is the way an individual fights a disease, at times supported by medicines or other interventions. It is like when a soldier fights with a gun – gun is important but far more important is fitness and competence of a soldier at the time of the fight. The same way, it is the immune competence of the host that would decide the outcome, irrespective of ideal treatment. Well, right treatment is vital but does not guarantee favorable outcome without ideal immune response of the patient. It has to be a balanced response – balance between pro-inflammatory and anti-inflammatory cytokines - that means it should be appropriate to the requirement of a fight – not in excess or deficient. Both excess and deficient response would end unfavorably in destruction.

Excess of inflammatory response is what is known as 'cytokine storm' or 'hyperinflammatory syndrome' or 'autoinflammatory syndrome'. Such a response is capable of affecting every organ in the body. Unfortunately, science as of now, does not know how to modulate favorable immune response in such situations. We do have immune-suppressants in the form of steroids and also immunoglobulins and biologicals to boost immune response. However, they often fail to modulate immune response to the need of the situation. It is the very reason that we are not sure of favorable outcome even in a treatable disease. It happens even when an antibiotic has been successful in curing infection but the patient may not improve. It is a situation where ;primary disease got cured but the patient succumbed.' All that we can do is to pick-up abnormal immune response early enough with the hope of reversing it. However, even then it does not guarantee good outcome.

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Why does an immune competent person mount abnormal immune response?

It is easy to understand poor host response in case of immune deficiency. Normally, an immune competent host is expected to respond appropriately but science is ignorant about reason behind an exaggerated immune response in an immune competent person – a response responsible for destruction when it should have been designed only for protection. What it means is the fact that a strong person must know when to start and when to stop a fight. If the fight starts late, one may lose but if the fight continues beyond the need, it may also cause harm.

A simile can help to understand such a paradoxical response. Imagine you are returning late at night all alone and three thugs confront you. You are a very strong person, so you may be tempted to fight three thugs. But if wisdom prevails, you would know that your strength may not be a match to the total strength of three thugs and if you fight, you may lose your life as well. The best way out would be to act weak and surrender. But at the same time, you don’t wish to be looted. Thugs are happy to get what they want without any resistance. Now, you walk to a next lane and call for your friends and then fight together with these thugs because now you are more powerful than them and you retrieve whatever was looted. A strong person must know when to act weak and when to show strength. Undue show of strength leads to destruction.

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Can science predict who would respond abnormally?

There are no tests to predict probability of exaggerated immune response in a given patient. Though we are aware of conditions which are likely to be at 'high risk'. Such conditions include pre-existent comorbidity like diabetes, hypertension or any other chronic organ dysfunction. It is logical to understand that an organ that is partly compromised in function due to pre-existent disease is likely to shut down at any further insult and danger to life.

Individuals who have suffered from immunological disorders such as malignancy or non-infective inflammatory disorders are at high risk. Also, those who are immune deficient run a high risk and such conditions include severe malnutrition. Young children and very old persons are at risk as well because of sub-optimal functioning of immune system. However, it is not true that individuals without any risk factors would not mount abnormal immune response.

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Why is it not possible to suppress hyper-immune response?

The immune system is complex. It broadly consists of pro-inflammatory and anti-inflammatory cytokines – factors that induce immune responses. Inflammation causes local damage that is helpful to contain the enemy, preventing its spread while soldiers of immune system attack. However, there has to be a balance between these two opposing factors to produce beneficial outcome.

The immune system must switch off in time after the job is accomplished but if it continues to act – hyper-inflammatory response ensues. So there is a need to modulate immune response – not just suppress or stimulate. We need a perfect combination to work. But as of now, science has not advanced to achieve it. Steroids suppress immune response while antibodies help to neutralise antigen but we are not able to understand how to achieve this balance. So we use both – naturally it does not work always. This is the limitation of science.

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Clinical correlates of abnormal immune response

Infections are most common in the community and their outcome depends on appropriate immune response besides need for correct drug treatment whenever available. Luckily, most individuals respond favourably but not all. Streptococcal infection is a classic example of how host response decides the outcome. Many may get infected but not suffer, few suffer from disease affecting throat and get better with an antibiotic while in fewer individuals, mild disease may get well even without treatment. Majority belong to one of these groups.

Rarely, in about one in three hundred infected persons, a disease is cured, but triggers immune response that damages the heart (rheumatic heart disease) or kidney (acute glomerulonephritis), at times with irreversible damage in case of heart disease. Extremely rare is the event triggered by infection which results in neuro-psychiatric manifestations (PANDAS). This varied response occurs in normal individuals with apparently normal immune system and one does not know who will go which way. One can trace similar events almost after every infection. It means even if we are able to find the germ and treat with the correct antibiotic, one may only hope for the best but there is always a small chance of the host’s abnormal response.

Patients wonder how doctors fail despite knowing correct diagnosis and treatment. Again to give a simile, when the teacher teaches a group of students, majority of students pass, few perform very well, but fewer fail. No one in this situation blames the teacher for the few who fail because the teacher cannot guarantee everyone passing because there are many other variables. Similar situation exists in medicine. But, the doctor is judged by the outcome of his performance; the teacher isn't. Immune response also decide outcome of non-infective disorders such as connective tissue diseases and malignancy. Hence, presentation of all diseases have a varied spectrum and they also end up with varying outcome after treatment.

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COVID-19 pandemic- Decision making under uncertainty and ignorance

Uncertainty and ignorance loom large in the present pandemic as has been in many other diseases. We know that it is a SARS-like virus, highly transmissible, bat being the primary reservoir. But, we don’t know how it reached humans and now we witness human-to-human transmission. However, recently, scientists believe that the virus can also spread through aerosols.

Initially, we thought the disease presented with fever and cough, without runny nose. But, as number of cases increased, we knew the disease presented with many more diverse symptoms including anosmia - loss of sensation of smell and the list of symptoms widened over time. Today, we realise that symptoms are so variable that clinical diagnosis is impossible and rests only on laboratory tests. We are also aware that an infected individual may remain free of symptoms. So, in the present situation, anyone of us at any time may be infected and even asymptomatic infected persons may also transmit infection to others. So in reality, no one is safe.

Initially, it was thought that the hot climate in India may reduce the risk of pandemic spread but it has proved to be wrong. It was also thought that children are at low-risk but now we know they are also at risk, including neonates. There have been reports of mother-to-foetus transmission of infection. Thus, age is no bar though prevalence may vary.

• 60% of infected persons in India are in the age group of 30 to 59 years and they contribute to 43% of total deaths
• 20% infected persons are beyond 60 years of age who contribute to 53% of total deaths

It is clear that middle-age adults with apparently well-developed immune system are also at fairly high risk of mortality. Science is ignorant about this paradox of immune response seen in healthy individuals. As discussed in the earlier part of this article, immune response is unpredictable and hyperinflammatory response may harm.

We are aware of how to avoid contact with infection but even every surface that we touch can carry a virus and so it is practically impossible to avoid contact. We can reduce the risk of contact to a great extent by social distancing, using face masks, washing hands, taking hygienic precautions and staying at home as much as possible. There has been a debate on the type of mask to be used; in fact any well-fitted mask will do. Of course, health personnel need much more high-quality protective gears.

Complete or partial lockdown was one way to contain spread of infection in the community though few countries like Sweden and South Korea have not imposed lockdown but left it to the population to follow stipulated rules strictly. This decision has been debatable in Sweden as the country has seen fairly large number of cases though South Korea seems to have managed well without lockdown. While most of the countries did announce lockdown for variable periods, they have also had a large number of cases.

Decision of lockdown, its further extension and unlocking in India had to be taken in absence of definitive criteria to balance between spread of infection and deteriorating economy. Obviously, the outcome of any decision in such circumstances is uncertain and it is only in hindsight that we will know if what was done was right or wrong. At present, we are ignorant, though some action has to be taken under presumption that it would work.

Initially, we started testing people coming to India from infected areas but soon symptomatic persons were being tested and also those in contact with confirmed infected persons. Now, there is a suggestion to test everyone irrespective of symptoms. Of course, feasibility is another issue. There has been a debate about the best method of testing- antibody, antigen, CBNAAT or RC-PCR. There is no test in science that provides 100% sensitivity and specificity. Test results also depends on the quality of a kit used for the test. All such variables add to uncertainty.

Majority of infected individuals would recover without complications but few develop immune-mediated complications – cytokine storm with hyper-inflammatory response in pulmonary vasculature resulting in poor oxygenation. It is known that virus induces production of cytokines- interleukins (IL 6, IL 1, IL 12, and IL 18), tumor necrosis factor alpha and other mediators. Then, it was realised that virus induces dose-dependent production of IL 6 by bronchial epithelial cells and is a major contributor to pulmonary vascular damage. Such a cascade of events is the rationale of using IL6 inhibitor such as Tocilizumab and Sarilumab.

Initially during this pandemic, radiological shadows caused by such inflammatory response were misdiagnosed as pneumonia and acute respiratory distress syndrome (ARDS). Later, it came to be known that it was pulmonary vascular obstruction that was responsible for lack of oxygen. Thus, focus of management shifted from antibiotics and mechanical ventilation to antiviral therapy and attempt to inhibit hype-inflammatory response by monoclonal antibodies, besides supportive therapy.

It is now understood that immunological complications arise 5-7 days after disease is cured. But we now realize that immunological response may be delayed even for few weeks. Hence it is important to monitor the wellbeing of a recovered patient for at least a couple of weeks. Meanwhile, there are occasional reports about reinfection within a short period, suggesting a possibility of early waning antibodies even after natural infection. We don’t know as yet whether such an occurrence is rare as an exception but it is scary. If natural infection fails to offer protection, then would most potent vaccine work any better? We are ignorant about it at present.

There is no drug known to be effective against this virus. Hydroxychloroquine was considered to be effective as per the article published in a western reputed journal only to know after some time that it was not true. Search for anti-viral drugs continued and Remedesivir was considered to be useful. IL 6 inhibitor- Tocilizumab has been studied in the last two months and it has shown some promise of controlling cytokine storm at least in some patients. However, there also exists a risk of super-infection with use of Tocilizumab and hence it is reserved for serious patients. One realises that every advanced step may also be associated with serious side effects and hence outcome of such therapy is uncertain. Science does not know how to get the best benefit without side effects.

Suddenly there is a great surge and competition of producing vaccine against this virus among many countries. More than science, commercial opportunities seem to be working hard. Normally it takes a much longer time before vaccine is made available to the community but in this case, many steps are likely to be bypassed. As of now, we remain uncertain about the future of vaccine, its safety and efficacy.

Well, there has been some progress in understanding the pathogenesis of this disease, based on which prevention and management strategies are planned. However, there remains uncertainty of outcome in spite of taking all measures, both in relation to an individual patient’s recovery and also in terms of control of pandemic. There have been occasional reports of reinfection within a short period and a concern whether naturally acquired antibodies last only for a short time. Like in many other areas of medicine, we will know retrospectively whether what we did was best or not.

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How true is the statement?- 'As we know more, we know how less we know.' It does not mean we should not strive hard to know more but we need to keep in mind our ignorance and uncertainty that will always haunt us. It will also serve us to continue the search for truth in science.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.