Dr Yeshwanth K. Amdekar, DCH, MD (Pediatrics), FIAP

Medicine is a science of uncertainty and art of probability – William Osler

Must devote part of your mind to constantly processing uncertainty – Scott Belsky

Chapter 2. Uncertainties in medicine in spite of advances

Introduction

Medicine unlike physics or mathematics is at best a scientific study rather than pure science. There have been rapid advances in medicine with the use of modern technology. However, as our understanding improves, it unfolds our increasing ignorance. “The more I learn, the more I realise how much I don’t know,” said Albert Einstein. Most of us experience Dunning-Kruger effect that describes a hypothetical cognitive bias stating that people at a task overestimate their ability and confidence. The wisdom curve attains quickly a peak of stupidity followed by valley of despair and then over time, the slope slowly moves upwards towards enlightenment.

Over last few decades, so called advances in each decade have partly become obsolete by the next decade, exposing our stupidity and resulting despair. Hopefully, this leads to the beginning of enlightenment though the progress is very slow that takes life time to realize what is right. Thus, uncertainty continues in medicine in spite of advances.

Disease manifestation result of a tripartite interaction

Presentation of a disease and its outcome depend on multiple variables and may not follow the standard pattern. Interplay of three major factors is involved in the manifestations of the disease and they include a primary triggering agent, a host and an environment. Triggermay exist in many different forms such as physical,chemical insult (poison, toxin or abnormal metabolite), infection being the most common besides many unknown forms. Detection of primary agent has been increasingly possible with modern technological advances but for various reasons (technological limitations and human irrationality), proof of a primary agent often remains elusive. Even if primary agent is detected, its characteristics are difficult to assess. For example, when infecting organism is detected, its severity or virulence is not known and so also in-vitro antibiotic sensitivity may not be the same as in-vivo efficacy. These are some of the technological limitations. Same is true about other primary triggering agents.

Host factors play an important role in manifestations of diseases. Nutritional and immune status of the host can be evaluated to a certain extent but it may not translate into a predictable pattern or outcome in a disease. This is because even an immune-competent host may underperform to a specific challenge or overreact to a primary agent with its consequences (immuno-reactive disorders with organ damage, MIS – multisystem inflammatory syndrome). Science fails to preempt such possible immune aberrations and even after they occur, the cause of such reactions is a conjecture.

Genetic predisposition is important but epigenetic factors decide the outcome. The role played by the “mind” in host response remains unclear. It is an irony that medical science has ignored the role of the mind in the causation of physical diseases though there is an attempt to correlate it with psychological problems. However, anatomy, physiology and pathology of the mind remain elusive but we know that communication and counseling with empathy do help “mind” of the patient with resultant healing. The environment also modifies disease manifestations. (Malaria in the hyperendemic zone may present without fever).Exposure to factors such as population density (overcrowding), state of general hygiene and seasonal variation may alter disease manifestations. Effect of drugs depend on pharmacodynamic and pharmacokinetic factors and vary with time of the day or night (circadian rhythm – steroids safe as a single dose in the morning), drug ingestion either on an empty or full stomach as well as the interaction between multiple drugs differ in their benefits as well as side effects. Such variables add to the complexity of medicine.

The host decides the pathology and hence the outcome

Hosts of the same age with normal nutritional and immune status respond to the same infection with such a marked variation that no modern technology can predict. This is how it is mainly the individual host who decides the pathology (type of response) and its outcome that is unpredictable. Streptococcal pharyngitis is a classic example. There occurs a wide spectrum of host responses to streptococcal infection that may lead to markedly variable outcomes such as asymptomatic infection without disease, mild vague symptoms, standard presentation with cure with or without antibiotic, asymptomatic carrier state, recurrent disease, immune complications after curing of disease like rheumatic fever with its different manifestations, glomerulonephritis, PANDAS (neuro-psychiatric disorder) and also serious streptococcal skin-scalded syndrome or toxin-induced manifestations. All these patients look similar to begin with but they progress unpredictably in a different way.

Modern science fails to preempt a specific pattern of response in a given individual and knows only after it occurs. Even then, treatment is not always helpful as management of immune complications is palliative and not curative and favorable outcomes cannot be guaranteed. Tuberculosis is another example. Immune response to mycobacterial infection is T cell-dependent and it is the balance between hypersensitivity and immunity – two sides of host immune response. Depending on such a balance, manifestations vary from favorable response such as primary asymptomatic infection (requiring no treatment) to treatable pathology with good outcomes such as primary complex, progressive primary disease and pleural effusion, treatable pathology but with permanent damage such as chronic fibrocaceous cavitary disease and disseminated diseases such as military or meningitis.

With such a different pathology, the outcome also varies from cure with or without permanent damage or even fatality. As mentioned earlier, drug-resistant tuberculosis is a challenge resulting from human irrationality (misuse by doctors and non-compliance by patients). It is clear that unpredictable response and outcome are a possibility in every disease. This is the reason that every disease may present with atypical or incomplete manifestations that pose a clinical challenge and the outcome is not certain in spite of early correct diagnosis and prompt compliant treatment.

Cause and effect is often a conjecture

Even when a cause of a disease is detected, one may not be sure whether the effect is related to the same. For example, isolation of a bacterium in a sample may not be the cause but simply a commensal or a contaminant. Similarly, in-vitro and in-vivo drug sensitivity may differ and the patient’s response to a drug may not correlate with the test result. The normal test result does not necessarily rule out the disease as much as an abnormal test result in isolation is not the proof of a disease.

Science does not know cause and effect in relation to congenital malformations Though few risk factors are considered but it is not rare to find no risk factors to explain such problems and on the other hand, one does see an absence of any malformation in spite ofthe presence of risk factors. It is clear that we are still short of complete answers in spite of advances. There is no doubt that research should and will continue to find more answers but I fear our understanding will always lag behind in this race and this is how uncertainties will remain. That is how medical practice is based also on the art of probability.

Controversies due to uncertainties add confusion The recent pandemic of coronavirus is a classic example. It has left many unanswered questions and “experts” differ adding confusion. We are not sure about the origin of the pandemic. It took time for WHO to declare a pandemic. No government was sure of immediate action though most countries announced lockdown, few did not. No one was sure when to release restrictions. Several countries including India have faced multiple “waves”. A balance between probable morbidity/mortality and economic losses were difficult to predict and there were controversies on every decision.

List of symptoms arising from covid infection kept on increasing to an extent that any symptom or even no symptom was considered possible to explain disease. There was confusion about different tests and their reliability besides affordability and accessibility. No test in medicine is 100%, afalse +ve and false – ve test results are inherent limitations. Treatment options were equally controversial with an initial favorable report about Hydroxychloroquine published in a reputable international journal that was soon confirmed to be wrong within the next few days. Several drugs have been tried with varying claims but not recommended and Remdesivirwas the only approved drug. Even then, no one was sure about for whom and when to use this drug. The use of steroids, IVIG, monoclonal antibodies and plasma therapy have been tried with unpredictable varying success and so there are no clear recommendations.

Finally, it was felt that the only life-saving measures were steroids and adequate oxygenation. However, steroids did result in Mucormycosis in a few patients. Similar controversies exist in the choice of vaccines and also the interval between two doses. The initial4-week interval (based on the need to hurry through an immune response) was replaced by 6-8 weeks interval (for better immune response). Such uncertainties lead to confusion that is further promoted by different self-made experts. We are not sure whether present vaccines protect against various mutant strains. There is even a lobby against vaccination -imagine how evidence is elusive and the consensus is debatable. But what is universally accepted is the old traditional wisdom -social distancing, masking and sanitisation.

Way forward in spite of uncertainties

Uncertainties in medicine are likely to be increasing as our knowledge improves with the unfolding of newer challenges. This is where experience and traditional wisdom come in along with scientific evidence. Experience is built over time with an open mind and willingness to accept mistakes and make necessary changes. Thus, we depend on consensus guidelines that at best represent a summary of the practical wisdom of experienced experts. Naturally, these guidelines need to be revised periodically as our knowledge (or ignorance) increases. It also underscores a fact that medical practitioners must continue to learn, unlearn and relearn forever.

Personal notes

I was more confident about the diagnosis of a disease and its outcome when I started to practice with little knowledge (ignorance is bliss). As I learned more, I developed a more cautious approach to being aware of a wide spectrum of presentations of a disease that may overlap with other possibilities. Similarly, I realized the outcome of correctly diagnosed and treated disease may not always progress in an expected pattern and hence there is always a need for constant monitoring. I have seen an unexpected recovery in a brain-damaged child and also met worst outcome even when disease was diagnosed early and treated in a best scientific way. It made me clear that there are other factors hitherto unknown.

Finally, I have realized that nature is so kind that most of our patients, but not all, improve in spite of uncertainties and we take the credit for the same. It should make us feel humbler not to take credit for success and be more watchful and try our best. I remember one of the pioneering cancer surgeons operated on a patient suffering from GI cancer and found an extensive spread that made him close the abdomen without any further resection and counseled relatives about the poor outcome. This happened in early 70s and to his and everyone’s surprise, the patient recovered completely. The surgeon considered his diagnosis of cancer was wrong but would not believe that cancer got cured by nature or any other measures followed by the patient. Such instances do occur though as mentioned before they are rare but make us aware of medical uncertainties.

Such instances also remind us to look beyond modern medicine to other systems of medicine. During the pandemic, medical experts were asked whether it was time to ease the lockdown – allergists were in favor of scratching it, dermatologists advised not to make a rash move, GI specialists had a gut feeling, neurologists felt the government had a lot of nerve, obstetricians felt everyone was laboring under a micro-conception, ophthalmologists thought the idea was short-sighted, pathologists could not opine without a post-mortem, pediatricians said ‘oh, grow up”, psychiatrists thought the whole idea was madness, radiologists could see through it, anesthetists thought whole idea was gas, cardiologists did not have the heart to refute it, in the end, proctologists won leaving the entire decision up to the asshole.

Take home message

There is no doubt about rapidly advancing modern medicine has opened many opportunities for better health care. However, there exist too many variables in the causation and outcome of every disease, many of such factors are not yet clearly understood. Such uncertainties in medicine require watchful monitoring and empathetic counseling without instilling undue fear in the mind of a patient but at the same time not giving false hopes. Physicians must understand the limitations of science but continue learning also from experiences based on deliberate observation.

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