TRUMP, THE CORONAVIRUS, MEDICINE, RESEARCH AND BELIEF

The POTUS Donald Trump has daily punted, in his own inimitable style, a management for the coronavirus, a medicine called hydroxychloroquine, (Trade name, Plaquenil). Plaquenil has been one of the many medications that have been hopefully and empirically administered, without scientific testing, in the current world wide pandemic, These interventions have been advocated in attempts to, prevent, cure and/or ameliorate the disease caused by Covid 19.  

Trump’s dogmatic emphatic endorsement has resulted in the widespread demand and usage for the drug by patients, doctors and hospitals to the extent that there is now a national shortage. In his enthusiasm he has been openly contradicted by scientific experts that deny his recommendation has been proven, that it has deleterious side effects and will cause shortages for patients that are on the treatment for registered indications. The POTUS’S phlegmatic counter is “What can you loose?”. 

Before Jay H. Ell can examine the basis of all the above claims it is essential to understand the basis of research in medicine and the roles anecdotal results and belief play in our decision making process. 

HISTORY OF RESEARCH INTO DISEASE IN ORDER TO EFFECT ITS MANAGEMENT.

In trying to find a cure or treatment there has to be the knowledge of the course of the disease, its complications, whom it may target and its outcomes. In medical terminology all the latter is termed the natural history. What is thus needed is research into the natural history of the diseases and interventions to prevent, ameliorate or cure them. 

With regard to natural history epidemiological research is the most powerful tool. That involves disciplined observations and measurements of a patients for the duration of the illness. These can be long term in chronic disease and short term in acute illnesses.The most famous of these epidemiological studies is the Framingham Study that documented and made observations of the natural history of Coronary Artery Heart Disease and its major risk factors. They were the first to identify high blood pressure, raised cholesterol and cigarette smoking as the causative factors. A whole range of therapeutic interventions followed for the risk factors as well as the complications.

Then there are observations of catastrophic outcomes that through the ages that have necessitated immediate intervention or death would occur. For example it did not take army surgeons treating many cases of gangrene of a limb to note that death followed unless the offending limb was amputated. Today emergency surgical management of a burst appendix, a ruptured ectopic pregnancy or a bleeding aortic aneurysm is mandatory. No decades long observational studies are needed for these management decisions.   

It stands to reason that the natural history of acute illness is of a shorter duration. Influenza, for example, is responsible for mortality in the very old and extremely sick. Before venturing into the researching of management or treatment into acute infectious disease such as the coronavirus it is crucial to recognize that what appears to be obvious or intuitively certain is often wrong. Below are a few of the commonest mistakes in making decisions on causation and treatment of disease.

CAUTION IN RESEARCH - ASSOCIATION OR CORRELATION DOES NOT NECESSARILY MEAN FACT

Observational or epidemiological studies - unless they are rigorously designed and conducted can be subject to all manner of false conclusions and biases. 

The commonest of these misapprehensions is a conclusion based on a what appears to be a logical association or correlation. This assumption results in an initiation of a management intervention. One example was the hypothesis or belief that women would maintain their premenopausal lower rates of cardiovascular disease if given hormone replacement therapy after menopause. The basis of this assumption was the differing natural histories of coronary heart disease in men and women. A scientifically designed multi center national study was conducted to test this hypothesis. It produced catastrophic results. Those on hormones suffered far more complications such as an increased risk of cancer and thrombotic episodes. The trial had to be stopped prematurely. 

The initial basis for the hormonal replacement study had been reinforced by earlier smaller observational studies which showed that women taking these postmenopausal hormone therapies had lower cardiovascular events rates than those that didn’t. However this causality or association was negated by the fact when the data was relooked at those that had taken the therapy were wealthier more educated and were more likely to be on dietary and exercise regimens as well. The confounding variables by the designers of the earlier studies had not been properly addressed.

There is yet another powerful variable that dictates management - belief and or fear.

BELIEF AS A MOTIVATING FACTOR IN DISEASE CAUSATION AND MANAGEMENT

With the evolution of more sophisticated diagnostic equipment there was a belief that earlier diagnoses could be made and therefore treatment instituted would prevent mortality. Annual routine mammography became the standard of care in all women from forty years of age. Careful epidemiological studies decades later showed that all routine mammography performed before fifty years caused far more harm than good. There were unnecessary biopsies anxiety and even more radical managements instituted with no improvement of the death rate from breast cancer. The new recommendation by the professional societies was that routine imaging start after the fifth decade. This raised an uproar which resulted in Congress passing a law that insurance companies still had to pay for those done after forty years! Fear ruled.

Not a dissimilar situation occurred in the male world with regard to prostate cancer. A test known as the prostatic antigen test (PSA) was introduced. A raised level of the latter was thought to be indicative of cancer and it was generally prescribed as a routine screening test. However not very soon afterwards the scene was flooded with false positives and false negatives. The picture became even more murkier when further studies were made available which were correlated with earlier post mortem studies, which showed a high percentage of men dying with prostate cancer not of it. So the danger was that the raised PSA would result in unnecessary prostate operations on very slow growing cancers. The muddied waters became muddier when it was realized that the death from the more fast growing prostate cancers were unlikely to be influenced one way or another by detection via the screening test. 

Several patients, particularly the anxious ones still desire the screen. The newest professional thinking on PSA screening is to offer the patient an “informed” choice as whether they wish to do one or not.

All the medications advised for the coronavirus at this stage would fall under the rubric of anecdotal or belief. 

FEDERAL DRUG AGENCY - OVERSEER OF SAFETY AND EFFICACY OF MEDICATIONS AND ITS APPLICATION TO CORONAVIRUS TREATMENTS.

Over the last century and a quarter the Federal Drug and Food Agency, (FDA), has grown into a gigantic organization entrusted to oversee, among other responsibilities, the safety and efficacy of all prescription medications. They have instituted an elaborate program whereby sanction is finally afforded for a medications to be prescribed by licensed health care providers. There are a number of phases that are designated from naught to four. This takes a medicine through from the creation of the molecule to animal testing, to volunteers for safety concerns, to administration for very serious conditions where everything else has failed and then finally to the crucial third phase highly scientific studies where the new medicine is tested against a standard of care or a placebo. Every drug has risk so that even when marketed the medicine is surveyed for safety, (Phase four). 

In the definitive third phase comparative studies neither the doctor or the patient know whether or not they are receiving the medicine being evaluated for effectivity and safety. The reasons for this are many. Firstly there is the placebo effect where the patient getting the non active drug Improves. This can either be attributed to patient belief that the medicine is “working” or the positivity exuded by a doctor in her desire for the resolution of the disease. An equally important basis for this type of study is to ascertain whether the patient would have become better whether or not they were administered the active drug. 

The FDA has provisions for fast track registration of drugs particularly in life or death situations such was utilized in the AIDS epidemic and are often set into motion for oncological conditions.  

 For any medication that has been approved for other conditions to be given the go ahead for a new indication they have to undergo rigorous scientific testing in third phase studies as to prove efficacy and safety in the new situation. The widespread usage of these medications in the current crisis have been "allowed” under the provision they can be administered if all other therapies have been attempted with no success. This provision has been liberally interpreted by the health care workers and widespread usage of particularly hydroxycloroquine, has been reported. 

One word of caution, results in double blind randomized trials are sometimes not clear cut. Statistical significance is essential in interpreting the results to eliminate chance as being responsible for the results. The participants characteristics have to be carefully analyzed to make sure the randomization resulted in apples being compared with apples. 

Thus too date there are no treatments or vaccines that have been registered by the FDA for the treatment of the coronavirus. 

MEDICATIONS THAT HAVE BEEN USED FOR TREATMENT OF CORONAVIRUS UNDER SPECIAL FDA PERMISSION PRINCIPLES

As outlined above with the lack of a defined treatment for this circumstance has resulted in the FDA liberally allowing medications that have been registered for other conditions to be used. The most commonly used medication utilized in this fashion is hydroxycloroquine, (Plaquenil), which has gained FDA sanction for the conditions of malaria, rheumatoid arthritis and systemic lupus. Hydroxycloroquinol has been found to have potent antiviral activity. 

The study quoted most for hydroxycloroquine usage is a tiny French study where it was combined with  azithromycin, (Zithromax). On analysis it was obvious that the study was far too small to come to any conclusion and if any thing it should be viewed as highly cautionary for the administration of this cocktail. The Journal in which it was published has issued an apology for its publication implying that it did not pass appropriate peer review standards as it was written by the editor.

 The medical scientists have been emphatic that all results quoted of treatment to date merely provide anecdotal knowledge. No one has a clue whether, hydoxycloroquine is effective  or not. In France as a result of arrhythmic deaths the utilization of this medication has been put on hold. The American Heart Association has also warned against the usage for the same reason. In addition lupus and rheumatoid arthritis patients have been unable to have their prescriptions filled because of the shortage evoked by the pandemic.

Another medication used on a widespread basis is Remdesvir an antiviral AIDS medicine which has shown strong activity in laboratory situations against coronaviruses and in mice experiments.

The Chinese experience, in particular, would indicate that a wide variety of modalities were tried such as generalized treatments such as vitamins and metals especially zinc. antivirals, Chinese medicines and monoclonal antibodies.

THE CORONAVIRUS AND WHERE WE ARE TODAY

On the immediate horizon the only known effective empirical treatment is isolation, the more draconian the better. The experiences of Singapore, Taiwan and South Korea versus those of Italy, Spain, and America are obvious glaring examples. Sweden’s attempt tp create herd immunity with only isolating the most vulnerable is about to get an answer and the earliest indications are not positive. South Africa and India who have large numbers of highly susceptible citizenry by acting early and even using the army to maintain lockdown have thus far had remarkable results.

The reason for total lockdowns being the only successful management thus far is because there is a large knowledge gap in the natural history of coronavirus. Nobody knows how many citizens have the condition asymptomatically or with minimal symptoms. If there was widespread testing this could be ascertained. In addition the approach is necessary to identify those to make an early diagnosis as those who are admitted to hospital have a far worse prognosis than  influenza patients. Besides the high rates of respiratory failure there is the startling statistic that that one out of ten middle aged patients admitted to hospital die. There would be a far better basis as to whom to quarantine and who to let back to work if testing were instituted. This knowledge is central to management and restarting the economy. 

There are a six hundred scientific trials in process at the moment with a broad spectrum of approaches from hydroxyclorquine to monoclonal antibodies to anti virals by the ton. These might yield results soon as some were started in February in China. To see the light of day in respected journals they will need to have been conducted under stringent conditions.

 Companies have claimed that their vaccines will be ready before the eighteen month predicted period. 

One fact is for sure that it is highly irresponsible on the basis of the anecdotal non scientific knowledge to recommend any of these managements as a “game changer”. More so if you are the President of the United States with tens of million followers on Twitter, a forty percent devoted following and a two hour daily exposure to the public on television. 

PS: Jay H. Ell’s anecdotal belief is that one of the children’s vaccines, probably for measles, is effective. Basis of belief is the fact that young children after starting on the vaccine regimen appear to be immune. The reason for the manifestation in older ages, he is arguing, is that the immunity has worn off. Maybe somebody will do a real study! Till that happens don’t run around vaccinating your grandparents.