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Inpatient Infectious Disease: Ambiguity Is Often The Rule Of The Day

Ambiguity. Medicine, like art, is filled with ambiguity, at least the way I practice it. Most of my practice is in the hospital. I am sometimes called to see patients that other physicians cannot figure out. And that puts me at a disadvantage, because the doctors who were referring patients to me are all bright, excellent doctors. Often the question is ‘Why does the patient have a fever?’ or ‘Why is the patient ill?’ Sometimes I have an answer. Most of the time I do not.

I am happy, however, to be able to tell the patient what they don’t have. I can often inform the patient and their family that whatever they have is probably not life-threatening or life-damaging, just life-inconveniencing, and most acute illnesses go away with no diagnosis. I always put the ‘just’ in air quotes, because illnesses that require hospitalization are rarely ‘just.’ Just without quotes is reserved for the antivaccine crowd and applied to the small number of deaths from vaccine preventable diseases in unvaccinated children. John Donne they ain’t.

We are excellent, I tell them, at diagnosing life-threatening problems that we can treat, and terrible at diagnosing processes that are self-limited. Of course diagnostic testing is always variable. No test is 100% in making a diagnosis, and often with infections I cannot grow the organism that I suspect is causing the patient’s disease. So for hospitalized patients, ambiguity and uncertainty are the rule of the day.

However, the situation is much better than they used to be. I am now one of the oldest physicians practicing in my hospital. After 21 years most of the prior old guard has retired or died, leaving me. I have gone from being the young whippersnapper to the old geezer in what to me seems to be a blink of an eye.

However, the advantage to being old is you get to bore people with the stories of your gloried past. I remember a time, I tell the residents, before CAT scans, before third-generation cephalosporins, before PCR diagnostics. I remember the beginning of the AIDS epidemic, when we saw young men dying of an unknown illness. I still vividly remember my first AIDS patient, dying from disseminated MAI, who offered me a chocolate from his box of candy. I declined. I told him I wasn’t hungry. He told me “I would have to spit in your mouth to give you AIDS.” I did not know that at the time. No one did. Today I would eat the candy.

Times have changed, mostly for the better. AIDS has gone from an unknown disease with a short life expectancy to a mostly chronic manageable illness whose pathophysiology is understood in remarkable detail. Medicine advances. It is often an uncomfortably slow and aggravating process, because diagnostics and therapeutics that look promising at the beginning often turn out to not live up to their promise. Kind of like many people I have known.

Some therapeutic interventions have remained in limbo my entire practice. Steroids, as an example, have been tried for every illness except for Cushing’s disease. In almost every instance they have been found wanting. When I was an intern, every patient with a neurologic event was put on aspirin and Persantine. I don’t think Persantine is used much anymore. Common admission diagnoses were an aminophylline toxicity and digoxin toxicity; both drugs are rarely used today since we have less toxic and superior alternatives.

Certainly my practices changed dramatically over the last 21 years. I used to make a living from diseases that are rapidly becoming of historical interest. Ventilator-associated pneumonia, line-related sepsis, AIDS opportunistic infections, neutropenic fever’s, diabetic foot infections in smokers, all used to be common admitting diagnoses that resulted in infectious disease consultation. No longer.

Despite the wackaloon opinion that doctors are in it for the money, combined with big pharma greed, the last 21 years has seen a concerted effort on the part of the medical industrial complex to decrease the diseases we treat for living. This is not only true in infectious diseases, but cardiologists have been at the forefront of stop smoking and lipid control. The same is true of pulmonary doctors. Every physician fights the battles of obesity in the outpatient clinic. Much of the time physicians try to put themselves out of work. And in infectious diseases it seems to be successful.

Medicine does advance.

There is an infectious disease therapy that superficially resembles acupuncture and homeopathy: ribavirin. A drug with few proven benefits. Like most SCAMs, case reports, uncontrolled series and wishful thinking has kept ribavirin alive and around for my entire practice. I say superficially as most SCAMs now have a proven lack of benefit. Ribavirin is an antiviral medication that has probably been tried on virtually every virus, but has never been shown to have efficacy by itself in almost any infection. It is of benefit in RSV, and combined with interferon for the treatment of hepatitis C.

Ribavirin is a broadly active antiviral has rarely been tested in randomized controlled trials. Many of the infections that are allegedly treated with ribavirin are not common in the United States. So when a question of West Nile virus, dengue virus, Tick-borne Encephalitis Virus, Yellow Fever Virus, Lassa fever, Crimean-Congo hemorrhagic fever, or Hantavirus appears, the answer is ribavirin. But is the answer the correct?

This leads to an interesting editorial from several years ago in the journal Clinical Infectious Diseases entitled How Medicine Advances. How?

The editorial concerned an article on a study that looked at the efficacy of ribavirin in the treatment of Japanese encephalitis virus. Significant time, money and effort has been expended using ribavirin for diseases like Japanese encephalitis. But there have never been randomized clinical trials to demonstrate or deny the efficacy of ribavirin in the treatment of Japanese encephalitis. Until 2009 that is.

In CID that year they published a randomized placebo-controlled double-blind study that evaluated the effectiveness of ribavirin in the treatment of children who had Japanese encephalitis. And ribavirin was found to do nothing.

What was striking about this trial, as pointed out in the editorial, was that the study was done in the poorest part of India, it was done in children, and it was done with a definitive rigor that allowed the issue of ribavirin (always with the caveats of orally and at the dose given) to be put to rest for the treatment of this one infectious disease. A little more ambiguity in medicine has been removed.

I think the final paragraphs of the editorial sum up nicely why we do science-based medicine and the importance of doing clinical trials to determine what does and does not work:

Kumar et al., whose study is published in this issue of Clinical Infectious Diseases, are to be commended for refusing to bow to any of the complexities reputed to make clinical trials impossible. In Uttar Pradesh, India’s most populous and poorest state, Kumar and colleagues sustained over 3 years the first randomized, placebo-controlled, doubled-blind trial of ribavirin for the treatment of the most vulnerable patients—children (age, 6 months to 15 years)—to be hospitalized with acute febrile encephalopathy, and they per-formed seroreactive testing for IgM anti-bodies to Japanese encephalitis virus. By so doing, they established that oral ribavirin, at the dosage used in their study, did not improve either early or late outcomes. By demanding scientific justification for investment in this mode of therapy, they have both encouraged searches for more-effective interventions and prevented the expenditure of scarce resources ineffectively.
Both faith and science are important components of the art of medicine. We ought not to mistake one for the other.

I wish, besides sarcasm punctuation marks, we had whiny little baby tags punctuation marks, since the lament of many a SCAM proponent is that their particular intervention can’t be tested because of “complexities reputed to make clinical trials impossible.” Riiiiggghhhhttttt, Mr. Powers. It is easier to curse the darkness than to light a candle.

There is then the more difficult application of applying the data. If someone has a long history of being committed to a treatment, it is surprisingly difficult to get individuals and groups to alter their behavior. I expect the urge to give ribavirin for Japanese encephalitis will rapidly fade. Not so the urge to balance qi, fix subluxations, or realign the energy flux. Wait. The last is either reiki or Galaxy Quest. The latter at least is recognized as fiction. Unfortunately, there are many other infections for which people will try ribavirin and for which there are no randomized placebo-controlled clinical trials. Ribavirin will continue to be a drug mostly searching for a disease.

But still medicine progresses. Studies get done, there is an incremental improvement in our understanding of the diagnosis or treatment of the disease. And slowly and painfully medicine changes. Emphasis on slowly. Change has to be balanced with the knowledge that much of the information we have in medicine is not final. When I talk about studies with residents, I try and be careful to mention the often endless caveats about the applicability of the results beyond the study population. Back in the day it seemed that all coronary artery disease studies were done in old, white male veterans. Probably widely applicable, but maybe not. But at least as an old white man, I can be taken care of.

There’s an old saying that goes something like ‘be neither the first to abandon the old nor be the first to use the new.’ I certainly feel that way about antibiotics. Over the years new drugs have been approved, released into widespread use, and then found to have serious side effects that resulted in their being withdrawn from the market. So I’m always a little leery about new medications and new treatments unless I do not have other options.

So I look back on 21 years of infectious diseases 25 years of being a physician and note the incredible changes that have occurred. Diagnostics that have improved, therapies that have improved, and more importantly diagnostics and therapies that have been abandoned. Abandoned because they were shown not to work. Medicine advances.

Contrast that with the bête noire of this blog: supplements, complementary and alternative medicine. Anybody who subscribes to reality-based medicine would say at this point that the preponderance of data strongly points to the conclusion that most SCAMs do not work. Acupuncture, homeopathy, energy medicines, etc. do not materially alter disease. Yet has any of these ever been abandoned? Nope.

It would seem that they are being embraced, at least in academic institutions. SCAMs are an archetype example of failing up. It has been noted that with SCAMs that better and better studies show less and less effect until well-designed studies show no effect. For the last decade it would seem the greater the failure, the greater the spread into academia and the more popular the SCAM. By the same standards we should be using internal mammary artery ligation for coronary artery disease, high dose chemotherapy with bone marrow transplant for breast cancer, and continue to suppress all abnormal cardiac rhythms in heart attack patients. All the interventions failed spectacularly, and so should be embraced, each with their endowed Chairs.

SCAMs probably are growing for the financial benefit. Since standard medicine has declining reimbursement and most alternative therapies are out-of-pocket, it’s a good cash cow for institutions that want a flow of money and are not picky about their intellectual standards. Not only are the standard SCAMs proliferating, they often combine in most peculiar ways to come up with new variations. Doctor Moreau would be impressed with the slow mutant reassortments: acupuncture (at least 6 kinds) morphing into acupressure, laser acupuncture, acupuncture with tuning forks and color, and soon there will be dark energy acupuncture. You heard it here first. Don’t get me wrong, I am jealous. I would love to combine ID with cardiac bypass surgery and make some real cash, but they just don’t mix. Sigh.

It is said that the majority of medical practice has no basis in science-based medicine. Certainly in the practice of infectious diseases in the hospital, that is often the case. I will see an organism in a odd place, for example a Gemella endocarditis, and there are no long-term randomized placebo-controlled clinical trials to determine what the best therapy is for the treatment of a Gemella endocarditis. There probably never will be. It is so rare that it is probably impossible to generate enough cases to do a clinical trial. I am stuck with the basic principles of biologic plausibility and in vitro antibiotic susceptibilities and that is often enough. I know that if I can kill the bug in the test tube, I can often kill it in the patient as well. In the absence of clinical trials, reality can reliably determine effective therapy.

It is quite a stark contrast between SCAMs and of medicine and how they are practiced. Medicine changes. Or perhaps it would be better to say medicine evolves. The old is be shown to be worthless. It is abandoned, and patient care overall improves. Even when there are no good clinical trials to guide therapies, often we have prior plausibility and biologic plausibility to help guide our therapies. Not always, as ribavirin demonstrates, but we have to fight the war with the armies we have. Advances have not been without their side effects and bad consequences, as no good deed ever goes unpunished, but medicine still adheres to the Victorian principle that human societies are perfectible. And while we always fall short of our goal, what has accomplished has been admirable.

SCAMs persist with no improvement, no evolution, and are increasingly discredited by reality. Nothing is ever abandoned, instead persisting, mutating and growing. With alternative memes, what determines replicative fitness is not, apparently, the real world. Oh well, it gives me something to write about.

*This blog post was originally published at Science-Based Medicine*

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