They All Add Up

With so much attention rightfully devoted to big ticket items in medicine such as the new drug for hepatitis C that costs $1000 a pill or high tech devices such as the continuous flow left ventricular assist device, which costs on average about $200,000 to insert, not many people are talking about the little ticket items. But the reality is that spending a small amount per person on a huge number of people adds up to just as much—or maybe more—than spending an enormous amount  per person for just a few individuals. So I was very pleased to see a research letter in JAMA Internal Medicine about that lowly test, the urinalysis. 

I was pleased that the authors looked at the consequences of the rampant ordering of urine tests in people with no symptoms suggestive of either an infection in the bladder or kidneys or acute kidney dysfunction, the only circumstances in which urinalyses have been found to be meaningful. The reason, quite simply, that most urine tests are useless or, as the article suggests, actually harmful, is that the majority of older people have bacteria in their urine. What this means is that the injudicious ordering of a urine test will far more often produce a “false positive” result than a “true positive.”

It so happens that twice in one morning of seeing patients this week, I was asked to order a urine test for no good reason. To be fair, the well-meaning daughters of the patients who requested the test, quite insistently, I might add, thought it was with good reason. Their mothers were being diagnosed with dementia, a condition that had developed insidiously over a period of at least a year and probably several, and they were hoping I would identify a “reversible cause” of this otherwise progressive, ultimately fatal illness. Neither patient, however, had any symptoms to suggest a bladder infection: they did not have burning on urination, they did not have urinary frequency, they had no fever or flank pain. One lady was 96; the other was 91. Since the majority of elderly women have bacteria in their urine, I was concerned that if we got a sample from these two (no mean feat if we wanted a “clean catch” specimen, uncontaminated by bacteria from the surrounding skin and from stool), it would show bacteria. But if we did anything with the result—and what was the point of getting the test unless we were planning to treat the ladies in the vain hope that a course of antibiotics would cure their dementia—we would do little more than expose them to a risk of another problem such as clostridium difficile colitis, a potentially serious, occasionally lethal infection common in debilitated older people that typically results from killing off other bowel bacteria with antibiotics.

So what did the new study find? The authors looked at 403 consecutive adult patients admitted to the general medical service of a hospital in 2014 and 2015. They found that in this group, who somewhat surprisingly had a median age of 79, 62% had a screening urinalysis at the time of admission. Fully 84% of these individuals lacked any symptoms suggestive of a urinary tract infection. Of the asymptomatic patients who were screened with a urinalysis, 30% had a positive test. Of those with a positive test, 22% were treated with antibiotics.

Maybe this is actually reassuring: only 30% of asymptomatic patients had bacteria in their urine, not the 90% the authors quote from the literature. And only 22% of the asymptomatic patients with a positive test were given antibiotics, not everyone. 

The research letter in JAMA Internal Medicine leaves many questions unanswered. We don’t know why so many asymptomatic patients had a urine test ordered—perhaps the physicians believed that the fall or fainting episode that triggered the hospitalization was in fact caused by a bladder infection, which is conceivable, even if dementia (what my patients suffered from) is not. We don’t know what proportion of those who were needlessly treated developed complications because of the antibiotics they received. We can’t measure just how much the injudicious use of antibiotics in situations such as this contributes to the development of bacteria that are resistant to multiple antibiotics, bacteria that go on to cause real disease that is phenomenally difficult to treat. 

We do know that there are over half a million people age 65 and over hospitalized each year according to the National Hospital Discharge Survey. If over half of them have an unnecessary test, and if a third of those tests are positive, and a fifth of those positive tests lead to potentially risky treatment, that’s still a lot of bad decisions. All those small ticket items add up, and we need to pay attention to the little decisions we make every day, not just to the big decisions we make once in a while.

The Methuselah Prize

A startling new project was unveiled last Tuesday in the San Francisco Bay area. No, not Apple’s iPhone 6 or its watch, but the Palo Alto Longevity Prize. Never heard of it? Well, you still have a few more months to sign up to enter the competition to win $1 million for unlocking the secret to immortality. Is this just hype or is there some hope here for an important scientific breakthrough?

The basic idea is this: what we are doing now, attacking the maladies of old age one at a time, is simply trading off one bad disease for another. We’re already succeeding: the death rate from cardiovascular disease has fallen over the past several decades—and the death rate from Alzheimer’s disease has risen. As long as human life expectancy remains stable, we’re talking about a zero sum game in which you fix one problem and substitute another. So far, it looks as though dementia will be the big winner, which makes research aimed at turning off the switch that triggers all the diseases of old age very appealing. The underlying assumption of longevity research is that the degenerative diseases such as cancer, heart failure, and dementia are the result of the aging process. Preventing all the conditions that both limit life’s duration and impair its quality seems far more attractive than the disease-specific approach. But is it feasible and is it ethical?

The majority of credible scientists believe that life-extension is a very hard problem whose solution is not around the corner. The Palo Alto Longevity Prize, to the credit of its mastermind at Palo Alto Investors, Yoon Jun, is focused on somewhat more modest and potentially achievable goals. Part one of the prize is $500,000, to be awarded in June, 2016. It will go to a team that can restore the adaptive capacity of a laboratory animal; specifically, an aging animal will need to regain the heart rate variability characteristic of its youth. Part two of the prize is another $500,000 award, to be granted a year later to a team that increases an animal’s longevity by 50%. In both cases, the scientists will have to achieve their goal by enabling the animal to preserve homeostasis—the ability to maintain the status quo (temperature, blood pressure, etc) in the face of a stimulus, a capacity that is gradually lost with aging. Is this a worthwhile goal?

Impaired capacity for homeostasis is at the heart of frailty. The reason people lose their balance and fall easily, or get pneumonia when they contract the flu, or become confused when they are hospitalized is that they are vulnerable to modest “stresses.” So the key to physical frailty, and quite possibly to cognitive frailty (dementia) as well, is maintaining homeostasis. The Longevity Prize seeks to figure out how to do just that, but it is not without risks. As the Struldbrugs of Gulliver’s Travels showed, immortality without eternal youth is tantamount to hell-on-earth: failing vision, declining hearing, impaired cognition with no escape through death. Suppose unlocking the key to immortality does indeed prevent cancer and heart disease—but not arthritis and visual loss? The idea is to prevent all the degenerative conditions of old age, but suppose there isn’t just one switch, but several?

Even if we had confidence that achieving a longer life would not create a race of Struldbrugs, is it a good idea to devote scarce resources to trying to find the key to immortality? As NIH funding shrinks and the need to prioritize research questions grows, surely there are more urgent medical questions than how to live longer. Most people would opt to prevent premature death (infant mortality, teen suicide, cancer deaths in middle age) before they seek life-extension past the biblical allotment of three score and ten. Most physicians who witness the numerous ways patients suffer throughout life’s trajectory would recommend focusing on quality of life before quantity. And many people worry that if researchers did come up with an elixir of life, it would be so expensive that only a very small number of people could afford it, creating a new elite of Immortals.  So perhaps government should not fund longevity research, but what about the private sector? Google invested in Calico, a biotech startup devoted to finding ways to reverse aging. Earlier this month, Calico opened a new research facility in San Francisco where many talented scientists will search for the elusive spigot that can turn off the aging process. People in a free society choose to do all kinds of surprising things: they go bungee jumping, they sign up to travel to Mars, they smoke cigarettes. If Google wants to invest some of its advertising revenue on preventing the degenerative conditions associated with aging, why not?

If it’s reasonable to work on longevity, is offering a prize the right way to go? This approach got quite a bit of media attention a few years ago when Netflix promised $1 million to an individual or team that could improve its predictions of the movie ratings of individual viewers by 10%. This challenge stimulated a great many computer science graduate students and faculty members to spend hours trying to solve the problem. I know because my oldest son was one of them and he wrote about the math underlying the Netflix challenge for the on-line science journal, Science 2.0 when, after 3 years, a winner was announced. It turned out to be a good strategy for Netflix: for a relatively modest investment, the company recruited many fine minds to work on what would prove to be a difficult problem, without having to pay benefits or to pin their hopes for a solution entirely on one individual. Other organizations have issued similar challenges: the Millennium Prize, for example, announced by the Clay Mathematics Institute in 2000, offers $1 million for the solution to each of 7 great unsolved mathematics problems. As of today, only one of the 7 has been solved (and the individual to whom it was awarded, the reclusive and quirky Russian mathematician Grigori Perelman, declined the prize).

Perhaps the earliest use of a financial incentive to solve a scientific problem was the “Longitude Prize,” offered by the British Parliament in 1714 for an answer to how sailors could correctly establish their position at sea. Sailors had long used the stars to determine their latitude, but until the clockmaker John Hunter got his 20,000 pounds (worth about $5 million today) for solving the longitude challenge in 1765, they had been unable to determine their longitude. In recognition of the success of the first Longitude Prize—it was probably the last great breakthrough in navigation before Global Positioning Systems—a public private partnership in England recently launched the Longitude Prize 2014. This competition took an old approach and added a new wrinkle. A panel of experts came up with a list of 6 scientific problems in desperate need of a solution, and then asked the British public to vote on which one to sponsor. The election was held in June and the winner was the problem of antibiotic resistance: designing an easy to use, cost-effective way to test for antibiotic sensitivity at the point of care (which in turn would prevent doctors from giving a drug to which the relevant germ would not respond, an all too common scenario that both fails to cure the patient and also promotes further antibiotic resistance). The winner will receive 10 million pounds (about $16 million). Whether the competition will achieve its objective remains to be seen.  In many such competitions, including the Millennium Prize discussed above, nobody ever wins.

In sum, I doubt very much that the Longevity Prize will result in immortality and I’m glad that it’s a hedge fund and not the NIH that is sponsoring the competition. That said, it’s entirely possible that there will be valuable spinoffs from the kind of research that the prize is fostering, much as 19^th century anti-aging experiments using animal gland extracts led to hormone replacement therapy and tissue transplantation was stimulated by early 20^th century experiments in rejuvenation through grafting. 

Acronyms of Doom

When I was in medical school, U.S. hospitals were plagued by only one kind of “superbug” or antibiotic resistant bacteria. Methicillin-Resistant Staphylococcus Aureus, abbreviated as MRSA and pronounced “mursa,” was the Enemy and it had been around since the early 1960s. I remember the yellow precaution signs on the door of rooms housing patients infected with this organism and the ritual donning of a yellow gown and surgical gloves before entering those rooms. Staph colonizes the skin of healthy people; if it enters the body through a break in the skin it can cause a serious infection, and if the staph is resistant to what was previously the best drug for treating it, the patient can be in trouble.

Then in the late 1980s, along came another bad actor, Vancomycin-Resistant Enterococci (VRE). Enterococci normally inhabit the gastrointestinal tract; sometimes they escape and when they do, for example through fecal contamination of a wound, they can cause significant mischief. Enterococcal infections had come under control with the antibiotic vancomycin—until they developed resistance. Now, MRSA and VRE have been joined by a new threat: Carbapenem-Resistant Enterobacteriaceae (CRE). According to a study published this month, the rate of detection of this infection has jumped five-fold in 5 years. And the mortality from these infections ranges from 48% to 71%. The Centers for Disease Control and Prevention (CDC) in Atlanta took the extreme measure of classifying CRE as an urgent threat. Only 2 other organisms currently share this honor.

The newest superbug, like MRSA and VRE before it, is something that healthy people don’t normally contract. Its victims are patients in nursing homes and hospitals, especially people who are connected to a medical device such as a ventilator or a catheter (whether urinary or intravenous). Debilitated older people are at particularly high risk. The CDC offers a 4-prong strategy for attacking the problem (preventing infection in the first place, tracking resistant organisms, improving the use of today’s antibiotics, and promoting the development of new antibiotics). I suggest an additional strategy that is rarely discussed: keeping frail, old people out of the hospital altogether.

From the time that the hazards of hospitalization were first recognized 50 years ago, the main way doctors have proposed dealing with them is to try to make hospitals safer. Old people become confused in the hospital? Don’t give them sedating medicines that make them confused. Old people fall in the hospital? Use bed alarms and chair alarms to alert nurses that they are getting up. These tactics and others can be helpful, but they don’t eliminate the dangers of the hospital and some interventions, such as side-rails on hospital beds, increase rather than decrease risk. Similarly, our first impulse as we try to control superbugs such as CRE is to reach for the precaution gowns to keep nurses and doctors from spreading the germs. Because antibiotic resistant bacteria are so great a problem, we need to respond with a multi-prong strategy. So yes, educating physicians to use antibiotics judiciously (preventing the development of resistance in the first place) and encouraging pharmaceutical companies to design new effective antibiotics are important. But let’s not forget that in most cases, the patient would not have gotten the infection if he or she hadn’t been in the hospital—these are generally hospital-acquired infections, not the reason for the hospitalization. Sometimes, frail old patients can be treated satisfactorily outside the hospital. Finding an alternative to hospital care is a way to avoid a growing list of “adverse reactions to hospitalization,” including delirium (acute confusion), incontinence, falls, and all those acronyms spelling doom, MRSA, VRE, and now CRE.