However, once reports started coming in from Mexico, worldwide epidemiological networks, and public health agencies in this country (the CDC for example), as well as the WHO started getting a handle on it, and quickly framed the outbreak as potentially alarming because in previous pandemics, influenza viruses had taken at least 6 months to spread as widely as the H1N1 influenza has done in 6 weeks. After much political wrangling from member states, the WHO declared a pandemic level 6 from level 5 on June 11, 2009. Phase 6 is characterized by sustained human-to-human transmission caused by community-level outbreaks in at least 1 country in 2 WHO regions (besides Central and North America, the other region was Europe.

As of June 11, 28,119 laboratory-confirmed cases, including 144 deaths, had been reported to the WHO from Canada (4), Chile (2), Costa Rica (1), the Dominican Republic (1), Mexico (108), Colombia (1) and the United States (27). Although 74 countries in 5 WHO regions have been affected, approximately 90 percent of reported cases have occurred in the Americas.

The H1N1 swine flu is called such because the majority of the RNA in the current strain has been shown to come from swine flu H1N1 viruses. Although we lack detailed data (surveillance in pigs in the last 10 years has been minimal) we can say with some degree of certainty that late last year or in early 2009, swine flu jumped from a pig to a human. This probably occurred in the U.S. or Canada although we will never know for sure. The presumed index case then infected another human and at some point someone in Mexico was infected, and perhaps the R0 increased suddenly; and so it began. Although the media frenzy suggested that the outbreak began in a pig farm in Mexico, and that a boy was the index case, this has been discounted.

Transmission
What made the spread of this pandemic happen so quickly was international travel, in which cases from Mexico and the USA seeded urban centers in other countries, and caused local outbreaks to quickly spread due to high intensity transmission (what we call a high R0, the basic reproduction number). Basically, R0 is defined as the number of people infected by one individual with the disease (the technical definition is more precise, but the basic definition suffices for our purposes). Early estimates of R0 varied from 1.2 to 1.6, but more recent models have placed the value around 2-2.4, compatible with the estimates of the 1918 influenza pandemic. One of the drivers for the high number is probably the explosive outbreaks observed in schools, and some studies have suggested that initial “overreaction” in shutting down many schools actually might have mitigated the transmission dynamics in some urban areas.

Clinical attack rates (CAR; percentage of the population that is infected—symptomatic or assymptomatic) for seasonal flu range from 5% to 15%, whereas CAR for the H1N1 has been estimated at 22%-33%, which suggests that transmission dynamics for the H1N1 strain are more aggressive compared to seasonal flu.

Lesson learned #1: although perceived as overreaction in many instances, shutting down schools for periods of time in affected areas appears to be worthwhile.

Age group affected
Seasonal flu tends to affect older adults (> 50 years of age) as well as the very young. In contrast, the 1918 pandemic had a W-shaped profile in regard to age (and mortality), meaning that children, healthy adults (20-40 years) and the elderly (60-65 years +) were most affected. In the current pandemic, most cases in all countries have occurred among adolescents and young adults. Males and females are similarly affected. (Data compiled by the WHO from Chile, countries of the European Union and the European Free Trade Association, Japan, Panama, and Mexico indicate that approximately 25% of cases were aged 0-9 years, 36% were aged 10-19 years, 17%were aged 20-29 years, 9% were
aged 30-39 years, 7% were aged 40-49 years, and 5% were aged greater than 50 years.)

At this stage we don’t truly know whether this strain of H1N1 has a predilection for children and adolescents, or whether we have some bias in terms of case reporting in regard of age. If the former is true, it would mean that the younger population is immunologically naïve, and older people have some resistance to the strain because of immunological cross-reactivity from exposure to other H1N1 strains.

Morbidity and mortality
The course of most cases has generally been mild, no worse that seasonal influenza. The duration of onset and resolution of fever has been 1-8 days (median, 3 days). Nevertheless, there have been some substantial numbers of hospitalizations. For example, the New York City Department of Health and Mental Hygiene reported 567 hospital admissions and 16 deaths. The hospitalized patients in this geographic area have been typically younger than those seen during seasonal influenza outbreaks; approximately 79% of patients were aged < 50 years; 46% < 18 years and 20% < 5 years; only 5% of hospitalized cases were aged > 65 years.

Due to the lack of clinical data (we hope to see many papers published in the next 2-3 months), we are not sure whether the severity of illness and the majority of deaths are attributable to underlying risks or diseases (what we term comorbidities), which is the typical situation in seasonal flu, or whether we are seeing violent reaction in immunologically naive populations. Anecdotally, many ER physicians have reported that only perhaps a third of all comorbidity and mortality is responsible for the severity of cases and deaths.

Many health centers in the U.S. were overwhelmed in April and May with individuals asking to be treated for flu. This was easily predictable. Had the numbers been twice as high, many hospitals would have been hard pressed to operate normally even if the mortality rate had stayed the same.

We lacked early accurate data regarding the clinical picture and how health centers in different countries were coping with the epidemic. However, it was clear from news media reports that the public did not understand that going to the ER or health care facility was a waste of time unless the individual was showing severe symptoms of the disease (i.e., severe respiratory symptoms, dehydration, fever, etc.). This is understandable; families want to know they are okay, and getting the best treatment. But because there is no truly effective treatment for influenza (antiviral drugs have to be administered within 48 hours to be effective, and even then can only mitigate the course of the disease), the treatment is largely supportive, and so going to a heath care facility for a mild case of influenza is not a good idea.

Lesson learned #2: Widespread multimedia campaigns must be instituted early to educate the public in regard to visiting health care facilities.

Health care facility issues
Although we have few studies on the subject, one report indicated that few health care workers were infected directly from patients. This is good news. At the same time, it was demonstrated that some health care facilities were lax in infection control. Of course, had the CFR been much worse, perhaps better precautions might have been taken. (CFR = case fatality ratio: number of individuals whose death is attributable to influenza/number of individuals infected.)

We are also lacking data on how many health care facilities actually implemented a prior influenza or biopreparedness plan, including triage. There were some suggestions that in the busiest ERs this occurred, but nationwide, we don’t know the whole story. This is a gray area because we don’t know if such plans weren’t activated because the CFR wasn’t any worse than seasonal flu.

Lesson learned #3: Many health care facilities are still too lax in regard to infection control, and some lack sufficient equipment protection for health care workers. Better procedures would also improve nosocomial infection rates of other diseases, too, so there are other benefits to be gained besides influenza-related issues.

Ongoing issues
Because the epidemic started in Central and North America and spread to Europe before further spreading to Asia and the southern hemisphere, containment strategies are still in operation in Australia and Asia, particularly China. What does containment mean? Typically travelers suspected of having H1N1, or unlucky travelers who are deemed to have been too close to individuals suspected of having been infected are quarantined. If you’ve read the headlines, you will have heard of many distressing stories of families being separated and quarantined in dingy hotel rooms. This practice must stop. At this stage of the pandemic, containment is an absolute waste of time, and only hurts individuals. There are plenty of studies showing the futility of quarantine or containment in regard to influenza. My advice? Unless you have an emergency, avoid travel to Hong Kong, China, or Australia.

Lesson learned #4: Containment strategies are futile. Education of public health authorities in countries in which this obnoxious practice continues to take place should be a priority for the WHO. Travel advisories to these countries should be mandatory; perhaps less tourism will wake these morons up.

The Future
There are 3 possible scenarios. First, the pandemic could peter out this summer and then disappear into the “background noise” of seasonal flu. Second, the pandemic could intensify over the summer in the southern hemisphere and continue in the northern hemisphere. This would probably make it equivalent to the 1968-69 influenza pandemic. Third, this H1N1 strain to could reassort with other strains or mutate. If it reassorted with H7N7 or H5N1 strains we could be in for some serious trouble and might expect a second much more lethal wave late this fall or winter (in the northern hemisphere). My bet is on scenario number 2 although the probability for scenario number 3 is not vanishingly small (maybe 5-10%).

Time will tell where we are going; we have much better surveillance apparatus in place compared to earlier years, and it is likely that trends will become quickly known.

I had refrained from completing this last part of our series on health care until the presidential candidates became known and their positions on health care elaborated. As it turns out, they are not as radical as I thought they might be.

Most western countries have a mix of socialized medicine and private health care, although the mix varies considerably. For example, the UK, Germany, France, and Sweden have mostly socialized systems with some private health care plans on the side; in the USA it is mostly private health care until one reaches the age of 65, when individuals become eligible for the government-run Medicare.

Although in the United States there seems an aversion to government-run systems, most socialized health care runs remarkably well. There are the usual gripes about waiting lists, particularly for elective operations, but most studies show that people get what they want 90% of the time within 6 months. So, most of the horror stories are myths propagated by folks who have a vested interest in maintaining the status quo.

Senator McCain offers tax credits ($5,000 for a family; $2,500 for individuals) for existing health plans, plus a lot of legislation aimed at ensuring that the uninsurable have access to health plans. Much of what he has to say makes good sense, but it’s not enough to make a large impact.

Senator Obama would offer some of what McCain has proposed, but says additionally “Individuals and families who do not qualify for Medicaid or SCHIP but still need financial assistance will receive an income-related federal subsidy to buy into the new public plan or purchase a private health care plan.” I’m guessing here that you will have to try and get Medicaid first, but we’ll see. He proposes lots of federally based plans and will make coverage of children mandatory.

Neither of these gentlemen are really providing radical approaches to health care. A lot of what they propose are steps in the right direction; however, they don’t go to the root of the problem. Any country that has a decent health care system has to provide a lot of money to support it, and in the end, resources are always finite, which means making tough decisions. In my opinion, we need to start from scratch.

Everyone needs affordable health care according to his or her ability to pay. That essentially means that rich folks subsidize poor folks. A socialized medical system means we finance it from wage earnings, and if you can’t earn for any reason, the government will pay for it. In our case that means paying a lot more from our wages into some kind of national health fund—like Medicare, but applicable to all. After that, if you still want private health insurance, it will be up to you. I very much doubt that this will happen in the USA because private health care has too much vested in its operations. But of one thing I’m sure: if we keep going the way we are the percentage of uninsured will keep going up and the cost to the insured will skyrocket. Eventually only millionaires will be able to afford health care and by that time the system will have collapsed. It’s your choice people; we can start really making a difference or we can keep struggling the way we are and pass the buck to our children and grandchildren. I know which one my money’s on.

In the year 2000, the World Health Organization ranked the United States 38th in regard to overall health care (World Health Report 2000). Whiners predictably said it was because the WHO does not like private health insurance. Yes, that’s part of the problem. Today an estimated 50 million individuals in the United States don’t have any kind of health insurance, and that rate is growing at 2 million per year, with health premiums and costs rising at 7% per year. But that doesn’t count the 15-30 million persons who are underinsured. That problem has been stated another way: 29% of people who have health insurance are not covered for catastrophic events, drugs, or even going to see a physician when they are sick.  Health costs have risen so much that they would be at the top of list for bankruptcy filings were subprime mortgages not also in crisis. At this rate within 10-20 years, the system is likely to collapse because the few people left who still might be able to afford insurance then will be in effect subsidizing the rest of us who can’t; moreover the rest of us will be so sick that by the time we arrive in the hospital we will need 10 times more work than had we been able to afford a physician visit in the first place. 

How did things get so bad? There are 4 pieces to this puzzle: evidence-based medicine; cost-effectiveness studies; infrastructure (electronic health records, etc); and health care funding. In part I of this series, we start by looking at the contributions of evidence-based medicine (EBM). 

What is EBM? Crudely, it defines what treatments and screenings work in medicine, and how well they work. More scientifically, it attempts to “rate the evidence” concerning a given procedure or treatment in series of scales using a hierarchy of different types of clinical trials or studies. The “gold standard” has always been the randomized controlled trial (RCT). In its simplest form, in this type of study, one group of patients is randomly allocated to the control drug, treatment, or procedure—whatever that may be, while the other group is allocated top to the experimental drug, treatment, or procedure. In the best design, neither the patient nor the physicians involved in the study know which group they are in. This type of design is called “double blind.” The results are then clinically and statistically analyzed by other persons not involved in the trial itself. 

Many factors also impact how well the results of the RCT are rated. For example, small numbers (typically < 20 in either group) make it harder to detect a difference in effects between the 2 groups, what we call the “effect size.” When patients or physicians know which group they are in or treating, this lack of masking or blinding can affect the outcome through a process that is termed bias. Finally, if the trial populations are not representative of more general populations, then the results of the RCT will not be applicable to more general populations. Until fairly recently, this issue was largely ignored, but is increasingly being raised as a problem. For example, if the exclusion criteria include a long list of diseases or clinical problems--hat are termed “comorbidities”--then you can imagine we will not know whether those individuals will benefit from the trial, regardless of the results. The quality of RCTs reported in the medical literature has always varied considerably. To make up for small-number RCTs, the results are often pooled in a study called a meta-analysis, which is conducted (hopefully) by investigators with no conflicts of interest. But, as many people know, the results of many of these trials have often sparked intense debate. Why? 

As we pointed out in a previous posting on statins, millions of dollars are often spent on trials with little chance of success. It’s their money you might say, so why should we be concerned? That may be so, but you’re going to pay for the results one way or another if you end up with a prescription for the drug that was tested. And those drugs can be very expensive. I’m not saying that all drug trials are like that; many are worth it, but we need to be far more selective in what trials are funded. For now, we won’t discuss problems with how RCTs are rated, but concentrate on the application of the results. Let’s use a simple treatment as an example. If you are diagnosed with a venous ulcer, the most effective treatment we know is to apply compression using a multilayer bandage. There are some contraindications to compression, primarily whether you have peripheral arterial disease, and usually a quick screening is done to know if you have that problem, too. (The test is called the ABI, and it is a ratio of the blood pressure measured at the ankle to the blood pressure at the wrist–technically the brachial artery.) So if you are diagnosed with a venous ulcer, and go visit your doctor, you would assume that 100% of the time you would be immediately prescribed compression treatment if the ABI is okay, right? Unfortunately, that’s not always the case. These were a few of the conclusions of a Canadian study carried out on venous ulcers: 

“During 1 month, 107 physicians reported having 226 patients with leg ulcers; only a few patients had had ultrasound assessment. Few physicians (16%) were confident about managing leg ulcers; 61% reported not knowing enough about wound-care products. More than 50% were unaware that compression is effective treatment for venous ulcers. Problems reported were lack of evidence-based clinical practice guidelines for leg ulcer care (82%); absence of evidence-based protocols in home-care agencies (72%); lack of access to wound-care products (69%) and wound-care centres (66%); and poor communication among health care workers (60%).” This and many other studies show that our overworked physicians don’t always know what to do. So what is the answer? 

Evidence-based clinical practice guidelines (CPGs) were developed precisely to help educate physicians and medical specialists. They started emerging in the mid nineties and have been growing more prolific every day, as one can see on the Agency for Healthcare Research and Quality (AHRQ) web pages. The problem is that not all health-care personnel are aware of them, although this number is generally rising. The other issue is that many treatments and practices have not been tested with RCTs or other kinds of clinical trials, and until they are, these treatments will remain unverified at best.  Medicare is getting in on the act too, and has a number of P4P (pay for performance) programs that are aimed at health-care providers. Essentially these programs, if they are all implemented nationwide, will force providers to comply with CPGs or lose payments; health-care providers that do well will be rewarded for their effort. How much money Medicare’s approach will save in the long run is unknown, and there are a lot of wrinkles to iron out, but it’s a good start even if it’s not perfect, because patients will get better more scientifically based treatment. The application of evidence-based medicine does promise to save lives, and help ensure that patients get the best treatment, but the major factor missing is how cost-effective treatments are. This is the subject of Part II. 

With the publication recently in BusinessWeek exploding the story about Vytorin, it is time to examine the role of statins, cholesterol, and heart disease. The results of the new drug trial, termed the ENHANCE study, which tested a combination of Zetia (ezetimibe), manufactured by Schering Plough and Merck, and Zocor (simivastatin), manufactured by Merck, were scheduled to be published in early 2007, but this was delayed. A press release on January 14, 2008 indicated that there was no benefit to be derived from the combination. Indeed, the randomized controlled trial, which randomly allocated either Vytorin (10/80 mg) or Zocor (80 mg) to 720 patients that had heterozygous familial hypercholesterolemia–a rare condition present in about 0.2% of the population–and measured the intima-media thickness (arterial wall thickness) at 3 sites in the carotid arteries of patients found that wall buildup increased by 0.0111 mm for the Vytorin-treated group, nearly twice of that of the Zocor-treated group (0.0058 mm). These results were not statistically significant, meaning that the probability of the difference happened by chance. (In statistics, we often use a probability of .05 as the minimum evidence that two results in a trial did not occur by chance, but were due to some effect.) The full results of the enhance study will be presented at the American College of Cardiology meeting in March, but probably won’t be published in a medical journal until the end of the year. Meanwhile, more trials of Vytorin are planned. I guess the drug companies are happy to spend your money on worthless trials, because they have invested so much time, money, and effort in them. So, are statins a complete waste of time and money? This depends in part on whether you believe the cholesterol “hoax.” Why do I say hoax? All the statins were developed on the principle that high cholesterol—specifically, low density, also know as “bad” cholesterol—is one of the major causes of heart disease. If you believe this, then we might as well believe the tooth fairy is real. Start by reading Anthony Colpo’s article about the myth of bad cholesterol published in Journal of American Physicians & Surgeons. If you want more evidence, go read the article by Krumholz et al. published in JAMA in 1994. (And if that doesn’t satisfy you, write me an email and I’ll send you a bunch more references.)  But, let’s pretend for the sake of argument that lowering cholesterol has some merit, and your physician, who has been liberally supplied with both samples and literature, checks your cholesterol and finds it’s high. You take a statin and deal with the side effects, the muscle pains, and so forth, and the increased risk of cancer (your doctor surely knew about that, and told you, didn’t he/she?) and wait for the drug to work. A few months later, your cholesterol comes down. Problem over, right? Wrong! Statins do lower cholesterol, but except in 1% of cases, they won’t stop you from getting a heart attack. How do we know that? Because of something called the NNT. The NNT, or number needed to treat is a parameter that is not often quoted in many drug trials, although it should be. It is basically the mean or average number of patients that have to be treated to in order to have 1 additional event happen. So, if you treated patients with an antibiotic for some infection, and the event was “cure,” and the NNT was 2, then that would mean that for every 2 patients treated, 1 would be cured of the infection. That’s a pretty good number. What’s a typical number for a statin? It’s about a 100 in regard to the mortality of coronary heart disease (see Table 2, statins). So for every 100 patients, we might expect 1 person to benefit. One! And this number does not take into account the number of people in that group of 100 who might be harmed by the drug, which is the number needed to harm.  Statins do actually have some interesting anti-inflammatory properties and have even been proposed as treatments or prophylactics in avian influenza (H5N1). But that’s another story.  So, what’s my advice? Unless you already have severe coronary heart disease, and actually might be a candidate for statin treatment, ignore the cholesterol mantra and stay away from statins. If your physician insists that your cholesterol is high and needs statin treatment, ask him or her to read some of the literature we have cited. See if your doctor understands about the NNT parameter. In terms of heading off cardiovascular disease, you are far better off leading a healthy lifestyle (no stress, now!) and eating a balanced diet free from processed foods. Consider taking supplements of unadulterated omega-6 and omega-3 cold-pressed oils in about a 2.5 or 3:1 ratio.    

Marissa J. Carter, PhD