Pfizer in Practice

This week brought a medical article worth discussing: the New England Journal of Medicine published the results of a study of the efficacy of the Pfizer SARS-CoV-2 vaccine in the real world. The article provides compelling evidence that the vaccine works extremely well.

The data come from Israel, which has been doing a superior job of vaccinating its citizens. As of a week ago, two-thirds of the currently eligible population in Israel had gotten both of the recommended doses (individuals under age 16 and those who have had Covid-19 are not eligible). In Israel, health insurance is mandatory for all permanent residents; they must join one of four healthcare organizations called “funds.” The new study reports data from Israel’s largest health organization (Clalit Health Services) and includes information on a stunning 1.2 million people.

The study’s authors, led by Dr. Noa Dagan, used Clalit's integrated electronic medical record to capture health data for 596,618 people who received both doses of the Pfizer vaccine between December 20, 2020 and February 1, 2021. They then matched them, based on demographic and clinical characteristics, with another group of identical size who had not received any vaccine. Next, they looked at five different outcomes: documented Covid-19 infection; symptomatic Covid-19 infection, Covid-related hospitalization, Covid-related severe illness, and Covid-related deaths. Because the sample was so large, they were also able to collect extensive information about a number of interesting subgroups defined by age or specific co-existing health conditions such as cancer or diabetes.

The article includes an enormous amount of intriguing data. The most exciting results, from my perspective, address outcomes a week or more after receiving the second dose of the vaccine. At that point, the vaccine conferred 94% protection against symptomatic Covid-19 (95 percent confidence interval 87-98), 87 percent protection against Covid-related hospitalization (CI 55-100), and 92 percent protection against severe Covid (CI 70-100).  The efficacy in people over 70 was identical to those in younger individuals, and the rate in people with one chronic health condition such as diabetes was only slightly lower than in people without the condition. 

These numbers strongly resemble the results that Pfizer and BioNTech reported to the FDA in their application for emergency approval.  But, as the study authors point out, Pfizer drew its conclusions based on 44,000 people; the Israeli study is based on 1.2 million people. As a result, when Pfizer calculated the efficacy against severe Covid-19, they drew on a total of 10 cases (one of whom had been vaccinated and 9 of whom had not been); when the Israelis calculated the risk of severe Covid, their estimate was based on 229 cases, vastly increasing the credibility and certainty of the calculation. Moreover, Pfizer’s data was based on the somewhat artificial conditions of a clinical trial: for example, the subjects were all highly motivated to optimize their health and may have regularly worn masks and practiced social distancing; the Israeli study drew on real life experience, in which participants’ behavior reflected community norms.

The new study, like all studies, has its limitations. It excluded people living in nursing homes and medical personnel working on Covid units in the country’s hospitals, arguing that the rate of the disease in their particular communities, i.e. the nursing home or the Covid ward, was highly atypical. The study was performed during a period when the South African variant was very rare in Israel so we cannot draw conclusions about the efficacy of the vaccine against this strain. The information on the ability of the vaccine to prevent Covid-related deaths is limited because of the short follow-up period: there were nine Covid deaths in the fully vaccinated and 32 deaths in the unvaccinated group, but these numbers might change when more time elapses. The data on deaths may also be difficult to generalize as Israel has an unusually low case fatality ratio: in Israel, according to Johns Hopkins' "Our World in Data," is currently 0.7 percent whereas in the U.S. it is 1.8 percent.

Some of the study’s greatest strengths are also potential weaknesses: the “real world” nature of the investigation means it is an observational study rather than a randomized controlled trial, raising the possibility that the differences in outcomes between the vaccinated and the unvaccinated were related to some factor other than their vaccination status. Despite these limitations, the study provides very encouraging information.

The fact that the Israelis could carry out their study sends another message over and beyond the efficacy of the Pfizer BioNTech vaccine. The study could only be conducted because Israel did a good job acquiring and distributing vaccine. Early on, the country developed mass vaccination sites. Since everyone is enrolled in a health plan and the plans all have electronic records, there was no need to waste as much time on bureaucracy as we do in the U.S, where more time is spent filling out forms than on administering the shot. The study could only be conducted because of Israel’s electronic health records, which assured that information about who got what dose when, and the age, sex, and chronic medical conditions of each individual was digitally recorded. Finally, the entire rollout was centrally coordinated, assuring efficiency and consistency: from the outset of the pandemic, the Israeli Ministry of Health collected Covid-related data from all four health plans, negotiated to purchase vaccine from Pfizer, and organized distribution. The good news reported in the NEJM article is a result both of the biological properties of an mRNA vaccine that was designed in record time to deal with an international health crisis of enormous proportions, and of the characteristics of a health care delivery system that can actually deliver.

The Next Big One

              As new cases of Covid-19 fall throughout the world but the US approaches 500,000 deaths from Covid-19 and the world nears 2.5 million deaths, it is time to start planning for the next pandemic. 

               We have known since the 1918 influenza pandemic, which killed upwards of 50 million people world-wide, that it’s not a question of if, but rather of when. Moreover, recent decades have seen the emergence of several new and terrifying diseases. These diseases have principally been caused by viruses, viruses that jumped species. They moved from their usual host, say a civet or a bat, into people for one of several reasons: climate change may have destroyed their hosts’ usual habitat, forcing them to find a new home where they came into greater contact with humans; alternatively, humans encroached on the hosts’ habitat by clearing forest or planting a crop that deprived the host of its usual food source, again leading the host to relocate; or humans may have developed a taste for certain types of wild animal, bringing the two species into unaccustomed contact and thus facilitating viral transmission.

              As a result of these factors, we have had Zika, SARS, MERS, avian influenza and now Covid-19 in the twenty-first century, and Ebola, Marburg hemorrhagic fever, and HIV in the last part of the twentieth century. These are only the best-known of “zoonoses.” Today, 75 percent of new infectious diseases are zoonotic in origin and their numbers have been rising steadily. 

            The good news is that we know a great deal about how to go about preventing outbreaks, detecting them early, and responding if they nonetheless occur. The bad news is that the world in general and the U.S. in particular have a poor track record of implementing the necessary strategies. Allocating scarce resources now to help alleviate problems that will develop at some unspecified time in the future has proved to be a hard sell. 

                The irony is that we in the U.S., as in many other countries, spend an enormous amount of money on our military. We have accepted the need to devote a large fraction of our budget to the armed forces and to equipment including both “conventional” and nuclear weapons. We have not yet acknowledged that the far greater threat to our national security and our well-being is from lowly viruses, strange biological entities that are not strictly speaking alive since they cannot survive outside a host organism, not from invading armies. 

            The current US budget consists of just under $3 trillion on “mandatory spending,” which includes Social Security, Medicare, and Medicaid; and another nearly $1.5 trillion on “discretionary spending,” over half of which is for military spending, including the VA and Homeland Security as well as the armed forces. The base budget for the Department of Defense is $636 billion.

             By comparison, the CDC (Centers for Disease Control), the site for most of the U.S. epidemic preparedness activities, has a total budget of $6.6 billion, of which $509 million is allocated to “Emerging and Zoonotic Infectious Diseases.” Other disaster preparedness activities are financed through various departments, including Homeland Security, which is part of the military. But as a very rough approximation, it is not far-fetched to say that the core budget for potential epidemics is $509 million compared to the core budget for the military of $636 billion, or .08 percent.  This comparison reveals an enormous imbalance between spending on the military and on epidemic preparedness, with too much to fight armed invasions and not nearly enough to combat microbial enemies.

            If we are to spend more on epidemics—and, arguably, less on bombs and fighter planes—what should we spend it on? A basic framework was outlined at a symposium called “Building Interdisciplinary Bridges to Health in a Globalized World,” organized by the Wildlife Conservation Society in 2004. The symposium called for an international, interdisciplinary approach to preventing disease, or “One Health, One World.” It articulated its views in a document called the Manhattan Principles which laid the foundation for what would become an international movement. The Manhattan Principles is built on  the recognition that modern epidemics stem from the inter-connections between humans, domestic animals, and wildlife, and that these interactions arise either directly from human behavior (eg agricultural practices, clear cutting forests, and eating wildlife), or indirectly, mediated by climate change that is in turn due to human behavior. Since the problem is fundamentally multidisciplinary, its solution must likewise be multidisciplinary. And since the modern world is interconnected, the solution must be international, involving sharing information.

            An implementation framework was drawn up in 2008 by a group consisting of representatives from UNICEF, WHO, the World Bank among others. Entitled “A Strategic Framework for Reducing Risks of Infectious Diseases at the Animal-Human-Ecosystems Interface,” it argued for the development of an international system of disease surveillance drawing on multidisciplinary expertise (to include veterinarians, physicians, wildlife specialists, and ecologists). In addition, it sought to help build robust public health systems across the globe and to promote good communication between those systems. Finally, it advocated support for strategic research, to be shared internationally. 

            The One Health approach was adopted by the CDC in 2009, which housed it within its National Center for Emerging and Zoonotic Infectious Diseases. It was formally endorsed by the UN, the World Bank, and the EU in 2010. More recently, the World Bank came up with a revised operational framework to fight EIDS as a means of fulfilling its mission to promote prosperity and decrease poverty.

            Our response to future epidemics, when they occur, will hinge on more than international and multidisciplinary collaboration. Scientific developments are likely to have a major impact when future EIDs arise. The new technique of vaccine design using mRNA is vastly accelerating the development of effective vaccines, the most powerful preventive tool available. Work on anti-viral medications is ongoing and could revolutionize treatment of viral diseases much as antibiotics revolutionized the treatment of bacterial diseases. Currently, the only virus for which there is effective treatment is HIV, and that treatment (which took years to develop) involves a multi-drug regimen that converts HIV into a chronic disease but rarely eradicating the infection. 

            We also need to strengthen the public health infrastructure in the U.S. Poor coordination, insufficient manpower, and inadequate communication to the public have afflicted domestic public health departments for years. WHO and the World Bank have focused on shoring up public health in much of the world but assumed that the richest countries would serve as models of success. 

            The One World framework could itself be expanded to address climate and the environment more expansively, but the basic formulation is sound. As Andrew Cunningham, Peter Daszak, and James Wood argue in their 2017 article, “One Health: Emerging Infectious Diseases and Wildlife: Two Decades of Progress?” little has been done at the policy level to address what remain major threats to health and well-being, as Covid-19 attests. It’s time to adjust our national priorities and focus on what counts. 

 

 

Vaccine Mania

Last Monday, the public woke to the news that the COVID-19 vaccine developed by Pfizer and BioNTech, which has been undergoing testing since the end of July, appears to be working. That is very good news for older people, who have been hardest hit by the coronavirus epidemic, as well as for the younger population, which is bearing the brunt of the current surge in cases. And the news is very timely, as the cumulative number of cases in the U.S. is now over 11 million, with the number of new cases every day higher than ever before. But what, exactly, do we know about how effective this vaccine is likely to be?

The statistic that is cited in the news reports is that to date, the vaccine is 90 percent effective. What that means is that among the 94 people enrolled in the Pfizer/BioNTech study who were diagnosed with symptomatic infection, only 10 percent or about 9 people had received the vaccine; the other 90 percent or about 85 people had been given placebo. This is very encouraging, since the clinical trial enrolled 44,000 volunteers, half of whom received active vaccine and half of whom received placebo: it is very unlikely that such a large differential could have happened by chance. On the other hand, there’s much we don’t know.

We don’t know, for instance, whether the 90 percent effectiveness rate will hold up in all age groups. The study population does include older individuals—the plan was to try to ensure that 40 percent of those enrolled would be over age 55, though it’s unclear what percent would be in the highest risk group, those in their 80s and older. But we don’t know anything about the age or other risk factors of the 94 people who were diagnosed with coronavirus. Since older people todare being far more risk averse on average than their younger counterparts, it’s possible that none of the 94 people with infection identified so far are older adults.

We also don’t know whether the vaccine protects people against developing asymptomatic infection. From a clinical perspective, it’s more important to know whether the vaccine prevents people from developing symptoms, but from a public health perspective, we would like to know whether the vaccine keeps the virus at bay just enough so they remain asymptomatic but not enough to prevent them from transmitting the disease to others. Since asymptomatic transmission accounts for many cases today, it would be desirable to know whether the vaccine allows people to become asymptomatic carriers. We are not going to know the answer to that question as the study protocol does not call for enrollees to be tested for COVID-19 unless they develop symptoms.

Finally, we don’t know how long immunity will last, assuming the promising early results are maintained when the study is completed, which will happen once 164 subjects have been diagnosed with COVID-19 (the pre-specified endpoint of the study). 

What does all this mean for everyone who is eagerly awaiting a vaccine to end this long period of isolation, anxiety, and loss? If the final data, when evaluated by the FDA, possibly by early December, do lead to approval and licensing of the vaccine, older people should be vaccinated as soon as possible—assuming the age-specific effectiveness holds up. 

How will life change after you have been vaccinated? First, it should be stressed that “being vaccinated” means receiving 2 injections, 3 weeks apart. The vaccine effectiveness is being measured starting one week after receipt of the second dose, so you cannot expect protection until one month after your first shot—and you should be sure to get both shots. Second, while 90 percent effectiveness is pretty good, it’s not perfect. No vaccine is perfect, so don’t wait around for a better one. While you will face a much smaller risk of becoming sick with Covid-19 if you have been vaccinated than if you have not been, how likely you are to encounter the virus will depend on how widespread it is in the surrounding community. If, to take the extreme but unfortunately not entirely improbable case in which the rate of infection in the community goes up ten-fold, then if your risk by virtue of vaccination goes down ten-fold, the net improvement is zero. Of course, if the rate in the community goes up by a factor of ten and you haven’t been vaccinated, your risk also goes up by a factor of ten. In short, you are much better off with the vaccine than without it, but how much better off you will be will be determined by what is going on around you.

So, yes, there is good news about vaccines and yes, you should get the shots as soon as they are available, assuming the early results are confirmed and apply to older people. But don’t throw out your masks and don’t expect to go to movies and concerts or other large indoor gatherings just yet.

As I prepare to publish this blog post, news is breaking about a second vaccine made by the pharmaceutical company Moderna in partnership with NIH. More to come about these results in my next post….

The Corona Century: Looking Backward, Looking Forward

For over, 50 years, epidemiologists had been expecting “the big one.” Like earthquakes in California, influenza epidemics have become an inevitable part of the landscape. From year to year, influenza mutates; every so often the strain is particularly virulent and it produces a world-wide pandemic, as happened in 1918 and, on a smaller scale, in 1957, 1968, and 2009. Every year, scientists scrutinize the prevailing type of influenza, anticipating that one day we will see the resurgence of a virus as virulent as the one that killed upwards of 50 million people in 1918-1919. Granted, we have vaccines today that prevent or attenuate many cases of the flu, we have antiviral medications with modest degree of efficacy against influenza, and we have sophisticated supportive respiratory treatments such as ventilators, none of which were available in 1918. As a result, any new influenza pandemic is unlikely to be as devastating as its counterpart 100 years ago—but nonetheless, could wreak havoc in our globalized world. So, it was very surprising when, in March, 2003, scientists in search of the causative agent of the newly described respiratory illness known as SARS (Severe Acute Respiratory Syndrome) peered through their electron microscope and discovered, not influenza, but corona virus.

Coronaviruses had first been identified in the 1960s; they were known to infect cattle, pigs, rodents and chickens; in humans, they were associated with about fifteen percent of colds, but not with any more illnesses. But there it was, with its characteristic crown-like ring of proteins—the agent responsible for the mysterious disease that had killed clusters of health care workers, families, and residents of an apartment complex, principally in China and Hong Kong.

Once the genetic identity of the virus had been established, the race was on to figure out where it came from. It was pretty clear that the virus had jumped species, making SARS a “zoonosis.” What species it came from was never definitively established, though palm civets and raccoon dogs sold in the wild meat markets of Guangdong province, China, to consumers eager for an “exotic” meal are the leading candidates. Growing evidence suggests that the true animal reservoir of the SARS virus (SARS-CoV-1) is the bat, with animals such as civets serving as an intermediary.

Due to good epidemiologic practice, the biology of SARS-CoV-1, and luck, SARS disappeared. The World Health Organization (WHO) announced the containment of the epidemic in early July, 2003, less than four months after it first issued an international alert about the dangers of the disease, and less than a year after it first appeared in China in November, 2002. A total of 8098 people developed the illness, of whom 774 died, or just under 10 percent.  All told, the virus appeared in 39 countries. Only China, Hong Kong, Singapore, and Canada had 50 or more cases each. The world breathed a sigh of relief; epidemic prevention programs were developed on paper—and shelved.

And then, in 2012, coronaviruses were back. Or rather, a new coronavirus made its debut: MERS-CoV (for Middle East Respiratory Syndrome). Originally found in Saudi Arabia, it soon travelled to the rest of the Middle East. And stayed there, with the only significant outbreak anywhere else in the world found in Korea in 2015 after the index case had travelled to the Middle East. Unlike SARS, MERS has never disappeared. It remains endemic in the Middle East, where it kills 35 percent of those it infects. Its animal reservoir is probably also a bat, but from bats it infects is camels, and from camels it reaches people. By limiting contact with camels and using case isolation and contact tracing, the total number of confirmed cases in the last eight years is only 2500. More lethal than its SARS-CoV-1 cousin, but less easily transmitted, MERS put coronavirus firmly on the map as a pathogen to be reckoned with, but a relatively minor one, compared to, say, the viruses causing Ebola or AIDS.

Until November, 2019, when yet another atypical pneumonia appeared in China, an illness that would prove to be caused by another coronavirus, this one dubbed SARS-CoV-2. The rest is history, although history that is still unfolding. As of October 30, 2020, according to WHO-COVID Dashboard, there have been a total of 44.59 million cases worldwide, with 1.18 million deaths.  In the US alone, there have been 8.83 million cases and 227,045 deaths. The pandemic is far from over, with the US reporting 81,599 new cases per day. This latest variant of the coronavirus has proved far more successful than its relatives: it seems to have found the ideal balance of transmissibility and lethality, which has enabled it to achieve far more extensive community spread than any previous coronavirus. COVID-19 (the name given to the disease caused by SARS-CoV-2) kills roughly 2.5 percent of those who are diagnosed with the condition, less than SARS (10 percent) and much less than MERS (35 percent), though in all three cases, the mortality is far higher in individuals over age 65. In addition, it ingeniously developed the ability to spread from asymptomatic hosts, allowing it to escape prompt detection and thus limiting the effectiveness of isolation to contain its spread.

Supported by governments and the WHO, several pharmaceutical companies along with university research labs are scrambling to produce a safe and effective vaccine. But with cases of COVID-19 continuing to rise in many parts of the world including the US and Europe, the prospects for an end to the pandemic any time soon are not good.  Several nations have reintroduced lockdowns: France just announced it would shut down from October 30 until December 1 and Germany declared a partial shutdown for roughly the same period. With the whole world suffering from pandemic fatigue—except, perhaps, Taiwan, which just celebrated its 200^th day in a row without a single locally transmitted COVID case—it’s hard to even think about life-after-COVID except in terms of “going back to normal.” Odds are that when the disease finally goes into retreat, we will breathe a collective sigh of relief and not want to think about viruses. But that would be a grave mistake.

The current century has already seen three coronavirus epidemics, each with a different variant of this wily microorganism. Most likely, all three normally live in bats and jumped from bats to non-flying mammals and from those mammals to humans. Coronaviruses are RNA viruses, known for their extraordinarily high mutation rates—as much as a million times higher than human mutation rates, which means they will continue to develop new variants. And these new variants will now and then develop the capacity to infect people, both because humans have encroached on the territory of animals with whom we previously had little contact and because global warming drives animals out of their traditional habitats and into new arenas that are occupied by humans. The really successful ones, like COVID-19, will be transmissible from asymptomatic individuals. They will have the ability to spread to other humans quickly, without or before killing their new human host. And then they will be spread by humans from person to person, from household to household, from country to country, from continent to continent.

In short, there is no reason to believe that even if we manage to kill or contain SARS-CoV-2, we will have seen the last of the coronaviruses. However appealing it will be to resume normal life, we must not let down our guard. We have to begin now to plan for the next outbreak. We must be sure to learn from our experiences. That means, first and foremost, taking basic preparedness measures such as stocking up on personal protective equipment. It means replenishing the supply of masks and gowns, even if we go for ten years without an epidemic, just in case. 

Planning for the future, as explained by public health lawyer Lawrence Gostin, entails investing in a robust public health system. Such a system must be able to institute traditional measures such as quarantine of those exposed to disease, isolation of cases, social distancing, and mask-wearing. We have to support scientific research so that new pathogens can be identified, tests developed, and treatments tested in a timely fashion. We must restore the FDA and the CDC to their former grandeur, two organizations that, until the current pandemic, were the envy of the world because of their sophistication, wisdom, and integrity. We have to engage in surveillance, constantly monitoring bats and other species for new diseases. 

We must recognize that we live in an interconnected world, which means collaborating with other researchers and laboratories across the globe, including those of China and of the World Health Organization. And when a new, disease-causing virus appears, we need to demand transparency from our leaders and our scientists: an informed public, armed with the tools of public health and the fruits of medical science, is crucial to combatting the threats that will inevitably appear. 

Lock 'em up!

            A provocative, contrarian position paper (somewhat ostentatiously and bizarrely entitled by its authors a “declaration”) is creating a stir by advocating “focused protection” as a means of dealing with the Covid-19 pandemic. The strategy of “focused protection” as defined by the 3 principal architects of the “declaration” recommends 3 different approaches for 3 different segments of the population: for those at highest risk of death from Covid-19, individuals over 85, they recommend a lockdown; for those at moderately elevated risk, including those who are “retired” (aka people over age 65), they advocate a “safer at home” policy—delivery of groceries and other essentials, and staying home  except for socially distanced outdoor visits with friends or family; for those under 65, they suggest a resumption of normal activities. This algorithm, they argue, would allow the development of herd immunity in the general population by assuring that roughly 70 percent of them be allowed to contract the virus, leading to the end of the pandemic.

            Scathing critiques of this proposal are appearing daily. They discuss issues such as the failure to take into account the burdens of Covid-19 short of death (for example, the long-term sequelae that have increasingly  been reported) and the ethical and practical problems of effectively locking up all older people who live in congregate housing of any kind, not to mention the ethical and practical problems of vastly restricting the activities of everyone over age 65 who doesn’t live in congregate housing. These are legitimate concerns. I’m going to add to the growing list of critics by focusing on two others: the ageism of the proposal and, what is more surprising, the failure to recognize that a rare event that afflicts a large number of people produces a commensurately large number of casualties.

            First, ageism.  The authors of the proposal never explicitly acknowledge that the total population over age 65 in the US is now over 53 million people. This number doesn’t include the millions of people who are in the high-risk category, who would also be locked down, who are under age 65 but have important underlying health conditions. The authors seem to imagine that the most vulnerable individuals, those over age 85, account for most of the excess deaths and that all of them live in nursing homes. In fact, only 4 percent of the elderly population live in nursing homes, or about 1.3 million people. The authors also seem to assume that limiting contact by older individuals with the rest of the world will prevent them from becoming infected; they have apparently forgotten that the effectiveness of sequestration depends on the prevalence of the disease in the surrounding community: if all the nursing assistants and grocery delivery people are allowed to get sick, then their chance of transmitting the virus, even with relatively limited contact, will go up.

             Perhaps the lead authors of the paper, all of whom are under age 60, assume that everyone age 65 or older is superannuated. They should be reminded that fully half of the members of the US Senate are over age 65, as of course is the current president and his challenger. Not only do many older people work (16.4 percent, or 8.69 million), but the 65+ set account for a disproportionate share of consumer spending. How will the rest of society be able to “go about their business” without older people to come to their restaurants, stores, and performance venues? And parenthetically, if the 8.69 million people over age 65 who are still working are exhorted to behave just like their younger counterparts, i.e. to “go about their business,” and even assuming that most of these individuals are 65-74 (though this is not strictly true—14 percent of senators, for example, are over age 75), then the projection is that about 152,000 of this group would also die of Covid-19).

            Second, a small number multiplied by a very large number can be a large number. Let’s look at the segment of the population among whom the “declaration” suggests the virus should run rampant. Americans aged 55-64, like their younger counterparts, are advised to go about  unfettered by regulations. As of 2019, this group included 42.44 million people. If herd immunity is to be achieved, an estimated 70 percent of them would have to contract Covid-19, or 32.68 million people. Now here’s the tricky part. We need to know what fraction of people in a given age group are likely to die from Covid-19. The number that is commonly cited is the case fatality rate, or the fraction of people with documented infections who die. But what we really want to know is the infection fatality rate (IFR), or the fraction of people who have contracted Covid-19, whether they know it or not, whether they are symptomatic or not, who actually die from the disease. Computing that rate depends on accurately determining the prevalence of Covid infection in a particular population and the death rate in that group. The best measure I have seen for the IFR for people age 65-74 is 2.5; the IFR for the 75-84-year-old group is 8.5; and the IFR for the 85+-year-olds is 28.3.

            But what about those who are 55-64? Their IFR is .75, so the authors of the “declaration” deem them safe. But if 32.68 million people in this age group contract Covid-19, and .75 percent of them die, then that means, by simple multiplication, that there will be 222,810 deaths in this group alone. A small number (.0075) times a large number (32.68 million) is a pretty big number when we’re talking about human lives. 

             For that matter, why stop with the 55-64-year-olds? Why not consider the 45-54-year-olds? They make up 40.88 million people. If 70 percent contract the virus (after which there should be herd immunity and the virus will vanish), that’s 28.16 million people. The IFR for this group is .068, which translates to 29,708 deaths. Is that acceptable?

            To determine what number of deaths is too many, some commentators have compared the numbers to flu deaths; others have compared them to automobile deaths. The fallacy is to assume that either you open society completely (to selected age cohorts) or you have a complete shut-down. That’s no more accurate than assuming that either people are allowed to drive cars and die in automobile accidents or they aren’t allowed to drive and no one dies. The reality for driving is that there are some mitigating steps we can take, such as seatbelt laws and speed limits on roads, which will significantly decrease the risk of death. In the case of Covid-19, mitigation means exactly what the majority of public health experts currently advocate: masks, social distancing, limiting the size of indoor gatherings, and substituting work at home for work in the office whenever possible. 

            When scientists band together to make an argument that is intended to influence public policy, they write a “position paper” or a “white paper” or an “open letter.” The “Great Barrington Declaration” reveals in its very name that it is something different. It is an ethical perspective masquerading as a technical brief. The authors claim their case for what to do in the setting of the pandemic arises logically from the data. In fact, their strategy, like all strategies for dealing with the outbreak, requires balancing personal freedom and the social good. The “declaration” implicitly assumes that the quality of life of older people is of no consequence and that a society has no special responsibility to its most vulnerable members. It dismisses the anticipated huge amount of death and disability among people under 65 by sleight of hand. Even if this policy could effectively be implemented—if allowing the virus to multiply unchecked would not overwhelm the health care system, causing people suffering from non-Covid conditions to suffer, if older people sheltering in place would remain uncontaminated as the disease becomes rampant in the workers who bring them their food and other services—this is not a policy that most Americans can endorse. The moral fiber of the American people may have been frayed in recent years, but it has not broken entirely.

Why Trump is Bad for Your Health

            For years, older people have been more likely to vote than have their younger counterparts: in the 2016 election, 71 percent of Americans age 65 and older voted, compared to only 46 percent of those ages 18-29. They are likely to exert a major effect on the election again in 2020, especially in those swing states with large older populations such as Florida, Pennsylvania, Michigan, and Wisconsin. 

            Four years ago, 53 percent of voters over age 65 voted for Donald Trump, compared to 44 percent for Hilary Clinton. Whatever these voters thought in 2016, older individuals today should know that Trump is bad for the elderly. He's especially bad for their health.

            Among the most explicit and egregious ways that Trump has adversely affected the health and health care of older Americans is his failure to lead the country effectively in the coronavirus era. His unwillingness to develop and implement a coherent national strategy and his refusal to accept the science underlying public health recommendations have contributed to the high incidence of COVID-19 and the correspondingly high death rate from the disease—and people over the age of 65 account for 80 percent of all COVID-19 deaths in the U.S. 

            In addition, the Trump administration has pursued a vigorous policy of seeking to privatize Medicare, the popular and successful source of health care insurance for the vast majority of older people. For example, Trump issued an executive order in October, 2019 entitled “Protecting and Improving Medicare for Our Nation’s Seniors” which, far from either protecting or improving Medicare, aims to bolster private Medicare Advantage plans (a popular choice for some well elderly) to the detriment of fee-for-service Medicare (the long-preferred option for frail older people) while dismantling safeguards on access and shifting costs to beneficiaries. 

            Then there are the more indirect effects of Trump’s policies on the health of our oldest citizens: dramatically curtailing immigration means cutting off the major source of personal care attendants and nursing aides. These are the people who take care of older individuals who need help bathing, dressing, feeding themselves, walking, and going to the bathroom—both in nursing homes and in their own homes. Deregulation is translating into more polluted air and water, worsening existing conditions such as emphysema and asthma. Rolling back steps to control climate change is contributing to relentless global warming, which is not some abstract future problem but a reality today—and it is frail older people who have suffered disproportionately from hyperthermia and death during the recent heat waves and from the fires that have been ravaging the western US.

            The future under Trump would bring new threats to the health of older Americans. The budget that Trump has proposed for 2021 would significantly cut Medicaid, the federal/state program that is the main funder of nursing homes, where 1.4 million dependent older people live. The budget would also cut SNAP (Supplemental Nutritional Assistance Program) benefits—the food stamps nd other nutritional support for millions of older adults. 

            Purely in terms of self-interest, older Americans should be terrified of four more years of Trump. And, as the NY Times argued two years ago, “senior power is the sleeping giant of American politics.” With the latest estimates from the US Department of the Census indicating that the 52 million Americans over age 65 comprise 16.5 percent of the population, gray power is here; it’s time to exercise it.

What's the Risk?

Nearly six months into the pandemic, we ought to know the important risk factors for serious illness or death from Covid-19. Whether because of poor record-keeping, lack of international cooperation, or sloppy statistical analysis, the information until now has been limited. 

Not just limited; the claims about risk factors to date have been quite misleading. I complained in my blog post in early May that the rates of certain conditions in patients dying of Covid-19 were actually no different from the rates of those same conditions in older people in general. For example, I noted that one study reported that the rate of high blood pressure in patients with severe cases of Covid-19 was 56.6 percent—but failed to comment that the rate of high blood pressure in the elderly population is 60 percent. Far from indicating that high blood pressure increases the likelihood of severe Covid-19 in older adults, this finding suggests that high blood pressure confers no extra risk or maybe is even protective. 

The only consistently observed risk factor for both severe illness and death has been older age, with age greater than 80 representing very high risk. Now, thanks to the existence of widespread, compatible electronic medical records in the British National Health Service (NHS), we have some useful data.

The study, published early on line in Nature Reviews, compares British patients who died of Covid-19 with all other British patients who are cared for in a group practice that used the necessary software (approximately one-third of the population). By using “a secure analytics platform inside the data centre of major electronic health records vendors, running across the full live linked pseudonymised electronic health records,” and after excluding people under age 18 and those with less than a year's worth of data, the investigators were able to collect health information on over 17 million individuals, including just under 11,000 with Covid-19 related deaths. The results confirm age as the single most potent risk factor, with a small number of other major risks.

To capture the most striking findings, I extracted data from the chart listing the hazard ratios (HRs) and 95% confidence intervals (CI) for Covid-19 death (Table 2) and present 3 separate tables: one highlighting very high-risk characteristics, one highlighting high-risk characteristics, and one showing characteristics associated with no or minimally increased risk. For added emphasis, I highlighted hazard ratios of greater than 3 in red and hazard ratios between 2 and 3 in blue.

Characteristics Associated with Covid-19 Deaths

The important difference between these charts and previous attempts at quantifying risk is that the hazard ratios reported have been age and sex-adjusted and have been further adjusted for other potential confounders along with age and sex.  

The conclusion from this analysis is that when we consider the age- and sex-adjusted hazard ratios, there are only four very high-risk conditions: old age, a hematologic malignancy diagnosed within the previous year, severe kidney impairment, and organ transplantation. Within the old age categorization, the hazard ratio goes from 8.62 to 38.29 as the age increases from 70-79 to 80 and older (the reference group is people aged 50-60). The only medical condition that comes close to this magnitude is organ transplantation, with a hazard ratio of 6. 

Another handful of conditions are in what I have classified as high-risk: obesity with a BMI of 40 or greater, poorly controlled diabetes, stroke or dementia, a hematologic malignancy diagnosed between 1 and 5 years earlier, liver disease, and other forms of immunosuppression. Incidentally, four out of six of these conditions drop out if we look at the “fully adjusted” column.

It’s worth noting some of the chronic conditions that were not associated with increased risk. High blood pressure, as I had previously suggested by comparing the rate in the very ill Covid-19 patients with the rate in the general older population, does not appear to be a risk factor. Mild to moderate asthma, defined in this study as someone with asthma who did not use oral steroids within the previous year, is also not a risk factor.

It’s also worth noting that the CDC has issued its own guidance about risk factors for Covid-19. Their conclusions, while overlapping with the NHS data, differ in important ways. Most important, their methodology differs. The CDC, lacking a domestic large, comprehensive data base, is forced to draw on evidence from small case series, cohort studies, and some meta-analyses, as well as a much earlier preliminary report from the NHS. The new NHS data, rigorously obtained and meticulously analyzed, should be seen as the gold standard.

When Will We Ever Learn?

Residents of long-term care facilities in the US have been hit harder by the COVID-19 pandemic than have any other group. They have almost all the known risk factors for becoming seriously ill with the disease: they are unambiguously old, with fully 41 percent over age 85, and almost all have one or more chronic diseases, generally multiple conditions that result in their needing personal care. To top it all off, they live in close proximity to one another, typically eating together in a common dining room and often sharing a room with another resident. As a result, nursing home residents account for at least one-third of U.S. COVID-19 deaths. In some states, such as Massachusetts, estimates by early May were that nursing home residents accounted for 60 percent of COVID-19 deaths. 

We learned from the devastating early experience with COVID-19 how to keep the corona virus from causing havoc in nursing homes. In particular, we came to understand the importance of protecting nursing home residents from staff members who might bring it into the facility. By testing staff regularly and mandating head to toe personal protective equipment, together with other draconian measures such as banning family visitors and restricting resident-to-resident interaction, the rate of illness, hospitalization and death among nursing homes residents plummeted. Now that the virus is again surging in the Sunbelt, with Florida, Arizona, and Texas reporting skyrocketing infection rates, how are nursing home residents faring in those areas?

The answer, in a word, is not well. The Florida Department of Health reported 3072 active cases in nursing homes and assisted living facilities as of July 13, up from 1408 on June 23. The rate had nearly doubled in two weeks.  Houston saw an 800 percent increase in cumulative new cases among nursing home residents between the end of May and the end of June—and Texas has more nursing homes than any other American state. 

Why is this happening? Only in mid-July did Florida announce it would test nursing home staff regularly. The government defined regularly as every other week—not likely to be often enough—but many facilities report no testing has taken place as yet. Phoenix nursing homes report a shortage of personal protective equipment, with 25 percent of facilities acknowledging they have only one week’s worth of masks, gowns, and gloves on hand for nursing assistants and other direct care personnel. 

So far, death rates have not soared the way they did in New York during the height of its outbreak, but they are beginning to rise. As epidemiologists point out, death is a “lagging indicator:” people first get sick, then some of them become sick enough to require hospitalization; next, some are admitted to the ICU, and then, over a period of weeks, the deaths start coming. The outbreaks began with younger people who ignored public health recommendations to wear masks, limit group gatherings (especially indoors), and maintain physical distance from others. Florida, Texas, Arizona, and other hot spots did not engage in a vigorous campaign to test people with symptoms, to isolate anyone with an infection, and to quarantine exposed individuals. The result was community spread. At that point, the outcome for nursing home residents is entirely predictable. Once COVID-19 is widespread in the community, it is going to make its way into nursing homes, carried by asymptomatic or minimally symptomatic staff members who do not wear adequate protective gear. And vulnerable older people who are dependent on staff members to go to the bathroom, to eat, to dress, and to bathe will themselves become ill. More and more of them will become very sick and many will die. 

States that experienced a major outbreak early in the course of the pandemic—in late March and much of April—learned through experience that in the absence of a vaccine or effective treatment, old-fashioned public health methods are the only scientifically sound and morally defensible way to act. The invasion of nursing homes has no doubt already begun in the states with soaring case rates; every hour of delay in instituting the only measures that we have just demonstrated can succeed will result in more viral transmission, more suffering, and more death.

What's the Risk?

            A new study of 5700 consecutive COVID-19 patients hospitalized in the New York area is making waves because it reports a high rate of underlying chronic disease, seemingly amplifying findings from Wuhan and elsewhere. But what is striking about this group of severely ill COVID-19 patients is not so much their associated chronic conditions as how similar they are to much of the general population.  

            The study, published in JAMA, reported obesity in 47.7 percent of patients, very much like the rate among adults generally: 44.8 percent of 40-59-year-olds and 42.8 percent of those over age 60 are obese. For high blood pressure and diabetes, the rates of disease in the COVID-19 patients closely resembled the rates in the older population in general. The study found high blood pressure in 56.6 percent of the COVID-19 patients; that’s awfully close to the rate of 60 percent found in the general population among people over age 65—and considerably higher than the rate of 33.2 percent found in the general population among people aged 40-59. And the study noted that diabetes was present in 33.8 percent of the very ill COVID-19 patients; that is fairly similar to the rate of 27 percent found among the elderly in general—and markedly higher than the 17.5 percent typically found in the general population of 45-64-year-olds.

            To better understand the significance of the observations about chronic conditions in the COVID-19 patients, the authors of the JAMA article need to examine age-specific rates of those disorders. Without this information, we can’t say very much about risk factors—except that obesity doesn’t seem to be much of a risk factor at all since its rate in the hospitalized COVID-19 is very similar to that in the general adult population. What about hypertension and diabetes?

            Since the median age of the patients in the JAMA study is 63, that means that about half the patients are elderly and about half are not. If all we know is that the rate of high blood pressure in the patients is 57 percent, then there are three possibilities: 1) that 57 percent figure applies across the board, regardless of age; 2) the rate among the half of the study population that’s over 65 is greater than 57 percent (in which case the rate among the half that are under 65 is less than 57 percent); or 3) the rate among the half of the study population that’s over 65 is less than 57 percent (in which case the rate among the younger patients is more than 57 percent). 

            Let’s put sample numbers on these 3 situations, comparing them to what we know about rates in younger and older people in general. In the first case, where the 57 percent applies to everyone, regardless of age, this would mean that the risk of high blood pressure in the older population is the same (or a little lower) than in older people without COVID-19, where it’s 60 percent; and much, much higher than in the younger population, where it’s 33 percent. In the second case, let’s suppose the actual rate of hypertension in the older COVID-19 patients is more like 70 percent (higher than the 60 percent in the well elderly); that would imply the actual rate in the younger COVID-19 patients must be around 44 percent (higher than the comparable rate in healthy younger patients of 33 percent). In the third case, let’s suppose that an average hypertension rate of 57 percent means the actual rate of hypertension in the older COVID-19 patients is 44 percent (much lower than among healthy elderly) and the actual rate among younger COVID-19 patients is 70 percent (much, much higher than among healthy younger adults). What’s noteworthy among these three possibilities is that only in one of them is hypertension a risk factor in the elderly (case 2); in the other scenarios it's either not a risk factor or is actually protective. Moreover, if it is a risk factor, it may well confer only modestly increased risk.

            Whatever the relationship between chronic disease and the severity of COVID-19, what is clear is that Americans as a whole have high rates of chronic disease. A recent international comparison of health found that the US has a rate of chronic disease and obesity that is twice that of other developed countries. Among fee-for-service Medicare beneficiaries, the latest statistics reveal that 20 percent have between 2 and 3 chronic conditions; another 23 percent have 4-5 chronic conditions, and fully 17 percent have 6 or more chronic diseases. 

            Before we make older people with diabetes or high blood pressure unnecessarily anxious about contracting COVID-19—or falsely reassure those older people who don’t have diabetes or high blood pressure that they are at low risk—we need a more careful analysis. Perhaps the real take-away message from the JAMA study is that the U.S. needs to do a better job preventing chronic disease.

Venting About Ventilators

Yesterday, the New York Times published a short article I wrote about what family caregivers can do to try to keep vulnerable older family members safe during the coronavirus epidemic. We as individuals and as a society should do our utmost to keep everyone healthy; my article suggests a few strategies to help those older people who live in the community but need help with personal care or other basic daily functions. 

In many cases, our strategies will succeed, but we have to be realistic and think about the possibility that, despite our best efforts, some older adults—those in their 70s, 80s, or 90s—will get sick. A minority will get so sick that physicians will propose transferring them to the intensive care unit (ICU); most of those brought to the intensive care unit will be breathing so poorly that doctors will advise a ventilator, or breathing machine. 

The popular press makes it sound as though with ICU treatment in general and a ventilator in particular, older patients infected with Covid-19 will live and without this form of treatment, they will die. The reality may be quite different. A report of the experience of nine Seattle-area hospitals just published in the New England Journal of Medicine sheds some light on the question.

The authors report on 24 patients with Covid-19 who were sick enough to be admitted to the ICU. Five of them were over age 80 and five were between 70 and 80. This is a very small sample, but the paper is one of the few published reports that included detailed information about each patient. The outcomes were sobering.

In this group of 10 very sick older Covid-19 patients, 8 died, for a mortality rate of 80 percent. By comparison, among the 14 very sick Covid-19 patients under age 70, 5 died, or 36 percent. A subset of the 24 extremely ill patients received mechanical ventilation—a tube was inserted into their lungs that was connected to a machine that breathed for them. Among the 7 patients over 70 who were both in the ICU and intubated, 6 died, or 86 percent, compared to 4 out of the 11 intubated patients under age 70 (36 percent). The sole case of an older patient with Covid-19 who was intubated and lived was notable for the complete absence of underlying chronic conditions (comorbid conditions, as defined by the study, include asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, infection with human immunodeficiency virus, immunosuppression, diabetes mellitus, chronic kidney disease, and ischemic or hemorrhagic stroke).

An earlier study from China found that among 52 patients admitted to the ICU with Covid-19, the survival rate for people over 70 was 10 percent compared to 45 percent among those under 70.  

Data from the National Health Service in England reporting on the British experience through March 27 found that of 157 patients admitted to an intensive care unit with Covid-19, 73 percent of those aged 70 or older died compared to 35 percent among those under 70. 

In summary, in these three reports, survival rates were low for older patients admitted to the ICU, particularly for anyone who was put on a ventilator. That doesn’t mean it never happens. But it strongly suggests that if you are over 70 and if, despite all the best efforts at prevention, you do get the virus, and if you are one of the minority who become extremely ill with the infection, the outlook is poor. 

Many though by no means all people, if they know the end is likely to be near, do not want aggressive medical treatment that offers little or no benefit. This goes for people with advanced cancer, severe heart disease, or any of a variety of other conditions that are usually fatal. They’d rather receive medications such as morphine to ease their shortness of breath and medications such as lorazepam to ease their anxiety than to undergo extremely uncomfortable treatment that has only a small chance of prolonging their lives. Severe Covid-19 is another condition for the oldest Americans to consider adding to the list.

We all hope we won’t get the virus and that if we do get it, we’ll have a mild case. We hope that if we have a more serious case, we won’t be sick enough for doctors to propose transferring us to the ICU and using a ventilator. But if you are over 70 and you become severely ill with Covid-19, you will be facing a situation that may be as dire as advanced cancer. To be sure, if you survive the coronavirus infection, you might have a good quality of life (though this, too, is uncertain as we know little about life-after-the-virus for those who have been in an ICU) and you might live for some time. If you benefit from treatment of advanced cancer, on the other hand, the benefit may be short-lived. But in both cases, you have a choice. You can decide that you want any and all treatments, however burdensome and however likely or unlikely they are to improve your condition. Or you can opt for a more palliative approach. You don’t have to accept treatment that you regard as excessively burdensome. You don’t have to spend what might be—but might not be—your last days in an ICU with a machine breathing for you, unable to eat or speak. You can choose instead to be treated with intravenous fluids, oxygen, assorted medications, and other forms of supportive care but to decline admission to an ICU and intubation. Your general state of health (before coming down with a coronavirus infection) and your personal preferences should guide your decision.

Most people with Covid-19 infections do not become so desperately ill that they are admitted to an ICU and intubated. Specifying in advance whether you would want this kind of treatment by signing a simple advance directive and discussing your wishes with your health care proxy is a type of insurance policy. Like flood insurance and fire insurance, you hope you will never need to make use of it. But it’s good to have it, just in case.