[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” years ago, is a longtime medical writer (not a doctor) who writes for us a couple times a month about health issues, marketing, and trends. He does not typically focus on specific investment opportunities, but has agreed to our trading restrictions… as with all of our authors, he chooses his own topics and his words and opinions are his alone]
I guess I’m lucky, nothing worse than a runny nose and a dry cough, at least so far. But in my state of Connecticut, 1,360 people had been hospitalized with the flu as of February 3rd, and 63 people had died. Of those 63, 52 were over the age of 65. And one ten-year-old child has died.
Connecticut is about in line with the rest of the US. According to the Centers for Disease Control, influenza was widespread in 49 of the 50 states, the only exception being Hawaii, where it was described as “localized.” Localized flu was also the description for the District of Columbia and the territory of Guam, and in the US Virgin Islands, the flu was described as “sporadic.”
The CDC has no way of tracking how many total cases of flu there are in the US, since it is thought that a considerable proportion of people with flu do not seek medical attention, but just tough it out. However, they do track the percentage of patients who present to the health-care system with what they term an “influenza-like illness” (ILI), and by the end of January almost 8% of patient-doctor contacts nationwide were due to an ILI. That’s more than three times higher than the baseline, and the highest rate recorded at this time of year in the past 15 years. The highest rates nationally were in Texas and the immediately-surrounding states, where 12.6% of patients reported a flu-like illness.
So, in terms of pervasiveness, it’s definitely bad. But how about in terms of severity?
By mid-January, the hospitalization rate for flu was 31.5 per 100,000 population. That is lower than the rate during the 2014-2015 flu season, which reached 48.4 per 100,000 at the same point in January 2015, and went on to peak at 64.2 per 100,000. So perhaps this year’s outbreak is not quite as severe as outbreaks in some recent years. (The CDC confirmed that view on February 12th, saying that the 2014 – 2015 flu season was worse than the current outbreak.)
It has to be immediately acknowledged that comparing the severity of influenza outbreaks in different years is extraordinarily difficult. Do we count the total number of patients seeking care, or the total number of hospitalizations, or the total number of deaths? And do we scrutinize which population cohorts are most at risk from a flu episode requiring hospitalization, or at risk of death from flu? Some flu variants primarily affect young children who have not developed acquired immunity either through prior exposure to the same or similar flu variant or through a vaccine. Conversely, some flu variants are more likely to cause serious illness or death in older or more frail patients.
However we try to estimate the severity of this flu outbreak, it will not begin even to approach the global flu pandemic in 1918 – 1919, which is thought to have caused 675,000 deaths in the United States alone, and perhaps as many as 50 million deaths globally. That single disease outbreak by itself caused a dip in the otherwise steady growth in global population, similar perhaps to the effect of the bubonic plague in the 1340s. That pandemic, remembered as the Black Death, is estimated to have killed at least 30% of Europe’s population. It took more than a century for the population of the most affected regions to return to their previous levels.
The 1918 – 1919 flu pandemic killed about 2% of all the persons who fell ill with the disease. No other flu outbreak has come anywhere close to that level of deadliness. In contrast, the Asian flu pandemic of 1957 – 1958 caused about 1.5 million deaths globally, and was estimated to have a fatality rate of 0.13%. The Hong Kong flu of 1968 – 1969 killed perhaps one million persons globally with a fatality rate less than 0.1%. The so-called “Swine flu” epidemic of 2009 killed about 18,000 persons, with a fatality rate of 0.03%. So, based on those estimates, the 1918 – 1919 pandemic was about 15 times more deadly than the Asian flu epidemic, 20 times more deadly than the Hong Kong flu epidemic, and more than 60 times more deadly than the Swine flu epidemic. How our present outbreak will compare with those previous events remains to be seen, but so far, it doesn’t seem to be shaping up to be anywhere close to those epidemics.
A trend that you may have noticed is that the succeeding outbreaks do seem to be getting less deadly. Why might this be? Influenza has been around for a long time, and epidemics in which large numbers of people became infected and many died have been recorded since the 16th century, when an outbreak began in Russia, and spread to Europe where it killed more than 8,000 people in Rome and nearly exterminated the populations of several cities in Spain. Pandemics continued to occur throughout the 17th and 18th centuries, particularly affecting the inhabitants of cities. The severity of pandemics peaked with the 1918 – 1919 pandemic, and has been diminishing since that time.
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Why might this be happening?
The likely answer is that the degree of immunity in the population at large has gradually been increasing, due to at least two factors. One is that with each succeeding influenza outbreak, whether a catastrophic global pandemic or merely a limited regional epidemic, more people have been exposed to some form of the flu virus and as a result have acquired a degree of immunity. A second factor (which some persons will vigorously contest) is that increasing numbers of people worldwide are getting influenza vaccinations, with the result that there are fewer hosts for the flu virus to affect and fewer infected individuals to transmit the virus.
Let’s look a bit more closely at immunity and how it works.
Immunity in general and in particular
A degree of immunity to organisms or toxins that have the capacity to inflict damage is common, and indeed essential, throughout the entire animal kingdom. For example, many non-human animals are entirely immune to a number of human diseases such as poliomyelitis, mumps, human cholera, measles, and syphilis. And conversely, humans are entirely immune to many animal diseases such as distemper, which kills most dogs that are affected by it; also to cattle plague, hog cholera, and other diseases that are lethal to animals.
The forces that we humans are able to mobilize against the legions of invaders that have the capacity to make us sick or even kill us are numerous and varied. The first line of defense is made up of a number of different kinds of cells that have the capacity to destroy invading bacteria and other microbes. The white blood cells (leukocytes) consist mostly of neutrophils and lymphocytes. They circulate in the blood and are transported to areas of serious infection and inflammation. White blood cells of the granulocyte and monocyte class attack invaders by ingesting them.
Another class of white blood cells called macrophages requires being alerted by other players in the immune system, but when so alerted they become much more powerful scavengers of invading microbes. In some cases they can eat and digest as many as one hundred bacteria, excrete the remains, and continue to function in their protective role for a considerable time after doing their job.
Another line of defense, which protects us against pathogens that we swallow, is the acidity of our digestive system, which kills and decomposes many organisms that we ingest with our food or accidentally permit to enter the digestive tract. We also secrete a number of digestive enzymes that can act against invaders.
Our bloodstream also contains a number of substances that have the capacity to recognize and destroy invading organisms or toxins. These include lysozyme, which attacks bacteria and causes them to dissolve; also polypeptides which can inactivate a class of bacteria termed Gram-positive; the complement complex, which can be activated to destroy bacteria as well as viruses; and, finally, the natural killer lymphocytes, which attack and devour invading cells, tumor cells, and also scavenge our own cells when they become infected.
The immune forces which are described above are in the class called innate immunity, meaning, essentially, that we are born with it. We inherit it mostly from our mothers, particularly if we are born the usual way through the vaginal canal and mostly breast-fed, at least for the first few months. (Babies who come into the world via Caesareans or who are mostly formula-fed tend to have lower levels of innate immunity.)
So, as you see, we are not born into this world utterly defenseless, the helpless prey of a host of evil pathogens. But our immune response by no means stops there. The other class of immunity is called acquired immunity. We start to develop immunity to potential pathogens very early, and this process continues throughout life.
The process through which we acquire immunity is exceedingly complex, and scientists continue to puzzle out the most intricate details. However, the broad outlines are certainly not beyond the comprehension of the highly intelligent denizens of Gumshoeland.
Let us start by postulating that all the invaders of our bodies are in some way different from our own cells – that is, they possess some features that are distinctly non-human and by which they can be recognized. We may call these antigens.
Antigens might be said to have faces – three-dimensional arrangements of molecules on their surfaces.
In response to the presence of substances whose faces are not recognized by the many components of our immune system, we develop antibodies. Think of these as analogous to facial recognition software that can recognize the precise arrangement of the molecules on the surface of the antigens. Antibodies possess receptors that are the mirror images of the antigens. (A single lymphocyte can have 100,000 antibody receptors on its surface – we don’t need separate antibody cells for each potential invader.) They are able to fit snugly over these unfamiliar faces, attach to them tightly, and take steps to eliminate them, usually by calling for help from other forces in the immune system, such as the complement system. The reaction triggered by the antibodies takes place in waves, as different kinds of forces are summoned to battle. In some cases, the process is short, the invader is dispatched, and we are not even aware of what our immune system has managed to accomplish. In some cases, however, the battle is protracted, and the consequences go far beyond the immediate battlefield. In some cases, as we all know, the battle is lost.
A great deal depends on the readiness of immune system. Specifically, are antibodies to the invader already present in our system? If so, the elimination of the invader can be rapid. For example, there are a number of diseases that a person only gets once, among them smallpox, polio, measles, typhoid, yellow fever, and diphtheria.
Immunity and influenza outbreaks
Immunity to some diseases, such as those mentioned above, is like an on-off switch. We’re either immune to those diseases, or we’re not. Immunity to the flu is different – it’s more like a dial. It might be at the maximum setting, in which case we can be exposed to the flu virus and not get sick at all, but it can also be at a lower setting, meaning that we do catch the flu, but we have a milder case than the person who has no immunity at all. That’s because the influenza virus is extraordinarily subject to mutation. A person can have robust immunity to one strain of the influenza virus, but limited immunity to a different strain.
However, even incomplete immunity has benefits, of two distinct kinds. The individual who has some immunity is likely to have a milder case of flu. And that person is less likely to pass the disease along to others. Therefore, a population in which many people have at least partial immunity to influenza is much less likely to experience the kind of devastating outbreak that took place in 1918 – 1919, in a population in which very few people had any degree of immunity. Then, following that global pandemic, in which enormous numbers of people throughout the planet had been infected with influenza, those who survived the disease emerged with immunity, at least to the particular strain of flu with which they had been infected. Thus, the population at large was less susceptible to another flu outbreak.
It’s worth taking a quick look at how influenza strains are classified.
Classification of influenza strains
Three types of influenza affect humans – influenza type A, type B, and type C. Type C is of relatively little concern, and type B is generally of much less concern than type A. In addition to affecting humans, type A flu affects pigs, horses, birds, and bats. As far as is known, type B flu affects only seals in addition to humans, and type C flu affects pigs and dogs in addition to humans. The distinction between types A, B, and C are based on a nucleoprotein in the core of the virus particle.
The influenza virus is encased on a spherical shell, which is composed of two surface proteins, called hemagglutinin and neuraminidase. There are 16 different hemagglutinin (H) subtypes and 9 different neuraminidase (N) subtypes. The classification of a specific influenza strain is based on which subtypes are present in the shell as well as on the nucleoprotein in the core of the virus. Thus, for example, the predominant strain responsible for this year’s epidemic is classified as Type A H3N2. It’s also usual to mention the origin of the particular strain and the date of identification; for example, the 1968 pandemic was also identified as the 1968 Hong Kong H3N2 flu. And when it is clearly known that the origin of the virus was in an animal species, that may also be part of the identification; for example, the 2009 pandemic may be identified as the 2009 Swine H1N1 flu.
How the mutation of influenza strains affects immunity
The influenza virus can change just slightly or it can change quite radically. The former change is called antigenic drift and the latter antigenic shift. These changes occur when the virus is replicating, which takes place only when the virus has entered a host – viruses cannot reproduce on their own, but require the resources of a living host of some kind to go about their nasty business. The virus essentially opens up, rearranges its parts, and puts together copies of itself, except that these copies may not be exactly duplicates. Tiny mutations in the viral genes that encode for hemagglutinin and neuraminidase account for the less radical changes, i.e., antigenic drift. But, in some cases, the viral genes are totally rearranged, so that the new virus that emerges bears little resemblance to the original, i.e., antigenic shift.
The difference between antigenic drift and antigenic shift is important from the perspective of the human flu victim. In the case of antigenic drift, the new viral strain hasn’t changed all that much, and if the human host had some immunity to the original virus, some of that immunity may persist against the slightly mutated virus, with the result that the individual may be able to mount a fairly robust immune response and fight off the invader, or at least experience a much milder episode of the flu. This is much less likely if the mutation falls under the category of antigenic shift.
Residual immunity may account for the intervals between major flu outbreaks, and may also account for the segments of the population that are most affected. For example, in the 2009 Swine flu outbreak, the highest mortality was in young adults, perhaps because they had no residual immunity carried over from the previous epidemic, which was the 1968 Hong Kong flu.
The role of vaccination
Vaccines consist of inactive proteins that elicit an immune response in the human host. The protein has the distinctive features of the actual live virus, such that when antibodies are formed in the vaccinated human, the antibodies will recognize the invading virus and inactivate it, as we described earlier. It is important to distinguish between vaccination and inoculation. Vaccination gives the immune system a means of recognizing the invader but does not introduce the disease-causing pathogen. It is like showing the sentinel a picture of the enemy agent that may try to sneak into the camp and telling the sentinel “Watch out for this guy!” Inoculation uses a version of the pathogen that has been modified so as to cause a mild version of the illness in question that is enough to create an immune response. Inoculation is now employed seldom if at all.
The process of identifying the key protein marker and manufacturing enough copies of it to make enough vaccine for the at-risk population is complicated and time consuming. For the influenza vaccine, the process is further complicated by the mutability of the virus. It is necessary to attempt to predict the identity of the predominant virus many months before the beginning of the next flu season, and there is always the risk that the influenza virus will throw a monkey wrench into the process by drifting or shifting off into a different mutation than the predicted strain.
News about the effectiveness / ineffectiveness of the current flu vaccine has been spread far and wide, with the result that a great many people are spurning vaccination. Allow me to say, with emphasis and gravitas, that not being vaccinated is a grievous error, not only for the individual, but for the greater community. It certainly seems to be the case that this year’s flu vaccine is considerably less effective than would be desirable, and also considerably less effective than previous years’ vaccines. But, without question, something is better than nothing.
Estimates as to the relative effectiveness of the vaccine generated for the 2017 – 2018 season vary from a low of about 10% effectiveness to a high of about 30% effectiveness. The vaccine was developed to provide immunity to a mutation in the Type A H3N2 from 2014 – 2015 that emerged in 2016. However, in the process of producing the vaccine in chicken eggs, the antigenic protein itself mutated, losing an antigenic site such that it did not result in effective immunity to the H3N2 virus that is currently circulating in the community.
There are methods of generating influenza vaccine other than in chicken eggs. A team of scientists at the Perelman School of Medicine at the University of Pennsylvania led by Dr Scott Hensley found that while egg-adapted versions of this viral strain lacked the antigen that would produce the desired immune response, other versions, not generated in chicken eggs, were much more effective, and humans inoculated with vaccines generated by other means demonstrated the necessary degree of immunity to the current H3N2 strain.
Dr Hensley said, “Our data suggest that we should invest in new technologies that allow us to ramp up production of influenza vaccines that are not reliant on eggs. In the meantime, everyone should continue to get their annual flu vaccine.” He noted that the current vaccine, although far from perfect, would provide at last partial protection against H3N2 viruses, and that other components of the vaccine, like H1N1 and influenza B, will likely provide excellent protection.
Most people are unaware that there are a now a number of different influenza vaccines, including some that are not produced in chicken eggs. One such vaccine, Flublok (Protein Sciences Corporation, recently acquired by Sanofi Pasteur), is produced in insect cells. Another vaccine, Flucelvax (Seqirus) is produced in animal cells, specifically Madin-Darby canine kidney cells in a liquid culture. Flucelvax is a quadrivalent vaccine, meaning that it will trigger the production of antibodies to four different flu strains.
At a meeting of the CDC Advisory Committee on Immunization Practices, a researcher urged the committee to put forward specific preferential recommendations for influenza vaccines that appear to have performance advantages over the competition. The CDC is highly unlikely to do this at the present for a number of reasons, i.e., there simply are not enough of those two vaccines to supply the total need in the US; also, those two vaccines named above are considerably more expensive than the egg-based vaccines. Finally, the evidence for the superior effectiveness of the non-egg-based vaccines is not robust enough for a sweeping recommendation.
All that being said, the importance of getting vaccinated cannot be overstated!
We hear all kinds of reasons why people skip the flu vaccine. “I never get the flu.” “I’ve heard that it’s the vaccine that gives you the flu.” “I don’t believe in vaccines.” I know a number of such people, and number them among my friends. I like and respect them, and I wrote the rest of this section with them particularly in mind.
For them, and for everybody else, I want to bring up what may be the most crucially important benefit of vaccination, which is herd immunity.
If you get vaccinated against the flu, even if the vaccine is only partially effective, the chances are that at worst, you will have a less severe bout than if you had not been vaccinated at all.
If you are in a crowd of people all of whom have been vaccinated against the flu, even if the vaccine is only partially effective, the chances are that at worst, you will have a much less severe bout than if those people had not been vaccinated. And this is true whether you yourself have been vaccinated or not.
As noted earlier, the reason for the time interval between flu epidemics or pandemics is that each outbreak results in a significant proportion of the community with a degree of acquired immunity. A community in which all or most individuals have been vaccinated has the same effect. The influenza virus has no place to roost, so to speak. Viruses, as has been observed many times, cannot survive for long outside of a host. In a community in which most people have been vaccinated – even if the vaccine is not 100% effective – the flu virus has a much harder time finding a host. The more people are vaccinated, the less flu virus there is out there.
According to the CDC, 59% of children got flu shots for the 2016 – 2017 season, but only 43.3% of adults. That in itself contributes to the severity of the flu outbreak.
I would prefer not to be in close proximity to persons who have not received the influenza vaccine. It’s like living next door to a house whose owners have not taken out homeowner’s insurance. If the house is severely damaged in a fire and the owners can’t afford to fix it, the value of my house is affected as well. Like insurance, vaccination protects the community as well as the individual.
Hopeful signs that improved influenza vaccines may be coming
The current methodology for creating flu vaccines focuses on recognition of the transmembrane proteins that constitute the surface of the virus. These are the hemagglutinin (H) and neuroaminidase (N) molecules that are subject to antigenic drift or shift, i.e., mutation. But the virus also has proteins in its core that are common to all flu viruses. Several pharmaceutical companies are trying to develop vaccines that take aim at the so-called “conserved” elements of the flu virus, those being the ones not subject to mutation. The difficulty, of course, is that these proteins are inside the virus, protected by the coating which consists of the H and N proteins.
This approach is being pursued by Imutex, a startup created by SEEK Group and hVIVO. Imutex has created a vaccine that targets viral proteins in order to elicit a B and T cell response against the virus. They are working with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) to advance their vaccine candidate into a Phase IIa trial.
Another approach is currently being pursued by scientists at UCLA. Their plan is based on research into the specifics of the interaction between the influenza virus and the human immune system. The flu virus has the capacity to disable a class of proteins called interferons, which are immune proteins in the immense cytokine family. The UCLA team has identified amino acid sequences in the flu virus that permit the virus to evade the interferon, and they have succeeded in deactivating those sequences in the virus. Up to now, other researchers have deactivated single amino acid sequences in the flu virus, but the UCLA team has succeeded in deactivating eight such sequences.
The UCLA researchers are planning to test their vaccine on two strains of flu in animal models. Next, they plan to move to clinical trials in human subjects. They aim to formulate the vaccine into a nasal spray, which they believe will not only be more convenient for patients but also lower the cost of vaccinating the public.
… but what should we do if we actually get the flu?
One reason that the influenza epidemics that came after the 1918 – 1919 pandemic had much lower death rates is that the supportive care that had become available was much, much better than what the victims of that catastrophic outbreak a century ago received. The likelihood is that during that pandemic, most patients stayed home, with at most a visit from a local doctor who didn’t have a lot to offer either to treat the disease or to maintain the patient’s strength and vitality.
That has changed. Hospitalized flu patients receive nutrition, hydration, and ventilation as needed. They are watched carefully in the event that they should develop a bacterial infection. Precautions are taken to prevent them from spreading their disease.
And it is certainly not the case that every patient with influenza needs to be hospitalized – it would depend on the severity of the infection, the patient’s general health condition, and the home situation. Patients with mild cases recover at home just fine, and even severe cases can usually be managed at home.
Among the flu symptoms, the cough and the runny mucous membranes may be the most annoying. It is a temptation to try to manage these with cough suppressants and drugs that dry the throat and the entire nasal tract. Many clinicians think that this is a bad idea. The cough and the overflowing mucous membranes are part of the inflammatory response, which is the body’s way of trying to expel the pathogen.
Instead, it is probably helpful to cooperate with the inflammatory response by providing the body with enough liquids – plenty of water, soup, juice, etc. Some doctors warn against caffeine and alcoholic drinks on the grounds that they tend to dehydrate us.
It’s also helpful to be out of bed as much as possible, since we humans breathe much better when we’re up and about than when we’re horizontal.
Aren’t there drugs that we can take if / when we get the flu?
Developing drugs that are effective in viral diseases is much more difficult than developing antimicrobials / antibiotics. Bacteria and similar microbes are little creatures that can live and reproduce more or less on their own. Trillions of them inhabit our bodies, and every shovel-full of earth from your garden contains hordes. The trick in developing antimicrobials is finding a molecule that will kill the target pathogen (or at least render it inactive) without harming human tissues, and without doing excessive damage to our beneficial bacterial tenants.
Viruses cannot long survive outside of a host. They invade our cells and co-opt our own physiology in their reproductive process. And in so doing, they kill our own cells and severely disrupt our function. Finding points in the viral life-cycle where the viruses are vulnerable to attack has been a major challenge. The earliest antivirals started to become available in the 1960s, and were effective in treating such conditions as shingles.
So, what about antivirals such as Tamiflu? When oseltamivir (Tamiflu) and zanamivir (Relenza) became available in the US, both in 1999, the official view was that those new drugs would take care of the flu problem, and quantities of those agents were stockpiled, at huge expense.
Both of these drugs turned out to be disappointments. A Cochrane review in 2014 came to the conclusion that Tamiflu did not reduce flu hospitalizations, and later meta-analyses suggested that the benefits did not outweigh the risk of side effects, even though these are mostly not serious. However, there are indications that either of these drugs may be effective in reducing the risk of infection in persons who have been exposed to the flu virus – i.e., as preventive treatment.
A relatively new antiviral is peramivir (Rapivab), which was approved by the FDA in 2014. Rapivab was evaluated in a head-to-head trial against Tamiflu, and performed only slightly better. It is injected rather than oral, and in 2017 it was approved for pediatric use in children over 2 years of age with relatively mild symptoms. It is also thought to be an option for persons who cannot tolerate oral medication.
The unfortunate truth is that these agents don’t work all that well. About the most one could say about these antivirals is that they might shorten a flu episode by about a day, and perhaps make the symptoms somewhat milder. For frail patients, for whom just about any intervention is better than nothing, those antivirals may be a good idea, or so says the CDC. For the rest of us, it’s a toss-up.
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Where does Doc Gumshoe come out? On the one hand, this year’s picture does not look so rosy. The current flu vaccine is not all that effective, the number of cases and fatalities is rising, and there’s not a whole lot that can be reliably recommended as treatment except drinking plenty of liquids. But on the other hand, even if the current vaccine is not so effective, a more widely-vaccinated population would significantly reduce the number of people getting influenza while reducing the severity of individual cases. And if everybody were vaccinated, the influenza virus would have no place to hide, and nobody would get the flu. Influenza would become – like smallpox and polio – a disease of the past.
That strikes me as an achievable objective.
LATE BREAKING FLU NEWS
On Thursday February 15th, the CDC reported that the flu vaccine this season is somewhat more effective than had been predicted – 39% effective overall, and 59% effective in children. According to Alex M. Azar, the CDC’s new boss, the flu vaccine is more effective in preventing death than in preventing the flu’s minor symptoms. A CDC study showed that of 675 children and teenagers who died of influenza between 2010 and 2016, about two thirds had not received the vaccine.