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Hello. My name is John McKinney.
I'm a professor with the Global Health Institute School of Life Sciences
at the Swiss Federal Institute of Technology
at EPFL in Lausanne.
Today I'm going to talk to you about a once and future plague:
tuberculosis -- a disease that has been with humanity
for about as long as humanity has existed,
but as you'll see, continues to be
one of the leading causes of morbidity and mortality even today.
So, I'd like to begin by reminding you
of how human history, in recent years, has differed
from human history at any time in the past.
That's shown here, where I have graphed
the total global human population versus calendar year
going back to about 10,000 BC -- about the time that agriculture
was invented and humanity began to congregate in cities.
As you can see, for most of human history and prehistory,
there was little change in the global human population.
That started to change quite dramatically a few hundred years ago,
when the human population started to undergo rapid growth
which continues to this day.
So, as you can see, there's rapid exponential growth
right up to the present time.
So, that is quite unprecedented in human history.
Even more strikingly, in the last 200 years or so,
the rate of urbanization of humanity
has outpaced even this incredible rate of population growth.
So, looking back about 200 years ago to the year 1800,
less than half of the human population lived in cities.
Now, more than half of humanity is congregated in cities.
Why do these factors matter? Population growth and urbanization.
Well, from a pathogen's point of view, our bodies are merely substrate for them.
So, having a lot of substrate congregated together in a small space
to maximize transmission potential
is optimal, obviously.
So, in a sense, things have never been so good as they are today
for pathogens that infect human beings.
Now, pathogens have learned how to exploit many different routes of entry into our bodies.
Some pathogens -- the malaria parasite being a notable example --
have learned how to exploit insect vectors to become directly injected
into the blood stream of our bodies --
a kind of optimal route of entry, if you like.
Others enter the blood stream through scratches, abrasions, and so on.
But, the fact is that most pathogens, including most bacterial pathogens,
enter through mucosal surfaces, including the respiratory tract,
the digestive tract, and the urogenital tract.
These pathogens have learned to exploit the food that we eat,
the water that we drink, and so on,
as their means of getting from one host to the next.
The tubercle bacillus that causes tuberculosis is a notable example
of a pathogen that has learned how to be transmitted through the air that we breathe.
So, I'm sure you all remember, when you were a kid,
your mom used to tell you to cover your mouth when you coughed or sneezed.
As usual, mom was right.
The reason that she told you to cover your mouth or nose when you sneezed,
is because when you cough or sneeze, you produce huge numbers of airborne particles
like this. And if this individual, who is coughing,
had tuberculosis, many of these airborne particles would contain viable tubercle bacilli,
transiting from this individual to the next host.
Now, when these bacteria are respired into the airways,
most of these bacteria will impinge on the upper airways,
where they will become trapped in the mucous lining the airways
that is secreted by these goblet cells -- the bare patches here.
Those trapped bacteria will then be swept up and out
by the mucociliary elevator -- the ciliary action of these ciliated epithelial cells
where they will end up in the mouth and then be swallowed and destroyed in the stomach.
So, in fact, in order to initiate infection,
the tubercle bacillus has to penetrate all the way down
into the terminal ramifications of the respiratory tree --
all the way down into the lung alveoli,
where they can implant, be phagocytosed by resident alveolar macrophages
(the cell type that they parasitize within the lung),
and initiate replication.
So, that's the sequence of events that leads to just about every new case
of tuberculosis infection.
What happens following these initial events, though,
is enormously variable from individual to individual,
which to my mind is one the chief mysteries and challenges
of tuberculosis, and is beautifully encapsulated, I think,
in this quote from a classic paper by the epidemiologist George Comstock
at Johns Hopkins,
in which he stated that, "following infection,
"the incubation period of TB" -- that is the interval between
exposure to the pathogen and the development of overt signs and symptoms of disease
can range "from a few weeks to a lifetime."
In other words, TB is a classic example of a persistent,
even a life-long infection,
in which disease may not develop for months, years, or even decades
after initial exposure.
It's very common in endemic countries
for individuals to be infected in childhood
and not to develop disease until immunity wanes with old age.
So, let's go through in some detail the steps that lead to the establishment
of a latent TB infection and reactivation from latency.
As I've indicated already, the principal route of entry
of the tubercle bacillus into the human body is through the airways.
And the bacteria, in order to infect, must travel all the way down into an alveolus,
where they can implant and initiate infection, replicating inside macrophages.
That's shown here in this micrograph from a human lung,
So, if you look carefully, you'll see that there are clusters here
of sort of bright pink staining rods.
These are tubercle bacilli that have been stained with a special stain
that stains only this type of bacterium.
As you'll see, they're clustered within groups, and that's because
they're contained within macrophages of the host.
Now, the macrophage, of course, is one of the front-line defenses
of the innate immune response in humans.
And the macrophage is perfectly capable of destroying most bacteria
that happen to enter the lung.
But, the tubercle bacillus, being a professional pathogen,
has learned actually how to exploit the macrophage as its niche
for replication and persistence in human hosts.
One of the strategies that it uses to do this
is to block the normal pathway of progression from the phagosome
that initially contains the bacterium
to the lysosome, which is the digestive compartment of the cell.
Now most bacteria, when they're phagocytosed by a macrophage
will end up within the confines of a closely apposed vacuolar membrane
("the phagosome") that undergoes a series of maturation steps,
leading to the sequential acquisition of different molecular markers,
gradual acidification, and finally, fusion with the lysosome.
This, of course, is the digestive compartment of the cell --
chock full of hydrolytic enzymes that break down most bacteria that enter the macrophage.
TB manages to avoid this fate, using mechanisms that have yet to be discovered.
It somehow blocks the progression of that nascent phagosome
along the phagosome-lysosome fusion pathway,
which means that, inside the parasitized macrophage,
the tubercle bacillus is residing within a phagosome
that does not acquire markers of maturation,
that fails to undergo acidification beyond about pH 6.5 (close to neutral),
and which fails, most importantly, to fuse with lysosomes --
this degradative compartment of the cell.
So, the bacterium actually lives within the phagosome, inside of the macrophage
and replicates within this niche.
So that's how infection initiates.
The bacteria replicate within a macrophage
until the macrophage is overwhelmed and lyses,
releasing those bacteria, which are then phagocytosed by other macrophages
that have immigrated to the site, drawn there through chemotactic signals
that are released by the infected macrophage.
Now, again, normally this is a defensive mechanism of the host
to bring macrophages to the site of battle where they can destroy the invader,
but in the case of the tubercle bacillus,
this is merely providing it with an additional niche within which it can replicate.
So, this process of growth within macrophage,
lysis of the macrophages, release of the bacteria,
phagocytosis by immigrating macrophages, and again, intracellular replication...
This cycle continues for a period of about a week or two.
And at the point, the bacteria escape from this initial primary lesion
that's been formed, initially into the lymph nodes that drain the region
of the lung that's affected by infection.
And then, they reach the bloodstream, probably carried there by the thoracic duct,
although we really don't know the details.
This process of dissemination through the lympho-hematogeneous route
is critical for establishing infection at secondary sites
within the lungs, as well as within extrapulmonary organs.
So, the lung is, of course, the primary target of tuberculosis.
That's its favorite niche.
And that is the location from which the bacterium disseminates to secondary hosts.
But, in fact, in about 10% of all cases of TB, there is involvement
of one or more extrapulmonary organs, as well.
And, TB, being a protean bacteria,
can adapt to almost any environment, and in fact can cause disease
of the spleen, the liver, the bone, the eye... you name it.
Any organ system can be susceptible to tuberculosis.
But, the lung is for sure the most important organ affected.
And, by seeding through the hematogeneous route,
all parts of the lung become infected with the tubercle bacillus,
which goes again through this process of infection of macrophages
and formation of what are called, now,
secondary lesions that are seeded by the bloodstream
rather than the airway.
Now, at about this point, the host normally
wakes up to the fact that it has been infected and mounts an adaptive immune response
against the organism.
And this is signaled by the arrival, in these lesions,
of T lymphocytes that recognize specifically antigens of the tubercle bacillus.
And, in about 95% of individuals who are infected,
that immune response succeeds in arresting the further progression
of the disease at this stage.
In about 5% of infected individuals, and in particular those
who are immune compromised for any reason,
disease will continue to progress soon after infection.
We call this primary tuberculosis.
But, the fact is, the overwhelming majority of individuals
control infection after this dissemination stage,
at a point where they are probably not even aware they are infected.
They have no obvious signs or symptoms of infection.
Now, latent infection can last a lifetime
and, in fact, in old studies from the 20th century,
it was shown that latently infected individuals who have died of other causes
will yield viable tubercle bacilli upon culture of lung homogenate.
So, we know that tubercle bacillus, once it has infected you,
is capable of persisting for a lifetime.
Most of those infections will remain latent throughout the remainder of the individual's life,
but in a minority of cases -- about 5-10% over the course of a lifetime --
individuals with latent TB infection will reactivate.
For reasons we really don't understand,
in a minority of latently infected individuals,
reactivation will occur at some time later in life.
So, that's about a 5-10% cumulative lifetime risk of reactivation
in people who are latently infected.
When reactivation occurs, it usually occurs in the upper, as opposed to lower,
lung fields. We really don't understand the reason for this,
but it illustrates the importance of this lymphohematogeneous
dissemination of infection that occurs as an early event of tuberculosis.
Infection normally occurs in the lower airways.
That's because this is, by far, the best ventilated part of the lung
when we are standing or sitting upright.
But, reactivation and progressive TB usually occur in the upper airways,
and those lesions are seeded by the bloodstream.
Now, let's look for a moment at the architecture of a tuberculous lesion
because it's a very common kind of tissue architecture for a chronic inflammatory process.
In an early granuloma, such as the one shown here,
the core of the lesion may have begun to undergo a process called
caseating necrosis. This is simply the death and breakdown of infected macrophages,
as I described before.
This core of caseation necrosis is surrounded by a mantle of intact macrophages,
which, if they were properly stained, would reveal large numbers of tubercle bacilli,
which are, of course, growing inside those macrophages.
Further out, there is another layer now of lymphocytes
that have arrived on the scene to try to control infection.
So, you can see there's a kind of striation of the lesion --
a core of caseation necrosis, a macrophage zone
where the bacteria are replicating, and a lymphocyte zone
where the adaptive immune response is taking place.
Now, somewhat later, as infection progresses,
that process of caseation necrosis can become quite extreme,
so that a large core within the lesion develops
where there is essentially no intact cells whatsoever.
There's still a mantle of heavily parasitized macrophages
surrounding that core, but now further out, in place of lymphocytes,
we largely see fibroblasts laying down a matrix of collagen and fibrin
and other extracellular matrix fibers.
It's as though the host is trying to contain the infection.
But, at the same time, this containment of infection within the granuloma
may prevent, we think, the development of an optimal immune response
against the pathogen.
So, it's thought that tuberculosis granuloma
may play a dual role in infection - both for protection and for pathogenesis.
Now, going back to our model,
if that core of caseation necrosis undergoes complete liquefaction,
this can lead to the excavation of an actual cavity
within the lung, as diagrammed here.
This is a large hole - literally a hole in the lung
where the tissue has completely broken down and has exited via the airway here.
This is very easy to see on a chest x-ray.
For example, here. This is a tuberculosis cavity
in the lung of a 19-year old, otherwise healthy male
who unfortunately was infected with multi-drug resistant tuberculosis,
requiring removal of this entire lung as a last ditch effort to save this patient.
So, this kind of extreme pathology
can indeed be life threatening.
And, within cavitary lesions, where the tissue has liquified as I described,
the tubercle bacillus, it's thought can, for the first time,
undergo extracellular growth.
And, as shown here, where the bacteria are stained pink with Kenyon stain,
they can reach absolutely enormous numbers
within the liquified tissue inside the cavity.
This is a prime breeding ground, obviously, for the development of drug resistance --
a problem that I'll come back to a bit later in the talk.
Now, once a cavity like this actually erodes into an airway,
the bacteria can enter the airway, and then when the patient
coughs, sneezes, talks, sings... does anything that expels air from the airways,
the bacteria can then exit the airway outward and enter the environment.
And, of course, then this is when transmission occurs.
So, that's the complete life cycle, if you like, of the tubercle bacillus
within the human host.
And, again, I want to emphasize that there can be a period of many decades
separating the initial infection step and the transmission of infection,
which makes it very, very difficult for this pathogen to be dislodged from communities
once it has taken hold.
We can look at this in another way.
So far, we've been talking about persistence of the tubercle bacillus
at the level of an infected patient.
But, this persistence within individuals
translates into persistence within human populations.
And this is nicely illustrated using the so-called SEIR model of epidemic dynamics,
in which susceptible human populations are broken down into four compartments,
if you like. A compartment of susceptibles
(that is, individuals who have not yet been infected, but who could be infected),
a population of exposed individuals (these are individuals who have acquired the infection
but are not yet transmitting it), an infectious compartment
(describing those individuals who both have the pathogen
and are actively transmitting it), and a recovered population
(indicating individuals who have gotten over the illness and are no longer infectious).
Now, if we look at a typical acute and transient infection
like the measles virus, which has been very well studied epidemiologically,
what we can see is that the transit through these four compartments
is very rapid and unidirectional.
So, an individual who is susceptible and becomes exposed to measles
will incubate the infection for a period of about two weeks
before he or she becomes infectious to others around them.
That period of infectiousness lasts for only about a week or two
before the individual either dies of the infection or hopefully recovers from infection.
Transit through these compartments is unidirectional
because the acquired immunity that develops during infection
is solidly protective against re-infection.
So, if you've had measles once, you're not going to get measles again.
In contrast, a persistent, chronic infection, like TB
shows very different dynamics.
First of all, when a susceptible individual becomes exposed to TB,
the period of time that elapses between exposure and the development of infectiousness
can last anything from months to, as I've said already, decades.
In other words, a latently infected individual can continue
to harbor the pathogen for a lifetime.
Furthermore, once an individual becomes infectious to others,
that period can last again, for a period anything from months to decades
before either death or recovery occurs.
In the pre-chemotherapeutic era, it was very common for individuals to have
relapsing bouts of tuberculosis over periods of many years or even decades.
This, obviously, maximizes opportunities for transmission in a community.
Furthermore, an individual who has recovered from tuberculosis
is not protected against reinfection.
So, unlike in the case of measles, where an individual
who has had measles is not going to get measles again
an individual who has had TB can be reinfected again one or many times.
So, the acquired immunity that develops in the course of infection
not only does not necessarily clear the pathogen, it does not prevent re-infection either.
This causes the epidemic dynamics of TB to be radically different
from those of sort of garden variety acute infections like measles.
And this translates into an epidemiological parameter that is startlingly different
between these two categories of diseases.
This is called the critical community size.
This is simply a measure of how large a population
of contiguous interacting individuals is required
to maintain a pathogen permanently without burnout
or reintroduction from another source.
In the case of measles, this number is about 300,000.
In other words, a minimum population of 300,000 is required to sustain measles indefinitely
without burnout or reintroduction.
In the case of TB, this number is on the order of 100-200.
Very small. And this explains, I think, why tuberculosis is such an ancient pathogen.
It's well adapted to surviving in small, scattered populations
of its host -- in this case, human beings --
which, of course, describes the state of humanity
until the very recent history, as I described earlier.
And I believe that it's this persistence... this unusual tenacity of the pathogen
that accounts for its enormous continued impact on global human health.
According to the World Health Organization,
of the 57 million or so people who die every year of various causes --
so this is of all causes combined, world-wide --
about 1 in 4 individuals die of 1 or another infectious disease.
Among infectious diseases, the big three are tuberculosis, ***/AIDS, and malaria,
which together account for something like 6-7 million deaths every year.
It's worth noting, in fact, that tuberculosis is the leading cause of death world-wide
among individuals who are infected with ***/AIDS.
These two diseases synergize in a really sinister way.
Obviously, being immunocompromised due to ***/AIDS infection
pre-disposes an individual to acquire all kinds of infectious diseases,
including tuberculosis, but it's become clear that having active tuberculosis
also somehow accelerates progression from *** infection to full-blown AIDS,
so it's a real synergy between these two diseases,
the convergence of which, in developing countries,
has spelled a real disaster for public health, globally.
So, 2 million deaths attributed to tuberculosis is obviously a large number,
but it's really only the tip of the iceberg...
what I like to call the iceberg of pathogenesis,
in terms of its impact on global human health,
which is illustrated in this pyramid diagram here.
It's a bit like an iceberg if you think about it.
We tend to focus on the bit of the iceberg that shows above the waterline
-- the tip of the iceberg,
but it truly is only part of the problem.
And in fact, the bulk of the problem -- the bulk of the iceberg if you like --
that is below the water line is in fact what's going to sink your ship if you run into it.
So, it's much the same in the case of tuberculosis.
We tend to focus on what we can see -- what's obvious --
which is the 2 million or so deaths attributable to TB each year.
But, in fact, that number is quite small,
compared to the number of active cases of tuberculosis at any given time,
which is in the range of 16-20 million.
That's a large number of individuals at any given time who are out there,
sick, transmitting the disease.
But even that number is dwarfed by the number of individuals
who currently harbor the tubercle bacillus, albeit in a latent form.
That number approaches 2 billion.
So, at this point in history, about 1 in 3 people on the planet
harbor the tubercle bacillus in their tissues and are at risk of developing disease.
Now, if these individuals who have latent tuberculosis and are not infectious
continue to harbor the infection only in a latent form,
this would be a sort of interesting medical curiosity, but not much more than this.
The problem, as I've already indicated,
is that individuals who are latently infected are at significant risk
for the remainder of their lives
of reactivating and developing full-blown, infectious tuberculosis.
The lifetime risk for an individual with latent TB
is about 10%. That number goes up to about 10% per annum
for individuals who become co-infected with ***/AIDS.
When you think of the implications of this, it's rather staggering
in terms of the future of global public health.
What it means is that, even if today we could intervene with some magic intervention
that blocked transmission and new infection from happening... let's say
a transmission-blocking vaccine, for example...
Of course, we don't have a tool like that, but let's say we did.
Even so, we could expect to see, over the course of the next 50 years or so,
something like 200 million or more new cases of tuberculosis arising around the world,
due to the reactivation of infections that already exist today.
So, clearly, there's an enormous need to tackle this problem
of latent tuberculosis and reactivation.
But the stark reality is that we currently have no tools whatsoever
that are both effective and practical to intervene against latent TB.
The only tool we currently have to use against latent TB
is 9 months of chemoprophylaxis with a drug called isoniazid,
and I don't need to explain why I think it's impractical to treat
2 billion people on a global basis
with 9 months of drug therapy. It's not going to happen.
So, this is an enormous unmet need -- something I'll talk about again later --
in global health.
And it has an impact on us,
here, in developed countries like the United States.
We don't think a lot about TB because most
of the burden of TB globally is in other countries,
particularly developing countries.
But, in fact, what's happening in developing countries
has a big impact on our health right here in the United States.
These are data from the CDC, where I've plotted the incidents per year
in the United States of tuberculosis among individuals born in the United States
(shown in blue) versus individuals born elsewhere
who have immigrated to the United States (in red).
So, following an upsurge in TB cases in the 1980s,
public health measures were instituted to prevent transmission
to identify individuals who were infected,
and case contacts were contacted and new infections
were detected early and treated and so on.
So this was quite an effective means -- these public health measures --
of bringing down the incidents of tuberculosis
among individuals born here in the United States.
But, as you can see, the numbers simultaneously, among individuals who were born abroad,
haven't budged at all.
And what we think is happening is that
almost all of these cases are occurring as a result of a reactivation of TB
from infections that were acquired in childhood.
So, individuals living in endemic countries acquired the infection in childhood,
they then immigrated with a latent infection to the United States
and reactivate and develop tuberculosis.
What these data, I think, clearly show
is that failure to control tuberculosis anywhere in the world
translates into a failure to control TB everywhere in the world,
including in the United States.
Now, one of the myths I'd like to dispel about TB is that it's an old people's disease,
and that it mainly preys on those whose immune systems have waned
due to old age or to immunosuppressive therapy, and so on.
In fact, the reality is that around the world, tuberculosis is overwhelmingly a disease
of young adults.
And that's illustrated in the graphs shown here,
where, as you can see, looking on this side
at the age distribution along the y-axis
versus number of TB deaths along the x-axis,
TB deaths are overwhelmingly concentrated among adults in the age group 15-59.
It's very similar, in fact, to the demographic distribution of AIDS cases around the world,
which again, primarily afflicts young adults.
This is in stark contrast to most other infectious diseases, shown here.
These are the data compiled for all infectious diseases, except tuberculosis and AIDS.
And, as you can see, in contrast to tuberculosis,
most infectious diseases prey overwhelmingly on the very young.
Why does this matter?
Well, it matters because TB and AIDS,
since they remove precisely those individuals
in whom society has already invested
and those individuals who are sort of the backbone
of the socioeconomic structure in societies
have a disproportionate impact. Yes, they kill large numbers of people,
but they also kill that segment of the population that populations can ill afford to lose.
This is particularly true in developing countries where social security systems,
for example, may not exist, and where young adults
usually have dependents in both the young and the old age categories.
In fact, it might surprise you to know that tuberculosis
continues to be the third leading cause of death worldwide
among young adults, age 15-59. ***/AIDS being first
and ischemic heart disease being second.
TB is also the third leading cause of morbidity among the young adult age group,
measured in terms of disability-adjusted life years,
rather than deaths.
So, this is a metric that was devised by Murray and Lopez
at Harvard University in the mid-1990s
which attempts to capture the disease burden caused by a condition
apart from simple mortality.
So, I think it's quite interesting in this context, for example...
just as an aside... that unipolar-depressive disorders,
which do not show up in the mortality charts at all,
have now become the second leading cause of disability-adjusted life years lost
worldwide, and are slated to become the leading cause within the next few decades.
This matters a great deal -- how we quantify the burden of disease --
because, of course, the allocation of resources follows the perceived need.
So, when we focus on morbidity, rather than mortality,
we target rather different conditions.