Asthma, The Breathtaking Disease

[Guest guest]

Asthma, The Breathtaking Disease

by Mike Field, Hopkins Bloomberg School of Public Health

http://www.imakenews.com/pureaircontrols/e_article000585426.cfm?

x=b7nCKsS,bvtv58G

Hopkins Bloomberg School of Public

Health

by Mike Field

Illustrations by Gibbs

photos by Colwell

In the last 20 years, asthma rates have soared to epidemic levels.

School

researchers are investigating the food we eat, the air we breathe,

and the

way our bodies work for clues to better asthma treatment and

prevention.

All her life, Elauna had struggled against the disease.

There were

many times when she could not make it to school, many anxious trips

to

the emergency room. There were pills that made her heart race, and

inhaled

drugs that left her feeling giddy and light-headed. Sometimes she

would

pass out, and wake up hours later in a doctor's care, her worried

parents

by her side. Hospitalizations—often weeks at a time—were an annual

event, most frequently in the springtime when the weather began to

change.

Like others with her condition, she learned not to push, to conserve

her

strength. Athletics were out. Unabashedly gregarious, she took to

theater

instead, where she displayed a natural talent. But when she was

offered a

generous scholarship to New York University, her parents demurred.

It

was too far, they said, we could never get to you in an emergency.

Reluctantly, she agreed to attend nearby University in

Washington, D.C., where she studied drama and dreamed of becoming an

actress.

" She was scrappy, " says her mother, Dale , manager of visitor

services at Baltimore's Walters Art Museum. " She never let it get

the best

of her. " " Daddy, " she would tell her father, " I can't just stop

living. " In

later years, she began keeping a gratitude journal, every page

beginning

exactly as the one before it: " I can breathe, " she would write, " I'm

alive. "

Between 1980 and 1994, the number of Americans with asthma shot up

by

75 percent. Officials hoped better reporting accounted for the

surge. It

didn't.

In March of 2001, just 11 days after her 28th birthday, Elauna was

performing in a professional production of Pearl Cleage's " Blues for

an

Alabama Sky " at Baltimore's Everyman Theatre, playing a naïvely

optimistic social worker. In fine health at the morning cast call,

she started

having difficulty breathing during the matinee performance, several

times

resorting to her albuterol inhaler while offstage. After the show,

her

condition suddenly worsened. She asked for an ambulance and then

collapsed. She never regained consciousness. " For months after her

funeral, " recalls her father, Alonzo , an insurance

executive, " people

would come up to me and they'd all say the same thing: 'I'm so

sorry. I

had no idea you could die from asthma.' "

Elauna

It is the disease that failed to sound an alarm—a disease that today

afflicts

more than 15 million people in the United States, about a third of

whom are

children. Starting in about 1980, the number of asthma cases in the

United

States and around the world began increasing steadily.

According to the U.S. Centers for Disease Control and Prevention,

between 1980 and 1994, the number of people with asthma in America

rose by 75 percent. Among children under 4, asthma exploded,

increasing

by 160 percent, and the number of asthma-related hospitalizations

increased by 20 percent. Perhaps most alarming of all, as new drugs

and

better treatment for asthma became available, the number of deaths

from

the disease did not decline but instead continued to increase—

defying the

trend of declining rates of death from most other diseases and

conditions,

including such stubborn opponents as heart disease and even cancer.

Yet even though the trends were unmistakable, surprisingly little

was done

to raise an alarm. For a time, it was supposed that heightened

awareness

and better reporting were creating an artificial increase—a

statistical

aberration—and that rates would soon level off. Only recently have

researchers and public health officials, prompted in part by work

done at

the School and other divisions at Hopkins, declared the obvious:

America

is in the grip of an epidemic of asthma. In the United States today,

no

chronic disease is increasing faster than asthma. More than two

decades

into the epidemic, very little is known about what causes asthma or

how it

may be prevented. And still the numbers continue to rise.

Faced with such a troubling increase, " you need to initiate an

appropriate

public health response, " says Lynn Goldman , professor of

Environmental

Health Sciences, who was lead author for an influential 2000 report

on

asthma.

" There is relatively little research under way identifying the

causal factors, "

says Goldman. " We know genetics is a part of it, but our genes

aren't

shifting rapidly over a 15-year period. It's something in the

environment,

but we don't know what it is. We need to know in order to bring the

rates

back to a reasonable baseline—something close to the 1970s rates.

This

should be our goal. "

The 2000 report, which grew out of the School's Pew Environmental

Health Commission, was an unusually blunt document titled Attack

Asthma: Why America Needs a Public Health Defense System to Battle

Environmental Threats . The report cited the 1999 Health and Human

Services budget, finding that less than 9 percent of the planned

$125

million expenditures on asthma research was to be spent on

prevention,

and less than 1 percent on the core public health activity of asthma

tracking. Most of the money was to be spent on improving asthma

treatment rather than preventing it from occurring in the first

place.

Lynn Goldman was lead author on a bombshell report in 2000 that

exposed the federal government's shortsighted asthma policy.

" We were very critical of what we found, " says Goldman, MD, MPH '81,

MS. " Our public health infrastructure was in such terrible shape.

Congress

isn't going to fix something it doesn't believe is broken. We had to

show

the system was broken. " Attack Asthma did just that, warning " we are

passive witnesses to an unfolding public health catastrophe. "

Following on the heels of Attack Asthma came a second important

report

in July 2001: Short of Breath: Our Lack of Response to the Growing

Asthma Epidemic and the Need for Nationwide Tracking. This report

was

released by The Trust for America's Health , a non-governmental

organization created a year ago to build upon the work performed by

the

Pew Environmental Health Commission. Short of Breath proposed a

three-year, $255 million program of beefing up state and local

health

departments to better track and monitor the asthma epidemic.

Together,

the two reports attracted considerable attention, both in the media

and in

Congress.

" Asthma rates are increasing for everyone. It's an equal opportunity

disease, " notes Hearne, DrPH, executive director of the

Trust for

America's Health and a visiting scholar in Health Policy and

Management.

Although African Americans, Hispanics, and the poor suffer higher

rates

of asthma than the general population, no amount of education,

income, or

social status can guarantee protection.

Finding out what causes asthma attacks—particularly the severe

attacks

that most often result in emergency room visits and

hospitalizations—clearly has enormous public health implications. In

land, asthma is the most diagnosed pediatric illness, and the

number

one cause of pediatric emergency room visits. It is also the number

one

reason why kids miss school. But perhaps most significant, recent

research indicates that children don't actually " outgrow " asthma as

was

once thought; the condition merely becomes quiescent, and very often

serious symptoms can reappear later in life. Peyton Eggleston, MD,

director of Hopkins' Center for Childhood Asthma in the Urban

Environment, says the implications of this new understanding are

important: " If we can prevent asthma in kids, then we'll end up with

healthier adults. " But the problem is, how? No one, at present, can

say.

Imagine trying to breathe in all your air through a pinched straw.

That is

how many asthma sufferers describe an acute attack. Medical

literature

describes asthma as an obstructive lung disease brought on by a

heightened reaction of the airways to various stimuli, yet even

today, the

exact mechanism of an asthma attack is not understood. Muscles in

the

airways can constrict, causing a feeling of tightness, or the lining

of the

airways can become inflamed and swollen, resulting in wheezing and

shortness of breath. In extreme cases, like that of Elauna ,

airway

muscles constrict, trapping air deep inside the lungs where it is

rapidly

depleted of oxygen. The asthma sufferer can take only brief, shallow

breaths insufficient to provide enough oxygen for the body and,

unless the

muscles are relaxed and fresh air brought into the lungs, can

suffocate.

The number of variables involved in developing asthma and in the

onset of

an attack has suggested to some researchers that asthma may not be

just

one disease. " I think of asthma as more like saying someone has

cancer.

There are all these different diseases we call cancer, but it's

really not just

one disease, " says Fryer , PhD, associate professor in

Environmental Health Sciences, who is investigating the role that

the

parasympathetic nervous system may play in asthma. " What is becoming

clear is that there are different kinds of asthma. There is exercise-

induced

asthma. There is cold, dry air asthma that affects people doing

winter

athletics like skiing. Those same individuals can get in an indoor

heated

pool, where the air is very warm and moist, and they won't have any

symptoms at all. "

Different asthmas point to the possibility of different causes for

the

diseases and, probably, different routes of prevention. At the

School,

researchers are investigating numerous pieces of this complex

puzzle.

the pesticide link

In her lab on the eighth floor of the Wolfe Street Building, Pam

Lein , PhD,

has been investigating the role of pesticides in the epidemic. A

specialist in

how environmental compounds affect nerve functions, Lein, an

assistant

professor in Environmental Health Sciences, is one of a team that

has

found evidence that certain pesticides may increase airway hyper-

reactivity,

thereby initiating or aggravating an asthma attack. " What this means

is if

you administer a stimulus that normally causes constriction of the

airway,

when these pesticides are present you get a much greater reaction, "

Lein

says. " This suggests that the pesticide somehow alters the nerve

function

controlling the smooth muscle lining the airway. It contracts, and

restrains

airflow, which is a hallmark feature of asthma. "

Pam Lein and her team found that certain pesticides can aggravate

asthma

attacks.

Lein says that many people misunderstand the implications of her

research,

assuming that pesticide exposure is largely an issue unique to

agricultural

workers. Not so, she says: " The general public is exposed to

pesticides

through a number of means. One common source of exposure is the food

we eat. [in addition], household pesticides used to control roaches

and

other insects have been detected as residue on toys and also as dust

particulates, so there are alternate routes for possible exposure. "

Exposure

in humans is measured through testing urine samples for the

metabolites of

pesticides. These tests have shown, Lein says, " measurable exposure

to

pesticides across a wide swath of socio-economic profiles, "

suggesting

that a pesticide-related increase in asthma would be felt across all

segments

of the population.

There is other evidence that pollutants (like pesticides) could be

at least

partly to blame for the growing asthma epidemic. Consider: During

the

1996 Summer Olympic Games in Atlanta, city officials instituted

draconian

bans on automobile use in the downtown area to prevent gridlock. A

24-hour-a-day public transportation system was put in place, and an

additional 1,000 buses were brought on line. According to a study

published last year in the Journal of the American Medical

Association ,

the resultant 28 percent drop in ozone concentrations during the

Olympic

Games was associated with a significant decline in asthma events,

including a 41 percent drop in Medicaid emergency care and

hospitalizations, and a 44 percent decline in asthma-related

emergency

care, urgent care, and hospitalizations. One immediate way to

decrease the

burden of asthma, the article concludes, is to decrease ozone and

particulate matter concentrations from automobile emissions.

are nerves involved?

There was a time when Fryer would receive skeptical

responses to

her grant applications. " Why are you doing this? " she'd be

asked. " The

nerves are not important in asthma attacks. " But Fryer, an

investigator into

human physiology, thought that perhaps they were. As a doctoral

student,

she'd looked at why the common class of blood pressure medications

known as beta blockers tended to cause bronchorestriction in

asthmatics.

At that time, the idea that the nervous system was somehow

responsible

for asthma attacks had been largely discounted. But using animal

models,

Fryer discovered that one of the neuromuscular blocking drugs she

was

testing caused a 10-fold greater constriction of the lungs when the

nerves

were stimulated. Armed with this insight, she abandoned beta

blockers and

went looking for—and found—specific nerve receptors on the

parasympathetic nerves controlling the smooth muscles in the

respiratory

system.

Fryer's research is convincing skeptics that nerves do

indeed play a

role in asthma attacks.

It has been known for more than 80 years that nerves can communicate

in

the body by releasing a substance called acetylcholine, which is

stored in

vesicles at the nerve endings. Acetylcholine acts as a transmitter

that can,

depending on the location, decrease cardiac contraction, increase

digestive

contractions, or stimulate a number of other bodily functions. These

changes occur when the presence of acetylcholine is detected by

specific

receptors, which are protein molecules in surface membranes of cells

that

serve to receive the message transmitted by acetylcholine from the

nerve.

Fryer discovered a specific subtype of receptor at the nerve endings—

now

known as the M2 receptor—that hadn't previously been observed in the

lung's parasympathetic nervous system.

" If you cough after inhaling an irritant, that reaction is all

mediated through

the parasympathetic nervous system, " explains Fryer. Parasympathetic

nerve fibers release acetylcholine to stimulate smooth muscle

contraction,

the underlying physiological response in a cough or an asthma

attack. But

what is the purpose of the M2 receptor, wondered Fryer, and does it

perhaps play a role in asthma?

Increasingly, it appears that it does. Fryer and her colleagues at

the School

are leading several investigations into an exciting new avenue of

asthma

research that may result in new classes of drugs for treatment and

control

of the disease, as well as a more complete understanding of how an

asthma

attack can turn fatal.

" Our research shows that when working properly, the M2 receptor

functions to inhibit the release of additional acetylcholine,

[acting] as a

brake on the process, " she says. But if the function of the M2

receptor is

blocked or turned off, additional acetylcholine can be released,

greatly

increasing the severity of the asthma attack. Fryer's experiments

with

neuromuscular blocking drugs while working on her dissertation

indicated

the drugs were doing just that.

The M2 receptor may help explain how asthma attacks can become

severe

enough to cause fatalities. Fryer and colleagues have shown that

eosinophils, the inflammatory cells long known to infiltrate the

airways in

an asthma attack, also surround the airway nerves in patients with

asthma.

Post-mortem biopsies of asthma fatalities have shown the

parasympathetic

nerves literally surrounded by eosinophils. Fryer believes a protein

released

by the eosinophils (called major basic protein) blocks the M2

receptor,

effectively " turning off the brakes " on an asthma attack, leading to

airway

hyper-responsiveness and, in extreme cases, death.

" Our research is the first to show there are M2 receptors on the

parasympathetic nerves and that eosinophils are interacting with

them in a

way that can greatly increase the severity of an asthma attack, "

says Fryer.

Scientists may use this insight to find ways to block eosinophils

from

surrounding the airway nerves or counter their release of the major

basic

protein and thus preserve the M2 receptors' ability to rein in

smooth

muscle contraction during an asthma attack.

is asthma an allergy?

To a man with a hammer, it is said, every problem looks like a nail.

So

allergist Peyton Eggleston may be forgiven for having a strong

inclination

to see a close association between asthma and allergy. " It's a

relationship

that is not completely understood at this time, " says Eggleston, a

Pediatrics professor with a joint appointment in Environmental

Health

Sciences. " But the pathology of asthma shows that eosinophils are

the

inflammatory cells in play during an asthma attack. This is

different from

the inflammation that results, say, from a burn, in which

neutrophils are the

inflammatory cells " —but the same eosinophils are found in the red

and

swollen tissues typical of an acute allergic reaction. So, says

Eggleston,

" the pathology suggests a link. "

Of allergens and asthma, Peyton Eggleston says: " I am absolutely

positive

the link exists. "

Over the years, research conducted at the childhood asthma center

that

Eggleston directs, and at other centers, has shown that allergens

like

cockroach saliva and dust mite fecal particles can make asthma

attacks

more severe. More recently, Eggleston and his team have been

conducting

intervention studies to ascertain if the removal of allergens can

improve

asthma. " We're still in the proof stage of this, " he says of his

conviction

that allergies play a key role in asthma. " Of the people who take

care of

[asthma] patients, about half believe allergies are important. We

still haven't

sold everyone. There is still a significant question and a need for

research

to keep testing the hypothesis and come up with a consistent answer. "

Part of the challenge is the nature of the intervention research

required.

" Compliance is a real issue in these studies, " Eggleston notes. " It

takes a

lot of effort on the families' parts. " He points, as example, to two

studies

currently under way at the Center. To reduce exposure to allergens

(including cockroaches and dust mites), fairly exacting standards of

cleanliness must be consistently maintained, with few or no lapses.

Cats

and dogs and other allergen sources must be banished from the house,

and

researchers must pay frequent visits to make sure the rules are

being

obeyed. " It's hard to convince people it's worth their time and

effort, "

Eggleston says. Nonetheless, he believes research at Hopkins and

elsewhere is close to showing that controlling allergens could be

key to

reducing asthma attacks. " I think it will be shown in another five

years, " he

says, " I am absolutely positive the link exists. But of course, I'm

biased.

Everywhere I look I see allergy. "

common cold as culprit

It has been known for some time that environmental factors can

exacerbate

asthma—provoking attacks in some asthmatics, or increasing the

severity

of those attacks. Most researchers also believe that environmental

factors

play an important role in initiating the onset of asthma. But

whether these

factors are one and the same is uncertain. " It is very important to

differentiate between two issues here: First, there is the issue of

the cause

and development of the disease; second, there is the question of

what

factors make the disease worse, " explains Spannhake , PhD,

professor and associate chair of Environmental Health Sciences.

Spannhake tracks viruses in his laboratory to determine if

they

work with oxidant pollutants to worsen asthma attacks.

The term " environmental factors " is itself potentially misleading,

since it

can mean any irritant, natural or man-made, that can cause or

contribute to

airway constriction in asthmatics. It can be pesticides, as in Pam

Lein's

research, or the ozone, particulate matter, and other pollutants

found in the

smog during the Atlanta study. It can be secondhand cigarette smoke,

or

naturally occurring allergens such as those associated with pets,

pollen,

mold, dust mites, and cockroaches. In recent years, considerable

attention

has been given to " bad air " in tightly sealed modern buildings and

homes

that endlessly recirculate allergens and other contaminants through

forced

air heating and cooling systems.

But of all environmental factors, the most common and troublesome

are

arguably also the most natural and unavoidable—the viruses and other

pathogens that move continually through human populations. For

children

in particular, colds and other common respiratory infections can be

some

of the most potent asthma triggers. " We know virus infections—even

the

common cold—in many asthmatics will lead to the exacerbation of

symptoms, " says Spannhake. " But the mechanism of how this happens is

not totally clear. " Rhinoviruses such as those responsible for the

common

cold have been shown to attack the epithelial cells lining the

respiratory

tract and provoke an inflammatory response, in much the same way

that

oxidant air pollutants such as ozone and nitrogen dioxide do.

Spannhake's

research attempts to discover if viruses and oxidant pollutants

somehow

work together to increase the frequency and severity of asthmatic

attacks.

the hygiene hypothesis

The genetic component of asthma is thought to be a key element in

understanding the disease. An asthma attack is often described as an

allergic response by the lungs, and not surprisingly, asthma tends

to run in

families along with other kinds of allergic disorders. Asthma, it is

commonly said, is a disease in which genetics loads the gun, but

environment pulls the trigger. Yet a purely genetic basis for the

explosive

growth in new asthma cases—the suggestion that humans have simply

bred more asthmatics since 1980—would defy current thinking about

how

changes in gene pools take place. " This is not an issue of

genetics, "

declares lin Adkinson, MD, professor of Clinical Immunology at

the

medical school with a joint appointment in Environmental Health

Sciences.

" We are not breeding more asthma. This idea has never been taken

seriously by scientists. " Nor, he says, is it likely that increases

in dust mite,

cockroach, or domestic animal allergens could be sufficient to

explain the

scale or consistency of the increase in asthma prevalence.

One recent, intriguing theory is the so-called " hygiene hypothesis, "

which

suggests asthma may be an outgrowth of normal human immunologic

response run amok. " The hygiene hypothesis suggests that the immune

system drifts naturally toward allergy unless it is pushed away from

allergy

at birth by having infection to fight, " says Adkinson, Baltimore

director of

the Childhood Asthma Management Program , the largest and longest

study conducted on children with asthma. " As we have become cleaner,

as

we have used increasing numbers of antibiotics and vaccines, the

immune

system has begun to drift back toward allergic reaction. "

Certain observations support this theory. For instance, early day

care

participation seems to protect against asthma, as does exposure in

the

home to cats and dogs, or farm life. Babies born into these

environments

tend to have less asthma, it is thought, because they are exposed to

sources of bacterial DNA that serve to push the immune system away

from

allergies. " It also suggests that if we want to do something about

the

asthma epidemic we are going to have to do something very early in

life—even in vitro, " Adkinson says. " This is one of the most

exciting

asthma theories out there right now. "

Exciting, perhaps, but also difficult to confirm and even more

problematic

to overcome. The implications of the hygiene hypothesis are hard to

miss.

Are we to give up antibiotics and vaccinations? Not any time soon,

if that

is what is required. " There are a lot of new experiments under way

to try to

reorient the immune system, but it's hard to do this research, " says

Adkinson of less extreme dietary and lifestyle measures under

study. " How

do you convince an asthmatic mother-to-be that there is maybe a 1 in

4

chance her child will get asthma and this potential therapy might

lessen the

odds? It's going to be hard to really get this done. "

* * * *

" We estimate asthma rates by extrapolating from drug sales or

telephone

surveys. Essentially, we're working in the dark. "

— Hearne

In the best of all possible worlds, researchers would find new drugs

or

therapies aimed not at treatment but prevention. Yet one of the

biggest

obstacles researchers face in the quest to prevent asthma is a lack

of hard

data. " To begin to deal with an epidemic, you've got to know where

your

numbers are, " says Hearne of Trust for America's

Health. " Right

now, we estimate asthma rates by extrapolating from drug sales or

telephone surveys. Essentially, we're working in the dark.

As a public health practitioner, I can't tell you for certain how

many

children in Baltimore suffer from asthma. Without this information,

we are

hamstrung from putting in place the most effective prevention

strategies. "

Asthma, it is commonly said, is a disease in which genetics loads

the gun,

but environment pulls the trigger.

Both the Attack Asthma and Short of Breath reports made strong cases

for a national surveillance and tracking system that would monitor

asthma

and other chronic diseases. Ironically, 9/11 has helped convince

legislators

that public health surveillance is a national priority. " The public

health

system needs to have its finger on the pulse at a very local level—

this is

how you get information collected fastest, and disseminate

information

most effectively. And that's how you minimize risk and terror, " says

Environmental Health Sciences' Lynn Goldman. " We've got the health

tracking legislation introduced with a real chance of moving

forward. The

CDC is establishing uniform data standards, which are an essential

component of this effort. There are pilot studies under way, and a

whole

confluence of events give me a tremendous amount of hope that we are

learning to put in place the systems that we need to monitor, track,

and

begin to address asthma and other pressing public health issues. "

Will there be a real commitment of the resources needed to

understand and

eventually reduce the growing incidence of asthma? Many would argue

we

don't have a choice. Asthma's estimated yearly cost to society is

$11

billion and growing rapidly. By the year 2020, the overall cost to

society

for the projected 29 million Americans with asthma will run to $18

billion.

Like many researchers, Lynn Goldman is unequivocal: " This kind of

investment pays off many times over. It's worth it. It's worth it. "