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of LIFE 


# 1 

An exhibition that examines 
the history of asthma, 
the experiences of people 
with asthma, and contemporary 
efforts to understand and 
manage the disease. 

National Library of Medicine 
National Institutes of Health 

Breath of Life 

National Library of Medicine 

National Institutes of Health 

U.S. Department of Health and Human Services 

Bethesda, Maryland 20894 

An exhibition March 23, 1999-March 28, 2001 

An exhibition that examines the history of asthma, the 
experiences of people with asthma, and contemporary 
efforts to understand and manage the disease. 

Exhibition Director 
Elizabeth Fee, Ph.D. 

Special Advisor 

Sheldon G. Cohen, M.D. 

Exhibition Curators 
Robert Aronowitz, M.D. 
Carla C. Keirns 

Catalogue Essay Author 
Charles Marwick 

This catalogue was made possible hy the generous support of 
the American College of Allergy, Asthma, and Immunology. 

This catalogue is published in conjunction with the exhibition Breath of Life, organized by the 
Exhibition Program of the History of Medicine Division, National Library of Medicine. The 
National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious 
Diseases, and the National Institute of Environmental Health Sciences provided additional 
support for the exhibition. 

All rights reserved. 

Friends of the National Library of Medicine 
1555 Connecticut Avenue, NW 
Suite 200 

Washington, DC 20036 

Printed in the United States of America. 

Cover photo credits (clockwise): 
Elizabeth Bishop 

Courtesy Prints and Photographs Division, Library of Congress 
John Locke 

History of Medicine Division, National Library of Medicine 
Moses Gunn 

Copyright Washington Post; reprinted by permission ofD.C. Public Library 

Nancy Hogshead 

Courtesy Tony Duffy/Getty Images 

John E Kennedy 

Courtesy John Fitzgerald Kennedy Library 

Table of Contents 


Director's Statement vii 

Breath of Life 1 

Symptoms of Breathlessness 5 

Asthma and Western Medicine 9 

Asthma: From Symptoms to Disease 13 

A New Century and New Knowledge • 23 

Immune System Research Clarifies Asthma 33 

Effective Medicines for Treating Asthma 39 

Asthma and Genetics 43 

The Future of Asthma Research 45 

The Faces of Asthma 48 

Exhibition Credits and Acknowledgements 57 

Breath of Life 

National Library of Medicine 
Director's Statement 

The creation of the exhibition Breath of Life at the National Library of Medicine reflected not only 
the intellectual enthusiasm and involvement of so many of my colleagues, but also a gathering sense 
of urgency. We all came to realize that great strides had been made in understanding — at least in 
large part — the bodily processes and treatment of asthma, and yet we saw enormous numbers of 
new cases — especially in children — -arising every day. Indeed, the basic incidence of asthma in the 
United States continues to soar. 

Thus we began to see the exhibition as more and more urgently needed as a means to help children 
and parents to understand the real nature of this treatable and manageable disease. 

Many distinguished administrators, scientists, and clinicians, and Congressman William Young, 
attended the opening reception of the exhibition on March 22, 1999. Joining the crowd were 
children from the National Institutes of Health Children's Inn, junior high-school athletes, local 
and national press, and a fascinated crowd of adults. Also in attendance were the Muppets, who 
introduced their asthmatic member, Dani, to the audience. In spite of being an event centered 
on medicine and science a good time was had by all. 

Three American winners of Olympic gold medals (Tenley Albright, figure skating, 1956; Nancy 
Hogshead, swimming, 1984; and Jackie Joyner-Kersee, heptathlete, 1988, 1992) presided over 
the evening's events. They gave assurances to the audience that great athletic feats — such as winning 
Olympic gold medals — are possible for people with asthma who collaborate with their physicians 
in striving for excellent management of their own health. I have personally seen on many occasions 
that children and adults are consistently gratified and sustained by this message of Breath of Life. 

The electronic (DVD) version of the exhibition has circulated widely and is available online at The DVD frequently offers a "gathering point" for conversation and 
planning by groups concerned about asthma and finding help for patients. This printed catalogue 
of the exhibition will also, I hope, find a wide audience. May it permit the unhurried and careful 
consideration of this vexing problem that a book affords. 

Lastly I congratulate and thank all those who helped in creating this fine exhibition. 

Donald A.B. Lindberg, M.D. 

Director, National Library of Medicine 

Breath of Life 1 

Breath of Life 

In the United States, fifteen million people are affected by asthma, and five 
thousand die of the disorder or its complications every year. Between 1980 
and 1 996 the incidence of asthma more than doubled, with children under 
five years old experiencing the highest rate of increase. 

Breath of Life is the story of our increasing knowledge and the continuing 
challenge of asthma, one of the oldest known human disorders. The causes of 
asthma are varied — some known, some unknown — manifested by symptoms 
of wheezing, shortness of breath, and tightness of the chest. The patient with 
asthma suffers from inflammation, constriction, and mucus plugging of the 
airways to and from the lungs — which obstruct the free flow of air through 
the bronchial airways. With air trapped in the lungs, the person with asthma 
has difficulty expiring air through the narrowed bronchial tubes. Forced 
air passes through mucus plugs like the reed of a wind musical instrument, 
producing the characteristic vibratory sound of wheezing. 

In susceptible persons, this chronic disorder may be triggered by a variety of 
factors: respiratory tract infections, industrial air pollutants, environmental 
agents such as airborne pollens and molds, allergenic foods, household 
dusts, inhalant allergens, and even sudden changes in the weather. It 
is becoming increasingly evident that asthma is the outcome of these 
triggers and their common roles in effecting bronchial inflammation. 

The Lord God formed man of 
the dust of the ground and 
breathed into his nostrils 
the breath of life; and man 
became a living soul. 
— Genesis 2:7 



Four Perspectives of Asthma 

The efforts to unravel the causes of asthma are challenging. 
Identifying the triggers of the disorder with precision remains 
elusive. Over the years, four distinct perspectives have evolved. 

First, asthma has been viewed as a disorder of the lungs. 
Physicians have adapted the tools and techniques originally 
developed for anti-tuberculosis therapy for the treatment of asthma. 

Winter Carnival parade at 
Saranac Lake, New York, ca. 1900 

In the late 1800s and early 1900s, Saranac Lake 
was one of the most prominent spa areas in the 
United States for patients with tuberculosis and 
other lung diseases. 




a i m i «" " ~ 



Uings during an asthma episode 

Open Airways for Schools 
flip chart, Curriculum Guide, 
and Instructor's Guide, 1998 

The American Lung Association 
has conducted public education 
campaigns, health advocacy, and 
research since the early 1900s. 
Asthma and other chronic lung 
diseases are now the focus of 
their work. 

Courtesy Adirondack Collection. Saranac Lake Free Library 

Courtesy American Lung Association 

National Library of Medicine 

Secondly, asthma has been viewed as an allergic condition. Consequently, 
researchers identified the character of the antibodies that cause allergic reac- 
tions and developed injection techniques for blocking and reducing antibody 
production by an immunization-like procedure known as immunotherapy. 

A third perspective linked asthma to emotional distress. In the 1940s and 
1950s, physician M. Murray Peshkin (1892-1980) of New York noticed 
that some of his most severe asthma patients markedly improved when they 
were removed from stressful situations. In the case of children, for whom 
he founded a retreat in a controlled environment at the Children's Asthma 
Research Institute and Hospital in Denver, he coined the term "parentectomy" 
to describe his therapeutic method involving separating children from 
their parents. 

Finally, asthma was viewed as the result of exposure to environmental irri- 
tants — one reason why asthma sufferers sought refuge in clear mountain air, 
warm dry climates, and air-pollution free atmospheres. Certainly it is now 
appreciated that a healthy environment at home and at work is critically 
important in the control of asthma. 

Each of these perspectives provided insights into causative, triggering, 
and exacerbating factors in asthma, and led to the design of corresponding 
approaches to managing the disease. Advances in the biomedical sciences have 
taken management of asthma beyond the historical panorama of balancing the 
four humors, the letting of blood, the smoking of tobacco, and the breathing 
of medicated aerosols. The search for the causes and treatment of this ancient 
disorder continues. 

Seventy-five allergen patch test kit 

When they began allergy injections 
in the 1910s and 1920s, allergists 
had to collect, purify, and sterilize 
allergen extracts themselves. In the 
late 1940s private companies began 
to manufacture extracts for skin 
testing and immunotherapy. 

Courtesy Mutter Museum, The College of 
Physicians of Philadelphia 

Skin Testing 

When a patient undergoes 
a skin test, diluted extracts 
from allergens are injected 
under the skin. A positive 
reaction is indicated by a 
small, raised, reddened area 
(called a wheal). The doctor 
measures the extent of the 
reactions by drawing a line 
around each of the wheals 
on the patient's arm. 

Courtesy National Institute of 
Allergy and Infectious Diseases 

Breath of Life 

North Shore Health Resort, Winnetka, Illinois, 
late nineteenth century 

People have long traveled to ocean or mountain locations — 
thought to have especially pure air or water — to improve their 
health. With widespread rail and steamship travel and extensive 
advertising, nineteenth-century spas and resorts opened in 
remote locations and attracted a broad clientele. People with 
tuberculosis, asthma, and hay fever often moved permanently 
to places thought to have air or water conducive to good health. 

M. Murray Peshkin and philanthropist 
Fannie E. Lorber with two children from 
the National Asthma Center (formerly the 
National Home for Jewish Children) in 
Denver, 1956 

A founder and former president of the American 
College of Asthma, Allergy and Immunology. 

Courtesy National Jewish Medical and Research Center 

Construction worker 

Bending over using a handsaw, 
this construction worker inhales 
a great deal of sawdust, which 
can trigger asthma as a general 
lung irritant or a specific allergen. 

Courtesy National Institute for 
Occupational Safety and Health 




A 4 * 














Breath of Life 5 

Symptoms of 

Virtually all cultures in all times have recognized the importance of breathing 
and have tried to identify the circumstances that inhibit airflow to and from 
the lungs. To cite one modern example, the student of yoga, learning to 
breathe properly during exercise postures, is practicing the spiritual discipline 
developed by ancient Hindu philosophers who linked adequate breathing, 
prana — to use the Sanskrit word — with the soul. The breath, they believed, 
builds a connection between the mind, the body, and the spirit. 

Perhaps the earliest description of what is assumed to be asthma dates back 
to ca. 2700 BC. Shen-Nung, sometimes called the Fire Emperor of China 
and regarded as a founder of Chinese medicine, described remedies for the 
treatment of multiple disorders including those that affected the chest. As the 
first known herbalist, he recorded what he had learned about the medicinal 
effects of many plants. 

Ma huang plant (Ephedra sinica): 
(female/male). Illustration from 
B.E. Read, Chinese Medicinal Plants: 
Ephedra, 1930 

Plants of the Ephedra genus are native to 
Asia and the Americas, but many varieties 
are not effective stimulants. Species from 
India and China are particularly potent; 
those native to North America are not. 

Courtesy Harvard University, 
Cambridge, Massachusetts 

Three Chinese Emperors 
of Medicine, 1798 
Artist unknown 
Japanese painting 

The legendary founders of 
Chinese medicine, Huang Di 
(r. 2697-2597 BC) (left), 
Fu Xi (center), and Shen-Nung 
(ca. 2700 BC), were thought to 
walk with the gods. In Chinese 
stories they are said to be 
among the first humans. Fu Xi 
is credited with introducing yin 
and yang, the principles that 
separate the universe into male 
and female, light and dark. 

Courtesy East Asian Collection, 
The Library and Center for Knowledge 
Management, University of California, 
San Francisco 

lit m 

'1 ilj M 1 




National Library of Medicine 

One of these was the plant ma huang, the botanical source of what is known 
today as ephedrine. Identified as a treatment for what Shen-Nung termed 
"coughing up," ma huang was used for centuries in China for the relief of 
cough and bronchial asthmatic symptoms. We believe that the condition 
described by Shen-Nung was asthma. 

To the Chinese, breathlessness was a symptom of the body's balance falling 
into disorder. Relief could be found in the restoration of balance. According 
to the ancient Chinese concept, health and well-being are controlled by the 
flow of energy — the life force they call ch'i — and breathing difficulties are a 
symptom of its imbalance. Indeed, for centuries, traditional Chinese medi- 
cine has advocated treating asthma by "restoring the balance" of the body. 

Lilly Syrup No. 110, 
Ephedrine Sulphate, 1932 

Lilly Inhalant No. 20, 
Ephedrine Compound, 1932 

Swan-Myers Ephedrine 
Inhalant No. 66, ca. 1940 

Courtesy National Museum 
of American History, 
Smithsonian Institution 

°NE Pint (475 CO 

-.SYRUP No. 110_ 




r**** in one fluid ounce | 100 cc. 

Sulphate lgr. |0^ Gm ' 

^-ChiUten, 1/2 to 1 fluid A*» 
7 4 «.) !a duks,lto 2 fluid dra»* (4 

10 8 «•) as directed by the physic* 1 ' 

§IHH- Y & CO- IndianapoUV^ 

Breath of Life 


Confirmation of Shen-Nung's observations of the therapeutic properties 
of ma haung came in the early 1920s when the Japanese investigator 
Jokichi Takamine (1854-1922) isolated ephedrine from the plant. Later, 
the research team of Ko Kei Chen (1898-1988), a Chinese physician, and 
American pharmacologist Carl F. Schmidt (1893-1988), conducted the 
first investigation of ephedrine's cardiovascular effects while working at the 
Peking Medical College in 1924. They found the effects of ephedrine and 
adrenaline on bronchial spasm to be similar, but they noted the advantages 
of ephedrine being taken by mouth compared to adrenaline, which required 
administration by hypodermic injection. For the relief of asthma, they 
suggested that it was reasonable to expect beneficial results from ephedrine, 
although the action of adrenaline was prompt and effective. 

Flegmaticvs i "3 



Breath of Life 

Asthma and 
Western Medicine 

The word "asthma" derives from the classic Greek word for gasping. 
Greek and Roman physicians used the term to describe a shortness of breath 
believed to be the result of an imbalance between the four body humors that 
controlled health — yellow bile, black bile, blood, and phlegm. Imbalances in 
the humors determined an individual's propensity to sickness and the kinds 
of disorders to which he or she was susceptible. Asthma, characterized by 
coughing, wheezing, and respiratory congestion, was regarded as an excess 
of phlegm. Treatment of the condition involved adjusting the balance of the 
four humors. One effort to achieve this objective, blood letting, influenced 
medical practice well into the eighteenth century. 

The first description of asthma as the disease we know today is attributed 
to a Greek physician, Aretaeus, who practiced in Rome after training at the 
Greek library and medical center in Alexandria. He noted the symptoms of 
"heaviness of the chest, difficulty of breathing when running or during other 
exertions, there is wheezing and hoarseness. The cheeks become ruddy, the 
eyes protuberant, there is a need for air, there is an incessant and laborious 
cough and if the symptoms persist, suffocation" (Aretaeus of Cappadocia. 
"On the Causes and Symptoms of Chronic Diseases." In Francis Adams, 
ed. and trans., The Extant Works of Aretaeus the Cappadocian [London: 
Sydenham Society, 1856] Book I, 
Chapter XI, pp. 316-18). 

Flegmaticus 3 

Virgilius Solis, the Elder 



An excess of phlegm made a 
person phlegmatic, and also 
lazy, sleepy, and languid. This 
was thought to be the most 
common cause of asthma in 
ancient Greek medical study. 


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• <"»'>V>|«lilw4>i l . 

- r,„ _ ■.. - .... , Wrvmm j m* *. ^ 

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De Cous/s et S/gn/s Acutorum 
et Diuturnorum Morborum, 
Libri Quatuor (Of the Causes and 
Signs of Acute and Morbid Disease) 
Aretaeus of Cappadocia (81-138?) 
Oxford, 1723 

Aretaeus of Cappadocia carefully 
described asthma, attributing it to 
thick and viscid phlegm caused by 
coldness and humidity experienced 
by the patient. 

"It,-'——- 3 "- 

II II A T O £ 

National Library of Medicine 

Following the decline of the Roman Empire in the fifth century, progress in 
medicine slowed as Western medical practice became embroiled in alchemy 
and astrology. As the seat of medicine and culture moved eastward from 
Rome, Byzantine physicians played important roles in preserving the writings 
of the Greek physicians by translating their works first into Arabic, and 
subsequently into Hebrew and then Latin. 

The first treatise on asthma was written in 1 190 by Moses Maimonides. 
Born in Cordova, Spain, the philosopher, rabbi, and physician fled to Egypt 
to escape religious persecution by Islamic invaders. There, as physician to 
the court of Saladin, Sultan of Egypt and Syria, Maimonides was given 
responsibility for the care of Saladin's asthmatic son, Almalik Alafdal. From 
this circumstance, Maimonides wrote De Regimine Sanitatis ad Soldanum 
Babyloniae (Regimen of Health for the Babylonian Sultan), in which he 
provided advice and recommendations for a program of prevention and 
treatment for the Prince to follow. 

Recognizing that he did not have a cure for asthma, Maimonides recom- 
mended measures for living with the disorder. He noted that dry air was 
preferable to the humidity prevailing in Alexandria, situated as it is in the 
Nile delta, and thus suggested that the Prince live in Cairo. He counseled the 
Prince to keep an even temper, and adopt a moderate lifestyle in food, drink, 
and sleep. One of Maimonides' recommended remedies was chicken soup. 

For all practical purposes Maimonides' advice was the only available course 
of action for the relief of asthma for the next several hundred years and in 
fact his advice is still given to the asthmatic patient today: avoid substances 
and factors that can trigger an asthmatic attack. 

Aretaeus, the Cappadocian 
Artist unknown 

Illustration from Johannes Sambucus 
(1531-1584), Icones Veterum 
aliquot ac Recentium Medicorum 
Philosophorumque (Images of Some 
Ancient and Recent Physicians and 
Philosophers), 1901 

Breath of Life 11 

Breath of Life 


Asthma: From 
Symptoms to Disease 

Following the Renaissance, with both the rediscovery of classical Greek 
thought and advancing knowledge of anatomy and pathology, asthma 
became more widely recognized as a specific disorder. The concept of its 
manifestation due to spasm of the bronchial tubes was proposed by the 
English physician and neuroanatomist Thomas Willis in about 1670. Willis 
had wide interests, among which were the convulsive and spasmodic nature 
of asthmatic paroxysms (from which he suffered) and their relationship to 
the innervation of the bronchi. These studies led to a better understanding 
of asthma as a bronchial disease. 

A generation later another English physician, Sir John Floyer, identified 
asthma as an entity distinct from other pulmonary diseases, and as different 
from simple breathing difficulties. His definition revolutionized approaches 
to the mechanism and management of the disease. 

Antoine-Laurent Lavoisier 
and His Wife, 1788 
Jacques-Louis David (1748-1825) 
Photographic reproduction of 
a painting 

Antoine-Laurent Lavoisier, a French 
chemist, is pictured in his study with 
his wife, Marie-Anne, whose drawings 
illustrated all of his works. To the 
right of the quill pens is a gasometer 
of the type Lavoisier used to deter- 
mine the composition of air in 
the 1780s. 

Courtesy The Metropolitan Museum of Art, 
Purchase, Mr. and Mrs. Charles Wrightsman 
Gift, in honor of Everett Fahy, 1977. 
(1977.110) 0 1989 The Metropolitan 
Museum of Art 

Of iht Orfmi tj 81 > ... ai ,t,„ 

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f. ....... .... 

Thomas Willis (1621-1675) 
Dr. IV/V/z's's Practice of Physick 
London, 1684 

English physician Thomas Willis 
was one of the first European 
medical scholars to synthesize the 
observation of symptoms, which 
was the province of physicians, 
and the careful study of the dis- 
sected body, which had been the 
realm of the separate professions 
of surgeons and anatomists. 

14 National Library of Medicine 

who have attempted 

M fcv?ry difficult, and frecjuent- 
1ul the true Natureoftto^ 
ifeij not thoroughly underftood by 
dwiuorthey have not yet found out 
the Medicine, by which the Cure may 
be cftfcd. B g 

Floyer is best known for his focus on counting the pulse. He used a watch 
to time different pulse and respiratory rates resulting from the influence of 
emotions, diet, climate, temperature, and various drugs and diseases. As an 
asthma sufferer, he wrote about his own experience after exercise, and after 
exposure to environmental factors such as tobacco smoke, dust, and specific 
foods. He noted the constriction of the bronchi and the wheezing that 
characterizes asthma, speculated on the causes, and was one of the first to 
note that asthma ran in families — that there was a heritable predisposition 
to the disorder. 

In his book, The Treatise of the Asthma published in 1698, 
Floyer described the condition: "I have assigned the immediate 
cause of asthma to the straightness, compression, or constriction 
of the bronchia. The slowness of inspiration and expiration 
depends on the stiffness or straightness of the lungs . . . which 
resist the action of the pectoral muscles: 'tis a long time before 
the air can be drawn in, and almost as long before it can 
be forced out, because of the constriction of the bronchia " 
(Floyer, Sir John. The Treatise on the Asthma [London: Richard 
Wilkins, 1698]). 

Sir John Floyer (1649-1734) 
The Treatise of the Asthma 
London, 1698 

Sir John Floyer, an asthmatic English 
physician, wrote his Treatise of the 
Asthma, which made the case for 
considering asthma a separate disease 
from other causes of breathlessness. 
The authoritative text on asthma for 
over a century, Floyer's book went 
through four English editions and 
was translated into French. 

About the same time Floyer was working in England, an 
Italian physician, Bernardino Ramazzini, published De Morbis 
Artificum (Diseases of Workers), his original observations on the 
sources and causes of illnesses among workers in a large number 
of occupations and trades. It was the first comprehensive 
account of occupational diseases. It is largely due to Ramazzini that many 
modern physicians note patients' social, environmental, and occupational 
circumstances as integral factors in recording and evaluating medical histories. 

Bernardino Ramazzini (1633-1714) 

De Morbis Artificum (Diseases of Workers) 

Padua, 1713 

Bernardino Ramazzini, an Italian physician, 
described "asthma" in bakers, miners, 
farmers, gilders, tinsmiths, glass-workers, 
tanners, millers, grain-sifters, stonecutters, 
ragmen, runners, riders, porters, and 
farmers. Ramazzini outlined health hazards 
of the dusts, fumes, and gases that such 
workers inhaled. The bakers and horse 
riders described by Ramazzini would today 
probably be diagnosed as suffering from 
allergen-induced asthma. The lung diseases 
suffered by most of the other workers would 
now be classified as "pneumoconiosis," 
a group of dust-related chronic diseases. 

Breath of Life 

Among the occupations Ramazzini studied were baking and milling, and the 
conditions he referred to as bakers' and millers' asthma. He noted that those 
who worked with wheat, barley, and other grains could not help inhaling 
floating particles of the grains liberated during the measuring and sifting pro- 
cess. He envisioned the formation of balls of dough that clogged the bron- 
chial tree. These particles, he said, "ferment in the salivary juice and stuff 
not only the trachea but the stomach and lungs with a sort of paste" produc- 
ing coughs, shortness of breath, hoarseness, and finally asthma (Ramazzini, 
Bernardino. Diseases of Workers. Wilmer Cave Wright, trans., De Morbis 
Artificum, 1713 [New York, London: Hafner, ca. 1964]). 

The Oxygen Revolution 

In the eighteenth century, advances in chemistry 
shed new Light on the understanding of the role 
and function of the respiratory system. 

In 1774, the English chemist Joseph Priestley 
devised experimental techniques for preparing and 
collecting gases that included focusing sunlight 
through a lens to generate heat directed to a 
sample of mercuric oxide in a closed vessel. 
The released gas vigorously enhanced the burning 
of a candle. In Priestley's own words, "I have 
discovered an air five or six times as good as 
common air." He named this "good air" dephlo- 
gisticated air and estimated that it accounted 
for some 20 percent of the atmosphere. A 
decade later, the French chemist Antoine-Laurent 
Lavoisier, repeating Priestley's experiment, named 
the "good air" oxygen. Subsequently, he demon- 

strated the body's requirement for oxygen 
to convert food into energy. 

Asthma is life-threatening when the disorder 
deprives the body's vital organs of oxygen. The 
shortness of breath in asthma is oxygen hunger. 

Joseph Priestley 
Artist unknown 

In 1791, the home and laboratory of 
English clergyman and scientist Joseph 
Priestley (1733-1804) were burned by 
a mob angered by his unconventional 

religious beliefs and support of the French 
Revolution. Priestley left England in secrecy in 1794, settling 
in Philadelphia, where he founded the first Unitarian church in 
North America. In 1804, he died in Northumberland, Pennsylvania. 

Plate 12 

Marie-Anne Lavoisier's illustration from Antoine-Laurent 
Lavoisier (1743-1794), Traite elementaire de chimie 
(Elements of Chemistry) , Paris, 1789 

Lavoisier's gasometer was the first instrument to make accurate 
measurements of gases. Because gases can be compressed, in order 
to measure the amount of a gas used in an experiment, Lavoisier 
had to find a way simultaneously to measure both changing volume 
and changing pressure or to hold one constant while measuring the 
other. He used a piston to hold gas pressure constant while mea- 
suring the volume of gases used in his experiments. In the 1850s, 
British and Australian physician John Hutchinson (1811-1861) 
modified a gasometer to make the first spirometer for measuring 
the volume of a patient's breath. 


National Library of Medicine 

"Almost all who make a living sifting or measuring grain are short of breath 
and cachectic and rarely reach old age," wrote Ramazzini. "The dust is so 
irritating that it excites intense itching over the whole body, of the sort that 
is sometimes observed in nettle rash. I have often wondered how so noxious 
a dust can come from grain as wholesome as wheat." Further, he suspected 
that the dusts these workers were exposed to harbored "minute worms 
imperceptible to our senses and that they are set in motion by the sifting 
and measuring of the grain and broadcast by the air; then they readily adhere 
to the skin and excite that great heat and itching over the body" (Ramazzini, 
Bernardino. Diseases of Workers. Wilmer Cave Wright, trans., De Morbis 
Artificum, 1713 [New York, London: Hafner, ca. 1964]). In conjecturing some 
hidden substance at work, he came close to the later concept of an allergic 
response. What Ramazzini attributed to plugging of the bronchial tubes by 
"dough balls" is recognized today as an allergic reaction to wheat and rye. 

John Bostock (1773-1846) 
Medico-Chirurgical Transactions 
London, 1819 

Hay fever or allergic rhinitis (known 
commonly as "allergies") can be 
brought on in sensitive individuals 
by many of the same substances that 
bring on asthma symptoms. In 1819, 
John Bostock described this condition 
as a "periodic affliction of the eyes 
and chest," presenting the details 
of the case of one "J. B."— himself. 

The view that there might be extrinsic factors that could trigger an asth- 
matic attack was further explored by the Scottish physician William Cullen 
(1712—1790), founder of the medical school at the University of Glasgow 
and a professor of medicine and chemistry. Since the disorder could not be 
easily treated, he reasoned that the patient could only escape the disease by 
avoiding "exciting" causes. 

Cullen noted that different asthmatic patients have different reactions to 
external factors: one asthma sufferer may find it easiest to live in the city, 
another cannot breathe except in the free air of the 
country. In also noting that asthmatic patients did 
better if the air was tolerably dry, Cullen could well 
have been reading Maimonides. 



k«rtl,tr un ulcroting I" the .-"ouei;, 
^Lolcofanunusoa. U* of symptoms 

tffjtil Motion, f-wn in having occurred m UK 
jhmb, of (he narrator. 

J.B.M. 46, is of a spare »n<l rather Mfc* 
fabt, but capable of considerable exertion, and 

;. no hereditary or constitutional affection, ex- 
cept >»riou< stomach complaints, probably con- 
noted with, or depending upon, » tendency lo 
int. About the beginning or middle of June in 
enrr year the following symptoms make their ip- 
psrjncf , with a greater or less degree of violence. 

Because there were no specific medicinal measures 
for treating asthma, Cullen's recommendations for 
avoiding asthmatic triggers evolved into a mainstay of 
asthma management well into the nineteenth century. 
Indeed, as noted, avoidance of substances such as 
pollens, house dust, and perennial airborne inhalant 
allergens, as well as some foods, remains a major tool 
in managing asthma today. It is bolstered by modern- 
day tests for determining the specific allergens to 
which the patient is sensitive and reactive. 

Although the term "allergic response" dates only 
from the earliest years of the last century, its general 
description goes back a century earlier. In 1819, English physician John 
Bostock linked excessive watering of the eyes and nasal congestion with the 
summer season. Since childhood, Bostock had had what is known as hay fever. 

Breath of Life 





*»l • t..inl SrST* , ' i, ' CCtl1 "' *« Sfci 

4 270. Though not ,, 
MlccUM for e.. of «>c dtrik , 

„ uu > experiment, * u - , } lh « I'Uc 

average city rc<i ,i,. n ^ " ■* » RO»d „ M , , ' «» 

0 would ha 

the kjsu ti wci,!,l i . no * rer ccntnj of H ■ 
(In •>, tX |««.d, : „ n j M u ; _ " » ™ only ,„„ 

} 271. The tnhlu oT curvn IT.M ill . 

I^U^Z:™'. ";*' ,J "> "" "l.ioL the" ftattal 
"how,, in T I I V " , '"""'■'J' «*artly tho *""C i, 
barinniii ' r manm ' t . too. there a at th e 

r> «nuux The highest pout in tl,„ scale w „ ~ "2 
l« W by the table, reached on June ; M «' , than i„ „,„ ymr ^ „„ ^ «« 

>>' "olc-hook to the following effect ' I ,„ 

mud, uiore -.Orel, , fcW th„„ | L»„ ^.„ on . « 
mi ee the attack commenced. The eye, are very ho, and 
itch intently, and havo a .light homing »ei„ati u „ „, u,e 
antcnorpart of the eyeball,, a» if hot Moid of M , ki „d 
had Inm dropped on lo thorn. The no.tril.havc div l„„..„| 
freely, and I fa ave had wvcral violent atlaek, of ■ 

About the middle of June every year, he reported, a sensation of heat and 
fullness of the eyes developed into an acute itching and smarting. This was 
followed by nasal irritation, sneezing, tightness of the chest, and difficulty 
in breathing. Although Bostock did not know the cause, he conjectured 
these symptoms came from flowering plants, thus establishing a seasonal 
connection to asthmatic attacks. 

The allergenicity of grasses and ragweed was established later in the century 
by two physicians with very different backgrounds working on opposite sides 
of the Atlantic. 

In Manchester, England, Charles Blackley established the cause of what we 
today call hay fever. 

Like Bostock, Blackley suffered from hay fever and asthma. Not content 
just to describe the condition, he designed an instrument to count pollen at 
different locations: at ground level and at various heights, which he investi- 
gated using a kite. In his home and office laboratory setting, he conducted 
systematic experiments into the role of pollen in triggering attacks of hay 
fever. In his greenhouse, Blackley cultivated various plants and grasses, and 
induced them to flower out of season, in the winter. Then, subjecting himself 
to inhaling their pollen, he showed that such exposure triggered the symptoms 
of hay fever. 

Charles Harrison Blackley 

Hay Fever: Its Causes, Treatment, 
and Effective Prevention, 
Experimental Researches 
London, 1880 

Charles Blackley invented the pollen 
counter in the late 1860s. The first 
pollen counter was simply a glass 
slide smeared with a sticky substance. 
Blackley used it to collect pollen from 
the air. He then counted the grains 
of pollen under a microscope. (Current 
models use the same principle.) Blackley 
and others used the pollen counter 
to collect extensive data on seasonal 
variations in airborne pollen in order 
to show why hay fever, asthma, and 
other allergic diseases were more 
severe at particular times of the year. 


National Library of Medicine 


Experimenting on himself, Blackley conducted what amounts to the first 
skin test for an allergic response. He put pollen on the abraded skin of his 
forearm and, recognizing the need for a control, also abraded an area of skin 
on his other forearm but did not apply pollen. Within a few minutes, on 
the arm that had been treated with pollen, a hive-like wheal appeared, along 
with intense itching. But the untreated arm experienced no such reaction. 
Blackley 's studies were not widely recognized at the time, largely because 
he was a private medical practitioner in Manchester, not associated with a 

university. Also, as a homeopathic physician, he was not part of 
mainstream medical practice, and his work was not disseminated. 


Concurrently, on the other side of the Atlantic, a contemporary of 
Blackley's, Morrill Wyman, initiated a similar line of investigation. 
Wyman suffered from hay fever. When studying the effects of 
another pollen source obtained from Roman wormwood, a plant 
member of the ragweed family, he identified it as the agent of 
what he termed "autumnal catarrh." 

Wyman noted that there was no hay fever in the White 
Mountains of New Hampshire and believed that its absence 
was due to the fact that Roman wormwood did not grow in the 
area. He collected and packed pollen from flowering plants in 
Cambridge, Massachusetts and took them to New Hampshire, 
where the packages were opened and both he and his son 
sniffed the pollen. He reported that they were both "seized with 
sneezing and itching of nose, eyes, and throat . . . my nostrils 
were stuffed and my uvula swollen" (Wyman, Morrill. Autumnal 
Catarrh [New York: Hurd and Houghton, 1872]). Serving as a 
control, his brother Jeffries Wyman, who did not have a history 
of autumnal catarrh (hay fever), did not develop any symptoms 
when he sniffed the pollen. 

Morrill Wyman (1812-1903) 
Autumnal Catarrh (Hay Fever) 
New York, 1872 

American physician Morrill Wyman's 
pollen maps of the United States 
helped physicians and patients select 
places (shaded area) for vacations 
or migration where hay fever and 
asthma sufferers might be less likely 
to encounter allergens. 

Wyman further observed that some families were more affected by autumnal 
catarrh than others; in his own family his father, two of his brothers, his 
sister, and his son were all affected. He also recognized that nonseasonal 
inhalants, such as the fumes of sulphur from burning matches or the gases 
emanating from burning coal, could induce difficulty in breathing because 
of what he described as a "peculiar sensitiveness of the respiratory nervous 
system." His observation may be one of the earliest on hyper-reactivity of the 
bronchial airways, appreciated today as a common pathophysiologic disorder 
of asthma sufferers. 

Breath of Life 


In 1860, the English physician Henry Hyde Salter wrote On Asthma: Its 
Pathology and Treatment, the most authoritative text on asthma at that time. 
His book was widely read well into the twentieth century and was considered 
the basic treatise on asthma. As an asthma sufferer himself, Salter recorded 
various triggers that could induce an attack, including animal dander, impure 
air, hay fever, and foods. He thought of asthma as a spasmodic disease, repre- 
sented by constrictions of the bronchial tubes. In later years, it was discovered 
that the pathogenesis of asthma was more likely due to swelling, rather than 
constriction of the airways. Salter's concept led to attempts at therapy with 
antispasmodic drugs that included the use of ma huang, or ephedra, thus 
explaining the benefit derived from the plant the Chinese had identified 
for managing breathing difficulty millennia before. 

Salter and the French physician Armand Trousseau (1801-1867) agreed that 
one way of controlling an asthmatic attack was to deliver an antispasmodic 
agent via bronchial intake through the breath, by smoking or inhalation. They 
studied several different medications for depressing irritability of the bronchial 
passages; one method investigated was the inhalation of smoke from burning 
paper that had been dipped in a chemical solution of nitrate. Additionally 
they found that one of the more effective treat- 
ments for controlling an asthmatic attack was 
to smoke a cigar — likely due to its nicotine 
content, which had pharmacological activity. 

Salter made the interesting observation that 
cigar smoking helped those who were non- 
smokers, but not patients who were habitual 
smokers. He was noting the fact that the 
treatment only worked for those who had 
not developed tolerance through frequent 
smoking. Largely because of Salter's authority, 
inhalation therapy for asthma (although not 
necessarily cigar smoking) became widely 
practiced, and indeed is still used today. 

Another therapeutic agent Salter recommended 
was coffee, based on his observation that 
asthmatic attacks were preceded by drowsiness 
and were often triggered when the patient was 
asleep. Drinking strong, hot coffee would keep 
the patient awake, he argued, thus avoiding an 
asthmatic attack. Additionally the caffeine of 
coffee or tea had the pharmacological property 
of relaxing bronchial spasms; the chemical 
analogs of caffeine, for example theophyline, 
worked even better in treating asthma. 

Henry Hyde Salter (1823-1871) 

On Asthma: Its Pathology and Treatment 

London, 1860 

National Library of Medicine 

Asthma Remedies 

The development of modern chemistry in the 
nineteenth century encouraged ingenious initia- 
tives to uncover and define agents to relieve 
airway constriction and reduce the excess mucus 
and bronchial swelling that produce the short- 
ness of breath, wheezing, and chest tightness 
typical of asthmatic attacks. Most early measures 
were aimed at reducing symptoms and were 
refinements of traditional, partially efficacious, 
herbal remedies. 

Pharmacists and physicians derived and com- 
pounded their own medicaments until chemists 
in the nineteenth century isolated what they 
believed to be the active ingredients of tradi- 
tional agents for alleviating asthmatic symp- 

toms. By the latter part of the century, these 
agents were being produced in quantity for 
the commercial market, and often extravagantly 
advertised. Drug companies promoted their 
products to asthma sufferers without the need 
for a physician's prescription. 

It is questionable whether most of these agents 
did in fact relieve asthma. Many contained alco- 
hol or narcotics such as cocaine or morphine, 
which, in addition to having pharmacologic 
actions, were more likely to mask asthmatic 
symptoms and permit the patient to feel better 
than to play a true therapeutic role. There 
could also be untoward side effects of morphine 
derivatives, such as depressed respiration. 

Directions for Using 
Kutnow's Anti-Asthmatic 
Powder and The Carbolic 
Smoke Ball 

Courtesy William H. Helfand 
Collection, New York 

Pastilles Salmon 

Courtesy William H. Helfand Collection, New York 

Dr. J. D. Kellogg's Asthma Remedy 

Courtesy William H. Helfand Collection, New York 

Marshall's Prepared Cubeb Cigarettes, 
ca. 1882 

Courtesy William H. Helfand Collection, New York 

Kutnow's Anti-Asthmatic Powder 
Dr. Whetzel's Powder for Temporary 

Relief of Paroxysms of Asthma 
Samuel Kidder & Co.'s Asthmatic Pastilles 
Brater's Powder for Spasms of Asthma and Brater's Powder 
Courtesy National Museum of American History, Smithsonian Institution 

Breath of Life 21 

Early Epidemiological Research 

The measures recommended for managing asthma in the nineteenth century, 
of necessity, relied on material gleaned from individual case reports, and 
represented the experiences of physicians involved in treating asthma. There 
were, however, some investigators, among them Salter, who innovatively 
searched for common features of asthma and tabulated information gathered 
from observations of large numbers of patients. Salter noted familial asso- 
ciations with asthma in 84 of 217 patients surveyed. This type of statistical 
investigation represented a divergence from the case-study approach to study- 
ing disease, which concentrated on each individual's experience rather than 
trying to understand the traits common to all sufferers. 

In the late nineteenth century, New York physician George Beard, looking 
for a common factor in hay fever and asthmatic disorders, sent out a detailed 
questionnaire to patients. Beard received two hundred replies and used the 
responses to assess the impact of such respiratory symptoms on the popula- 
tion. He observed that more men than women and more tradespeople than 
professionals were affected, that symptoms occurred more frequently among 
married persons, and that symptoms occurred more frequently in "persons of 
nervous temperament." 

These efforts represent early steps toward epidemiologic investigation of 
hay fever and related respiratory disorders. While case studies of individual 
patients are always useful, epidemiology adds to knowledge of a disease 
through the study of its effects on populations. By Beard's time, it had long 
been recognized that without a good measure of the incidence and preva- 
lence of a disease it is difficult to mount effective attacks against it. Adequate 
epidemiologic study of any disorder is the cornerstone of effective public 
health practice and a useful guide for the clinician. 

By the nineteenth century, epidemiologic investigation was well established 
as a means of measuring the impact and discovering the cause of disease. In 
1740, Percivall Pott (1714-1788) identified soot as the cause of scrotal cancer 
among London chimney sweeps, and in 1857, John Snow (1813-1858) 
linked cholera to the water supply from the Broad Street pump. Adequately 
performed surveys of diseases such as asthma had not yet been mounted. It 
was only in the mid-twentieth century that data began to provide a more 
reliable picture of the impact of asthma on the general population. 


New York Hospital 

4k . 

-Patient department 



^ 7 ^ 3 i> 



^-vy f_ 

Breath of Life (23 

A New Century 
and New Knowledge 

At the turn of the twentieth century, a distinguished Philadelphia physician, 
Solomon Solis-Cohen (1857-1948) proposed that the immediate mechanism 
resulting in an asthmatic attack was the obstruction of respiration from a 
swelling of the bronchial mucosa, related to angioneurotic edema. Suggesting 
that increasing the bronchial vascular tone might prevent these attacks, he 
introduced a therapeutic extract of adrenal glands from animals to treat his 
own hay fever. He reported that it cut short an asthmatic paroxysm, was 
useful in preventing a recurrence, and relieved the fear of attack. Solis-Cohen 
proposed the use of adrenal extract as a "measure applicable in certain cases." 

The real importance of Solis-Cohen's preliminary work with adrenal extract 
lay fifty years in the future. His was probably the first use of an agent to 
modify an immune mechanism in asthma. In 1949 the work of Philip Hench 
(1896-1965) and Edward Kendall (1886-1972) made it possible to use 
adrenal gland-derived cortisone in treating autoimmune disorders when they 
isolated the adrenal hormone. Solis-Cohen's finding also marked the beginning 
of an increasing interest in the immune system — the body's reaction to foreign 
invaders — which furthered much of twentieth-century biomedical research. 

By the last years of the nineteenth century, largely due to Louis Pasteur's 
(1822-1895) work on germ theory, an increasing interest developed in the 
mechanisms by which the immune system recognizes and rejects disease- 
causing invaders such as bacteria. To many researchers interested in asthma, 
it must have seemed a natural step from studying bacterial pathogens and 
the efforts to neutralize them, to studying the adverse reactions of asthmatic 
patients to plant pollens and animal proteins. 

Robert A. Cooke's patient notes, 1916 

Robert Cooke set up the first allergy 
clinic in the United States at New York 
Hospital in 1920. Patients' skin was 
exposed to concentrates of common 
allergens to learn which substances 
brought on each individual's allergic 
responses. Patients could then either 
avoid the substances that made them 
sick or undergo "immunotherapy," 
periodic injections of specific allergens 
designed to reduce the immune response 
that caused asthma and other symptoms. 

Courtesy Sheldon G. Cohen, M.D. 

In the late 1870s, a German physician, Robert Koch (1843-1910), working 
with the tubercle bacillus, pioneered the development of techniques for 
staining pathogenic microorganisms, thus marking them for identification 
by microscopic visualization. His work made possible the identification of 
microbes associated with infectious processes and the diagnosis and treatment 
of several bacterial diseases. Information thus gained stimulated efforts to 
develop antisera against disease-causing organisms and their toxins. 

Anaphylactic Shock 

One of the earliest antisera, anti-streptococcal horse serum, had been 
developed to treat the complications of scarlet fever. In the early years of the 
twentieth century, the Viennese physician Clemens von Pirquet (1874-1929) 
noted the development of altered reactivity in some persons treated with the 
anti-streptococcus serum produced in horses. After they had been sensitized 
by a previous injection, they manifested evidence of hypersensitivity to horse 
serum proteins. 

Clemens von Pirquet coined the word "allergic" — from the Greek words 
alios meaning "other" and ergon meaning "work" — to describe this altered 
reaction and pointed out that horse-derived allergens, the substances that 
induced this adverse effect, were antigenically different from the substances 
that stimulated antibody production against the streptococci. "The term 
allergen is far more reaching," he wrote. "The allergens comprise, besides the 
antigens proper, the many protein substances which lead to no production 
of antibodies but to super-sensitivity" (von Pirquet, Clemens. "Allergie," 
Munch Med Wochenschr, 1906; 53:1457. C. Prausnitz, trans, in P.G.H. Gell 
and R.R.A. Coombs, eds., Clinical Aspects of Immunology [Oxford, Blackwell, 
1963]). He went on to note that allergens included mosquito bites, bee stings, 
the pollen that causes hay fever, and the swelling and itching caused by 
substances such as strawberries and crabs. He would later learn that allergens 
do engender production of antibodies of a different type, not detectable by 
test-tube techniques, but identifiable only by their untoward reaction against 
susceptible tissue cells. 

In addition to a hypersensitivity serum-sickness reaction which may take as 
long as ten days to develop, another type of allergic reaction became known 
as immediate hypersensitivity. Within minutes, seconds sometimes, a sen- 
sitive individual after exposure is struck with symptoms of hives, itching, 
swelling, respiratory difficulty, even a precipitous drop in blood pressure and 
shock. If the situation is not immediately neutralized, it may lead to death. 
This immediate systemic allergic reaction is called anaphylaxis. The reaction 
was initially observed in experimental animals by two French physicians, 
Charles R. Richer (1850-1935) and Paul J. Portier (1866-1962). The 
manner of their discovery is a colorful story of scientific research. 

Breath of Life 

When Portier and Prince Albert I of Monaco became friends, the Prince 
often invited Portier to cruises on his yacht. On one of these occasions 
Richet was also invited and the Prince asked them to try and solve a problem 
for him. He was concerned that visitors to Monaco were unwilling to swim 
in the Mediterranean because it was becoming overpopulated by stinging 
jellyfish. He was losing tourists and in Monaco, then as now, tourism was 
its lifeblood. He asked them to develop a vaccine against jellyfish stings. 

The idea of a vaccine was then popular because in the 1870s Pasteur had 
shown the protective effect of an attenuated strain of anthrax bacillus in 
sheep, similar to the action of English physician Edward Jenner's cowpox 
vaccine against the development of smallpox. The idea that one might 
be able to prevent illness by immunization against jellyfish toxin had 
some appeal, especially in the light of Emil von Behring's (1854—1917) 
development of an effective diphtheria antitoxin. 

Edward Jenner 

The body's ability to neutralize foreign pathogens 
has been utilized therapeutically for centuries. 
As early as the eleventh century, the Chinese, 
noting that patients who had once experienced 
smallpox were immune to subsequent attacks, 
inoculated persons against the disease with 
small amounts of fluid or powdered scabs recov- 
ered from skin lesions. From China, the method 
spread westward to Turkey, then to England and 
to other parts of the world. The procedure was 
risky, in that it could induce a full-blown case 
of the disease and deaths sometimes occurred. 
It was considered an acceptable risk only 
because smallpox was such a serious disease 
in which a quarter of those infected died. 

A safer method of inoculation was developed by 
the English country physician, Edward Jenner in 
a 1796 experiment. Following the experience of 
English milkmaids, Jenner inoculated a boy with 
cowpox, a milder disorder related to smallpox. 

He subsequently 
tested this method 
of inoculation with 
fluid from smallpox 
pustules and found 
that the tested 
recipient did not 

develop smallpox. I . 

Edward Jenner (1749-1823) 

Jenner, although 

unaware of the specific mechanism, was making 
use of what we now recognize as an antigenic 
similarity between two biologically related disease- 
causing microorganisms: i.e., through shared 
chemical character, the ability of one to induce 
an immune response to another. For example, 
the recent introduction of childhood immuniza- 
tion against chickenpox virus also carries the 
potential for preventing or at least mitigating the 
occurrence of herpes zoster (shingles) in later life 
since the two agents are antigenically similar. 

The Prince had outfitted a laboratory on his yacht for the two scientists to 
extract the incriminated component of the jellyfish toxin, which they then 
injected into dogs in increasingly potent doses to test for a possible vaccine. 
Although some of the animals died from the poisonous effects, those that 
survived were given a second injection of the toxin to see if they were protected. 

"At this point an unforeseen event occurred," wrote Portier and Richet. 
"The dogs which had recovered were intensely sensitive and died a few 
minutes after the administration of small doses." In one experiment they 
reported that a few seconds after the second injection "the animal became 
extremely ill, breathing became distressful and panting; it could scarcely 
drag itself along, lay on its side, was seized with diarrhea, vomited blood and 
died in twenty-five minutes" (Portier, Paul and Richet, Charles, "De Taction 
anaphylactique de certain venins," Comptes rendes Societe de Biologie (Paris), 
1902; 54:170). The animals had experienced, a newly recognized phenomenon, 
anaphylactic shock. 

The two essential and sufficient requirements for inducing this response, 
Portier and Richet noted, were "increased sensitivity to a poison after previous 
injection of the same poison and an incubation period for this increased 
sensitivity to develop." For this pioneering discovery of anaphylaxis, Richet 
(not Portier) received the 1913 Nobel Prize in physiology or medicine. 

During this same decade, in 1905, two physicians working in the Laboratory 
of Hygiene in Washington, D.C., the predecessor of today's National Institutes 
of Health, were studying a very similar response in guinea pigs. Milton J. 
Rosenau (1869-1946), the laboratory's director, and John F. Anderson 
(1873—1958), the assistant director, were following up on reports of severe 
reactions, some fatal, in patients who had been treated with diphtheria and 
tetanus antitoxins. In addition to the studies by Poitier and Richet, 
anaphylaxis had by this time been reported by others. 

In carefully controlled experiments with guinea pigs, using horse serum- 
derived diphtheria and tetanus antitoxins, Rosenau and Anderson studied 
anaphylaxis in great detail. They demonstrated the requirements for specific 
antigen-antibody interaction, the amount of the dosages, and the time inter- 
vals between the first sensitization dose and the second challenging injection. 
Their studies eliminated a long list of possible cofactors on the anaphylac- 
togenic properties of sera such as aging, drying, heat, irradiation, filtration, 
dialysis, and treatment with enzymes. 

They noted that reactions differed between species, indicating some distinction 
in species-specific target organs. In one demonstrated example, they found 
that while a guinea pig suffers bronchial spasm and dies of respiratory failure, 
a rabbit, by contrast, dies of cardiac arrest. Nevertheless, they concluded: 
"The fact that humans, guinea pigs, and other animals react to a second 
injection of horse serum would seem to indicate that we are dealing with 
one and the same action." 

During this period, related studies led some investigators to believe that 
immunology was a useful model for studying human asthma. Theobold Smith 
(1859-1934), a microbiologist at the Rockefeller Institute, reported findings 
that guinea pigs get bronchial spasms when pre-sensitized to an antigen and 
then challenged. Although the guinea pigs had respiratory deaths, their pathol- 
ogy was not similar to human asthma, in which there is also inflammation of 
the bronchial membranes and sputum formation. 

American investigator William Schultz (1873-1953), a member of the 
Laboratory of Hygiene in Washington, D.C., described an experiment of 
suspending sensitized guinea pig ileum in a physiologic solution. He noted 
that, as susceptible target tissue, it would contract when the corresponding 
antigen was added to the solution. The following year, Sir Henry Dale 
(1875-1968), working at the Wellcome Physiological Research Laboratories 
in England, took up the study of anaphylaxis — an immediate and severe 
systemic reaction to antigens — in guinea pigs. 

Dale, interested in the chemical transmission of nerve impulses, then used 
a smooth muscle strip taken from another target organ, sensitized uterine 
tissue. He exposed it to a chemical, beta-iminazolylethylamine, otherwise 
known as histamine, and showed that the muscle contracted when histamine 
was added to the solution in which it was suspended — the reaction is known 
today as the Schultz-Dale phenomenon. Dale concluded that released hista- 
mine was the cause of anaphylaxis. In 1936 Dale shared the Nobel Prize for 
physiology or medicine with the German physician-physiologist Otto Loewi 
(1873-1961) for their work on the chemical transmission of nerve impulses. 

Today histamine, along with other chemical mediators, is known to be 
released from a class of cells — named mast cells in 1877 by Paul Ehrlich 
(1854-1915) — following stimulation by an allergen reacting on its surface 
membrane. Histamine plays an important role in some immediate allergic 
responses, such as the swelling and itching experienced by hay fever sufferers, 
but it plays a lesser role in asthma. Histamine was later synthesized, and in 
1933, another Nobel Prize winner, Daniel Bovet (1907-1992), developed 
the first antihistaminic drug. However, antihistamines only relieve symptoms 
and do not prevent or remove the underlying cause of the allergic state or 
its reactions. 

The concept that allergens such as ragweed and grass pollens are foreign 
bodies much like bacteria and could, therefore, be countered by mounting 
an immune response was the driving force behind an experiment in London 
in 1902. Sir Almroth Wright's (1861-1947) Inoculation Department at 
St. Mary's Hospital became world-famous for its studies in immunization. 
The department was particularly recognized for Wright's immunization 
of the British Army in India against typhoid fever. 

28 National Library of Medicine 

Robert Anderson Cooke, 1940 

Wright had assembled a small group of investigators, among them Leonard 
Noon (1878-1913) and John Freeman (1877-1962). Noon, an immunolo- 
gist, had studied tetanus toxins and antitoxins and, believing that the caus- 
ative agent of hay fever was a toxin in pollen similar to those in microbes, 
prepared extracts of grass pollen with which he attempted to immunize 
affected subjects by subcutaneous injection. There was some success in that, 
as his coworker and successor, Freeman, later reported: "Where a patient 
has been inoculated for one year he has in the next year complete, or almost 
complete, immunity, but in the third year he has only slight immunity left. 
Where patients have been successfully inoculated for two years they have, 
as might be expected, complete immunity during the third year, and time 
will show how long this complete immunity will last" (Freeman, John. 
"Vaccination against hay fever: Report of results during the last three years," 
Lancet, 1914; 1:1178). 

Noon and Freeman believed they were producing a protective immune 
response, that is immunizing their patients against pollen toxin. But, reexami- 
nation showed that they were inducing a lessening of a hyposensitization of 
their patients, a form of immunotherapy. Regardless of their misunderstand- 
ing of the cause, their work had a major influence on the clinical management 
of allergic disorders for the next several decades. The injections of pollen 
extract were the beginnings of what are popularly called today "allergy shots." 

Noon's and Freeman's approach was adopted by many clinicians, most 
notably two American physicians, I. Chandler Walker (1883-1950) in 
Boston and Robert Cooke in New York, who figured prominently in taking 
this idea further. Walker and Cooke were among the first to set up allergy 
clinics using injection treatments for asthma and allergic diseases. Between 
them they popularized the treatment of asthma by desensitization. 

Robert Cooke (1880-1960) 
Allergy in Theory and Practice 
W.B. Saunders Company, 
Philadelphia and London, 1947 

In 1916 Cooke began seeing patients and in 1920 set up a laboratory and 
allergy clinic at New York Hospital where he developed standards for diag- 
nosis and treatment and for training programs in allergy. In that setting, he 
was responsible for training a large number of physicians who then returned 
to their home cities to develop their own clinics along similar lines. He 
became a dominant force in the field and through his leadership created 
the subspecialty of allergy in internal medicine in the United States. 

Cooke himself suffered from asthma, a factor that, as with so many other 
earlier investigators, influenced his professional interest. His investigations 
covered a broad spectrum of problems in allergy in addition to asthma. He 
developed a system for standardizing the protein extracts used in hyposensiti- 
zation therapy, examined drug reactions, and studied the role of heredity. 
He noted that sensitized individuals transmitted to their offspring, not their 
own specific sensitization, but the unique hereditary capacity for developing 
a reaction to foreign proteins. Cooke was getting close to the underlying 
factor of allergic disorders in general, and asthma in particular, when he 
found that there was a genetically transmitted aberration that made the 
subjects susceptible to sensitization to foreign proteins. 




f 7 


3 » £a ? -i^^^sa - - 

iJLj fa i£~Z.L, f Kj.c 

Robert Cooke's patient notes, 1916 and 1919 
New York Hospital Out-Patient Department 

Courtesy Sheldon G. Cohen, M.D. 

Another influential member of the select New York study group that founded 
the Society for the Study of Allergy and Allied Conditions was Francis M. 
Rackemann (1887-1973), the Society's second president after Cooke. Early 
in his career, Rackemann became interested in research in experimental 
anaphylaxis and the developing field of clinical allergy. On returning to 
Boston and joining the staff of the Massachusetts General Hospital and the 
Faculty of Medicine at Harvard University in 1916, he turned his attention 
to asthma. Two years later he published his noteworthy study of 150 patients 
with asthma. In a monumental effort he followed some of them for up to 
thirty years. 

From this work came his most frequently quoted conclusion: that bronchial 
asthma was a symptom that might have multiple causes, which he defined 
as either "extrinsic" or "intrinsic." Extrinsic causes related to allergenic, 
skin test-positive agents; intrinsic causes of asthma were the result of some 
constitutional disorder. 

One of Cooke's associates, Oscar M. Schloss (1882-1952), a pediatrician, 
developed the scratch test as a diagnostic procedure for detecting hypersen- 
sivity, using it to detect diagnostic leads in studies of patients sensitive to 
various foods. Schloss had become interested in von Pirquet's scratch test 
for tuberculosis and Bela Schick's (1877-1967) intracutaneous test with 
diphtheria toxin. Concerned over what he called the alarming reactions to 
toxic foods, he reasoned that a skin test, rather than actual feeding of the 
suspected food, was needed to identify adverse reactions. 

Schloss found that, within five to fifteen minutes after an active substance 
was rubbed into the skin, like Blackley's study years before with pollen, 
a distinct wheal was raised at the inoculation site. The reaction was always 
immediate and disappeared within thirty minutes to an hour. He did exten- 
sive experiments that showed the reaction was specific for the test food and 
not caused by chemical or mechanical irritation. 

For many years the scratch test and the intracutaneous modification were 
the bases for the investigation and treatment of allergic disease: first, skin 
testing for allergens to which the patient was suspected to be sensitive, then 
development of injection treatments designated to hyposensitize the patient. 

Breath of Life 31 

At first glance it might seem as if these and the continuing studies on allergic 
responses had little to do with asthma. Persons who have experienced skin 
reactions from substances to which they are allergic do not necessarily have 
coexisting or complicating asthma. There is, however, an association. Studies 
during the latter half of the twentieth century have demonstrated that sensi- 
tization among those genetically susceptible to some indoor allergens, such 
as house dust mites, animal dander, and cockroaches, poses a risk for develop- 
ing asthma, particularly in children. There is less risk from outdoor pollens, 
although grass and ragweed pollen have been associated with seasonal asthma. 
It has also been found that sensitivity to perennial inhalant allergens as a cause 
of asthma declines with age. Food allergens may, but do not commonly, give 
rise to symptoms of asthma. Even those who are highly susceptible and may 
experience anaphylaxis as a result of eating certain foods do not have lower 
respiratory tract symptoms. 

There is also clinical evidence that an allergic reaction in the airways, as a 
result of exposure to allergens, leads to an increase in inflammatory responses, 
increased airway hypersensitivity, hyperreactivity, and an increase in eosino- 
phils, white blood cells contained within the bronchial effusions that play 
a role in effecting immune-mediated allergic reactions. These findings are 
bolstered by evidence that when exposure to allergens, such as house dust 
mites, is reduced, asthmatic symptoms in those predisposed to allergies 
are also reduced. These and similar studies emphasize the importance of 
minimizing or eliminating exposure to allergens in treating hypersensitivity- 
related respiratory tract disorders, and they open doors to new knowledge 
of asthma. 

R. Voorhorst, F. Th. M. Spieksma, 
H. Varekamp, MJ. Leupen, and A.W. Lyklema 
"The house-dust mite (Dermatophagoides 
pternyssinus) and the allergens it produces. 
Identity with the house-dust allergen," 
The Journal of Allergy, June 1967 

In 1967 the Dutch research team of R. Voorhorst, 
F. Th. M. Spieksma, H. Varekamp, M.J. Leupen, and 
A.W. Lyklema explained why millions of allergic and 
asthmatic patients were sensitive to common house 
dust— their pillows, mattresses, couches, curtains, 
and clothes were infested with millions of invisible 
dust mites. 

Courtesy Mosby Publishing Company 

Breath of Life 33 

Immune System 
Research Clarifies 

Recent research into the mechanisms of allergy has thrown new light on 
the role of the immune system. Researchers have discovered that when the 
immune system deviates from normal function, there are powerful secondary, 
inflammatory, and constricting effects on bronchial tissues. Hence, studies 
on immune function and hypersensitivity mechanisms in allergic individuals 
have played major roles in clarifying some of the causes of asthma. 

The immune system is the body's defense against the microbial world. 
Without adequately functioning immune systems, animal populations could 
not survive infection. We live in a world of potentially deadly germs — viruses, 
bacteria, fungi, protozoa, and parasitic worms. We survive because the body 
has evolved a complex defense system able to recognize these invaders; attack, 
destroy, or neutralize them; and keep them under control. 

As we have seen, the existence of the immune system has been recognized 
for hundreds of years and through intervention has been manipulated to 
control disease, by Jenner and others. But not until after Pasteur advanced 
the germ theory of disease did the specific components of the immune sys- 
tem come under close study. The last half of the twentieth century has seen 
remarkable progress in our understanding of the components and products 
of the immune system and their function. As a result, the diagnosis, preven- 
tion, and treatment of many disorders, including asthma, have improved. 

Kimishige Ishizaka (1925- ) 
and Teruko Ishizaka (1926- ) 

Working together, in 1967 husband-and- 
wife team Kimishige and Teruko Ishizaka 
showed that people with allergic disease 
have a type of antibody that healthy 
people do not have. Every person with 
a healthy immune system has antibodies 
to many different substances, and these 
antibodies begin the process of immune 
response to disease-causing microbes. 
People with allergies and allergic diseas- 
es, though, have IgE antibodies, a kind 
that healthy people do not normally 
possess. IgE antibodies are the key to 
allergic asthma because allergic people 
form these antibodies upon exposure 
to common and harmless substances, 
resulting in immediate and chronic 
symptoms of the disease. 

Courtesy William Coupon 

National Library of Medicine 

Sometimes the immune system malfunctions and mounts an attack on the 
host's own tissues. The result is an autoimmune disease, examples of which 
include rheumatoid arthritis, systemic lupus erythematosus, and glomerulo- 
nephritis. It has been suggested that, in some instances, asthmatic syndromes 
may also be the result of such an aberrant immune response. Whether 
autoimmune reactivity plays a role in asthma remains to be determined. 


The first time the allergy-prone 
person runs across an allergen 
such as ragweed, 

.he or she makes IgE 
antibody against ragweed. 


These IgE molecules attach 
themselves to mast cells. 

The second time that person 

has a brush with ragweed, 

the IgE primed mast cell 
will release its powerful chemicals, 

"-'vi •*••:♦'' and tnat person will suffer the 

chemicafs SympiOmS wnee2| ng and/ or sneezing, 
"• runny nose, watery eyes 

and itching of allergy. 

The Immune Response 

The immune response in allergic disorders such 
as hay fever and asthma begins with exposure 
to a causative agent, the allergen, an inhaled, 
injected, or ingested foreign protein. When 
the allergen reaches the lungs, it encounters a 
macrophage, which engulfs the foreign molecular 
particle. As the macrophage ingests, degrades, 
and processes the allergen, it undergoes changes 
on its surface through expressed proteins that 
send out a signal to attract a precursor of the 
T lymphocyte called the T-helper cell. 

The T-helper cell picks up the signal 
carrying the imprint of the allergen from the 
original encounter, and, in an evolving matura- 
tion process, migrates to a lymph node where 
it encounters a B lymphocyte and transmits the 
allergen-derived imprinted message. This begins 
the transformation of the B cell into a mature 
immunoglobulin-producing cell known as the 
plasma cell, which generates antibodies that 
switch on and off depending on the need. 

In essence, the T-helper cell's job is to try and 
keep the foreign agent, whether infectious or 

When allergic people are exposed to allergens, their immune 
system responds by producing antibodies called IgE. 

allergenic, under control and localized as much 
as possible, while the other arm of the immune 
system, the B cell, creates antibodies directed 
against the antigen. 

The symptoms of asthma result from a series of cellular events in the human 
immune system. There are several specific cell types involved: the macrophage, 
so named because of its large size and its ability to ingest particles from 
outside its own cell walls; the lymphocytic T and B cells; the plasma cells 
which evolve from the B cells and produce different classes of antibodies; 
and, finally, the mast cells, a particular type of cell whose intact granules 
contain chemicals that on release are capable of inducing inflammation, 
a reaction that plays a role in allergic asthma. 

Antibodies belong to a group of proteins known as immunoglobulins (Ig), of 
which there are five major classes: IgA, IgD, IgG, IgM, and IgE as identified 
by their molecular structures and sites of formation and action. Each plays a 
role in forming defenses against foreign substances that challenge the body. 

The immunoglobulin of most interest to the study of asthma is IgE. It is 
now known that IgE is responsible for the majority of allergic reactions of the 
immediate skin test positive type. The main protective immune function of 
this immunoglobulin is to protect against or repel invasion by tissue-invasive 
parasitic worms. Thus IgE levels in the blood of those who live in those 
parts of the world where these tissue— invasive parasitic worms are common 
are generally elevated. In persons not normally exposed to such parasites, 
IgE is present in very small amounts. Allergic persons synthesize IgE against 
allergens such as extrinsic or atmospheric pollen, dusts, animal danders, 
molds, and certain foods. When IgE was identified in 1966 by Kimishige 
Ishizaka and his wife Teruko Ishizaka, it opened a door to an approach to 
asthma therapy through efforts to suppress or modify IgE formation. 

Working as an immunology team at the Children's Asthma and Research 
Institute in Denver, Colorado, they isolated the antibody responsible for the 
skin sensitivity in specifically allergic people. The Ishizakas showed that IgE 
was, by molecular structure and by its demonstrable effect on allergically 
susceptible tissues, a "distinct class of immunoglobulins," unrelated to any 
of the other immunoglobulins. It could be differentially identified in test 
tube reactions. They named it immunoglobulin E. 

National Library of Medicine 

New Discoveries: Leukotrienes 

Not all allergic reactions are mediated by agents 
from mast cell granules. A group of chemicals 
known as leukotrienes are produced by the action 
of antigen on sensitized tissue. They are of 
special interest to the study of asthma because 
they are potent constrictors of the small 
bronchial airways. 

Leukotrienes have only recently been chemi- 
cally characterized, but the discovery of their 
role in allergic reactions dates back to 1930. 
An American physician-investigator, Joseph 
Harkavy (1890-1980), working at the Institute 
of Pharmacology in Leiden, The Netherlands, dis- 
covered a substance in the sputum of asthmatics 
that caused spasms in isolated smooth muscle 
strips. In experiments, somewhat similar to those 
of Sir Henry Dale with histamine, he recorded 
the pattern of the contractions of the suspended 
test muscle strip. The contractions were immedi- 
ate, suggesting, he said, that there were two 
substances responsible for the spasms. Histamine 
was one; the other remained unknown. 

Harkavy's studies were followed up in the late 
1930s by two Australian investigators, Charles H. 
Kellaway (1889-1952) and Everton R. Trethewie 
(1913-1984). Studying the antigen-antibody 
reaction of anaphylaxis, they showed that the 
substance Harkavy had postulated was present 
in the sputum of asthmatic patients and caused 
a slow, long-lasting, and profound constriction 
of the bronchial airways. They called it the slow 
reacting substance of anaphylaxis or SRS-A. 

Its exact nature remained a mystery until forty 
years later, when Bengt I. Samuelson (1934- ), 
of the Karolinska Institute in Stockholm, 
identified and chemically characterized SRS-A. 
He named the group of component chemicals 
leukotrienes because they are made by leuko- 
cytes (white blood cells). He and his associates 
demonstrated the role of leukotrienes in asthma, 
showing that they are potent bronchial constric- 
tors, cause increased vascular permeability, stimu- 
late mucus secretion, and have pro-inflammatory 
effects. In 1982 Samuelson shared the Nobel 
Prize in medicine or physiology with scientists 
working in the same biomedical area, Sune 
Bergstrom (1916- ) and the English scientist, 
John Vane (1927- ). 

Leukotrienes originate from the breakdown 
products of cells that are disrupted following 
injury, infection, hormonal stimulus, or an 
allergic response. The membranes of the cell are 
converted by enzymatic action into a substance 
called arachidonic acid. This in turn is broken 
down into biologically active compounds, one 
of which forms the leukotrienes. 

When Samuelson summarized his studies in 
1983, he noted that their discovery opened the 
way to developing new and more specific agents 
designed to antagonize the key inflammatory- 
producing leukotrienes. In fact, at least two such 
agents have since been developed that function 
in this way and are now available. They represent 
a major advance in the management of asthma. 

When allergic persons respond to an allergen to which they are sensitive, 
they produce specific IgE antibodies. This first encounter does not produce 
an allergic reaction but it primes the sensitive individual so that when that 
individual re-encounters the same antigen it triggers an allergic response. 
Thus an individual who is allergic to horses, dogs, or cats makes IgE in 
response to a particular protein in horse or dog dander or cat saliva, although 
that individual may tolerate exposures to other animals perfectly well. Similarly 
a person allergic to oysters makes IgE that recognizes and interacts with a 
protein in oysters, but that person is able to eat non-mollusk foods without 
any reaction. 

IgE does not mediate the allergic reaction itself; rather it primes an effector 
cell — the mast cell first identified in 1877 by Paul Ehrlich. Ehrlich noted 
that these cells were stuffed with large granules. It was assumed at the time 
that the granules had been engulfed by the cells, hence, the name "mast" 
from the German word for a fattening feed. However, it is now known that 
the granules are produced within the cells and are filled with histamine and 
other chemical mediators of the allergic reaction. 

When an IgE antibody on the mast cell encounters its specific corresponding 
allergen, the granules move to the surface of the mast cell, and, through 
a process known as degranulation, release chemical mediators into the 
surrounding tissue. 

Breath of Life 

Effective Medicines 
for Treating Asthma 

While one of the best methods for treating asthma and allergic disorders 
is careful management of the environment to avoid substances that trigger 
reactions in sensitive persons, there are a number of effective drugs available 
for treating and, in some cases, preventing asthma. 

Some drugs have been derived from remedies used in the past. In recent 
years scientists have isolated the active chemical components from many of 
the botanical agents favored by the ancient healers, and constructed synthetic 
versions of them. 

One such agent is sodium cromoglycate, known by its trade names Intal® 
or Cromolyn. It is an anti-inflammatory agent that inhibits the release of 
histamine and thus prevents swelling and inflammation of the airways, 
allowing air to flow more freely. 

The leading figure in the development of cromoglycate was Roger E.C. 
Altounyan, an Armenian physician who worked in England. He is recog- 
nized for his determined pursuit of a single idea — the development of an 
anti-allergic, anti-asthmatic agent from a weed called khellin, derived from 
a herb indigenous to Egypt and North Africa. A soup made from khellin 
was used 5000 years ago in ancient Egypt to relieve spasmodic muscular 
contractions. Reasoning that khellin might relieve the bronchial contrac- 
tions that occur during an attack of asthma, Altounyan and his associates 
decided to try and improve on its action by isolating and synthesizing 
derivative compounds. 

May 9, 1963 chart 

Roger Altounyan (1922-1987) tested 
hundreds of extracts of khellin on 
himself, taking it before and after 
exposing himself to a solution of 
guinea pig hair — to which he was 
allergic. Extract K84, which would 
later be shown to contain sodium 
cromoglycate, reduced his response 
to the allergen, and he wrote 
"Hurrah!" on his chart. 

112 Mete 
NDC 0585-0675-02 

?d inii., i., i, 

Intal Inhaler 

(cromolyn sodium 
inhalation aerosol) 


CAUTION: Federal law prohibits 
dispensing without prescription 

Carton contains one canister with 

(8.1 g) 

Courtesy Mrs. Hello Altounyan and Family, 
Cheshire, England 

Intal Inhaler inhalation aerosol, 1998 
Rhone-Poulenc Rorer Inc. 

Courtesy Robert Aronowitz, M.D. 



40 National Library of Medicine 

Altounyan suffered from asthma and, like many medical researchers through- 
out history, experimented on himself. He would induce asthmatic attacks by 
inhaling mixed pollen antigens to which he was allergic and then determine 
if the compounds isolated by the chemists had any mitigating effect. Over 
the course of eight years, he tested 670 compounds. While most of them 
failed to relieve his asthma during an actual attack, he found one compound 
that, if inhaled before he induced an attack, stopped the attack from devel- 
oping. The compound was identified as sodium cromoglycate. 

Cromoglycate is delivered by inhalation into the airways. Altounyan devel- 
oped a device called the spinhaler to move the drug efficiently. The device 
works on the same principle as an airplane propeller, with whose mechanism 
Altounyan was familiar, having been a Royal Air Force pilot during World 
War II. Inside the device is a miniature propeller. When the patient breathes 
in, the propeller rotates and this releases the drug into the air stream. Thus 
there is an automatic coordination between the drug's entry into the airways 
and the patient's intake of breath. 

Cromoglycate prevents or at least slows the release of chemical mediators, 
such as histamine, which are released by the degranulating mast cell and 
trigger an attack of asthma. Once degranulation occurs, treatment has to 
be directed at blocking the effects of the mediators on their target tissues 
or otherwise counteracting them. In this respect, theophylline, a bronchial 
muscle relaxant; the corticosteroids, which have an anti-inflammatory effect; 
and the long-standing first choice in an emergency, epinephrine, which 
enlarges the bronchial airways, are all useful. 







• - u <~/U» . nil 

1 5-<J 




May 9, 1963 chart 

Courtesy Mrs. Helta Altounyan and Family, 
Cheshire, England 

Breath of Life 41 

Unfortunately most of these agents have side effects. Theophylline, a chemical 
analog of caffeine (thus explaining the beneficial effects some asthma sufferers 
obtain from coffee), needs strict monitoring. Too high a dose and gastroin- 
testinal effects, headaches, and high blood pressure can occur. Too low 
a dose and it is ineffective. 

Side effects of epinephrine include an increased heart rate, central nervous 
system symptoms such as anxiety, and sometimes nausea and vomiting. 
However, newly developed drugs known as beta adrenergic agents have an 
epinephrine-like action. They are longer acting and have fewer side effects 
than epinephrine itself. 

Corticosteroids reduce inflammation and airway irritability, and decrease 
mucus production and swelling. Unfortunately, if taken orally over the long 
term, steroids cause severe side effects, including the characteristic "moon 
face," osteoporosis, acne, and cataracts, as well as increased blood pressure and 
elevated blood sugar levels. They can also suppress the normal growth pattern 
in children. Some of these undesirable systemic effects can be avoided by the 
use of inhaled steroids, which primarily act locally on respiratory tract tissue. 

Report No. 18, January 20, 1961 

Physician Roger Altounyan's first 
report on the khellin extract project 
includes diagrams of some of the 
molecules he thought might prevent 
or treat asthma attacks. 

Courtesy Mrs. Hella Altounyan and Family, 
Cheshire, England 

Spirometer, mid-twentieth century 

Altounyan used this spirometer from 
1959 to 1967 during his tests to find 
the active ingredient of khellin, a 
Middle Eastern folk remedy for asthma. 
It measures the volume of air entering 
and leaving the lungs. 

Courtesy Rhone-Poulenc Rorer Ltd. 

Breath of Life 

Asthma and Genetics 

Studies suggest that humans develop asthma because of an interaction 
between their predisposing genes and the environment in which they live. 
The earliest students of asthma, such as the seventeenth-century English 
physician Sir John Floyer, noted that the condition runs in families. In the 
coming years, the data anticipated from the Human Genome Project at the 
National Institutes of Health, supplemented by findings by other institutions, 
will help to elucidate the mode of inheritance of asthma. A recent report from 
the University of Southampton, England, reported a gene for asthma located 
on chromosome 5. However, the current thinking is that there is likely to 
be more than one gene involved. Identifying a person who is genetically 
susceptible to asthma is not expected to be a simple matter. 

One reason is that not everyone who carries the familial susceptibility to 
allergy expresses it clinically. A study of twins in Sweden suggests that about 
18 percent of the population carries a genetic susceptibility to allergy but 
that less than half of that number are clinically affected. 

Another indication of the variability of the genetic expression of such disor- 
ders as asthma comes from a study in the United States that found that two 
clinically allergic parents had a 58 percent chance of having an allergic child. 
Where one parent was clinically allergic the risk of an allergic child was 
38 percent and where neither parent was clinically allergic the risk was only 
12.5 percent. 

Courtesy National Institute of 
Allergy and Infectious Diseases 

Breath of Life 

The Future of 
Asthma Research 

Asthma affects fifteen million Americans, and causes, directly or indirectly, 
five thousand deaths annually, but what especially concerns public health 
authorities is the increasing number of people with the disease. Between 
1980 and 1994 the incidence of asthma rose by 75 percent. In children 
under the age of five, asthma increased by 160 percent. 

The need to manage and control asthma is urgent. From an economic stand- 
point, the disorder is a major burden on the population. In the United States 
alone, it is estimated that the costs of asthma to the health care system are over 
six billion dollars a year. Nearly 500,000 persons are admitted to hospitals 
and 1.9 million visit hospital emergency rooms for asthma-related conditions 
each year. 

The National Institutes of Health has mounted a major effort to discover 
effective ways to manage and treat asthma by supporting and funding scientists 
conducting research on the disease throughout the world. Three Institutes 
lead the effort: the National Heart, Lung, and Blood Institute, the National 
Institute of Allergy and Infectious Diseases, and the National Institute of 
Environmental Health Sciences. Some examples of specific research projects 
currently underway include a study of the role of respiratory infections in 
childhood asthma, a study on the origins of asthma in early life, and a study 
on environmental intervention in the primary prevention of asthma 
in children. 

Asthma affects persons of all ages, races, and ethnic groups but not equally. 
In the United States, low income, minority, and disadvantaged inner city 
populations have significantly higher numbers of emergency room visits, 
hospital admissions, and fatalities due to asthma. This may be because of a 
higher level of exposure to environmental allergens and air pollutants. But it 
is also likely to reflect a number of complicating socioeconomic problems, 
such as the reduction in use and availability of health care services, a lack of 
education and guidance on management needs, and difficulties maintaining 
a management program, rather than a greater susceptibility to the disease. 

Courtesy National Institute of 
Allergy and Infectious Diseases 

Ir is not only in the United States that the prevalence of asthma is increasing. 
Asthma is on the rise practically everywhere in the world, with rates increasing 
in all age groups, but particularly in children. It is probably the most com- 
mon chronic disease in children, according to World Health Organization 
(WHO) data. 

The most striking increases are occurring in Australia, where about one- 
quarter of primary school children are diagnosed with asthma, a prevalence 
higher than in any other nation. In Western Europe asthma has doubled in 
the past ten years. In Switzerland 8 percent of the population suffer from 
asthma compared with only 2 percent twenty-five to thirty years ago. In 
Finland, from 1981 to 1996, the number of asthmatic sufferers increased 
threefold. In the Latin-American countries of Brazil, Costa Rica, Panama, 
Peru, and Uruguay, the prevalence of children with asthmatic symptoms is 
between 20 and 30 percent. In Japan there are an estimated three million 
asthma sufferers, in India there are fifteen million. The worldwide cost of the 
disease is greater than that of tuberculosis and AIDS combined, according 
to WHO. 

The situation is raising widespread concern among public health officials 
throughout the world, because the reasons for the increase in asthma 
are unknown. The WHO describes it as one of the "biggest mysteries 
in modern medicine." 

There is a general consensus that the increase is not a result of improved 
diagnosis, although that may account for some of it, according to the 
U.S. Centers for Disease Control and Prevention. 

Certainly there is no lack of hypotheses attempting to account for the 
increase. They include exposure to diesel fuel exhaust, diet, smoking, viral 
infections, cold air, the increase in obesity, changes in nutrition, and 
alterations in living patterns that have reduced physical exercise. 

One conjecture is that something has occurred in industrial countries in the 
past four decades that has resulted in some new environmental exposure. 
For example, housing construction practices have changed since the 1970s. 
People are more likely to be exposed to allergens at higher critical concentra- 
tions than in the past. At the same time, though, there are no reliable data 
on what these allergens might be. 

One view gaining increasing support is that there's been a change in the kinds 
of exposures that children are now experiencing early in their lives. This sets 
the juvenile immune system on track for an increased allergic response. 

Another theory includes an increase in air pollution and what has sometimes 
been called the hygiene hypothesis. In terms of chemical pollutants, it has 
been clearly demonstrated, for example, that components of diesel particles 
enhance allergic responses. The hygiene hypothesis focuses on the early 
treatment of infectious diseases and argues that it is to the benefit of infants 
and children to be exposed to endotoxins and to undergo some experience 
with infections, which have the potential to move them away from the 
allergic phenotype — susceptibility and aberrant immune responses to 
environmental allergens. 

The present consensus is that there are at least three factors that underlie 
asthma: the allergic response, viral infections, and air pollution. They can 
act singly or in concert in ways that are not yet fully understood. 

The story of our search for the causes of asthma is far from complete. There 
are basic biomedical and clinical aspects of the disorder that are obscure and 
need active investigation. Certainly, there are new tools available to scientists 
today, such as developments in molecular biology that allow detailed study 
of the immune response. Ultimately the results of such studies will help us 
understand the immune system and will put new therapies and avenues of 
management at the disposal of physicians and patients. 

But laboratory science, by itself, is unlikely to provide all the answers. To be 
successful, the attack on asthma will need scientific research, environmental 
studies, public health investigations, and improvements in health and medical 
services. Based on accumulating evidence, society will have to be willing to 
implement measures and adopt policies aimed at minimizing the disease. 

Courtesy National Institute of 
Allergy and Infectious Diseases 

48 National Library of Medicine 

The Faces of Asthma 

Asthma has many different faces: it is more than just the symptoms that patients experience. 
Asthma is also about people— individuals and their families, communities, health care providers, 
and medical scientists. 

Some people who have asthma benefit from current asthma treatments and achieve great honors 
in their chosen profession. Others learn to manage their asthma and lead full and productive 
lives. The faces of asthma are many and varied — some of these people may be your family 
and friends. 

Baruj Benacerraf (b. 1920) 

American immunologist and Nobel Prize winner 

Baruj Benacerraf shared the 1 980 Nobel Prize in medicine for his 
discovery of the genetic basis of autoimmune diseases. His child- 
hood experiences with asthma fostered his interest in immunology. 
Benacerraf continues his work at Boston's Dana-Farber Institute. 

Courtesy Baruj Benacerraf, M.D. 

Leonard Bernstein (1918-1990) 

American composer, conductor, and pianist 

As a sickly infant, Leonard Bernstein sometimes turned blue from 
asthma. He became a prodigious pianist, conductor, composer, 
and lecturer, although he suffered from asthma throughout his 
life. Audiences often heard him wheezing above the orchestra. 

Courtesy Carl A. Koenig 

Elizabeth Bishop (1911-1979) 

American poet, teacher, and author 

Elizabeth Bishop won almost every important literary prize of 
her day, while battling asthma unsuccessfully throughout her life 
with injections of adrenaline, calcium, and antihistamines. Her 
treatments also included transfusions, electroshock, cortisone, 
and alcohol — all to no avail. 

Courtesy Prints and Photographs Division, Library of Congress 

Breath of Life 49 

Bruce Davidson (b. 1949) 

American equestrian champion 

Bruce Davidson manages his allergic asthma with medications 
so he can continue to compete in equestrian events. He has won 
a silver and a gold Olympic medal, seven American and two 
world championships. 

Courtesy Bruce Hewitt/Getty Images 

Charles Dickens (1812-1870) 

British novelist 

Charles Dickens found relief from his "chest troubles" only 
with opium, a popular asthma remedy of his day. Mr. Omer, 
one of the asthmatic characters in the autobiographical novel, 
David Copperfield, reflects Dickens's own suffering. 

Courtesy Prints and Photographs Division, Library of Congress 

Benjamin Disraeli (1804-1881) 

British statesman and author 

For Benjamin Disraeli's disabling asthma, Queen Victoria's 
physician prescribed mustard poultices and a change of scene. 
Other physicians recommended arsenic, a popular new remedy, 
but all treatments were unsuccessful. 

Courtesy Prints and Photographs Division, Library of Congress 

Tom Dolan (b. 1976) 

American swimming champion and spokesperson for asthma 

Despite severe chronic asthma, Tom Dolan is a fierce competitor 
and often trains to exhaustion. He is an Olympic gold medallist 
and a world champion swimmer. 

Courtesy Reuters/Gary Hershorn/Archive Photos 

50 National Library of Medicine 

Robert Donat (1905-1958) 

British stage and screen actor 

Sudden explosive asthma attacks shortened Robert Donat's career 
and life, despite the efforts of physicians around the globe. Donat 
starred in dozens of films and plays, sometimes with oxygen tanks 
ready to treat his asthma. 

Courtesy of the Academy of Motion Picture Arts and Sciences 

Kurt Grote (b. 1973) 

American swimming champion 

Kurt Grote's doctor recommended he start swimming at age 
fifteen to help his chronic asthma. He won an Olympic gold 
medal in 1996 in the breast stroke. 

Courtesy Tony Duffy/Getty Images 

Ernesto (Che) Guevara (1928-1967) 

Argentine physician and freedom fighter 

Although he was weakened by asthma from infancy, Ernesto 
Guevara fought in three revolutions, sometimes using his rifle 
as a crutch. During a skirmish in Bolivia, he suffered an asthma 
attack, was captured by government troops, and executed 
shortly thereafter. 

Courtesy Prints and Photographs Division, Library of (Congress 

Moses Gunn (1929-1993) 

American actor 

Moses Gunn won nominations for a Tony and an Emmy award 
for his work on stage and television, in addition to awards for 
his Off-Broadway theater performances. During his final years, 
he required annual hospitalizations for asthma, and he died of 
complications of the disease. 

Copyright Washington Post; reprinted by permission of D. C. Public Library 

Breath of Life 

Helen Hayes (1900-1993) 

American actress and author 

Helen Hayes, often called the "First Lady of American Theater," 
made frequent trips to hospitals because of asthma attacks 
aggravated by backstage dust. When asthma ended her theatrical 
career, Hayes wrote books and raised funds for organizations 
that fight asthma. 

Courtesy Culver Pictures, Inc. 

Nancy Hogshead (b. 1962) 

American swimming champion and spokesperson for asthma 

Despite breathing difficulties, Nancy Hogshead won three gold 
medals and one silver in the 1984 Olympics. When a bronchial 
spasm kept her from winning medal number five, a physician 
discovered the problem was asthma. 

Courtesy Tony Duffy/Getty Images 

Robert Joffrey (1928-1988) 

American dancer, choreographer, producer, and teacher 

Robert Joffrey began dancing at age six to counteract his asthma. 
Founder of the Joffrey Ballet, a world-renowned innovative modern 
dance company, Joffrey battled lifelong asthma with acupuncture, 
herbs, and medications, but hardly ever missed a performance. 

Courtesy ©Herbert Migdoll 2002 

Jackie Joyner-Kersee (b. 1962) 

American track and field champion 

Olympic triple gold medalist Jackie Joyner-Kersee became the 
world's top woman athlete in the heptathlon and long jump 
competitions despite severe asthma. She retired from track 
competition after the 1996 Olympic Games. 

Courtesy Tony Duffy/Getty Images 


National Library of Medicine 


John F. Kennedy (1917-1963) 

Thirty-fifth president of the United States of America 

Asthma resulting from allergies to dogs, horses, and dust troubled 
John F. Kennedy throughout his adult life. Steroids prescribed to 
treat his Addison's disease probably also helped control his asthma. 

Courtesy John Fitzgerald Kennedy Library 

Alyce King Clarke (Alyce King) (1915-1996) 

American singer 

Best known as one of the four King Sisters, Alyce King performed 
for six decades with members of her musically gifted family. 
Asthma plagued her as a child and caused life-threatening attacks 
in her sixties and seventies. 

Courtesy Brown Brothers 

Bill Koch (b. 1956) 

American cross-country skier 

The only American ever to win the World Cup overall 
cross-country title, Bill Koch also won a silver medal at the 
1976 Olympic Games. He manages his asthma with medications. 

Courtesy David Cannon/Getty Images 

John Locke (1632-1704) 

British physician, philosopher, and scientist 

As a political leader, John Locke was drawn to London, the 
seat of English government. But persistent asthma, unrelieved 
by physicians, forced Locke to live in the country, away from 
London's polluted air and political life. 

Breath of Life 

Ernest (Dutch) Mortal (1929-1989) 

American political, legal, and civil rights leader 

Ernest Morial, a two-time mayor of his native New Orleans and 
pioneer in civil rights and government, broke the color barrier at 
every stage of his municipal and national career. Twenty-five years 
of asthma led to his untimely death at age sixty. 

Courtesy Marc H. Morial 

George Murray (b. 1947) 

American wheelchair marathon champion 

George Murray began racing in his chair to manage his asthma. 
He became world wheelchair marathon champion, was first 
to break the four-minute mile, and first to cross the country 
in a wheelchair. 

Courtesy AP/World Wide Photos 

Peter the Great (1672-1725) 

Russian czar 

An ambitious ruler with an insatiable drive to reform Russia, 
Peter the Great seemed unhindered by health problems. 
But during his last ten years, severe asthma and other diseases 
seriously hampered his ability to function and govern. 

Courtesy Hulton Getty/Liaison Agency 

Joseph Pulitzer (1847-1911) 

American publisher and philanthropist 

Although Joseph Pulitzer consulted physicians worldwide, none 
was able to remedy his asthma. After forty-three years of suffering, 
he died on the yacht the breezy deck of which often alleviated 
his breathlessness. 

Courtesy Prints and Photographs Division, Library of Congress 

54 National Library of Medicine 

Theodore (Teddy) Roosevelt (1858-1919) 

Twenty-sixth president of the United States of America 

Severe asthma made Theodore Roosevelt a sickly infant and 
a virtually homebound child. His parents tried all available 
remedies and traveled worldwide to find him a salutary climate. 
But it was vigorous exercise that helped turn him into a healthy, 
productive adult. 

Courtesy Prints and Photographs Division, Library of Congress 


Arnold Schdnberg (1874-1951) 

Austrian composer 

Undaunted by chronic asthma, acclaimed Viennese composer 
Arnold Schdnberg revolutionized music by composing in a 12-tone 
scale. Schonberg's healthiest, most productive years were spent 
in Los Angeles, far from the Nazi terror in Europe and the harsh 
winters that compounded his asthma. 

Courtesy Arnold Schdnberg Center, Vienna 

Martin Scorsese (b. 1942) 

American film director 

Martin Scorsese dropped out of seminary to study film. An 
asthmatic youngster, he watched movies on television and became 
an insatiable fan. Scorsese recently received the American Film 
Institute's Life Achievement Award. 

Copyright Washington Post; reprinted by permission of D. C. Public Library 

William Tecumseh Sherman (1820-1891) 

American general in the Civil War s Union Army 

Asthma was William Tecumseh Sherman's lifelong enemy. 
Ironically, although he led an infamously destructive march 
through Georgia, it was the Souths temperate climate that 
brought him relief from his symptoms. 

Courtesy Prints and Photographs Division, Library of Congress 

Breath of Life 55 

Howard Thurman (1900-1981) 

American clergyman, educator, and author 

Howard Thurman struggled against poverty and racism in the 
South as a child and against asthma in later years. He became 
a world-renowned spiritual and intellectual leader, pursuing a 
dream of unity — one community that would cross all lines of 
race, religion, and national origin. 

Courtesy the Howard Thurman Educational Trust 

Tseng Kuo-Fan (1811-1872) 

Chinese statesman, general, and scholar 

Tseng Kuo-Fan's asthma caused incessant coughing and an 
inability to work. Diagnosing a yin deficiency, his physician gave 
him "an excellent prescription, but I really detest medicine and 
therefore did not take it," Tseng wrote. 

Courtesy Prints and Photographs Division, Library of Congress 

John Updike (b. 1932) 

American writer 

John Updike, prolific writer of novels, poetry, short stories, 
and essays, thought he was dying during his first attack of 
breathlessness in his twenties. The diagnosis was bronchial 
asthma, aggravated by his cats. 

Courtesy Frank Capri/Archive Photos 

Amy Van Dyken (b. 1973) 

American swimming champion 

Amy Van Dyken's doctor suggested she start swimming to relieve 
her severe asthma. Diligent training and asthma medications 
helped her become the first American woman to win four gold 
medals in one Olympic Games. 

Courtesy Reuters/Gary Hershorm 'Archive Photos 

56 National Library of Medicine 

Benjamin Ward (b. 1926) 

American police commissioner and criminal justice specialist 

Brooklyn-born Benjamin Ward joined the New York City Police 
Department, the nation's largest, in 1951, becoming the city's first 
black police commissioner in 1984. He resigned after six years. 
"I am yielding," he wrote, "to the chronic asthma that has sapped 
my strength." 

Courtesy Benjamin Ward 

Harold D. West (1904-1974) 

American medical educator, administrator, 
scientist, and humanitarian 

As president of Meharry Medical College, Harold D. West 
fostered remarkable expansion of academic offerings, facilities, 
and endowments. West was plagued and often hospitalized 
by severe asthma, which hastened his death. 

Courtesy Meharry Medical College 

Edith Wharton (1862-1937) 

American novelist and short story writer 

Edith Wharton suffered from occasional bouts of asthma 
throughout her literary career. Wharton wrote short stories, 
travel books, and many successful novels, including 
Age of Innocence, which earned her a Pulitzer Prize in 1921. 

Courtesy Archive Photo 

Woodrow Wilson (1856-1924) 

Twenty-eighth president of the United States of America 

Exhausted by eighteen-hour work days at the Versailles Peace 
Conference, weakened by severe asthma, and impaired by 
arteriosclerosis, Woodrow Wilson was virtually incapacitated. 
Yet even after he was paralyzed by a stroke, his health problems 
were kept secret from the American public. 

Courtesy Prints and Photographs Division, Library of Congress 

Breath of Life 

Exhibition Credits and Acknowledgements 

The National Library of Medicine wishes to thank Sheldon G. Cohen, M.D. for his inspiration and persistence 
without which this project would not have been possible. In addition, the Library extends its appreciation to 
Anthony S. Fauci, M.D., Claude Lenfant, M.D., and Kenneth Olden, Ph.D., for their collaboration on this exhibition. 

Donald A.B. Lindberg, M.D., Director 
National Library of Medicine 


Elizabeth Fee, Ph.D. 
National Library of Medicine 
Exhibition Director 

Patricia Tuohy 

National Library of Medicine 
Head, Exhibition Program 

Robert A. Aronowitz, M.D. 

Robert Wood Johnson Medical School 

Visiting Curator 

Carla C. Keirns, M.D.-Ph.D. candidate 
University of Pennsylvania 
Visiting Curator 

Dot Sparer 
Athens, Georgia 
Exhibition Scriptwriter 

Edwina Smith 

Washington, D.C. 

Exhibition Graphics Coordinator 

Christina A. Popenfus 
Washington, D.C. 
Collections Manager 

Athena Angelos 
Washington, D.C. 
Image Researcher 

Michael Sappol, Ph.D. 
National Library of Medicine 
Research Consultant 

Abigail Porter 
Washington, D.C. 

Roxanne Beatty 

National Library of Medicine 

Bibliographic Researcher 

Carol Clausen, M.L.S. 
National Library of Medicine 
Conservation Coordinator 

Mary Parke Johnson 
Orange, VA 
Book Conservator 

Melanie Modlin 

Paul Theerman, Ph.D. 

Elizabeth Tunis, M.L.S. 

Anne Whitaker, M.L.S. 

National Library of Medicine 



Claude Lenfant, M.D. 
Director, National Heart, Lung, 
and Blood Institute 

Suzanne Hurd, Ph.D. 
Scientific Advisor 

Virginia Taggart, M.P.H. 
Exhibition Advisor 

Ellen Sommer, M.B.A. 
Exhibition Advisor 


Anthony S. Fauci, M.D. 
Director, National Institute of Allergy 
and Infectious Diseases 

Daniel Rotrosen, M.D. 
Scientific Advisor 

Marshall Plaut, M.D. 
Scientific Advisor 

Karen Leighty 
Exhibition Advisor 

Judy Crowell, M.P.A. 
Exhibition Advisor 


Kenneth Olden, Ph.D. 
Director, National Institute of 
Environmental Health Sciences 

George Malindzak, Ph.D. 
Scientific Advisor 

William Grigg 
Exhibition Advisor 


Sheldon G. Cohen, M.D. 
National Institute of Allergy and 
Infectious Diseases 

William H. Helfand 
New York, New York 

Esther Sternberg, M.D. 

National Institute of Mental Health 


Margaret Feng 
Candace Keirns, M.D. 
Rosita Lecuona 
Marta Melendez 
Ekaterini "Katy" Perry 
Roma Samuel 
Emanuel Stadlan, M.D. 
Anne Whitaker, M.L.S. 


Lou Storey 
Red Bank, NJ 
Exhibition Designer 

Exhibits Unlimited, Inc. 
Alexandria, VA 

Exhibition and Graphics Fabricator 

MFM Design 
Washington, D.C. 
Graphic Identity, Website, Brochure 
and Catalogue Designer 

Andrew Petitti 
Knowtis Design Inc. 
Graphic Designer 

Anne R. Altemus 

National Library of Medicine 

Audiovisual Coordinator 

58 National Library of Medicine 

Thomas I leld 

c iermantown, MI) 
Faces of Asthma Producer 

John M. Harrington 

Madison Film, Inc. 

Faces of Asthma Video Producer 

Renate T. Funk 

Rodel Productions, Inc. 

Erica's Story Audio Producer 

Kyle Chepulis 
Technical Artistry 

Video System Design and Lighting Design 
Young Rhee 

National Library or Medicine 
Online Resources Design 
and Programming 

Lillian Kozuma 

National Library of Medicine 

Online Resources System Design 

John Gibb 
Medical Illustrator 

Jennifer Parsons 
Medical Illustrator 

Jennifer N. Gentry Illustrator 

A dynamic interactive soccer game 
for young people that highlights facts 
regarding exercise-induced asthma. 

James S. Main 

Wun mi. il 1 ibrar) ol Medicine 

Anne R. Altemus 

National Library of Medicine 


Glive Downey 
EA Sports/FIFA 
Licensing Arrangements 

Thomas Held 
Germantown, MD 
Instructional Design 

Sonalysts Studios 

Graphic Design and Programming 


Mrs. Hella Altounyan and Family 
American Lung Association 
Daniel Aronowitz 
Robert Aronowitz, M.D. 


College of Physicians of Philadelphia 

Sheldon G. Cohen, M.D. 

Donna King Gonkling 

Kathleen Cravedi 

Dura Pharmaceuticals, Inc. 

Mrs. Margaret Egeberg and Family 

Joe Fitzgerald 

Food and Drug Administration 
Glaxo Wellcome Inc. 
Global Equipment Company 
Asal Goldschmidt 
Miss Sylvia Grauer, in memory 

of Miss Rhoda Grauer 
Maxcy G. Hanna II 
William H. Helfand 

The Johns Hopkins Medical Institutions, 

The Alan Mason Chesney 

Medical Archives 
Candace Keirns, M.D. 
Library of Congress, African and Middle 

Eastern Division, Hebraic Section 
Dr. and Mrs. M. Stephen Miller 
Melanie Modlin 

Mutter Museum, College of Physicians 

of Philadelphia 
National Jewish Medical and 

Research Center 
National Museum of Health and Medicine- 
Nat ra Bio'"- 

New York Daily News 

New York Transit Museum 

New York University Medical Archives, 

Frederick J. Ehrman Medical Library 
National Heart, Lung, and Blood Institute 
National Library of Medicine 
Parke-Davis Pharmaceutical Research 

Division Library 
Christina A. Popenfus 
Newsweek Inc. 
Rhone-Poulenc Rorer Inc. 
Rhone-Poulenc Rorer Ltd. 

Schering-Plough Corporation 
Smithsonian Institution, National 

Museum of American History 
Spirometries Medical 

Equipment Company 
University of California, San Diego, 

Medical Center 
University of California, San Francisco, 

The Library and Center for 

Knowledge Management 
University of Michigan, Historical Center 

for Health Sciences 
University of Pennsylvania, Walter H. and 

Leonore Annenberg Rare Book and 

Manuscript Library 


Academy Foundation 
Stephen (Steve) Allen 

Allsport* Photography (USA). Inc. 

American Lung Association 

AP/Wide World Photos 

Archive Photos 

Brown Brothers, Sterling, PA 

The British Museum 

Albert Bonniers Fcirlag 

Angelika Buske-Kirschbaum, Ph.D. 

Children's Television Workshop 

College of" Physicians of Philadelphia 

Sheldon G. Cohen, M.D. 

Francis A. Countway Library of Medicine 

Culver Pictures Inc. 

The Dallas Morning News 

The Denver Public Library 

District of Columbia Public Library, 

Martin Luther King Memorial Library 
Alan M. Edwards, M.D. 
FPG International 
Glaxo Wellcome Inc. 
Harvard University, Economic Botany 

Library of Oakes Ames 
Hulton Getty/Liaison Agency Inc. 
John Fitzgerald Kennedy Library 
The Johns Hopkins Medical Institutions. 

The Alan Mason Chesney 

Medical Archives 
Library of Congress, Prints and 

Photographs Division 
Library of Congress, Geography and 

Map Division 
Mayo Clinic Scottsdale, Charles B. 

Carrington Memorial Pulmonary 

Pathology Leaching Collection 
Meharry Medical College 
The Metropolitan Museum of Art 
Herbert Migdoll, Joffrey Ballet of Chicago 
Jon Naso, New York Daily News 
National Archives and 

Records Administration 
National Jewish Medical and 

Research Center 
National Library of Medicine, 

History of Medicine Division, 

Prints and Photographs Collection 
New York Philharmonic Archives 
National Heart, Lung, and Blood Institute 
National Institute of Allergy and 

Infectious Diseases 
National Institute of Environmental 

Health Sciences 
National Institute for Occupational Safety 

and Health 
Eric O'Connell 
Katherine Ott, Ph.D. 
Pan American Health Organization/ 

World Health Organization 

Rockefeller University 
Saranac Lake Free Library 
David Scharf 

Arnold Schonberg Center, Vienna 
Science Source/Photo Researchers 
Esther Sternberg, M.D. 
Teresa Teng Foundation 

Breath of Life 

Uniphoto Picture Agency 
University of California, San Diego, 

Medical Center 
Benjamin Ward 
Jean Weisinger 
Ann J. Woolcock, Ph.D. 


Peter L. Allen, Ph.D. 

Al Abrams, Bethesda MD, print broker 

Bridie Andrews, Ph.D., Harvard University 

Liz Antry, Dalloz Safety 

Janet Banks, Glaxo Wellcome Inc. 

Rosalynn Benson, National Human 

Genome Research Institute 
Abigail Bosk 
Charles Bosk, Ph.D., 

University of Pennsylvania 
Emily Bosk 

The Collateral Group, Baltimore, 

brochure printer 
Chandra Buie, New York Transit Museum 
Caron Capizanno, New York University 
Medical Archives, 

Frederick J. Ehrman Library 
Judy Chelnick, National Museum 

of American History, Smithsonian 

Kim Clough, National Institute for 

Occupational Safety and Health 
Thomas V. Colby, M.D., Department of 

Pathology, Mayo Clinic of Scottsdale 
Luke Demaitre, Ph.D., 

University of Virginia 
Luigi Di Rico, 

Global Equipment Company 
Carol Doughty, Spirometries Medical 

Equipment Company 
Alan M. Edwards, M.D., 

Vectis Allergy Ltd., England 
Steven Feierman, Ph.D., 

University of Pennsylvania 
David Fridberg, MFM Design 
Veronica A. Graham, Glaxo Wellcome Inc. 
Charles B. Greifenstein, Curator, 

College of Physicians of Philadelphia 
Cedric F. Grigg, Medical/Science Focus 

Groups & Education, New York 
Veronica G. Grosshandler, 

Glaxo Wellcome Inc. 
Li Gwatkin, National Jewish Medical 

and Research Center 
John Hart, M.D., Rhone-Poulenc 

Rorer Ltd., England 
Thomas F. Harrington, 

New York Transit Museum 
Andrew Harrison, The Johns Hopkins 

Medical Institutions, The Alan 

Mason Chesney Medical Archives 
Alan Hawk, National Museum of Health 

and Medicine 
Tish Holbrook, MFM Design 
Keith Johnson, Cardionics 

Tambra Johnson, Library of Congress 
Ruth Kasloff, American Lung Association 
Maneesha Lai, Ph.D., 

University of Wisconsin 
Margaret L. Lyman, Mutter Museum, 

College of Physicians of Philadelphia 
Greg Mann, Dura Pharmaceuticals, Inc. 
Patricia Mansfield, National 

Museum of American History, 

Smithsonian Institution 
Howard Markel, M.D., Ph.D., University 

of Michigan, Historical Center for 

Health Sciences 
Laurie McCarriar, McCarriar Graphics 
Russell R. McGuire, American Society of 

Composers, Authors and Publishers 
Christopher Meehan, University of 

Michigan, Historical Center for 

Health Sciences 
Nicole Mitchell-Weed 
Jon Naso, New York Daily News 
Delia Naughton, 

American Lung Association 
William Obermeyer, Ph.D., Food and 

Drug Administration 
Samuel Page, Ph.D., Food and 

Drug Administration 
Pan American Health Organization 
Deborah Parrish, Priorities® 
Wendy P. Phipps, Rhone-Poulenc 

Rorer Ltd. 
Charles Rosenberg, Ph.D., 

Harvard University 
Michael T. Ryan, M.D., University of 

Pennsylvania Van Pelt-Dietrich Library, 

Department of Special Collections 
Charles L. Sachs, New York 

Transit Museum 
Nathan Sivin. Ph.D., 

University of Pennsylvania 
Lisa Sparer, New York Daily News 
Tom Stewart, Exhibits Unlimited, Inc. 
Joanne Eunhee Suh, M.D., University of 

California, San Diego, Medical Center 
Wendy Thurman, National Museum 

of Health and Medicine 
Steve Turner, National Museum 

of American History, 

Smithsonian Institution 
Jeff Watts, Arlington VA, 

catalog photography 
Luise White, Ph.D., University of Florida 
Leona Williams, Parke-Davis 

Pharmaceutical Research 

Division Library 
( Iretchen Worden, Mutter Museum, 

College of Physicians of Philadelphia 


Bill Boyd, Systems Support, 
National Library of Medicine 

Linda Brown, Medical Arts 
and Photography Section, 
National Institutes of Health 

Becky Cagle, Website Designer, 

National Library of Medicine 
Pat Carson, Special Assistant to the 

Director, National Library of Medicine 
Kathleen Gardner Cravedi, 

Public Information Officer, 

National Library of Medicine 
Bob Cross, Facilities Coordinator, 

National Library of Medicine 
Michael J. Detweiler, Editor, 

National Library of Medicine 
Rebecca Dittmar, Library Associate, 

National Library of Medicine 
Joe Fitzgerald, Graphic Designer, 

National Library of Medicine 
Friends of the National Library 

of Medicine 
Adam Glazer, Reference Librarian, 

National Library of Medicine 
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National Institutes of Health 
Alvin Harris, Deputy Chief, Office of 

Administration, National Library 

of Medicine 
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National Heart, Lung, and 

Blood Institute 
Troy M. Hill, Graphic Designer, 

National Library of Medicine 
Betsy L. Humphreys, Associate Director, 

National Library of Medicine 
Karlton Jackson, Staff Photographer, 

National Library of Medicine 
Bill Leonard, Producer, 

National Library of Medicine 
Lockheed Martin Technical Support 
James S. Main, Chief, Audiovisual 

Program and Development Branch, 

National Library of Medicine 
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Communications and Public Liaison, 

National Library of Medicine 
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Melanie Modlin, Public Affairs Specialist, 

National Library of Medicine 
Donald C. Poppke 
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Administrative Officer, 

National Library of Medicine 
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Arts and Photography Section, 

National Institutes of Health 
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National Library of Medicine 
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National Heart, Lung, and 

Blood Institute 
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National Library of Medicine 
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Theodore E. Youwer, Chief, Office of 
Administration, National Library 
of Medicine