Asthma

Asthma war gar nicht so schwerwiegend in der Vergangenheit. Die heutige Behandlung ist blinder Aktionismus. Siehe
A HISTORICAL ACCOUNT OF DEATH FROlVI ASTHMA
Il. I,. Alexander, X.D.,* St. Louis, Xo.
ENOUGH material has now accumulated on the subject of death from asthma
to formulate an appraisal of it. The history of bronchial asthma dates back
to the ancients. The literature is characterized by periods in which observers
presented concise descriptions of the disease as well as intervals in which it
could not be distinguished from many disorders to which the designation
“asthma” had been applied. However, clear records hare been available since
the latter half of the last century, a time when extensive anatomical and physiological
experimentation on bronchial occlusion was performed, particularly in
Germany and in France.
One may now recognize three periods during which the occurrence of death
from asthma showed a characteristic trend. The first is measured by a century,
the second by a few decades, and the third by a few years.
In assembling available material on the subject, it became necessary at the
outset to establish a precise definition of death from asthma. Some asthmaties
die eventually from a complication of the disease. A small number succumb
from the immediate lesions of asthma during a paroxysm, and these are the cases
with which this report is concerned. At first, patients were limited to those in
whom lesions were revealed at postmortem examination. Some who died during
a paroxysm and on whom no autopsy had been performed were then compared
to the first group in terms of age, age of onset, and duration of the diseasr.
The two groups were almost identical in these respects, so they were combined.
Although it is realized that, in the absence of post,mortcm examinations, there
mny have been concealed factors that contributed to death, t,hese would not
contradict the findings of this report.
Cases in which death inadvertently was due to drugs, to the administration
of excessive amounts of allergens, or to other causes that did not reflect
t,he natural history of the disease were excluded.
THE FIRST PERIOD
Of the recognizable periods into which fatalities have been separated, thtb
first ended about the year 1930. Prior to this date, death during an asthmatic:
attack was almost unknown. To be sure, in that era there was less clinical
material in terms of hospital populations, fewer autopsies, fewer medical periodicals, and fewer opportunities to present cases at medical meetings, compared
to facilities of the present day. Moreover, in the earlier years there
were no allergists with a particular interest in asthma. Nevertheless, the evidence
that death during an asthmatic paroxysm was exceedingly uncommon
is overwhelming.
Perhaps the earliest recorded recognition of this phenomenon is the often
quoted remark of Trousseau who lived during the first half of the last century,
“Asthme n’est pas fata,le.” Andral in his Cours de Pathologie, published
in 1839, made the quaint statement that asthma is a brevet of long life. Oliver
Wendell Holmes, commenting on his own symptoms, said essentially the same
thing, and there is an aphorism of Osler, “The asthmatic pants into old age. ”
This belief was amply documented in textbooks and didactic teaching of
the day, both in this country and abroad. In Riegel and Fraentzel’s Handbuch
der Respirations, published in 1877, the statement is made that rarely is life
threatened during an asthmatic attack. No mention of death is made in the
chapter on asthma by Hyde Salter in Reynolds System of Medicine that appeared
in 1880. Strtimpell’s Textbook of Medicine published in 1888 states,
“There is hardly ever any danger to life, even in the most intense paroxysms.”
In Stedman’s extensive Twentieth Century Practice of Medicine of 1896, the
following appears: “Although paroxysms of asthmatic dyspnea are so alarming
to witness, death rarely, if ever, occurs during a fit.” Andral’s Practice of Medicine,
1899, states, “There is rarely any danger to life excepting emphysema.”
In Albutt and Rolleston’s System of Medicine, published 10 years later, the
chapter on asthma, written by Goodhart and Springgs, does not mention death.
Ameville and Bordet wrote the chapter on asthma in Trait4 Pathologia Me’ditale
et Therapeutique Applique’e compiled by Rabideau and Babonneix and published
in 1922. They stated, “Asthmatic paroxysms by themselves do not lead
to any danger.”
In the earlier years of this century, this doctrine was adhered to in leading
medical schools in this country. Particularly important, with one minor exception,l
is the absence of any other point of view in the literature of the day.
In 1922 a classical article by Huber and Roessler2 appeared. These authors
had assembled all of the published autopsy reports of death from asthma in
which microscopical examinations had been made. There were but 15 in all to
which they added 7 more. A review of these cases3 indicated that most of the
patients did not die primarily from asthma, but from causes such as acute complications
of cardiac and renal diseases, disseminated cancer of t,he lung, and,
in one case, drowning. With this revision, there were but eleven deaths primarily
from asthma recorded by the year 1926. Some new reports were published
before 1930, but by that year no more than 30 cases of death occurring
during an asthmatic paroxysm are on record.
THE SECOND PERIOD
During the succeeding 25 years there was, at first, a gradual increase in
the number of reported deaths from asthma (187 instances had been assembled
in 1937, without distinguishing those in which death occurred in
status asthmaticus), and after that there was an acceleration in the number
of fatalities. Experiences in several hospitals and clinics were published where
death during a paroxysm of asthma was recorded. There were 19 such instances
at the Massachusetts General Hospital (1944) ,4 37 at Barnes Hospital
in St. Louis, 36 at the Mayo Clinic, 5 101 reported from Cardiff, Wales6 and 49
at the Westminster Hospital in London,’ including some previously reported
cases. These instances averaged approximately 20 per cent of the total deat’hs
from asthma which included deaths from complications.
According to the National Vital Statistics Division of the United States
Public Health Service, under the designation “Deaths from Asthma,” the peak
occurred between the years 1951 and 1953. During the latter year there were
6,737 such deaths, and in this period the death rate rose from 2.5 per 100,000
population in 1937 to 4.5 in 1951.
More dramatic still was the New Zealand experience where the death rate
from asthma rose from 1.7 in 1939 to 10.4 in 1953. Although no distinction was
made concerning those which occurred during a paroxysm, in view of the
average percentage stated in other series, the actual numbers of such deal,hx
may have been considerable.
Comparative data between the first and second periods were found to be
of a wholly different order of magnitude.8
THE THIRD PERIOD
Approximately after the year 1953, there appeared to be a decided
diminution in the number of asthmatic deaths. It is difficult to estimate how
great the decline may have been for there is little literature on the subject.
Perhaps so much had been published previously about deaths from asthma
that further accounts were no longer newsworthy, or there may have been too
few deaths to report. In one of the few publications on the subject,D the decrease
in fatal cases is noted and, according to vital statistics, deaths from
asthma dropped from a rate of 4.5 in 1951 t,o 3.6 in 1955 and 2.8 in 1959.
The apparent abrupt decline in fatalities appeared at a time when cortisone
and related hormones were coming to be used extensively in the treatment
of asthma. It seems probable, and this is the opinion of others,” that
these products were largely responsible for reversing the trend. At the Barnes
Hospital, where 4 asthmatics on the medical wards succumbed during
paroxysms in 1949, such deaths have been negligible since 1951 when hormone
therapy was instituted. Time alone will tell whether the decreased death
rate will continue.
There well may be other reasons for the apparent diminution of fatalities
in comparison to the incidence during the second period, but expla.nations
for this must be postponed until the cause of the acceleration during that
period is revealed.
POSTMORTEM OBSERVATIONS
Until some 25 years ago there were few decisive observations concerning
the cause of death in bronchial asthma. The prevailing theory implicated
bronchial constriction from contraction of the bronchial musculature. There
was considerable experimental support for this presumption, dating back to
the last century. Hubcr and Koessler2 found hypertrophy of the bronchial
muscles in asthmatics that came to autopsy, and this they interpreted as an
indication of frequent contraction. These authors described, although without
emphasis, other postmortem lesions.
It was later realized that several of the anatomical findings described by
Huber and Koessler were not specific for asthma, and other theories of etiology
were debated. In 1930, Coke”’ wrote, “Pure asthma, no matter how
severe the spasm leaves little to be found post-mortem and no evidence on
which the condition can be diagnosed or which in the absence of a clinical
history, the patient can be said to have died from asthma.” In Coca, Walzer,
and Thommen’s classical treatise Asthma and Hay Fever in Theory and Practice
published in 1931, it is stated that the reason so few deaths had been reported
was that no pathological entity existed. Tuft, in the 1937 edition of his
Clinical Allergy, said essentially the same thing, but he recognized a few lesions
that appeared consistently in reported cases. Moreover, he listed one group of
fatal cases in which suffocation had been attributed to excessive mucus, a
significant observation.
As more autopsy material became available, it was increasingly evident in
cases in which death occurred during a paroxysm that the conspicuous lesion
was partial or complete occlusion of bronchioles by mucus. It was Mallory
who demonstrated this fact conclusively in a lecture before the Society for
the Study of Ast,hma and Allied Conditions in 1941.
Although abundant mucus has been reported in a large majority of
autopsies in which death occurred during a paroxysm, it has not been observed
in some cases. Although other lesions, such as the accumulation of
products of infection which is frequently present along with probable bronchospasm,
may encroach upon the airways, it is difficult to assess their contribution
to the suffocation that occurs during an asthmatic attack. It may
be noted that the distribution of mucus can be irregular so that it is seen only
in some sections of bronchioles. In these instances, it becomes necessary to
examine sections of bronchi at various levels before the participation of mucus
can be excluded. The presence of emphysema or car pulmonale has not been
regarded as important in contributing to immediate death, since in many cases
these lesions were present to no more than a moderate degree, if at all. This
was particularly true where the duration of symptoms was short.
In view of the importance of bronchial mucus in status asthmaticus, it
seems remarkable tha.t until the past decade no systematic study of this material
or of the mucous glands in asthma had been published. One recent significant
observation revealed the distinction between normal bronchial mucus
and that which appears in asthma and chronic bronchitis. The former contains
a mucoprotein in the form of a mucous gel. The mucus in asthma contains, in
addition, desoxyribonucleoprotein (DNP) derived largely7 from the nuclei
of desquamated and inflammatory cells. The DNP is thought to be drawn out
into thick tough bundles by respiratory and ciliary movements. With infec-
DEATH FROM ASTHMA 30!4
tion, the large numbers of inflammatory cells greatly enhance t,his effecat.
An early observation, which later was rtgardetl of much importance. was
made by Moore” in 1925. He was concerned with ciliated bronchial rpithelium
in asthma. Moore referred to the studies of Moffatt, then in press. Both t,hese
authors pointed out that cilia which have a rrmarkable ability to move mucus
may be impaired in bronchial asthma. The cells t,o which these bodies a~*(~ attached
form the outermost cpithelial layer ant1 may bc tlisplaccd easily. If
asthma is not, intmse, regeneration may OWUI’ ; but, when scvcrc, thcrcl may
be actual loss of cilia with degeneration of the epithclial cell. Some 20 years
later, Hiltlig” enlarged upon these observations and demonstrated clearly thts
degeneration and tlcsquamation of ciliated cpithclium in the prcscnct~ 01
excessive mucus. These findings wcrc t~laborat&l further by Houston and his
a.ssociates.‘” They found instances where thcrc was a continuous mass of mucus
extending from the major bronchi to the bronchiol(~s with some separation
from the walls. These authors stated it is not genc>rally apl)rcciated that widcspread
detachment of ciliated epithelium is a constant finding in death l’rom
status asthmaticus. They believe the dcstructiol) of the ciliary mechanism
permits mucus to accumulate and thus cause suffocation.
From a historical point of view, mention should be tnade of a substantial
literature in which death during a paroxysm of asthma had been attributecl
to opiates to a point where, at one time, it was considered essentially the solo
cause of exitus. Undoubtedly many fatalities have occurred -from ovcrsedation.
but no good systematic study of the problem is available. It is of some int,rrtbst
that, before the introduction of rpinephrint~, tnorphinc was the trratmcnt OI
choice for asthmatic paroxysms, and addiction was not uncommon ; and this
was at a time when deaths from asthnta w(‘rc .1’ow.
CLINICAL DATA
In several reported series of deaths during status asi,hmaticus,“, :, 14 there is
close agreement with ages at death and ages at onset, of symptoms, from which
the duration of the disease was derived. Average figures indicate that some 10
per cent of fat,alities occurred in infants and rhildren under 2 years of age, and
a few more up to the age of 5 years. Then there was a long period of comparative
immunity during the following 30 years wherein less than 15 per cent ol
the total deaths occurred. ,4t the age of 35, the rat,e began to climb and somt’-
what over 50 per cent of the fatalities appeared bet,wcen the fortieth and sixtieth
year of life.
Excluding t,hose under 2 years of age, statistics indicate that, over 15 pet
cent of those who died during status asthmaticus had asthma less than one year.
This highly malignant process is matched by few chronic diseases. Thirty-t,hrer
per cent had symptoms no more than 2 years and in some 50 per cent, thcl diseascl
was apparent less than 5 years. In these instances, asthma was scarcely “a brevet
of long life. ”
There was a striking difference between the images of most of those who
died in an acute attack and those who had the familiar syndrome of asthma ant1
July-August, 1963
bronchitis for many years and died eventually from emphysema, infection, or
of something else.
Although detailed descriptive case reports are not abundant, it appears that,
in addition to onset in middle age and comparatively short duration of symptoms,
very many patients had an initial respiratory infection, and a similar
process ushered in subsequent acute asthmatic attacks. It was not possible to
assess the participation of atopic factors, other than the frequent statement that
none was found. This pattern conforms to the criteria described as “intrinsic” or
“infectious” asthma.
The associat.ion of apparent infectious asthma with many immediate deaths
led to a review of this type of the disease, particularly in the earlier years when
deaths were few. From available case histories, the majority of fatalities at that
period seemed to be in patients with infectious asthma. However, there is reason
to believe that there was a decided increase in this syndrome in subsequent years,
at the time that the death rate was accelerating. Although this type of the disease
existed, certainly, it was not recognized in the early years of clinical allergy.
Classifications of asthma at that time by Cooke,15 Walker,“j and RackemanrP
separated those who were sensitive to extrinsic allergens from those who were
not. The latter group was ident,ified with designations such as “intrinsic,” “bacterial,”
“reflex,” “ unclassified,” etc., and in one series this group had the highest
incidence before the age of 10 years.
It was not until 1940 that the pattern of infectious asthma was clearly
presented. Rackemann I8 then described the syndrome (he used the term “intrinsic
asthma”) and pointed out its seriousness. He recorded in a later series
283 such cases with 20 deaths whereas there were no fatalities in 2,000 instances
of atopic asthma. He described two expressions of infectious asthma
in which the duration was not short. One was typical “extrinsic” asthma in
early years of life, followed by a free interval of many years. When asthma
recurred in middle age, the atopic element no longer could be detected and the
case took on the pattern of “intrinsic” asthma, namely, its appearance in the
middle decades, the tendency to increased severity of symptoms, association
with respiratory infections, and resistance to specific treatment. There were
also instances of continual asthma in which hypersensitivity to specific allergens
in earlier years seemingly became lost and intrinsic asthma ensued.
Soon after Rackemann’s communication, there were others who described
the syndrome.ls, 2o That it was not well known at the time is reflected in three
textbooks on asthma that appeared a few years later in which intrinsic asthma
received scant attention and there were prominent allergists who questioned
its existence and attributed specific etiologies in terms of allergy to. these cases.
An apparent increase in the incidence of infectious asthma during the
ensuing years, when fatalities rose, is indicated in the Barnes Hospital experience.
The records of all patients who entered with a primary diagnosis of
bronchial asthma over a period of 35 consecutive years (1924-1958) were reviewed.
There was a striking contrast between the number of admissions
identified with infectious asthma in the earlier period when compared to that
of the later years of the series. In 1924 they constituted 20 per cent. Although
the hospital had been in operation at that time for 8 years, no deaths from
asthma had occurred. Most of the patients were young ancl specific hypersensitivity
was commonly found. (Adults only are admitted.) There was a gradual
increase of cases identified as infectious asthma which in 1958 constituted
slightly over 70 per cent of admissions. The average age was 51 years. After
factors such as an aging population and more available beds for older patients
arc taken into account, the difference in the incidence of admissions of cases
of infectious asthma seen in the earlier years and that of the later periods is
evident.
DISCUSSION
From the data presented, it would appear that t,he characterization of
bronchial asthma was transformed from a benign to a malignant disease during
the past few decades. The symptoms of the disorder do not appear to have
changed except in their intensity.
There is reason to believe that in the first period, when deaths were Sew,
most cases of asthma were atopic. In the Barnes Hospital series a large majority
of asthmatics admitted in 1924 had this type of the disease. Had infectious
asthma been prevalent at the time, patients with it would have sought hospital
care just as they did in the following decades. Death in uncomplicated atopic
asthma is a very unusual event if one excludes infants and accidents, such as
occur in drug hypersensitivity. Few deaths have been described, and Rackemann’s
observations on 2,000 consecutive cases of this type of asthma without
fatality is impressive.
The recognition of the clinical pattern of infectious asthma came later.
According to a few early case histories of death from asthma, this type of the
disease apparently existed. That it was not prevalent at the time, however, is
indicated by its omission from several early classifications of asthma. The
designation “intrinsic” then referred, in part, to the chronic asthmatic with
emphysema and bronchitis (who panted into old age), a familiar figure, particularly
in out-patient clinics.
Not only were there differences in clinical patterns and in death rates t,o
be observed in the first and later periods, there was also a marked discrepancy
in autopsy observations. The repeated statements 30 years ago that there was
no discernible lesion, post mortem, in cases of bronchial asthma is in sharp
contrast to t,he striking appearance of bronchial occlusion by mucus seen suhscquently
in most cases in which death occurred during paroxysm.
The recognition of infectious asthma with which most fatalities arc associated
and the identification of excessive mucus as the cause of suffocation
during an asthmatic paroxysm were both reported approxirnat,ely the same
year. A relationship between the two phenomena is no more than suggestive
since the underlying factors that mediate infectious asthma remain unknown.
From the standpoint of etiology, one consistent factor is its identification with
infection of the respiratory tract. Bronchial infection, however, has long been
recognized as a common complication of asthma so that. one might inquire
whether the patterns of infections may have changed. This seems to be the case.
312 ALEXANDER J. Allergy
July-August, 1963
The years that marked the apparent increase of infectious asthma were
also historical ones in the field of infectious diseases. With the expanding use
of chemotherapeutic agents, particularly of antibiotics, certain bacterial infections
susceptible to these products gave way to disorders dominated by
gram-negative organismsZ1 ; viral pneumonia and unrecognized diseases of the
respiratory tract became clinical ent,ities; and, with newer culture methods,
an ever widening spectrum of virus infections continues to unfold.
One scarcely can speculate whether death from asthma may have been
influenced by these changes. There is little evidence that allergy to bacteria
or viruses plays an important role. However, certain possibilities suggest themselves.
One is related to the discovery that destruction of cilia, the presumable
cause of death during status asthmaticus, occurs in some virus infections of
the respiratory tract. Hers and MuldaZ2 clearly showed this in influenza1 infection
in man. Likewise, denudation of cilia-bearing cells, ciliocytophthorea,
has been found in many cases of respiratory infections identified with adenoviruses.Z3
Moreover, some respiratory infections add DNP to asthmatic sputum
and thus make it more difficult to discharge the mucus.
These off-hand suggestions merely serve to indicate how much remains to
be learned about why patients with asthma died, some so quickly, during the
years under consideration.
REFERENCES

Walzer, M.: Coca, Walzer, and Thommen in Asthma in Theory and Practice, Springfield,
Ill. 1931, Charles C Thomas, Publisher, p. 136.
Huber k., and Koessler, K. K.:
.‘,‘m
The Pathology of Asthma, Arch. Int. Med. 30: 689,
.lYijZ.
Rackemann, F. M.: Fatal Asthma. Report. of a Case With Autopsy, Boston M. & S. J.
167: 809 1926.
Rackemann, F. M.: Death From Bronchial Asthma J. ALLERGY 15: 249 1944.
Messer J. W Peters J. A and Bennett W. A.: ‘Causes of Death and Pathological
F$dinas”in 304 %ases zf Bronchial Asthma. Dis. Chest 38: 616. 1960.
Williams, 6. A., and Leopold, J. G.: Death F&m Asthma, Tr. 3rd Internat. Gong.
Allergol., Paris, 1958, p. 119.
Earle. B. V.: Fatal Asthma. A Series of 15 Cases With a Review Frbm the Literature,
Thorax 8: 195, 1953.
Bachelor, J.: Statistician, Consultant, Operations research. Personal communication.
Sheldon, J. M.: An Allergist’s Rebuttal to Oliver Wendell Holmes, Proc. Medical Section
of American Life Convention, 46th Meet., 1958, p. 105.
Coke, F.: Asthma, Baltimore, 1930, Williams & Wilkins Co., p. 89.
Moore. W. F.: Ciliarv Inhibition or Destruction in Tracheobronchial Asthma. Am. J.
id. SC. 169: 799 1925.
,
Hildig, A. C.: The Relation of Ciliary Insufficiency to Death From Asthma and Other
Respiratory Diseases, Ann. Otol., Rhinol. & Laryngol. 52: 5> 1943.
Houston. J. C.. de Navesauez. S.. and Trounce. J. R.: A Clinical and Pathological
Study of Fatal Cases-of ‘Status Asthmatic&, Thorax 8: 207, 1953.
Alexander, H. L.: Death From Bronchial Asthma, Tr. 3rd Internat. Cong. Allergol.,
Paris; 1958, p. 109.
Cooke, R. A.: Studies in Hypersensitiveness. New Etiologieal Factors in Bronchial
Asthma, J. Immunol. 7: 147, 1922.
Walker. I. C.: A Clinical Studv of 400 Cases of Bronchial Asthma, Boston M. & 5. J.
159: 288, 1918.
17. Rackemann, F. M.: ‘A Clinical Classification of Asthma, Am. J. M. SC. 162: 202, 1921.
18. Rackemann, F. M.: Intrinsic Asthma, J. ALLERGY 11: 147, 1940.
19. Alexander, H. L.: Allergic Syndromes in the Absence of Allergens, J. ALLERGY 11:
163, 1940.
20. Cohen, M. B.: Bronchial Asthma. Classification Based on Etiological and Pathogenic
Factors, Ann. Int. Med. 20: 590, 1944.
21. Finland, M., Jones, W. F., and Branes! M. u’.: Occurrence of Serious Bacterial In22.
Hers,
fections Since Introduction of Antibacterial Agents, J. A. M. A. 170: 2188, 1959.
J. F., and Mulder, J.: Broad Aspects of thP Pathology and Pathogpnesis of Human
Influenza, Am. Rev. Resp. Dis. 83: 84, 1961.
23. Pierce, C. H., and Hirsch, J. G.: Ciliocytophthorea. Relationship to Viral Respiratory
Infections in Humans, Proc. Sot. Blol. &- Med. 104: 492, 1960.
With the author’s approval, a number of interested people were
asked to comment on Dr. Alexander’s stimulating and challenging
article. The following are being published in the order of their receipt
in the hope that it will increase interest in this type of article and result
in the submission to the Journal of others of equal caliber.
EDITOR
COMMENTS ON PRECEDING ARTICLE
D R. ALEXANDER’S paper is an excellent review, and it contains a number of
interesting implications. Fkst, he finds that the incidence of death from
asthma varies according to three periods of history.
In the first period, ending about 1930, all the textbooks of that epoch
agree that deaths from asthma do not occur. After that time, however, deaths
were recognized. Is there reason to think that in the nineteenth century
asthma was different from what we see of it in the twentieth century? Can
we assume that in “the old days” people were more exposed to “house dust”
of various kinds than they are in this modern time? It is true that bathtubs
were scarce--people were dirty ; streets were dusty ; animals-horses as well
as dogs and cats-were everywhere. I can recall that in 1.920 asthma causetl
by horses was a common affliction. It is quit,e proper to assume t,hat extrinsic
asthma due to a sensitiveness to dusts in the environment was more common
then than it is today, and now we know that this type of asthma is not often
dangerous.
On the other hand, older people must have had asthma then as now, and
presumably it was quite as serious and as dangerous then as it is boday. Was
it called asthma? The sudden onset of difficult breathing at the age of 50 was
probably ascribed to heart disease, or emphysema, or perhaps “fibrinous bronchit,&,”
but it was very likely the same disease that today I call “intrinsic
ast,hma” ; it was due to infection.
In Dr. Alexander’s second period-after 1930-deaths from asthma were
recognized and described, but in the third period, beginning about 1953, t,hey
fell off again. It is obvious that this later cha.nge has depended upon t,he use
of cortisone and its relatives in treatment. (~‘ertainly the steroid drugs have
done much to remove the terrors of status asthmaticus.
As for the lesion in asthma, there is, first of all, good evidence that
asthma-the wheezing-is a symptom of a constitutional disease, the tendency
to which is inherited. Besides asthma, the disease includes eczema of the atopic