1970-2000: Does rescue medicine make asthma worse?

The 1970s saw a third spike in asthma related deaths, and this time the location was isolated to New Zealand.  This prompted researchers to further investigate the relationship between asthma rescue medicine and asthma morbidity and mortality.

According to Ann Janet Woolcock, data from death certificates were investigated from Australia, New Zealand, U.S.A., West Germany, Canada, Japan, Britain and Wales.  Regarding these results, she said:

Deaths were lowest in about 1975 in all countries and then increased somewhat (dramatically in new Zealand) until about 1985, but since then, and especially since 1990, mortality has decreased or remained steady in all the countries shown.  There has been much speculation about the reasons for the fluctuations, but it is difficult to draw conclusions about these figures in the absence of accurate data about the prevalence and severity of the disease, and methods of treatment used in this age group (which was 4-34) in each country.

So did the same medicines that were supposed to make life better or asthmatics cause the rise in morbidity and mortality.  Lawrence K. Altmon suggests that perhaps Dr. Parkinson, in 1995, may have been right on when he suggested that morbidity and mortality was negligible prior to the arrival of adrenaline (epinephrine) in 1902.  (8, page 8)

 Altmon said:

Dr. parkinson wrote that it is "possible that mortality from asthma first appeared when adrenaline (epinephrine) became available.  It was identified in 1902.  Theoretically, lethal asthma could be the result of adrenal medullary suppressoin secondary tothe exogenous administration of its own hormones." (8, page 8)

 "The pattern of events of no adrenaline, no deaths; some adrenaline, some deaths; powerful adrenaline analogues prescribed generously, an epidemic of deaths; withdrawal of the more potent drugs, the epidemic disappears; and supports the thesis of iatrogenic adrenal medullary suppression.  (8, page 8)

There was no doubt that by review trends from New Zealand, rises in asthma morbidity and mortality rates corresponded with the sales of fenoterol.  Sales started to spike when the medicine was introduced to the market in the mid 1970s, and they began to decline when the product was pulled from the market in the early 1990s.

The trend was similar to that of which occurred during the 1940s when asthma morbidity and mortality rates spiked in New Zealand, Australia, Britain and Wales as sales of isoprenaline forte increased.  When the medicine was later pulled from the market, the death rate likewise declined.

Statistics showed similar trends for the rest of the nation, although the rise in morbidity and mortality was more subtle and gradual.  There was a gradual increase following the introduction of isoprenaline solution in the 1940s and again following the introduction of the the rescue inhaler in 1957.

There were now two questions researchers set out to answer:

1. Do beta adrenergics make asthma worse
2. If so, why?

The neat thing about this latest spike in asthma morbidity and mortality was, unlike those that occurred in the 1940s and 1960s, the experts now had an array of data to learn from.

The following were the theories to explain the rise in morbidity:

1.  High doses of beta agonists increases the risk for cardiac arrest.  The was especially the case with non-specific B2 agonists such as epinephrine and isopreterenol.  The high dosing provided by use of this medicine was suspected of  of  overworking the heart, thus causing cardiac arrest.  Beasley, Pearce and Crane suspect this to be most likely to be the case in cases "relating to their overuse in the situation of a life-threatening attack of asthma, in which the cardiac side effects are likely to be particularly harmful in the presence of severe hypoxia." (1, page 20)

Janet Woolcock suggests that "there is little evidence that it (fatal asthma or near fatal asthma) results from a cardiovascular event).  Likewise, she also suggests that "on the other hand, drugs such as albuterol, terbutaline, and salmeterol are partial beta-agonists (specific to the lungs only), and there is no substantial evidence that they increase the risk of death from asthma."  (2, page 190)

2.  High doses use of beta agonists increase tolerance to the medicine:  This subject was taken up by Benoy, Fellah, and Schneider in 1975.  They said that: (11)

The longer animals were pretreated and the higher the dose of bronchodilator given (isoprenaline or adrenaline) the greater was the degree of tolerance developed in the isolated lungs.  Tolerance could develop to such a degree that regardless of the dose of bronchodilator used to challenge the lungs (adrenaline, isoprenaline or aminophylline) no significant bronchodilation was produced.(11, pages 551-552)

Benson &Periman (1948) and Laurence & Moulton (1960) reported that tolerance developed in the brochodilator effect of adrenaline after excessive use of this drug in man...(11, page 552)

These results suggest that asthmatic patients who are heavy users of bronchodilators may become resistant to these drugs.  the valueof these drugs in relieving mild asthmatic attacks in such patients becomes less.  In an extreme case, a patient may die because the drug he is using has become completely ineffective.  A young asthmatic has been found dead clutching an empty bronchodilator aerosol container (Pickvance, 1967).  The same conclusion was reached by  Herxheimer (1973)...(11, page 552 )

Conolly et al. (1971)... suggested that in asthmatic patients who use sympathomimetic pressurized aerosols excessively cross-resistance developsto both exogenous sympathomimetic amines and to the natural transmiter release by the adrenergic nerves, and that this may lead to a deterioration of the asthmatic state and explain the rise in the asthma mortality rate.  The cross tolerance experiments described here may exlain the good results which were obtained only after the withdrawal of adrenergic bronchodilator therapy from some asthmatic patients (Keighley, 1966, Reisman, Friedman & Arbesman, 1968)...(11, page 553 )

The work described in this paper has demonstrated that the tolerance which developed as a result of the repeated administration of isoprenaline or adrenaline remained for periods of upto three weeks after the last administration of isoprenaline or adrenaline to guinea-pigs. (11, page 553)

Developing a tolerance to rescue medicine may result in worsening severity.

3.  High doses of beta agonists increase severity of asthma.  Some studies showed that high doses of beta adrenergics may increase the severity of asthma.  This may result from high dose beta adrenergics such as isoprenaline forte and fenoterol, or from frequent use of regular doses of beta adrenergics such as isoprenaline.  Later studies showed that frequent use of epinephrine, terbulatine, metaproterenol, and albuterol also resulted in increased severity.  (2, pages 189-190)(3, pages 468-470) Some experts have gone as far to suggest that albuterol should not be used on a regular frequency, and should only be used as a rescue medicine as needed.

Regarding these studies, Malcolm R. Sears said the following:

These studies suggest a class efectof regular B-agonists which is likely to be more evident if higher doses of more potent B-agonists are given, and perhaps also more evident in patients with more severe asthma. If this is so, then the natural  tendency to use higher doses of B-agonist in subjects with worsening asthma, and to change to more potent B-agonists for those patients when a new drug is marketed, would escalate the adverse effects (developing a vicious circle of worsening asthma), leading to increased opportunity for a fatality in disadvantageous circumstances. (2, page 469)

The "more potent B-agonists" being referenced to here would be isopreterenol forte and fenoterol. Sears further notes that:

"Strong support for the hypothesis that B-agonists increase the severity of asthma ocmes from the abrupt reversal of both morbidity and mortality in New Zealand in 1990, when, on advice from the drug regulatory agency, fenoterol was effectively withdrawn from use over a period of a few months." (2, page 469)

Other evidence that supports this theory is the decline in asthma morbidity and mortality following increased warnings regarding the risks of isoprenaline forte that resulted in decreased sales(1, page 18) Likewise, following warnings regarding the overuse of the medihaler epi and medihaler iso, morbidity and mortality declined as well.

4.  Over reliance on beta agonists results in delay in seeking help.  Various studies showed that those asthmatics who were found dead with a rescue inhaler clutched in their grasp may have had a false sense of security, and a belief that the medicine would eventually make their asthma better.  Buy the time they realized this was not true it was too late. (2, pages 471-473)

5.  Lack of use of inhaled corticosteroids:  Woolcock said that some patients may develop worsening asthma and have an increased risk of death, "but the lack of inhaled coticosteroids (ICS).  Where salbutamol and ICS are used otgether, there is no increased risk.  One message that is clear an dcan be used in educational campaigns is that increasing frequency of use of beta-agonists such as albuterol is a sign of increasing severity of asthma and thus of increased risk of death. (2, page 190)

These continue to be theories debated by the medical community. Albert L. Schefler, the editor of Fatal Asthma, sums up

A recent study in this regard explored the effect of regular beta agonist use on the bronchoprotective effect of beta agonists. Among a small group of persons with mild, stable asthma, subjects were randomly assigned to use either albuterol or placebo 2 puffs four times daily; both groups could use as-needed albuterol for "rescue." Although the bronchodilator effect of albuterol was not changed by regular use of albuterol, the bronchoprotective effect of albuterol was reduced. Albuterol did not blunt methacholine- or allergen-induced bronchoconstriction as effectively after regular beta-agonist inhalation for two weeks as it did in the placebo group. Tolerance to the bronchoprotective effect of beta agonists may be one way in which overuse of inhaled beta agonists might contribute to fatal outcomes in asthma.

Molecular studies of the beta-agonist receptor have revealed polymorphisms in the general and asthmatic populations. Some genetically determined beta-receptor types may be more susceptible to phosporylation and thereby to down-regulation, a potential mechanism for the development of tolerance to the bronchoprotective effects of beta agonists. An estimated 5-10% of the population have this particular phenotypic expression of their beta receptor and may as a result be at increased risk for severe, potentially fatal asthma. 

The message here is not that beta agonists are dangerous. Used properly, they can be life- saving. The key point is that their role in asthma is as rescue medication for relief of acute asthmatic symptoms. We do no longer prescribe albuterol for regular use on a Q.I.D. basis. Frequent use of albuterol (more than one cannister [=200 puffs]/month should be a warning sign for poorly controlled asthma requiring an intensification of anti-inflammatory therapy. (10)

6.  Rescue medicine by metered dose inhaler (MDI)  causes inert bronchospasm:  A 1985 study by J. Yarbrough, L.E. Lansfield, and S. Ting concluded that the alupent inhaler was likely to cause bronchoconstriction in the smallest air passages of the lungs. They concluded that high doses from frequent use may worsen some cases of asthma.  (12)

7.  Socioeconomic status:  Some studies suggest that asthma is more likely to be uncontrolled and more severe in people who live in poor economic conditions.  The following have been shown by various studies:

• The asthma mortality rate is 5.6 higher in blacks compared to whites (13, page 238)
• Studies in Chicago showed that the highest mortality rates are among a city's poorest neighborhoods (13, page 238)(3, page 471)
• The highest death rates were in the nations poorest communities (13, page 238)
• Morbitity and mortality were highest among the nations least educated (13, page 239)
• Impoverished people are more likely to be exposed to their asthma allergens, such as dust mites, cockroaches, etc. (3, page 472)  
• Impoverished people (including children) are more likely to be exposed to cigarette smoke
• Studies in Philadelphia showed that that areas of the city with the highest percentage of minorities (particularly African Americans) had the greatest chance of using beta agonist medicine as the sole Treatment, as compared to beta agonists combined with inhaled corticosteroid therapy.  (3, page 472)
• Crowding increases risk of severe asthma, perhaps due to increased risk of being exposed to viruses that have been shown to worsen asthma (13, page 239, 244)
• Impoverished people are less likely to have the educational knowledge to adequately care for their own, or their child's, asthma.  (13, page 247)
• Poor children are 40% less likely to visit a doctor, compared to non-poor children (13, page 247)
• Poor children are 40% more likely to require hospitalization, compared to non-poor children (13, page 247)
• Poor children are "more likely to utilize the emergency department." (13, page 247)
• A study in Boston showed that minority children were "less likely to have been on preventative therapy prior to hospitalization, and were less likely to receive a nebulizer at discharge. These differences were not explained by source of payment.  Instead, the racial diferences in outpatient medication use were attributed to practice site, with hospital-based clinics and neighborhood health centers differing from private practices." (13, page 249)

It has also been established that poverty makes it unlikely for an asthmatic to:

• Escape from potential asthma triggers (mainly from poorly maintained homes) (13, page 244)
• Afford asthma medicines, either rescue or preventative
• Afford to see a physician (i.e. family practice, internist)
• Afford to see an asthma specialist (allergist, pulmonologist, etc.)
• Have access to well located medical clinics, hospitals (i.e. physician), resulting in delayed treatment. This increases the risk of near fatal and fatal asthma. 
• Be educated on the proper management of asthma (i.e. have an asthma action plan, the need for 
• Escape from family conflicts, single parent families, substance abuse, crime, etc., all of whihc have been linked with worsening asthma. (13, page 245)
• Escape inner city pollution that has been linked with worsening asthma (13, page 245)
• Escape "psychosocial variables associated with asthma death."  This is particularly true for impoverished asthma children (emotion due to family dysfunction, separation from parents or one parent, etc. (13, page 245)

So it is possible that worsening asthma morbidity and mortality due to socioeconomic status may skewer statistics, making it appear as though asthma is getting worse in a particular nation overall. 

Conclusion:  Keep in mind that all of these theories based on just a few studies, and further studies are definitely indicated.  Experts continue to wonder whether the results from the studies listed above are isolated to particular beta adrenergic medicine studies (such as adrenaline and isopreterenol only) or if they are indicative of a class action effect of the medicine.

Ann Janet Woolcock said the following:

On the other hand, drugs such as albuterol, terbutaline, and salmeterol are partial beta agonists specific only to the lungs, and not the heart), and there is no substantial evidence that they increase the risk of death from asthma. Regular use of albuterol did not increase the severity of disease in patients with mild asthma. (2, page 190)

 I added the emphasis there. Albuterol is specific to beta 2 adrenergic receptors in the lungs only, and not to beta 2 adrenergic receptors in the heart.  Is it possible, therefore, that this makes albuterol exempt from all the studies mentioned above?

"Regular use of albuterol did not increase the severity of disease in patients with mild asthma."

Albuterol is the best selling asthma medicine of all time, and part of the reason is that it relieves asthma symptoms and it comes with essentially negligible side effects.  Some studies do suggest, however, that high doses due to frequent use of albuterol may increase asthma severity.  Further studies are ongoing to determine if this is true, and, if so, to determine the reason why.

References.

1. Beasley, Charles Richard William Beasley, Neil Edward Pearce, Julian Crane, authors of chapter two in the book "Fatal Asthma" edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc. Chapter two is titled "Worldwide trends in asthma mortality during the twentieth century." 
2. Woolcock, Ann Janet, author of chapter 14 of the book, "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc. Chapter 14 is titled "Natural Histor of Fatal Asthma." 
3. Sears, Malcolm R., "author of chapter 29 in the book "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc.  Chapter 29 is titled "Role of B-Agonists in Asthma Fatalities." 
4. Jackson, Mark, "Asthma: The Biography," 2009, New York, Oxford University Press 
5. Bisgaard, Hans, Chris O'Callaghan, Gerald S. Smaldone, editors, "Drug Delivery to the Lung," 2001, New York, Marcel Dekker, Inc 
6. Mittman, Gregg, "Breathing Space," 
7. Speizer, F.E., R. Doll, P. Heaf, "Observations on Recent Increase in Mortality from Asthma," British Medical Journal, February 10, 1968, 1, pages 335-339 
8. Altman, Lawrence K., "The Public Perception of Asthma," Chapter one of the book "Fatal Asthma," edited by Albert L. Sheffer, New York, Marcel Dekker, Inc, pages 3 and 11 
9. Speizer, F.E., R. Doll, P. Heaf, and B. Strang, "Investigation into use of drugs preceding death from asthma," British Medical Journal, 1968, 1, 339-343Sheffer, Albert L, "Partner Asthma Center's Grand Rounds," asthma.partners.org, http://www.asthma.partners.org/newfiles/ShefferFatalAsthma.html, accessed 10/5/13 
10. Bendy, Christine J., E.L-Fellah, R. Schneider, "Tolerance to sympathomimetic bronchodilators in guinea-pig isolated lungs following chronic administration in vivo," 1975, British Journal of Pharmacology, 55, pages 547-554 
11. Yarbrough, J., L.E. Lansfield, and S. Ting, "Metered dose inhaler induced bronchospasm in asthma patients," , Annals of Allergy, Asthma and Immunology," July, 1985, (55)1, pages 25-27 
12. Grant, Evalyn N., Kevin B. Weiss, "Socioeconomic risk factors for asthma mortality," chapter 17 of the book, Fatal Asthma," edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc.

1960s: Did rescue medicine cause a spike in asthma deaths?

A spike in asthma related deaths forced physicians to take a closer look at this disease. Upon review of the available data, they began to surmise that the very medicines meant to make life better for asthmatics was responsible.

The spike in asthma rates correlated with the releases and increased advertising of the new metered dose inhaler that was introduced to the market in 1957.  The first to be released to the market were the Medihaler Epi (epinephrine) and Medihaler Iso (isoprenaline).  As word got out there were devices asthmatics could carry in their pockets or purse that would give instant relief from asthma, sales of the device skyrocketed.  (5, page 11)

This followed a rise in the death rate.  According to Speizer, Doll and Heaf in 1968:

It is evident that an increase in mortality began to occur in about 1961 and that all ages between 5 and 64 years of age have been affected.  The greatest increase in mortality has taken place at ages 10 and 14 years, the ages the rate has increased eight times, from 0.3 to 2.5 per 100,000 persons.  The increase has, however, been substantial at all ages from 5 to 34 years, and at these ages the annual number of deaths increased by 308 and the death rate trebled from 0.7 to 2.2 per 100,000 persons.  (7, page 336)

They further noted that that for the purposes of their study, the investigated only data obtained for the age group of 5-34, mainly because as asthmatics get older "mortality from bronchitis begins to exceed that from asthma."  (7, page 336)

Initial studies involved questioning the attending physicians of the patients who died from asthma.  F.E. Speizer, Doll,  Heaf and Strang  in 1968 reported their findings.  (9, page 342)

Excessive use of pressurized aerosols was reported by 29 general practitioners without specific inquiry having been made.  The reports ranged from  a vague implication, such as "tended to use aerosols too frequently" or "suspicion of excess aerosol at death," to direct observation such as "died clutching aerosol" and a detailed account of the amount consumed.  In extreme cases the use of as many as two canisters per day or two in two hours was reported. (9, page 342)

Investigators speculated that, perhaps, such asthmatic were victim of the false sense of security provided by the inhalers.  Instead of seeking help, they continued to puff on their inhalers.  By the time they called for help it was too late.  (5, page 12-13)

Upon further review of the data, they learned that asthma death rates remained stable in most nations where asthma death statistics were available. However, there were significant spikes in six Western countries: England and Wales, Scotland, Ireland, New Zealand, Australia, and Norway. (1, page 15) (2, pages 15-19)

In England, in particular, the asthma death rate was stunningly high.  According to Speizer, Doll and Heaf in 1968, the asthma death rate in England "accounted for 5.7% of all deaths at ages 10 to 14 years, it ranked sixth in the list of causes of death." (7, page 336)

Since the sharpest rise in asthma deaths was limited to six nations, investigators searched for something that was particular to these regions.  What they learned was reported by Beasley, Pierce and Crane. They noted that isoprenaline forte... contained a concentration of isoprenaline two to eight times greater than the standard isoprenaline metered dose inhaler available in other countries. Epidemics occurred only in countries where the high-dose preparation of isoprenaline was available; and in the two countries which marketed the high dose preparation and had no increase in mortality, it was introduced late into their markets per-capita sales were low." (1, page 16)

When the product was later pulled from these markets and the death rate declined, this proved to many researchers that this was probably the cause.

References; ???

1. "Asthma Statistics, "AAAI.org, http://www.aaaai.org/about-the-aaaai/newsroom/asthma-statistics.aspx, accessed 9/29/13
2. Beasley, Charles Richard William, Neil Edward Pearce, and Julian Crane, "Worldwide Trends in Asthma Mortality During the Twentieth Century," chapter two in the book "Fatal Asthma," edited by Albert L. Shefer, 1998, New York, Marcel Dekker, pages 13-29
3. Woolcock, Ann Janet, "Natural History of Fatal Asthma," chapter 14 of the book, "Fatal Asthma," edited by Albert L. Shefer, 1998, New York, Marcel Dekker, pages 179-196
4. 1940s: Why did asthma morbidity and mortality increase
5. Altman, Lawrence K., "The Public Perception of Asthma," Chapter one of the book "Fatal Asthma," edited by Albert L. Sheffer, New York, Marcel Dekker, Inc, pages 3 and 11

References:  See "1940-1970:  Asthma morbidity and mortality spikes"

1960s: Spike in asthma death rate earns worldwide attention

A gradual rise in asthma deaths began during the 1940, although it gained little attention from the medical community, let along the general public.  However, a rising tide of asthma deaths in the 1960s not only gained the attention of the medical community, it resulted in an increase in research and studies into our disease.  This would have a significant impact on the millions of asthmatics around the world, and for the better.

The asthma death started to rise sharply in 1961.  Then, according to Beasly, Pearce and Crane:

In the mid-1960s, asthma mortality increased dramatically in at least six Western countries: England and Wales, Scotland, Ireland, New Zealand, Australia, and Norway.  In these countries, the mortality rates increased 2-10 fold within a 2-5 year period.  Other countries such as the United States, Denmark, Canada, and Germany did not experience epidemics, although in some countries such as Japan, significant increases in asthma mortality were noted within more narrowly defined age groups. (1, page 15)

It was the goal of researchers to discover the likely cause.  A variety of theories were postulated and investigated by the experts.

A.  Accuracy of physicians certifying the cause of death:  This was investigated and pretty much ruled out as a probable cause (7, page 337

B.   Changes in the way asthma was diagnosed:  While it was determined that asthma might be misdiagnosed or under diagnosed, this was ultimately ruled out as a likely cause in an increase in asthma fatalities (7, page 335)

C.  Increase in the number of cases of asthma:  This was actually considered as a likely cause noted by Speizer, Doll and Heaf in 1968.  They said, "In the absence of evidence t the contrary, it would seem that an increase in the case fatality rateis the most likely explanation of the increased mortality rate, and we have accepted this as a working hypothesis." ( 7, page 338),

D.  Environmental factors:  As noted by Speizer, Doll and Heaf in 1968:

"Certainly the increase could not be due to smoke pollution, which has decreased in English towns over the last decade, nor could it be attributed to pollution with sulphur gases, which has remained approximately constant (Ministry of Techology, 1967).  Motor traffic has increased considerably, and one of the constituents of motor fumes could perhaps have had a harmful effect.  If this were the case, however, a substantial difference in mortality would be expected between urban and rural areas, and we have failed to find any evidence of this in the national mortality data for 1966.  The death rate as 2.0 per 100,000 persons aged 5 to 34 in conurbations, 3.0 in urban areas of more than 100000 population, 2.2 in urban areas under 50,000 population, and 1.9 in rural districts. (7, page 338)

Similarly, Lawrence K. Altman said:

We often yearn for the "good old days." For instance, it is often said that there is more pollution today than before, but that statement i snot necessarily correct. Think back to those earlier eras.  Think of the stench from humans who found it dificult to keep clean when bathtubs were scarce. Imagine what it was like when horse manure constantly filled the streets.  It is said that in the 1920s asthma from horses was a common affliction. Dr. Sheffer told me about how a horse trotting along the street could trigger an asthma attack inDr. Robert Cook of Roosevelt Hospital in New York City.

Think also of the dust in the environment and pollution from wood-burning and coal-burning stoves.  Recall the inversions that caused so much sickness and death in Pennsylvania and London, England, a few decades ago. 

Many ofthe offending environmental hazards have been removed. Public health campaigns and legislation have reduced the amount of tobacco smoke and dangerous chemicals in the air.  Those changes have created a widespread impression that we live at a time when we breathe cleaner air (8, pages 5-6)

So, needless to say, environmental causes were ruled out as a factor. This is not to say that environmental factors are not likely factors in asthma morbidity in mortality.  It merely rules these out as likely culprits or the spike in morbidity and mortality during the 1940s and 1960s.

E.   Aging population:  This was not considered an adequate reason because a majority of the data collected by the experts is generally collected for asthmatics between the ages of 5 and 35 years of age, or some similar range.  The reason for this is because the older a person gets the greater the chance asthma will be complicated, or confused with, other medical conditions people normally get as they get older.  Asthma under the age of 5 is difficult to diagnose.  (1, page 13)

F.  Improved ability to recognize and diagnose asthma: This may result in an increase in the number of people diagnosed, but it would not explain the increase in morbidity and mortality.   (1, page 18)

G.  Change in mode of treatment.  There were actually two new modes of treatment on the market during the 1960.  They were:

1. Systemic Corticosteroids
2. Metered Dose Inhaler (MDI).  This was often referred to as pressurized aerosol (asthma rescue inhaler)

Systemic corticosteroids were never ruled out as a culprit.  However, Speizer, Doll and Heaf note the following: 

Corticosteroids were introduced into the management of the disease in 1952, but the increase in mortality did not begin until nine years later.  This discrepancy, however, is not sufficient to exculpate them entirely.  The frequent and prolonged use of corticosteroids spread slowly, and the risk of harmful effects may be at a maximum only after patients have been under treatment for several years.  

If patients were on a high dose of steroids and the patient suddenly stopped taking the medicine, this would result in adrenal gland suppression, which may result in death.

The asthma rescue inhaler was introduced between 1957 and 1960:  According to Speizer, Doll and Heaf:

These were introduced in England and Wales in 1960 and began to gain wide acceptance in 1961; and in the next five years their consumption is estimated to have increased more than fourfold (Ministry of Health, unpublished data).  The closeness of the correlation justifies inquiry into the possible harmful effect of the preparations, but a temporal correlatoin of this sort, taken by itself, is a poor basis for drawing conclusions about cause and effect." (7, page 335)

Ultimately, while there were many likely causes for the spike in asthma deaths during the 1940s and 1960s, the finger was pointing at beta adrenergic medicine as the likely culprit.  Whether this was the actual cause was never fully determined.

References.

1. Beasley, Charles Richard William Beasley, Neil Edward Pearce, Julian Crane, authors of chapter two in the book "Fatal Asthma" edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc. Chapter two is titled "Worldwide trends in asthma mortality during the twentieth century."
2. Woolcock, Ann Janet, author of chapter 14 of the book, "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc. Chapter 14 is titled "Natural Histor of Fatal Asthma."
3. Sears, Malcolm R., "author of chapter 29 in the book "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc.  Chapter 29 is titled "Role of B-Agonists in Asthma Fatalities."
4. Jackson, Mark, "Asthma: The Biography," 2009, New York, Oxford University Press
5. Bisgaard, Hans, Chris O'Callaghan, Gerald S. Smaldone, editors, "Drug Delivery to the Lung," 2001, New York, Marcel Dekker, Inc
6. Mittman, Gregg, "Breathing Space," 
7. Speizer, F.E., R. Doll, P. Heaf, "Observations on Recent Increase in Mortality from Asthma," British Medical Journal, February 10, 1968, 1, pages 335-339
8. Altman, Lawrence K., "The Public Perception of Asthma," Chapter one of the book "Fatal Asthma," edited by Albert L. Sheffer, New York, Marcel Dekker, Inc, pages 3 and 11
9. Speizer, F.E., R. Doll, P. Heaf, and B. Strang, "Investigation into use of drugs preceding death from asthma," British Medical Journal, 1968, 1, 339-343Sheffer, Albert L, "Partner Asthma Center's Grand Rounds," asthma.partners.org, http://www.asthma.partners.org/newfiles/ShefferFatalAsthma.html, accessed 10/5/13
10. Bendy, Christine J., E.L-Fellah, R. Schneider, "Tolerance to sympathomimetic bronchodilators in guinea-pig isolated lungs following chronic administration in vivo," 1975, British Journal of Pharmacology, 55, pages 547-554
11. Yarbrough, J.,  L.E. Lansfield, and S. Ting, "Metered dose inhaler induced bronchospasm in asthma patients," , Annals of Allergy, Asthma and Immunology," July, 1985, (55)1, pages 25-27
12. Grant, Evalyn N., Kevin B. Weiss, "Socioeconomic risk factors for asthma mortality," chapter 17 of the book, Fatal Asthma," edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc.

1940: Asthma death rate begins a gradual rise

The 1940's was a significant decade in the history of medicine, as advances in medicine resulted in declines of morbidity and mortality from some of histories deadliest diseases, such as consumption and influenza.  Our asthma history saw an opposite trend.  While asthma morbidity and mortality were negligible through the 1930, they started to gradually climb during the fourth decade of the 20th century.

Considering these other diseases were in the forefront of the general public, the spike in asthma deaths nearly went unnoticed. Some experts may have seen what was going on, although they had no way of even guessing at the cause.  The reason was because most of the public's attention remained on other diseases, with all public funds, therefore, not going for asthma research.  For this reason there was very limited data regarding asthma available to review.

That left researchers to reviewing death certificates.  However, many experts wondered if methods of certifying death certificates were even accurate.  There were probably times when asthma was misdiagnosed and under diagnosed.  A middle aged man with bronchitis may have been misdiagnosed with asthma.  A child with asthma may have been misdiagnosed with asthma. Likewise, a child with asthma may have gone unrecognized, and therefore un-diagnosed.

It actually wasn't until the 1960s when all eyes were opened to the rising death rates that death certificates were reviewed.  The experts decided to limit their research to asthmatics between the ages of 5 and 35.  The reason was that the likelihood of having pure asthma was greatest among this age group.  Those under five were hard to diagnose, and those over 35 had a a greater likelihood of having some other disease combined with asthma.  Figuring out which one resulted in death could sometimes be difficult to determine.

Data was collected from as far as 1900 for this age group.  According to Beasley, Pearce and Crane in 1968, here is what was learned:

Those Western countries in which relevant data have been published indicate that asthma mortality was uniformly low and relatively stable between 1900 and 1940.  The death rate began to increase gradually in the 1940s in a number of countries including New Zealand and Australia, in which a threefold increase over a 15-year period was observed.  Mortality declined again in the late 1950s in New Zealand, England, and Wales, but not Australia.  In contrast, little change in asthma mortality rates was observed in the United States during this period.  Although the interpretation of death rates over such an extended period is difficult, the historical data are likely to be acceptable accuracy in this age group." (1, page 14)

They also made one other observation:

It is interesting to note that isoprenaline was introduced in a nebulizer formulation during the 1940s when mortality began to increase, but whether this had a role in the increase in mortality was not examined in detail at the time. (1, page 14)

Trends in asthma related deaths were not significantly studied until the 1960s.  When this was done, one of the theories that arose for the rise of asthma deaths in the 1940s was the availability of nebulized isoprenaline at home.  Theorists sense this may have created a false sense of security among asthmatics, particularly children.  Where they once would have sought help, they now simply resorted to their rescue medicine.

Isoprenaline was a new line of sympaththeomimetic medicines, also known as beta adrenergic medicine, more recently as asthma rescue medicine.  Regardless of what it is called, it has the tendency to provide immediate relief from an asthma attack.  Having access to such medicine was a godsend for asthmatics, because it meant that they could get immediate relief in the convenience of their own homes.

While physicians were happy to provide such an opportunity to asthmatics, they were not ready for the potential consequences.  Allowing asthmatics to have quick access to such rescue medicine resulted in two things.

1. Overuse of isoprenaline may have resulted in cardiac arrest. This would have resulted in suden death from isoprenaline overdose secondary to asthma. 
2. Overuse of isoprenaline may have resulted in tolerence to the medicine. This would have made the asthma refractory to the isoprenaline, resulting in increased dosing. By the time the asthmatic gave up on the isoprenaline, it was too late. 

These were simply theories that were never proven.  It as impossible for researchers to question these asthmatics after they died, and therefore it was impossible to know how much isoprenaline they used, if any.  

However, in many instances, there were reports from family members and friends of these asthmatics using their rescue medicine prior to death.  

For these asthmatics, however, such theories were trivial and too late. Although data obtained from studying how they died may have resulted in safety precautions that saved the lives of many future asthmatics.  In this way, the experts made sure these asthmatics did not die in vane. 

Another good thing that came out of the rise in asthma deaths during the 1940s, and later in the 1960s, was better recognition of our disease by the medical community.  This ultimately resulted in better recognition by the public, and therefore better funding for future research.  

However, as morbidity and mortality from asthma still remained low in comparison to other diseases, the rise in public awareness continued to pale in comparison.  While it's sad to say, many asthmatics continued to suffer from their disease because the general public simply was not paying attention.  

References.

1. Beasley, Charles Richard William Beasley, Neil Edward Pearce, Julian Crane, authors of chapter two in the book "Fatal Asthma" edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc. Chapter two is titled "Worldwide trends in asthma mortality during the twentieth century." 
2. Woolcock, Ann Janet, author of chapter 14 of the book, "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc. Chapter 14 is titled "Natural Histor of Fatal Asthma." 
3. Sears, Malcolm R., "author of chapter 29 in the book "Fatal Asthma," edited by Albert L. Sheffer, 1998, New York and Hong Kong, Marcel Dekker, Inc. Chapter 29 is titled "Role of B-Agonists in Asthma Fatalities." 
4. Jackson, Mark, "Asthma: The Biography," 2009, New York, Oxford University Press 
5. Bisgaard, Hans, Chris O'Callaghan, Gerald S. Smaldone, editors, "Drug Delivery to the Lung," 2001, New York, Marcel Dekker, Inc 
6. Mittman, Gregg, "Breathing Space," 
7. Speizer, F.E., R. Doll, P. Heaf, "Observations on Recent Increase in Mortality from Asthma," British Medical Journal, February 10, 1968, 1, pages 335-339 
8. Altman, Lawrence K., "The Public Perception of Asthma," Chapter one of the book "Fatal Asthma," edited by Albert L. Sheffer, New York, Marcel Dekker, Inc, pages 3 and 11 
9. Speizer, F.E., R. Doll, P. Heaf, and B. Strang, "Investigation into use of drugs preceding death from asthma," British Medical Journal, 1968, 1, 339-343Sheffer, Albert L, "Partner Asthma Center's Grand Rounds," asthma.partners.org, http://www.asthma.partners.org/newfiles/ShefferFatalAsthma.html, accessed 10/5/13 
10. Bendy, Christine J., E.L-Fellah, R. Schneider, "Tolerance to sympathomimetic bronchodilators in guinea-pig isolated lungs following chronic administration in vivo," 1975, British Journal of Pharmacology, 55, pages 547-554 
11. Yarbrough, J., L.E. Lansfield, and S. Ting, "Metered dose inhaler induced bronchospasm in asthma patients," , Annals of Allergy, Asthma and Immunology," July, 1985, (55)1, pages 25-27 
12. Grant, Evalyn N., Kevin B. Weiss, "Socioeconomic risk factors for asthma mortality," chapter 17 of the book, Fatal Asthma," edited by Albert L. Sheffer, 1998, New York, Hong Kong, Marcel Dekker, Inc.