1980s: Steroids for asthma

By the 1980s, steroids were ordered with increased frequency, although at low doses. (1) Inhaled steroids were also introduced to the market, and they were basically reformulations of the steroid molecules.

During this decade asthma continued to be treated as an acute disease. Again, this means that when you felt good you usually didn't take any medicine for it, and you only sought treatment when you felt symptoms.

If you were having moderate to severe symptoms and you went to the emergency room you would be given an intramuscular shot in your shoulder or butt of methylprednisolone, marketed as Solumedrol. This would probably go along with an albuterol breathing treatment, and possibly a shot of epinephrine or susphrine.

If you had a mild or moderate symptoms and you saw your physicians, you may be given a prescription for Methylprednisolone pills, marketed as Medrol. They were organized in packets by how many you were to take each day: seven in top row, five in the second row, four in the third row, three in the fourth row, two in the fifth row, and one in the sixth row.

This sequence made sure you obtained the a therapeutic dose on day one and then that you slowly weaned yourself off steroids so your adrenal medulla gradually started producing it's own cortisol again. The dose was relatively low to prevent side effects, although high enough to reduce inflammation and control asthma.

In the mid 1980s, the way asthma was approached started to come under question. Despite all the new and improved asthma medicines on the market, asthma death rates were on the rise. Between 1977 and and 1985, the asthma death rate rose from 0.7 per 100,000 to 0.8 per 100,000. Asthma prevalence rose 29% between 1980 and 1987, and hospitalization rates for children rose 4.5% annually during the 1980s. (2)

I have some more information about the suspected causes of the rise in asthma related deaths, and my own personal opinions. I also have my own story to tell. I will save those stories for another post. For now, I just want you to know that these concerns, these statistics, are what lead to researchers putting their heads together to figure out what could be done to lower asthma death rates, regardless as to the cause.

1980, I think, is one of the key years in our asthma history. This was the year that National Heart, Blood, and Lung Institute's (NHLBI) National Asthma Education Program coordinated efforts to get all the world's leading asthma and allergy experts together to review all the data and current wisdom regarding our disease and to formulate asthma guidelines.

The NHLBI asthma guidelines were published in 1989, and highlighted the following facts:

• Asthma is often under-diagnosed
• All asthmatics have some degree of chronic inflammation
• A small amount of steroids in asthmatic lungs obtained from inhaled corticosteroids is often all that's needed to control this inflammation and prevent asthma symptoms.
• The amount of steroid inhaled from an inhaler is very small compared to systemic steroids, and therefore side effects are rare and minimal at worse. For this reason, the benefits far outweighed the risks for asthmatics with uncontrolled asthma.
• The emphasis for asthma treatment was changed from treating acute symptoms toward preventing asthma symptoms with daily use of asthma controller medicines to reduce underlying airway inflammation. This was thought to prevent asthma, or at least make asthma less severe when it did occur. 
• Inhaled steroids should be used daily to prevent asthma, and rescue inhalers should always be available to treat acute asthma symptoms when they occur.
• Inhaled steroids are safe to use for mild asthma to prevent airway remodeling that may cause asthma to become moderate to severe. 

These conclusions were significant to asthma management. Back in 1985, when my asthma became severe and uncontrolled, my regional doctor was unable to help me, and I had to spend six months at an asthma research hospital called National Jewish Hospital/ National Asthma Center (now National Jewish) to gain control of my disease. What they did was put me on a low dose of steroids to control my asthma, and then weaned me off them and onto an inhaled corticosteroid, which at the time was Azmacort.

The guidelines essentially made the wisdom that was available at research hospitals available to regional physicians. So, instead of being scared to use inhaled steroids, they were now noted to be safe and effective for controlling asthma. T'his was a significant point in asthma's history.  This fact cannot, and should not, go underestimated.

From this point on, regional physicians, an not just hospital physicians, began prescribing daily use of inhaled corticosteroids. Rather that tell patients to quit taking them when they felt good, asthmatics were encouraged to continue taking them, even when they felt good (especially when they felt good).

This, you might say, was the breakthrough that greatly improved asthma control, especially for the 75% of asthmatics with allergic asthma. At the time, asthma was essentially considered an allergic disease. It would be another 20 plus years before it was learned that some asthmatics have a subgroup of the disease that is not responsive to corticosteroids.

Still, the asthma guidelines caused an increase in corticosteroid inhaler prescriptions, and this lead to an inhaler boom in the 1990s.

References:

1. Buer, Jonas Kure, "Origins and Impact of the Term "NSAIDs," inflammopharmacology," July, 2014, file:///home/chronos/u-48b0af7d8a6e832f841243beb1bf56db699d3e12/Downloads/NSAID%20accepted%20version%20for%20self-arch.pdf
2. Mitmann, Gregg, "Breathing Space:  How allergies shape our lives and landscape, 2007, page 247

1970s: Steroids for Asthma: Part II

By the 1970s, most drugs that contained cortisol were called corticosteroids, or glucocorticosteroids, or simply steroids. They were mainly prescribed in low doses to end severe asthma episodes, and usually in conjunction with epinephrine, or a longer acting version of epinephrine called susphrine.

And then you were gradually weaned off of them over the course of about a week. This allowed your adrenal cortex time to start gradually producing its own cortisol in order to prevent the risk of sudden onset symptoms that occur when cortisol production is shut off, which includes the risk of dying a sudden death.

Steroids were only used when the short term benefits were determined to outweigh any risks of long term side effects. One such circumstance would be if a physician believed the risk of dying from an asthma attack remained high despite aggressive treatment with the bronchodilators such epinephrine or Isuprel, plus the intravenous application of aminophylline, then the option left on the table intramuscular steroids.

It usually took about an hour for steroids to start working. One doctor explained to me a few years back that this was the reason susphrine became so popular among emergency room physicians. He said an asthmatic would come to the emergency room struggling to breathe, and would be given an intramuscular injection of susprine.

Susphrine was a long acting version of epinephrine that lasted several hours as opposed to just a few. He said it was well liked because it would be given at the same time as an intramuscular steroid. The susphrine would open airways within five minutes, and would last long enough for the steroid to take effect.

He said this was nice because it allowed emergency room physicians to send patients home knowing that they would be breathing easy long enough for the steroid to start working. It was a nice combination of medicine.

I know, because I was given these two medicines nearly every time I entered an emergency room for severe asthma. I remember I'd come into the ER, and I would be given an Alupent breathing treatment. I knew the treatment wasn't going to do any good, but remember politely puffing it while the nurse, respiratory therapist, and doctor waited to see if it would work. But all along I would just wait for the shot -- the susphrine shot.

I didn't know this at the time, so the susprine was the only medicine I looked forward to. I would watch the clock, while clutching the edge of the bed with my shoulders high working hard to suck in air, knowing that at the five minute mark I'd be able to take in a deep breath. Oh, what relief that felt like, to finally be able to take in a deep breath after suffering for so long. Lord knows I would never tell my parents to take me to the ER until after I had suffered long and hard, and knew that it wasn't just in my head.

So really, while I thought it was the susphrine that was helping me, it was the combination of both the epinephrine product and the steroid product. One opened my airways short term, and one kept them open long term.

I remember having asthma attacks at home, and mom would walk me to the bathroom, where a medicine that helped me breathe better was kept in the medicine cabinet. I remember it tasted horrible, which makes me think it was probably a steroid solution.

1950: Seroids for asthma

In 1949, a report was published noting the benefits of steroids for rheumatoid arthritis. This inspired researchers to experiment with cortisol and ACTH for other diseases, including asthma and allergies. By 1950, the results of the first studies using steroids for asthma came back positive. (1, 2)

The first study showing the benefits of steroids for asthma and allergies was published in 1950 by Carryer and company. They showed that oral cortisone benefited patients with allergies and asthma induced by ragweed pollen. (1, 3)

In 1951, Maxwell F. Gelfand reported on the benefits of inhaling aerosolized cortisol on the treatment of allergic asthma. This was the first study showing the benefits of inhaled corticosteroids for asthma. (3, 4)

In 1955, the first synthetic version of cortisol was approved by the FDA and entered the market as prednisone under the brand name Meticorten by Schering.
That same year, the first synthetic version of ACTH entered the market as prednisolone under the brand name Delta-Cortef by Upjohn. Subsequent studies confirmed the efficacy of these synthetic steroids for the treatment of asthma. (1, page 18) (need more references)

In 1959, methylprednisolone was approved by the FDA and entered the market as Depo-Medrol. Dexamethasone also entered the market in the 1950s as Decadron by Merck. It was shown to produce greater anti-inflammatory effect with less side effects as the other corticosteroids. (9, 10)

Dexamethasone was actually the first corticosteroid to be marketed as a solution to be nebulized, and this was shown to benefit asthmatics in studies performed in the 1960s.  (8)

In 1956, another study was performed by the Medical Research Council in Britain confirming the benefits of cortisol for the treatment of acute and severe asthma episodes. This and other similar studies showed how well oral or intramuscular cortisol worked to end severe asthma exacerbations.  (3, 5)

These and other similar studies confirmed the benefits of steroids for moderate to severe asthma, and they were prescribed generously, mainly because doctors and patients alike could see their benefits.  Sales of systemic corticosteroids boomed during the late 1950s and early 1960s.

However, it did not take long for the harsh side effects of long-term use to become a concern.

Steroids were learned to cause fluid retention, which results in a moon-face, thinning skin that easily bruises, acne, hypertension and diabetes. It also causes weakened bones, osteoporosis, and increased risk for bone fractions. It was also shown to stunt growth, obesity, and glaucoma.

It also became apparent that the diminished immune response responsible for reducing airway inflammation and controlling asthma also slowed healing, which was particularly concerning for those requiring surgery.

Various subjects died as a result of steroids use, some dying as a result of rapid cessation of the medicine. It was soon learned that when a person was taking steroids, their adrenal cortex stopped making natural cortisol.

By 1960, the systemic side effects were such a grave concern that the medical profession all but shunned the use of them. They went from "miracle cure" to condemnation after less than a decade of use. (6)

In the early 1970s, steroids were prescribed for people with moderate to severe asthma to control moderate to severe asthma. These were still only prescribed when oral and inhaled bronchodilators failed to work. (1)

By the 1980s, low dose steroids were used with regularity to control moderate to severe asthma, although they were used only when absolutely necessary. Inhaled corticosteroids were also an option, and even these were used sparingly due to fears of side effects.

References:

1. Brenner, Barry E, editor, "Emergency Asthma," 1999, New York, Marcel Dekker Inc., page 18
2. Cromptom, Graham K, "A Brief History of Inhaled Asthma Therapy," Primary Care Respiratory Journal, 2006, 15, pages 326-331, https://www.researchgate.net/publication/6704067_A_brief_history_of_inhaled_asthma_therapy_over_the_last_fifty_years
3. Byrne, Paul M., "Future Trends in the Use of Corticosteroids in Asthma," 2000, pages 120-140, http://link.springer.com/chapter/10.1007%2F978-3-0348-8480-8_7, in the book "Asthma: Epidemiology, Anti-Inflammatory Therapy and Future Trends," edited by Mark A. Giembycz and Brian J. O'Conner, 2000
4. Gelfand, Maxwell L, "Administration of Cortisone by the Aerosol Method in the Treatment of Bronchial Asthma," New England Journal of Medicine, 1951, August 23, 245: 293-294, http://www.nejm.org/doi/pdf/10.1056/
5. Jackson, Mark, Asthma: The Biography," 2009, New York, Oxford University Press, page 136
6. Buer, Jonas Kure, "Origins and Impact of the Term "NSAIDs," inflammopharmacology," July, 2014, file:///home/chronos/u-48b0af7d8a6e832f841243beb1bf56db699d3e12/Downloads/NSAID%20accepted%20version%20for%20self-arch.pdf
7. Pfeiffer, John E., "How Hormone Team is Saving Lives," Popular Mechanics, pages 97-99, 
8. Schleimer, Robert P., et el, "Inhaled Steroids in Asthma," vol. 163, 2005, New York, page 5
9. http://pmj.bmj.com/content/36/411/26.full.pdf
10. http://archderm.jamanetwork.com/article.aspx?articleid=525922

file:///home/chronos/u-48b0af7d8a6e832f841243beb1bf56db699d3e12/Downloads/NSAID%20accepted%20version%20for%20self-arch.pdf

1950: The discovery of steroids

Now in our quest through the annals of history, we come to steroids. If we consider the discovery of epinephrine the most significant to our asthma history, then the discovery of steroids must be a close second.

While epinephrine was isolated in 1901 from the adrenal medulla, cortisol wasn't isolated until 1936. However, interestingly, the history of both substances can be traced back to 1714, when Eustachius described the adrenal gland.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760737/

However, the story of steroids probably began in 1849, where Thomas Addison, working for Guy's Hospital in Britain, was looking to learn more about diseases and define them for the medical community. This quest lead him to making the link between Addison's Disease and the Adrenal Gland, and then to define the disease that would eventually take his name.

This discovery lead to further research on the adrenal gland. In 1894, researchers isolated a hormone from the adrenal cortex that they referred to as "cortin." In 1900 Solomon Soles-Cohen, working for Jefferson Medical College in Philadelphia, described the benefits of using adrenal extracts in asthmatics.

http://jama.jamanetwork.com/article.aspx?articleid=477214
Jackson, Mark, Asthma: A Biography," 1989,

Then, in 1901, researchers isolated a hormone call epinephrine from the adrenal medulla. The significance of cortin was not immediately recognized. However, the significance of epinephrine was recognized, and it was soon learned to have end asthma attacks, and this spearheaded a quest that lead to our modern understanding of asthma.

So, despite all that, the significant portion of the history of steroids, the part that is most recognized by historians, begins in the mid 1930s. And it did not begin with asthma in mind: it began as part of a quest to find a treatment for rheumatoid arthritis.

It began when Dr. Philip S. Hench, who was working for the Mayo Clinic. During the 1930s he observed that pain symptoms subsided during pregnancy and jaundice. His theory was that this was the result of increased cortisol levels. (1, 2, 3)

Hench believed a "substance x" was produced by the adrenal gland in response to stress, and that it would reduce inflammation in joints that occur in people with rheumatoid arthritis, a disease associated with pain in the joints due to chronic inflammation.

Beginning in 1935, this lead him to performing experiments with Edward C. Kendall at the Mayo Clinic to isolate the compound in the adrenal cortex. (1)

In 1936, Kendall succeeded in isolating compounds from the adrenal gland, and he named them in the sequence they were discovered: compound A through F.  Upon further research, he realized that compound E and substance X were one and the same. Hench named this substance cortisone. (2, 4)

In 1943 they extracted cortisone from the adrenal gland for clinical trials. And in 1944 they injected it into a patient with rheumatoid arthritis. They described how this patient was able to walk up and down stairs without discomfort. (1)

In 1948, Tadeus Reichstein, a Polish born chemist, perfected the method of extracting adrenal hormones, and this opened the door for further research. So Kendall and Reichstein had succeeded in isolating cortisol, and then Adrenocorticotropic hormone (ACTH).

That same year, a man was given cortisol as a treatment for rheumatoid arthritis. This was synthetic cortisol, making the medicine readily available for experimentation.

In 1949, a report was released in Mayo Clinic Proceedings showing the benefits of cortisol for the treatment of arthritis. (2)

It was described as the "miracle cure." In 1950, for their work in this great discovery, Kendall, Hench, and Reichstein were awarded the Nobel Prize for Physiology in Medicine.

This inspired researchers to study the affects of cortisol on various diseases, including asthma and allergies. At the time it was believed inflammation was part of the inflammatory response, although it was not known that some degree of inflammation was chronic. This discovery would not be made for another 30 years of so.

In the meantime, cortisol was hailed as a miracle cure, and was prescribed liberally. This was despite knowledge that it caused side effects, such as fluid retention, moon face, acne, and depression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1591822/pdf/canmedaj00640-0008.pdf

References:

1. http://rheumatology.oxfordjournals.org/content/38/2/100.full.pdf
2. https://books.google.com/books?id=9_DLCQAAQBAJ&pg=PA60&dq=history+of+corticosteroids&hl=en&sa=X&ved=0ahUKEwizoNPZyJXMAhUGKCYKHTZsAIcQ6AEIUTAG#v=onepage&q=kendall&f=false, page , page 11
3. https://www.nobelprize.org/nobel_prizes/medicine/laureates/1950/hench-bio.html
4. https://www.researchgate.net/publication/6704067_A_brief_history_of_inhaled_asthma_therapy_over_the_last_fifty_years