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.

1985: My Journey To To The Asthma Hospital

January 9, 1985

On January 8, 1985, I boarded a plane in snowy Grand Rapids, Michigan, with my mom, and three hours later we arrived in an equally white Denver, Colorado. This was not a vacation. The purpose of the trip was for mom to have me admitted to a hospital that specialized in asthma. The estimated time of stay was 6-8 weeks.

While my first ride in an airplane went great, that night at the hotel the asthma beast that I was oh too familiar with struck again.

"Do you think I should take you across the street," mom said as we both stood looking out the window of the hotel room at the unfamiliar complex of the asthma hospital. Undoubtedly we could see the 7-Goodman building and the 2-May building, both future homes for me, but at this moment neither of us were aware of this.

"I don't know," I said, taking a hit of my Alupent inhaler, pretending to be fine. "I think we can wait."

The truth was I was very short-of-breath that night. When mom fell asleep I sat up on the edge of my bed gasping for air. "I should wake her up," I thought. Instead, I took more hits of my inhaler.

The next morning mom and I walked to a nearby restaurant. I concentrated on every minute, thinking each was my last of normal life. When finished we walked back to the hotel room. Mom said, said, "They say you'll only need to be here 6-8 weeks. It's only a short time. Just think of every weekend as a marker of one more week gone by."

I suppose it was mom’s optimism that kept my anxiety under wraps. I was excited about meeting other asthmatics my age, but I was nervous about the unexpected.

Back in the hotel room mom grabbed one end of my trunk. I sighed and grabbed my end, and we were off. While walking across the street I looked up at the buildings wondering which one would be my new home, and what floor?
***

Mom was sitting in the business office filling out paperwork while I sat twiddling my thumbs on a chair in the hall. A few days ago, he called and introduced himself to me, “I will be your counselor during your stay at the asthma hospital. If you have any problems at anytime I will be available.”

He appeared to be of amiable disposition, and his voice was very calm. I looked forward to meeting him. For now, though, I had to wait for mom to finish filling out papers, and “It’s taking forever,” I thought as I peered down the hall where there were several offices.

I leaned forward and thought about going into the office where mom was, but mom told me specifically to stay put. I could hear the muffled sound of mom’s voice followed by the muffled sound of the secretaries, followed by shuffling of paper, and then, for what seemed like an eternity, the click clack of a typewriter.

What would he look like – the social worker? Would he be as nice as he sounded on the phone? I sure hoped so, because I couldn’t handle a mean person. What would the nurses be like? What would my doctors be like? And, perhaps most important, what would it be like to meet a bunch of other asthmatics who were just like me? Would they be just like me? Who would become my friend? Will I find a friend?

These thoughts rolled around in my cranium like balls on a billiards table until finally, the click clacking stopped. I stood up and peered into the crack of the door and saw the tip of mom’s jeans where they covered the knees and the front of a desk with paper scattered about. Why was she still sitting there? How much paper work could there be?

The door opened and there stood mom in her blue top and blue jeans. Her dark hair set in a new perm over her beautiful phlegmatic eyes. She was a young person, only 38, but to me, she was a sagacious god, a permanent barrier to any harm and the answer to all the problems of the world. I know this wasn’t the normal mom/son relationship of your typical teenager, but I wasn’t normal by any means – I was chronically ill. Funny thing was, though, I didn’t think of myself that way. In fact, I didn’t think of myself as chronically ill until 23 years later when I’d send for, receive, and read my medical records from my stay at the asthma hospital.
“He should be here any minute now,” she said, her voice soothing.

“Who?” I said, shaking my head.

“Ric Dexter. She called him. She said he’s a tall man with a well kempt dark beard and is really nice. She said you’d like him.”

“Yeah, I know,” I said.

It seemed like forever, but from around the corner appeared a man who fit the description. "
Hi, I’m Ric Dexter,” he said. “I talked to you on the phone.”

I looked at mom. She said, “Hi. I’m Alice Frea and this is my son, Ric.”

“Hi, Rick, I hope you are as excited as I hope you are,” he said. “Let’s get rid of this trunk, and then I’ll take you on a tour. Then I’ll show you your new room and introduce you to your new room mate.”

Lamely, all I could think to say was: “Okay.”

He grabbed one handle of the trunk while mom and I looked on. “Normally I’d say your son should grab that other handle,” he said, “But he doesn’t look so well right now.”

I took a deep breath as I watched mom grab the handle and HEAVE the trunk. I lagged behind Ric and mom. We were walking down the hall, through a door I suspected would take us back out into the cool winter air that was Denver, Colorado. But the door took us to a hallway that wended this way and that, through this door and that door until finally, we were in some sort of lobby that smelled of cooked bacon.

“This is the lobby of the Goodman building,” he said. He pointed left at a set of see through doors where I could see what appeared to be a restaurant with a few people seated at many tables eating what I suspected was bacon and eggs and toast and whatever came on the early morning menu. “That’s the cafeteria,” he said. He peered down at me. “You won’t be eating here, Ric.” He looked up at mom. “But you will become really familiar with the food here, which is pretty decent for a hospital.”

“I never had good hospital food before,” I wanted to say, but held my tongue.

“Around this corner,” Ric said, “ ah here it is, is the elevator that will take us to the 7th floor where you will be staying.”

He pushed the little round, red button. Ric continued to explain about the hospital to mom and me, and mom occasionally responded with an “uhum,” or “okay, I see.” I stood by the elevator door listening to the thump-thump of my heart in my chest. I wondered if mom and Ric could here it

“This is 7-Goodman,” he said as the door swung open revealing a long hall with bright orange carpet. “This is where my office is,” he said as we passed a window revealing offices set apart by dividers. He opened the door.

“Hi, Sarah,” he said. “This is Ric Frea and his mother Alice.” Sarah was a heavyset lady with dark, curly hair. She smiled pleasantly and offered a hand, which I took. “You will see her several times a week as many of your appointments will be with me and Linda.”

“Who’s Linda?” I asked. “She’s one of your doctors. Her office is right next to mine.” He pointed to an office that had “Ric Dexter” printed on the door. Then he pointed to a door that had “Linda
Hepper” printed on it.

“Okay,” he said, “I can show you around here later. I suppose you want to meet some kids. Right” He patted me on the shoulder and he walked to the door and opened it. “Come on. It’s time to have some fun.”

I felt a lump in my throat as I stepped back into the hallway and waited for mom and Ric to take the lead. I then followed Ric down the hall to a capacious room with the same bright orange carpet that filled the hall. To my right was a large nurses station. Two nurses were sitting there with their heads stuffed into charts.

The majority of the room was filled with square, white tables with chairs pushed neatly in place. Straight ahead I saw a pool table. The long wall to my right was replete with several doors and windows blocked by curtains on the other side. The same scene was on the opposite, Western wall.

A bulletin board on the Western wall had a head of Beetle Baily and Garfield with the words, “WELCOME TO 7-GOODMAN” neatly printed on them. Under that was written, “My way of drawing Garfield. I call him Crashfield.”

While I was busy looking around the room, I didn’t notice the nurses had noticed us and had been now standing beside us. Mom and Ric set down the trunk.

"This is Karen," Ric said, introducing me to the first nurse. She was a young, fine looking curly haired nurse. She bent down before me so I could see right into her pretty blue eyes. She said, "You're blue!

"We better consider this a code blue," said a short, pudgy nurse in a white dress who stood behind Karen. Her nametag read Linda.

Karen grabbed my hand and nearly dragged me across the room. "Have a seat," she said motioning to a chair by the wesst side of the lobby (which I later would learn was the girl's side)You need a treatment NOW."

Mom followed close behind. She kept her distance as Karen took my vitals while Linda disappeared somewhere behind the nurses' station. I groaned as the pressure from the sphygmomemometer exceeded my pain threshold on my right forearm.

“Sorry,” Karen said, “We like to start out high when we have new patients.”

While I listened to the air leave the sphygmomanometer, I looked over Karen’s rich head of hair at mom and Ric. Ric stood there with a cool expression on his face, as though he had been through this many times. Mom looked worried.

My mom recounted her anxieties in a recent email:

"Here we were at the leading asthma institution in the world and they were running a code blue on you. If they were taking it that seriously, it meant you really were THAT bad."

“Ric wanted to take me on a tour,” I said to the nurses, vaguely hoping it might get me out of this predicament.

“Ric understands that we need to do our jobs,” Linda said. She stood beside me now holding a nebulizer. She plugged it into the compressor that sat on a table. “Right Ric?”

She clicked the nebulizer on so it hummed audibly. Over the hum, I could barely hear Ric. “I certainly do. Hey, I’m going to go back to my office while you finish up here. When you are done you can call me and I’ll finish the tour. I’ll put the trunk in Ric's room.”

“Great,” mom said. “Thank for—“

The rest of that conversation was lost as Linda blocked my view of mom and Ric, turned on the compressor, and the nebulizer rumbled to life. She then handed me the misting nebulizer.

"I feel fine," I said.

"You're just used to it," Karen said.

"I feel fine," I thought, forcibly preventing myself from rolling my eyes.

I put the misting mouthpiece into my mouth the way I did many times before in hospitals.

"Sit straight," Karen said, "Your stomach should go out when you breathe in slowly through your mouth, inhaling the white mist. Exhale slowly through your nose."

"I know all that," I said.

"We're going to re-teach you many things," Linda said.

"Plug your nose when you inhale," Karen said, "When you inhale count to three when you exhale count to six... sit up straight... Ric, sit up straight."

Lots of rules for one silly treatment, I thought. But these were the rules I had to follow for the next 6-8 weeks. I sure so hope I'm out of here in 6-8 weeks.

Finally, the treatment was done. "Shake it good," Karen said. "You want to get the most medicine you can out of it."

Several minutes later the comperssor was off and I watched as a petite, dark haired lady in a brown dress walked up to mom. "I'm Dr. Betty," she said, "I'll be your son's doctor. We'll take good care of him."

"That's what we're hoping," mom said, and she told Betty about the asthma attack I had last night

"By the looks of things here," Dr. Betty said, "You should have brought him in. In fact, he should have been in a hospital the past week. She looked mom in the eyes, "Really, HE IS THAT BAD. I just want you to know you did the right thing bringing him here."

Finally, after an hour with the doctor, the smell of spaghetti was in the air and a congregation of asthmatic kids of all sizes shuffled in one by one for lunch and noon meds.

I barely had a chance to meet the other kids when Karen called me to the nurse’s station where Ric was standing. “Well,” he said, “I don’t see your room mate, but how about if we finish our tour now that you’re feeling better?”

He took me to a door on the east side of the room. “This is the boy’s rooms,” he said.

"This place is clean for a boy's dorm," mom said as she entered the room and looked around. I followed closely behind.

"Well," Ric said, "We have a level system here. If the kids follow the rules they can move up to honors and get special privileges. It's a good incentive to keep your room clean." He smiled and looked at me.

On the far side of the room, the eastern side, the wall was basically a huge window with a view of the city around the hospital set amid overcast skies. "If you look north," he pointed, "you can see the Rockies on a clear day."

I followed him to the next room where the bed by the window was unkempt, and books and papers scattered about. "Eric is your room mate. He's a good kid, but he's kind of sloppy."

There were two other beds in the room. "The one by the door is yours," he said. "You have to be close to the nurses until you move up to the next level. If you get to honors you can pick your own bed and even have a chance to get a TV."

After showing me around the boy’s rooms Ric showed mom and me around the rest of the hospital. By the time we were back on 7-Goodman the other kids slowly carted into the room. A plump black kid, who would later introduce himself as Willie, was playing pool with another boy with messy black hair.

“Hey, there’s your room mate,” Ric said. I looked around the room at all the kids that were now scattered about, two boys were sitting at tables involved in a project that was perhaps homework, a conglomeration of girls were standing in the far corner perhaps chattering about the latest gossip, and perhaps the topic of the day was, “Who is the new boy? Gosh, will he turn out to be a cool kid or a chump?”

Ric led mom and me to the pool table to where the messy haired kid was aiming his cue at the black ball. Click. “Aha, I won!” he yelled as the black eight ball bounded into a corner pocket. “Finally I beat you.”

“Ah, that’s fine,” Willie said, “We’re just having fun.”

“Fun, my butt. It’s all about winning.” The messy haired boy’s grin filled his face as he twirled his pool stick over his head.

“Hey, Eric, how’s it going,” Ric said. The pool stick flew out of Eric’s hand and clattered on the floor.

“What? Who?” His smile instantly wiped away and filled with an expression of concern.
“I want you to meat someone.” Ric motioned for me to move forward. “This is Ric Frea

"This is your new roommate. Rick, this is Eric Groch.”

I offered my hand, but Eric walked away. He bent down, picked up his pool stick, and leaned on the table, facing the door to his –and my—room.

Beside me, mom was standing with her camera out. She tried to take a picture of Eric, but he quickly darted out of the range of the camera. Mom aimed through the camera again, but he darted, ducked under the pool table. The camera clicked. The picture of the pool stick and parts of Eric’s red shirt still show in the picture today, the only one of him I have.

Only fitting, though, as he would turn out to be a big thorn in my side – a drug addict, criminal mind moron you might say. The kind of person no mom would ever want her son to meat, and here I was his roommate.

Willie said, "Well, if you're not going to play pool, Rick can play."

"Cool," I said, "I'll play."

Eric plopped himself out from under the table, but when he saw my mom was eagerly standing by waiting to snap another picture, back under he went. An ominous sign of the chump Eric would turn out to be.

Willie would turn out to be a good pal.

(Dean and his mom and dad were standing nearby. Mom talked with his mother. Introduced me to Dean, who was admitted the day before. The next day mom and Dean’s parents went shopping while I participated in an array of tests.)

Later that day, after a ton of appointments with doctors and testing, mom asked my doctor if she could take me to the museum. Dr. Betty said I was too unstable. I understood, but it was a disappointing none-the-less considering mom was in town five days and I couldn't do anything with her.

Finally, on the 14th of January, I kissed her good-bye. I really didn’t have a lot of time those initial days to be homesick as the activities were abounding. Still, there were some dark moments.

This was not a normal hospital where you sat in bed all day. It was more of an institution where you went about your normal daily activities, which were blended in with various tests and appointments. The intent was to get our asthma under control in the process of making us gallant asthmatics.

The next morning I got up at 6 a.m. and walked out to the lobby in my jimmies. A short, curly haired blonde female teenager I had yet to be introduced to was taking a breathing treatment. I could hear the soft audible purr of the machine.

“I can see your underwear,” Eric teased. “Hey everybody, you can see Rick's underwear through his witto jimmies.”

Of course growing up with four brothers I didn’t care and proceeded to the nurse’s station. The night nurse placed three pills on the counter. “this one here tastes really bad, so you might want to take it with grape juice,” she said.

The grape juice was good, but that pill tasted NASTY at the back of my throat regardless. It was the steroid pill. Even through the strong grape flavor, there was nothing I could do to prevent the pill from sliding over the sour receptors of my tongue.

The other pill was Theo-Dur, a bronchodilator in pill form. That pill was relatively bulky, but I had no trouble getting it down.

“Can I take my treatment now?” I asked. I was tight.

“Well, you are gonna have to wait a while. Deana is taking a treatment now, and then comes Eric, Dean, Willie and then Stan. They were up before you. If you want to take a treatment first, you’re going to have to get up a lot earlier than this.”

“Oh, come on. I need one now.”

“Well, you should think about that before you sleep in,” she said, as she set the next kid’s meds on the counter.

“But I didn’t’ sleep in. I’m up right on time.”

“Well, you’ll have to reconsider.”

I sat in a chair by the door of my room while I waited for my turn on the nebulizer. Finally, Stan sat in the treatment chair. Another girl was in the other treatment chair. I walked to the med room behind the nurse’s station. Here, on a counter, where several brown, glass bottles of medicine.

I filed through cardboard papers in a box to the right and pulled out the one with my name on it. Listed on the card was the meds I was supposed to take in the nebulizer: Alupent 0.3cc and Atrovent 0.5mg. As I was reading the card Cathy, my head nurse, came into the room and poked her head over my shoulder. Willie was also in the room doing something with his nebulizer, but I paid him no attention.

“I’ll just watch you do it today,” she said. Before this day she drew up the meds and I watched. So this was progress.

To the left, on a rack hanging on the wall, were plastic bags with our nebs in them. I grabbed the one with my name, heart thumping but only because I had cute Cathy breathing down my shoulder, and dumped out the contents on to the counter. I set it up so the cup was open.

I grabbed the syringe and set it in front of me. I reached for the large, brown bottle of Atrovent and twisted the cap until it was off. On the inside of the cap was a black squeeze bulb. I squeezed up the correct dose as Karen showed me the earlier, and squeezed it into the nebulizer cup. I did the same with the Alupent.

The treatment now together, I walked back to the lobby. Cathy followed me out of the med room, but instead of following me to the treatment chair she went to the nurses' station. My chest was tight. I was audibly wheezing. I was huffing as I walked by the nurse’s station. Stan still had his hand over his nostrils and the neb in his mouth, but I could hear it was close to finished.

“John, can I talk with you,” Cathy said.

I approached her. As I did so Stan got up and another kid took his place in the treatment chair. I had missed my turn. Thank you very much, Cathy. How the heck could I miss my turn when no one came into the med room the whole time I was in there.

On a table near the nebulizer three girls were seated and giggling. Al three were looking at me. One of them got up, giggling the whole way, and walked to the med room.

“John,” Cathy was leaning on the counter looking at me. She whispered as I stood next to and leaned on the counter. I could not hear what she said, so I leaned in the same time she did. We were nearly face-to-face. “I didn’t want to say this in the med room in front of Willie.” She paused and held back a smile before she finished. “First of all, you really ought to wear a bathrobe over your pajamas. Either that or you should get dressed before you come out here for your meds in the morning. We can all see your underwear through your pajamas.”

“You already said that,” I said.

“Well, I guess you didn’t hear me. Do you hear me?”

“Yes,” I said. “I hear you. Tomorrow I’ll get up earlier. What time is good?”

“Well, if you want to get up before the other kids, you better be here by 5:30. You don’t have to, it’s your choice. Remember, you can take your morning treatment anytime between 5:30 and 6:30. But if you need a treatment as bad as you do, you ought to be up earlier.”

“Okay,” I said. From now on the other kids are gonna wait for me.

I turned and started for the nebulizer. Stan was STILL puffing on that thing. Is there anything coming out? I don’t see any mist. I turned to Cathy who was still leaning on the counter looking at me. “Cathy?”

“Yes.” She let her smile show this time. You look darn good-looking for a nurse. I wonder how old you are.

“How did Stan beat me to the treatment chair. I didn’t see him in the med room.”

“He was up earlier and prepared his treatment so he was ready to go. You can do that to if you want.”

The next day my alarm went off at 5 a.m. sharp. I leaned across my bed, hit the off button, and could hear my room mate snoring, his radio still blaring. I hopped out of bed in my pajamas, and I grabbed my green fluffy bathrobe I had set on my nightstand. As I opened the door to the lobby I saw there were no kids up yet. I had all the med room and the nebulizers to myself.

When 5:30 arrived I had my butt in the nebulizer seat. From this point on the other kids had to wait for me.
***
It was my responsibility to know when my meds were due and to take them as instructed. If I missed one dose or used an improper technique, I would lose my allowance for the week. Without allowance, I’d have no money to spend at the weekly field trip. (Which didn't matter at this point anyway because Dr. Betty wouldn’t allow me to go even if I had the points.)

The point sheet is what I used to keep track of my progress. On it was all the things I had accomplished in a day. If I lost it, that was like losing all my points. And it is pointed that determined how I moved up the levels.

As I popped my pills with grape juice, I looked up at the board behind the nurse’s station. Dean’s name and mine were printed on the bottom written in blue marker, while all the other kid’s names were written in black. Next to our names was written the level we were on. My level was 2. Alongside the other names were 1, 2, 3, 4 or H for honors. The goal was to move up to honors, and the place no one wanted to go was level 1, because that meant no allowance and no privileges at all.
***
I followed Eric and the other kids to the elevator and down to the basement. It was time for my first day of school. I followed the other kids through the tunnels.

Mr. Rose was a nice teacher. He seemed a bit obnoxious though, but I suppose when your teaching a bunch of chronically ill kids you have to be a bit different. "We have a new student, today," he said, "This is Rick Frea. Rick, tell us about yourself."

"Um..." I said, "I'm from Michigan and I... uh... I have asthma and it got really bad and so now.. uh.. now I am here to get my asthma under control."

"As is the case with all of us, right guys?"

The class shouted in unison, "Right Mr. Rose."

A short-stout kid with loose fitting clothes and long blonde hair sat in a seat right before Mr. Rose's desk. He never stopped talking for the first 30 minutes of class. Finally Mr. Rose said, "Chico, I think that bandana of yours is tied too tight over your skull and squeezing your brain because it sure doesn't seem to be working today."

"That's because I'm hip," Chico said.

"That's because you're a dip," Mr. Rose said. "Now stop talking a minute so we can educate the rest of the class because obviously, you don't have any interest in education. I'm not even sure it's possible to educate you."

"I'm already fully educated," he chided.

"We can all see how educated you are, Chicohead. Now hush."

At noon I followed the other students back through the tunnels to 7-Goodman. The nurses gave me my noon meds. Karen was there. She told me I had appointments the rest of the day and wouldn't be going back to school.

The second day of school, and many of the days that followed, I had to leave many times for "lots of appointments, which included a PFT," according to my personal diary.

By the time I got back from testing the other kids were done with school. I was told after school was supposed to be our time to relax, do homework or socialize, but up to this day, I never had a chance to do either.

After dinner, at 7.pm., it was time for aerobics. I was told I had to go down to participate, but I wasn't able to do anything physical. It surely wasn't fun standing there while the other kids were playing kickball.
***

The next day I talked to Dr. Betty between appointments and she said I could participate in aerobics if I wanted to that night. But, when I did, my chest got tight, I started to wheeze, and one of the kids had to show me how to get back to 7-Goodman.

"Get an epinephrine ready," a pudgy nurse said as she started a breathing treatment and handed it to me. "Concentrate on your breathing. Sit straight. Concentrate on your breathing."

I did as I was taught those first few days. I concentrated on my breathing, and soon I was able to take in a normal breath, but it didn't come until the treatment was almost finished. I almost bought myself my first Denver Epi that night, but it wasn't needed.

The next day I had to do a barium swallow. That's a test to determine if there were any stomach abnormalities. I'm telling you, while I was there they did every test imaginable. They even did an EEG one day because I had constant headaches.

For obvious reasons, I didn't do very well in school on these initial days. In my diary I kept writing, "School was boring today. I have to study for exams and I hate it." I was probably antsy about all these tests they were doing on me. Well, plus I was homesick being so far away from home.

Finally, it was Friday of week two. I marked my diary: 4-6 weeks to go.

Up to this point, I wasn't allowed to participate in any off campus events -- like there was any time for it anyway. Still, it was something that I was really looking forward to. I walked down to the business office during lunch break with one of the other kids and got money.

Along with seeing Ric on regular basis, I also had to see a psychologist weekly. I didn't understand it then, but she was scoping me for the psychological consequences of asthma.

Every night we either had aerobics or swimming. I had to go but was not allowed to participate that first week. I was wheezing and my chest remained tight.

On day #13 my new friends wanted me to go to the mall with them. I "begged" Dr. Betty to let me go, and she said I could. She also said I could participate in aerobics that night.

But, as I ran around the gym trying to be normal, the asthma beast struck and I became anxious and insisted that I needed a treatment. One of my friends escorted me upstairs, "where Kathy almost had to give me an epi," according to my diary.

The next day school went great. At lunch, I rushed up to the bank to withdraw money to spend at the mall and rushed up to 7-Goodman to eat lunch and get my noon meds. I was wheezing.
After school, and still wheezing after my treatment, Dr. Betty approached me. I had a bad feeling about this.

She said, "John, I've decided you would benefit from being on steroids. We tried you on the basic meds and you don't seem to be responding. Your lips are blue as we speak. I want you to go upstairs to our hospital where we can watch you more closely."

And so slipped my good mood. Here I was at the best asthma institution in the world and my Asthma wasn’t getting any better at all -- it was getting worse.

To be continued.....

1979: Tedral Related Depression?

I wrote about my experience with Tedral and Tedral Side Effects. I have come up with another side effect that I think might have been related to Tedral: Depression.

I remember the first time I experienced it was in 1976 when my grandpa Howard died. He was my Great Grandfather, and he was 82-years-old. I did not know him very well, although I did visit him a few times with grandma at the nursing home, and maybe the occasional Christmas party at grandma's house.

So, in November of 1976, he died. And I remember getting severely depressed. It lasted for quite some time. I remember feeling like I wanted to cry even in the days leading up to, and the days following the funeral.

In fact, I remember the class singing "You Light Up My Life" in music, and I had to work hard not to cry.

The same thing happened in 1977. It happened again in 1978. My Aunt Mary worked at K-Mart. They had a special "Blue Light Special" day where those who worked at K-Mart could invite their friends and relatives to this special day where they would have all sorts of deals.

I remember being severely depressed every year this happened. And one year I won a radio. And that sort of ended the depression for a little while. But then it came back.

I learned to dread November. I learned to dread the day of the K-Mart special party because I knew I'd get depressed.

And then, one year, I think it was 1983 or 1984, the depression didn't come. I kept thinking it would, and it didn't. I remember concentrating on not letting the depression come, and it didn't. I prayed. I was so happy when it stopped.

I have, to the best of my knowledge, not been depressed in November ever since.

Mom said that when I was a kid I used to pace the living room for hours. She said she knew I was depressed. I do not ever remember her acknowledging it. I don't ever remember being treated for it until 1985 when I was at the asthma hospital.

Recently, however, as I was thinking about this, and about Tedral, a thought occurred to me: what if I was going through withdrawal symptoms?

I only took Tedral during allergy season, and then I was told (or my mom was told) to stop taking it or to have me quit. See? I probably became addicted to it over the summer. And when they took me off, probably near the end of October or early November, I went through withdrawal symptoms.

No one ever noticed.

Tedral contained theophylline, which is a xanthine just like caffeine. Like caffeine, you can develop both a psychological and a physical addiction to it.

I think it ended because my asthma got so bad that I ended up taking theophylline year round. My doctor switched me to Theovent at some point. I probably only took it in the summer at first. But, by 1984, my asthma was so bad he just kept me on it year round.

So, the depressions ended. They ended because my body developed a tolerance to it. My body expected it to always be there. It expected me to continue putting it into my body. And when I quit, my body had to readjust, hence the withdrawal symptoms; hence the depression.

I know that when I forgot to take my theophylline over the years, it resulted in severe asthma episodes. So, I never experienced depression because, I think, asthma hit before the depression ever did.

Anyway, this is just me thinking here. I could be wrong. There's really no way of knowing.

1968-2010: Mast Cell Stabilizers for asthma

Intal Spinhaler used by asthmatics in the 1970s, 80s and 90s

In the early 1980s, my doctor introduced me to the Intal Spinhaler that crushed a capsule with a medicine called disodium cromoglycate or chromolyn.  It was a white powder that was proven to improve lung function by decreasing inflammation. 

It was also proven to improve exercise related asthma. 
Each month you'll pick up a small white and yellow box from your pharmacist that contained a bunch of small capsules called Spincaps wrapped in tinfoil.  You unwrapped one and set it aside. 

Then you the inhaler and held it so the mouthpiece was facing down.  You unscrewed the cap and
placed  it onto a cup on the propeller, screwed the body back on the mouthpiece, and slide the outer sleeve (the blue part in the picture) down as far as it would go and then back up again.  This pierces the capsule and makes the spinhaler ready for use. (1)

You exhaled as much air as you could (just like using any inhaler), placed your mouth over the mouthpiece, and inhaled.  As you inhaled, the powder would enter your airway, with a good portion going to your air passages.  You could feel the powder as impacted in your upper airways, even taste it when it landed on your tongue. This is how you knew you did it right, I suppose

This was the first mass produced dry powder inhaler that hit the market.  It was a great medicine, and when used with an inhaled corticosteroid it worked great to prevent asthma.

Mast cells are white blood cells that are randomly scattered around your respiratory tract. They are granulocytes, meaning they contain tiny grains. When told to do so, they release their contents, which contain histamine, leukotrienes, cytokines, and chemokines. These are tiny proteins that are responsible for airway inflammation.

Mast cell stabilizers like cromolyn prevent mast cells from releasing their contents, thereby preventing them from causing inflammation. The idea was that this would result in better asthma control.

There are a variety of environmental triggers that might trigger mast cells. One is when you inhale allergens, such as dust mites, pollen, animal dander, cockroach urine, mold spores, and certain foods.  Another is rapidly breathing in air that is not properly warmed and humidified, such as what might occur while you are exercising. This irritates cells lining airways, causing mast cells to release their contents.

So, cromolyn was prescribed for allergy and exercise induced asthma. Back then, these were essentially considered the hallmarks of all or most cases of asthma.

When I was a kid I had what my doctors referred to as high risk asthma. I was allergic to pretty much everything outdoors, and had exercise induced asthma (EIA).  Unless I was in an allergy proof bubble, my asthma was usually acting up.  By the time I entered the 9th grade in September of 1984, I pretty much stopped going to gym class per my doctor's instructions.

By January of 1985, I had made so many trips to the emergency room I was admitted to NJH/NAC in Denver.  Once they managed to get my asthma under control, they did some pulmonary function testing on me to see what medicine might help me with my EIA.

In one test I took no medicine and ran on the treadmill.  My lung function dropped significantly.  A week later I did another PFT, this time taking two puffs of Alupent before I ran on the treadmill.  My lung function once again dropped significantly, indicating Alupent had no effect. 

A week later I used my Intal Spinhaler before exercise, and while my lung function declined it wasn't as steep of a decline, indicating that disodium cromoglycate prevented EIA, at least in me. (You can see my PFT tests here).

Intal Inhaler

I was using this inhaler four times a day (which was a pain in the butt), so there was no need for me to use it prior to every time I exercised.  I think the thought was that it would act as an asthma controller medicine to be used either in conjunction with or (ideally) as a stand alone medicine.

In a way, it worked the same way inhaled steroids worked, yet apparently not as well.  Prior to being at NJH/NAC my doctors had me using my Intal every day all the time, and only using my inhaled steroids as needed.  Yet by the time I left NJH/NAC in July of 1985, I was using both medicines four times every day, along with a ton of other medicines as you can see here.  Yes, this was a lot of medicine.

Yet the Intal Spinhaler was a good medicine for asthmatics since it was introduced to the market in 1968.  The medicine disodium cromoglycate was isolated by Roger Altounyan who had bad asthma himself and decided to test a variety of substances that were already proven to benefit asthma. He was working at Bengers Research Laboratories.  (2)

Cromolyn Nebulizer Solution

Khella was used by local natives living in Eastern Mediterranean countries for quite a few years to treat asthma with some success.  They made various "concoctions" from the seeds of the plant Amni Vasnaga, from which the substance Khellin was extracted in 1879.  (3)

Various studies in the 1940s and 50s showed the medicine relaxed smooth muscles throughout the body, including the muscles surrounding air passages in the lungs.  Yet the bronchodilating effect was less than epinephrine.  The various studies showed the medicine accumulated in your system if used regularly, and was proven effective for both asthma and other lung diseases. (4)

In 1953 The American Journal of Physical Medicine published the results of a study that showed inhaling aerosols of  7mg of Khellin improved lung function.  Perhaps it was studies like this that inspired Altounyan to study this extract.  (5)

Amps of Cromolyn solution

By experiments in the lab Altounyan produced a safer version of khellin called disodium chromoglycate.  While his goal was to improve his own asthma, what he ended up with was a new product.  It was marketed by Fisons and sold as the Intal Spincaps and Intal Spinhaler.  It became yet another option for many asthmatics worldwide suffering from asthma and allergies. 

Along with being the first dry powder inhaler, it was also the first mast cell stabilizer.

A problem with the spinhaler was that it couldn't be used during an asthma attack, and the dry powder entered your airway at such a force it was known to cause reflex bronchospasm, a fit of coughing and, thus, cause some asthma attacks.  I never experienced this problem however.  It was a nice option for me until modern inhaled steroids made it unnecessary.

Tilade inhaler

Nedicromil Sodium was approved by the FDA in 1992 as an alternative to Intal, and was marketed as the Tilade inhaler. (6) Studies showed it was equally effective in treating inflammation and reducing allergy and asthma symptoms as Intal.  I never used Tilade, and I have little clinical experience educating it to patients either.

By 1995, Cromolyn was available as a solution to be nebulized, and this was ultimately a good option for pediatricians to prescribe for kids with asthma.  I have no recollection of ever giving this via aerosol to an adult, and rarely gave it to kids either for that matter.  As of 2010, I believe we were no longer carrying it in our stock. 

The Intal Spinhaler was ultimately phased out in the U.S. and Europe in favor of an inhaler, and the inhaler was ultimately phased out on December 31, 2010.  By a simple Google search, I see it's can still be purchased over the Internet, and may act as a viable alternative to top-line asthma medicines.

Tilade was phased out on June 14, 2010.  Altounyan's product was a great option for many asthmatics for many years, and for that we owe him thanks.  Perhaps some form of this product will make a comeback someday and replace the need for inhaled corticosteroids. 

References: 

1. "Intal Spincaps Powder for Inhalation, Sodium cromoglycate, Consumer Medicine Information, " package insert for the Intal Spinhaler and Intal Spincaps, 2005
2. Jackson, Mark, "Asthma: A biography," 2009, New York, page 187
3.  Kennedy, M.C.S, J.P.P. Stock, "The Bronchodilator Action of Khellin," Thorax, 1952, 7, 43, pages 43-65
4. Kennedy, ibid, page 43
5. Braun, K, E. Eilender, "Khellin Aerosol in Bronchial Asthma," American Journal of Physical Medicine, Dec., 1953, Vol. 32, Issue 6,
6. "Tilade approved by FDA; Fisons Announces Co-Promotion Agreement with Rhone-Poulenc Rorer," Press Release, TheFreeLibrary.com, http://www.thefreelibrary.com/TILADE+APPROVED+BY+FDA%3B+FISONS+ANNOUNCES+CO-PROMOTION+AGREEMENT+WITH...-a013101159

Brief COPD History

Did you know that for most of history, nearly every lung disease, including COPD, was lumped under the umbrella term asthma? It’s true. In fact, it’s only been over the past 100 years that COPD has been plucked from under this asthma umbrella to become a disease entity of its own with its own remedies. That said, here is a brief history of COPD.

2697 B.C.: Nei Ching Su Wen (Classics on Internal Medicine) is the oldest known medical document. In it, Huang Ti, The Yellow Emperor, is involved in dialogue with Ch'i Pai, his physician. The Emperor makes many references to asthma or COPD-like symptoms such as noisy breathing and troubled breathing.

1500 B.C. Asthma and COPD-like symptoms were also described by the ancient Egyptians. The Ebers Papyrus is a medical document that describes over 700 remedies for asthma, including placing herbs on heated rocks and inhaling the smoke.

800 B.C. Homer is the first to use the term asthma to define difficulty breathing after exertion in battle, or from wounds caused by battle.

400 B.C.: Hippocrates defines asthma for the medical community as difficulty breathing.

1679 A.D.: For the first time in history, physicians were allowed to perform autopsies to search for the true causes of diseases. A Swiss physician named Theophile Bonet performed over 3,000 autopsies on patients of his who died and became the first to describe emphysema as a medical condition. He defined it as “voluminous lungs.”

1769: Giovanni Morgagni described 19 cases of “turgis” lungs, and verified the findings of Dr. Bonet.

1784: Dr. Samuel Johnson was a long-time sufferer of “asthma.” However, Dr. James Arthur Wilson, who was only 19-years-old, performed an autopsy on Dr. Johnson. Based on his description of Dr. Johnson’s lungs, later physicians determined that Johnson didn’t die of asthma, he died of emphysema.

1799: Matthew Baillie, who also studied the body of Dr. Johnson, was the first to describe emphysema (“enlarged air spaces”) and publish his description in a book with pictures.

1814. Charles Badham became the first physician to use the term bronchitis when referring to inflammation of the mucous membrane. He referred to a chronic cough and increased mucus secretion as being caused by chronic catarrh. He also described chronic bronchitis as a disabling condition.

1819: Rene Laennec, the inventor of the stethoscope, became the first physician to accurately describe emphysema and chronic bronchitis as related conditions.

1837: Dr. William Stokes became the first to use the term chronic bronchitis.

1846: English Surgeon John Hutchinson invented the spirometer. It was a device used to measure slow vital capacity (SVC) or the amount of air that can be exhaled after a deep inhalation. Later on, forced vital capacity (FVC) was described, or a forced exhalation after a deep inhalation. How fast can you get the air out after a deep inhalation?

1885: Mendelssohn observed an increased incidence of “grinder’s asthma,” or what was often diagnosed as tuberculous among metal grinders. Before him it was believed inhaling coal dust was harmless, but he believed it was the cause of asthma. He was the first to observe a link between inhaled irritants like coal dust and smoke with lung disease. (1)

1947: The ability to measure FEV1 was developed. This is the amount of air exhaled in the first second of FVC. Tiffeneau-Pinelli described inspiratory vital capacity (IVC) and created the formula FEV1/IVC This gave physicians the ability to differentiate between obstructive lung diseases (like asthma and chronic bronchitis) and restrictive diseases like emphysema and kyphosis. The formula used today is FEV1/FVC. Due to airway obstruction, FEV1 is reduced in people with COPD, resulting in a reduced FEV1/FVC. A normal FEV1 value is 80% of predicted. So, a diagnosis of COPD was determined to be a FEV1 less than 80% of predicted, along with a FEV1/FVC less than 70%. This is a good indicator of airflow obstruction and airflow limitation. In a restrictive lung disease, FEV1 and FVC will each equally be diminished to do lots of space for lungs to expand, and so FEV1/FVC may be close to normal or even slightly elevated.

1958. American and British physicians defined the same disease differently up to this time. It was referred to as a chronic obstructive bronchopulmonary disease, chronic airflow obstruction, chronic obstructive lung disease, nonspecific chronic pulmonary disease, and diffuse obstructive pulmonary syndrome. This was confusing as it seemed as though each researcher, or each physician, was referring to something different. In order to unify efforts to learn about this disease, it was decided that a unified name must be created. The CIBA Guest Symposium, a gathering of various medical professionals, convened from Sept. 24-26. They were the first agree to use the term Chronic Obstructive Pulmonary Disease (COPD) in referring to the comorbidity of chronic bronchitis and emphysema. The results of the symposium were published in 1959.

The 1950s: Antibiotics were increasingly used to treat lung infections (pneumonia) caused by increased secretions in airways. Potassium Chloride was used as a mucus thinner and theophylline as a bronchodilator. Epinephrine was used either as an injection or nebulized inhalant in emergency rooms. Epinephrine nebulizer solution was available for home use, and, after 1957, epinephrine inhalers were available. While systemic corticosteroids were available, they were rarely used to treat COPD. Isoprenaline nebulizer solution was also available, although used less regularly than epinephrine due to cost. An isoprenaline inhaler was also available after 1957.

The 1960s: Isoprenaline was increasingly used, and corticosteroid and oxygen use continued to be rarely used to treat COPD.

1960: Fry and Hyatt devised the flow volume loop, which displays the FVC as a graphic. This allowed physicians to physically see the difference between obstructive and restrictive disease. This made it easier to use spirometry as a means of differentiating between restrictive and obstructive diseases.

1962. Now researchers and physicians needed a unified definition of chronic bronchitis and emphysema. The American Thoracic Society Committee on Diagnostic Standards (Committee Diagnostic Standards for NonTuberculosos Respiratory Disease) defined chronic bronchitis as a cough lasting three months for at least three years, and emphysema as enlarged air spaces and loss of alveolar walls. Asthma was defined as airway hyperresponsiveness to a variety of stimuli. Asthmatic bronchitis was defined as a combination of asthma and COPD. For the first time, asthma and COPD were officially defined as unique diseases.

Also, it was well known during the 1950s and 1960s that COPD was caused by cigarette smoke. So, in 1962, Donald O. Anderson and Benjamin Ferris reported in the New England Journal of Medicine the results of a study performed in Berlin clearly linking the effects of cigarette smoke with chronic bronchitis.

1964. In the November issue of American Journal of Public Health, Donald O. Anderson said, “There seems little doubt whatever that cigarette smoking, and to a lesser extent other forms of tobacco smoking, are associated with mortality from lung cancer. This association has been amply demonstrated by both case history and cohort studies in a variety of countries and has been thoroughly summarized at countless symposia and in innumerable review articles. The controversy, instead, is whether this association has the attributes of a cause-effect relationship..”

1965: William Briscoe became the first person to use the term COPD at the 9th Aspen Emphysema Conference.

2001. Pauwels, et al, 2001, defined COPD as chronic airflow obstruction, or airflow limitation, due to airway obstruction that progressively worsens over time and is only partly reversible (compared with asthma, which is considered to be completely reversible with medicine or time). This was the first time COPD was defined based on physiologic criteria, as opposed to clinical or anatomic criteria.

2004: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) went with the definition of COPD as defined by Pauwels, et al, in 2001. Since then COPD has been considered a disease of airflow limitation.

2006: COPD is the 4th most common cause of death in the United States, and, among the top five causes of death, is the only one rising in morbidity and mortality.

2013: According to the CDC, COPD becomes the 3rd leading cause of death in the United States, surpassing accidents and strokes, and close behind heart disease and cancer.

References::

1. Klotz, Oskar, Wm. Charles White, ed., "Papers on the Influence of Smoke on Health," Bulletin #9, 1914, page 36

1968: Concerns about rescue inhalers lead to improved improved safety regulations

Prior to 1968, rescue inhalers were available over the counter (OTC) in Britain. Yet it was about this time that it was realized that the rising tide of asthma related deaths correlated with the introduction of the Medihaler Iso.  As prescriptions and sales of the inhaler spiked in 1960, the death rate started to rise a year later.  The link was obvious.

This revelation generated not just concern among the medical community, but among lawmakers as well.  As a result of this new wisdom, in 1968 OTC sales of the inhalers were banned in Britain under Schedule 4B of the Poisons Regulations Act.  (4, page 162) 

At about the same time, "In June 1967, the Committee of Safety of Medicines issued a warning about the need for care in prescribing and using aerosols, emphasising their great value in treatment, but advising patients or parents to call their doctors if they failed to achieve the relief they usually experienced," according the authors of "Drug delivery to the lungs."

The death rate in Britain duly fell in the succeeding years.  Furthermore, as noted by the authors of "Drug delivery to the lungs:"

When the changes in death rate were compared with estimates of prescriptions, it could be seen that the rise and fall of the death rates had followed the graph of sales of pressurized aerosols almost exactly." (5, page 12)

Similar warnings were  regulations and warnings were issued in other nations, including the United States. Gregg Mittman, in his book "Breathing Space," explains that:

The bronchodilator scare abroad prompted American physicians in the late 1960s to reflect critical on the therapeutic use of inhalers in Asthma treatment in the United States.  As the sales of inhalers jumped form 3.3 million in 1964 to 5.1 million in 1968 in the United States, disturbing reports of patient abuse began to appear.  Many asthmatic patients had become addicted to their bronchodilator inhalers, often grasping them for dear life.  Some asthmatics admitted to going through an inhaler in a day. (6, page 235)

Physicians around the world realized that drugs alone were not going to work, that the entire environment around the patient would have to be investigated.  Likewise, the patient would have to be educated not just about asthma, but about the medicines used to treat it. (6, page 236)

As physicians and their patients became better aware of the risks of overuse of these inhalers, prescriptions and sales declined.  The result of this was a national decline in the asthma death rate, although it still remained higher than the pre 1930s era when asthma morbidity and mortality was considered negligible.

What did not fall, however, was asthma mortality. Studies performed during the 1970s would reveal that asthma morbidity trends have been gradually increasing since the introduction of rescue medicine.  This would be investigated during a spike in asthma deaths that occurred in New Zealand in the 1970s.

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

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.