Understanding Asthma: Where We Have Been and Where We Are Going?

Summary of Lecture given at 2003 POSTGRADUATE PLENARY SESSION by Charles Reed, MD FAAAAI at American Academy of Allergy Asthma & Immunology (AAAA&I) 60th Annual meeting in Denver, March 7-12, 2003.

Charles Reed’s opening statement very eloquently summed up the history of the Understanding of Asthma as follows: “Over the years there has been a constantly changing consensus about the nature of asthma, and looking back over this time I am greatly impressed by how strongly the concept of the nature of asthma in vogue at the time has been dictated by fashion rather than by logical consideration of all the facts. When data accumulate that supported one concept of the disease, it seemed that everyone assumed that this meant that all other concepts were wrong. In reality, each new concept has added to our understanding, but did not invalidate what had gone before”.

The first description of Asthma in the medical literature was by William Osler in The Principles and Practice of Medicine in 1892, which stated “Bronchial asthma is a neurotic condition characterized by hyperemia (redness) and turgescensc (swelling) of the mucosa of the smaller bronchial tubes and a peculiar exudate of mucin”.

Asthma as “Neurosis”

In the 1930’s and 1940’s “neurosis” became “psychoneurosis” and asthma became a psychosomatic disease. Our understanding has made a complete circle, as we now know that:

  • Anxiety disorder and hyperventilation can trigger or exacerbate asthma attacks.
  • Psychological factors influence compliance
  • Stress can increase severity of inflammation.

Asthma as Hyperreactive Airways Disease

In the 1960’s asthma became “hyperreactive airways disease”

  • Max Samster first described excessive response of the airways to histamine in 1933
  • Pasteur Valery-Radot described excessive response to acetylcholine in 1934.
  • Methacholine test became standard in 1975 and is still probably the best diagnostic test for asthma to date.

Asthma is still considered “Hyperreactive airways disease causing bronchoconstriction from:

  • Airborne irritants
  • Airborne allergens
  • Exercise or cold air
  • Acetylcholine, histamine, leukotrienes, bradykinin, propanolol.

These stimuli provoke bronchospasm through different pathways. And although individual asthmatic patients tend to respond to them all, the magnitude of the responses to different stimuli do not necessarily correlate with each other.

Asthma as an Allergic Disease

  • In the first decade of the 20th century it became clear that the anaphylactic type of allergy was responsible at least in some asthmatics. This became known as “immediate”, “atopic” or “Type 1” hypersensitivity.
  • By 1920 skin testing and immunotherapy were widely used.

Asthma as Allergic Airway Inflammation (1975 – 2003)

Between 1975 and 1988 the study of the inflammation focused on the mucosa and exudate in the bronchial lumen. The role of eosinophils and mast cells in causing injury to the airways was followed by interest in cytokines.

Asthma as a genetic disease

Now more than 50 genes have been identified that account for different abnormalities in the complex pathways of neurotransmission and inflammation.

Future directions of Asthma: Asthma as a Regional Disease

We are overlooking the fact that the obstruction in asthma is not uniform throughout the airways: it is more severe in some bronchi than others.

Charles Reed closed his lecture with the following poignant statement: “Charles John Floyer , who also had asthma, wrote the first book devoted to the disease in 1698, If Floyer’s ghost appeared and wrote a current book this is what he might say: "Since all physicians who treat asthma realize that despite up-to-date management the disease can only be reasonably well controlled, not cured, I may infer that they do not fully understand the environmental provoking factors or the molecular and cell biology of the inflammatory and neurological pathways of the disease, and they do not yet have the medication to cure it”

First real treatment for Peanut Anaphylaxis

All the major newspapers internationally and even the Time Magazine as featured this major breakthrough, which was also presented at this conference.

The new drug is TNX-901, which is an anti-IgE antibody, and has proved to be “the first ray of hope” for people allergic to peanuts.

“It is not a cure, but is clearly a major advance,” said Dr Donald Leung of National Jewish Medical and Research Center, Denver, Colorado, and lead author of the study. Not only might you have to take it for the rest of your life, but also you will still have to avoid peanuts. And if it ever becomes available, it will cost about $10,000 a year.

In trials at National Jewish and six other sites nationwide, the drug TNX-901, gave every patient who took it increased protection against allergic reactions to peanut.

TNX-901 is a genetically engineered antibody that grabs hold of the IgE molecule and prevents it from setting off the allergic response.

In the double-blind trial, 84 patients were randomized to receive either TNX-901 at 150, 300 or 450mg, or placebo by injection every 4 weeks for 4 doses. Two to four weeks following the last dose of the study medication patients were rechallenged to peanut, in gradually increasing doses.

At the 450mg monthly dose, TNX-901 provided significant protection allowing patients to ingest a median of 9 peanuts without symptoms. TNX-901 was well tolerated by all patients and the next phase (Phase III) of the trial is now pending.

Three companies – Genetech, Tanox and Novartis have been working in partnership since 1996 to develop anti-IgE therapies. The first anti-IgE developed is called Xolair, which might be approved by the FDA by the end of the year to treat asthma. Xolair and TNX-901 are based on the same science.

Unfortunately the future of TNX-901 looks bleak as lawyers for Genetech and Novartis have argued that Tanox had no right to go off on its own and develop TNX-901. In October 2002, an arbitration panel agreed. That decision has put on hold the next step in the approval process for TNX-901, as further trial are halted by the court.

Psychosocial Impact of a Diagnosis of Anaphylaxis on the Patient and their Family

– Deena Mandell, MSW, PhD

Summary of above presentation given at Symposium 3701 on March 9, 2003:

This is one of very few studies done on the emotional and social impact of living with anaphylaxis. Health care proffessionals often encounter extreme expressions of anxiety in the families, particularly in the parents.

17 parents from families with children with peanut allergy were interviewed.

What they learned:

  • All parents interviewed reported they had been given insufficient information at the time of diagnosis to enable them to cope on a daily basis.
  • Parents reported receiving support and help (including information) from: anaphylaxis organization / support groups, physicians, friends relatives, spouses, the child with anaphylaxis. 13 of the 17 were affiliated with a support group.
  • Anxiety was found to rise predictably at specific development points. For example, as children enter school, go off to camp, and gain independence in their teen years.
  • On the whole, parents perceive the child bearing the diagnosis as being appropriately responsible and cautious for their age and stage.
  • Parents of adolescence reported that the focus of their own anxioety had shifted from avoidance to emergency preparedness (i.e. was the adrenaline injector always available?)
  • The induction of relatives, friends, and community (especially school personell) in keeping young children safe is one of the greatest stresses experienced by families.
  • Inadequate / inadequate food labelling was considered a major stressor in families coping with anaphylaxis to foods.
  • The following 3 events tended to trigger renewed anxiety:
  • Accidentan exposure, particularly if it led to a severe reaction
  • The discovery of new information regarding potential risk
  • Developmental changes, which threatened to expose the child to, increased risk.
  • If anxiety level fell too low (usually after a prolonged period free of reactions), the level of vigilance tended to drop as well. When anxiety was extremely high, family members experienced a disabling level of stress and fear. They borrowed the term “Goldilocks principle” to describe an optimal level of anxiety that is “just right”.

Recommendations

1. Professionals can help families by becoming fully aware of how anaphylaxis impinges on daily life, family routines, and relationships, and individual stress levels.

2. Provide families with relevant accurate information related to day-to day coping strategies.

3. Parental anxiety should be interpreted in the context of the overall coping patterns. Withholding pertinent information in the belief that it will make the parents unnecessarily anxious may be counterproductive and ultimately may increase the risk to the child.

4. Plan to meet the family more than once. The first meeting, soon after diagnosis, should be followed within a month or two by a meeting with the entire family or at least both parents.

5. Invite the family to return on a regular basis (perhaps annually).

6. Help families, where necessary, to adapt safety management strategies to existing family lifestyle and dynamics.

7. Provide families with suggestions regarding reliable community support groups where available (e.g. Allergy New Zealand), and to appropriate on-line and published materials. Work cooperatively with local support groups to optimize services by both groups and professionals.

8. Development of community educational and support programs, guided by further research, may be a valuable alternative or adjunct.

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