Clinical Practice Guideline

for

ASTHMA

Developed for the

Aerospace Medical Association

by their constituent organization

American Society of Aerospace Medicine Specialists

 

Overview: Although it’s unlikely that asthma has ever been a rare disorder, over the past twenty years the prevalence has increased by roughly 40%.  The mortality rate from asthma has increased by a similar proportion.  Numerous hypotheses have been advanced to explain the rise in prevalence, such as decreased air exchange in energy-efficient buildings, or decreased childhood infections resulting in an upregulation of IgE-mediated immunity, but no consensus exists.  Given the concurrent rise in mortality, and the fact that asthma as a cause of death is rarely confused with any other etiology, the increase in prevalence is unlikely to be an artifact of inconsistent diagnostic criteria.

 

That being said, variations in diagnostic criteria do affect epidemiologic studies of asthma, and clinical practice as well.  For such a common disease, it has been surprisingly difficult to agree on a definition.  (Asthma has also had more than its share of aliases, such as reactive airways disease, reactive bronchitis, and others.)  For practical purposes, it is reasonable to view asthma as inflammation of the airways in response to trivial or enigmatic stimuli, typically manifesting with bronchospasm and/or cough.  Excluded from this definition would be airway inflammation that accompanies other structural lung diseases, or that results from serious insults, such as toxins (e.g., smoke inhalation) or significant infections (e.g., influenza).  The qualification that the infection should be significant is important, albeit hard to delimit; to give an example, several weeks of persistent cough following a common rhinovirus infection should raise a suspicion for asthma, and if this is a recurring pattern, the diagnosis is probable.  (Prolonged symptoms after viral infection is considerably more common in children, as discussed below.)

 

Asthma often shows an atopic association, particularly with allergic rhinitis, and on occasion treatment of allergic rhinitis with immunotherapy leads to marked improvement in asthmatic symptoms.  Chronic rhinitis may be accompanied by sinusitis, and treatment of sinusitis may yield better control of asthma.  There is also an association of asthma with gastroesophageal reflux, but it is unclear which is cause and which is effect, since pressure excursions within the thorax may predispose to reflux.  Acid suppression with proton pump inhibitors rarely leads to clinical improvement, and most reviews have failed to support a role for reflux in asthma pathogenesis.  (Rarely, reflux with nocturnal aspiration of gastric secretions may mimic asthma.)  In the great majority of cases, no underlying etiology for the asthma can be implicated.  Exacerbating factors are usually easier to identify, and often tend to be idiosyncratic to the individual.  Attacks can be precipitated or exacerbated by breathing cold, dry air, by exercise, or by exposure to pollutants (e.g., exhaust fumes), to name a few common culprits.

 

Exacerbation of chronic or intermittent asthma by exercise is an extremely common symptom, reported by 70-90% of asthmatics; since it is well documented that many individuals fail to symptomatically differentiate asthma from normal exertional breathlessness, even this percentage may be an underestimate.  In addition to exercise exacerbating bronchospasm in established asthma, there is a separate phenomenon of solitary exercise-induced bronchospasm (EIB).  (Unfortunately, published reports of EIB often fail to separate the two conditions, making interpretation of results difficult in those studies.)  Solitary EIB appears to be due to airway hyperosmolarity induced by hyperpnea and free water loss, and/or cooling and subsequent rewarming of the airways.  There are no published reports of death from solitary EIB.  (In contrast, asthmatic deaths as a result of exercise in those with established asthma are well documented.1)  Solitary EIB occurs in recreational as well as high school and collegiate athletes; the prevalence is significant, typically affecting about 9-12% of children in athletic programs.  (This percentage is based on results of post-exercise spirometry; many did not have significant symptoms.)  The phenomenon has been best studied in professional athletes.  Endurance sports have a higher risk than intermittent activities.  Among cross-country runners in one study, 14% of those without a history of asthma showed objective evidence of EIB.  The greatest risk involves winter sports, which is consistent with the likely mechanism of EIB.  Screening of the 1998 Winter Olympic Team using sport-specific challenge showed an overall rate of EIB of 23%, with cross-country skiing showing a prevalence of 50%.  Another study found a 35% prevalence of solitary EIB in figure skaters.  Unlike the case in established asthma, inflammation is generally not believed to play a role in solitary EIB, though endurance athletes in winter sports may actually show inflammatory changes on histopathology.

 

The major symptoms of asthma include wheezing, shortness of breath, chest tightness, and cough.  Studies have shown that subjective reporting of symptoms does not correlate well with severity of obstruction.  Patients tend to adapt to chronic airflow obstruction, so that symptoms correlate better with the rate of fall of FEV1 during an attack rather than with the absolute degree of obstruction.  Spirometry utilizing the forced vital capacity maneuver is the standard method for measuring obstruction.  Assuming adequate effort by the individual, a ratio of FEV1/FVC less than 0.75 indicates airflow obstruction; an increase of 15% or more in absolute FEV1 after treatment with an inhaled bronchodilator denotes reversible airflow obstruction.  A 15% or greater change in FEV1 over time (an interval anywhere from minutes to months) also indicates reversible obstruction.  Whether the finding of reversible obstruction signifies asthma depends on the clinical setting.  As noted earlier, serious respiratory infections such as influenza are often accompanied by airway inflammation, which may persist for weeks, and the presence of reversible airflow obstruction during this period would not equate to asthma.  Reversible obstruction is often a feature of other chronic diseases involving the airways (e.g., sarcoidosis); the aeromedical significance of the underlying disease is likely to determine disposition in that case.

 

Children are prone to asthma; as many as a third will have symptoms compatible with asthma at some point, most often in pre-school years.  Many of these probably represent a prolonged response to viral inflammation, in particular respiratory syncitial virus.  The longer that symptoms persist, the more likely that the problem truly represents asthma.  Selection of aircrew for military aviation is complicated by the fact that many asthmatics are free of symptoms in their late teens and their twenties, only to have the problem recur in their twenties or early thirties.  In general, about 30-35% of remitted childhood asthmatics will relapse.  Numerous natural history studies have attempted to correlate a variety of factors (e.g., maternal smoking, childhood pets) to the risk of persistence or relapse of asthma, but results have been contradictory.  That has even been true of whether or not the subject smoked, which probably reflects a bias known as the “healthy smoker effect” in which those with more sensitive airways avoid taking up the habit.  Cofactors that have appeared to predict the risk of relapse in a more consistent fashion have included a history of atopy, and the frequency and severity of attacks in childhood.  Although the latter has correlated reasonably well, it is surprisingly difficult to quantify when one is looking at pediatric records of an aviation applicant.  Age shows a clear association with asthma prevalence, with a steep decline in prevalence in the preschool years and a progressively slower decline until age 16.  Clearly, most who remit do so at a younger age, and it seems probable that those who remit at a later age are at greater risk of subsequent relapse.  That pattern is clearly true for those who remit at a very early age; those with wheezing confined to infancy (<2 years old) have been shown to be at no greater risk of adult asthma than those who never wheezed.  Whether there is less risk of adult relapse in those who stop wheezing at age 8 vice those who remit at age 12 is not known.

 

A number of studies have shown that airway inflammation and/or hyperreactivity frequently persists in those who have clinically remitted.  Whether disease activity has been measured by bronchial eosinophils, histopathology, or methacholine challenge testing, anywhere from a quarter to a half or more of those in apparent remission have evidence of continued subclinical activity.  Not unreasonably, this has led to a perception that bronchoprovocation testing of individuals in remission would identify those at greater risk of later relapse.  Reasonable or not, it has proven to be incorrect.  The prevalence of methacholine reactivity from childhood to adulthood mirrors the prevalence of asthma; many of those who show normal reactivity in their early twenties show a recurrence of reactivity at a later age.  A study of allergic rhinitis patients showed no difference in the risk of developing asthma between those with positive and negative bronchoprovocation tests.  Most convincingly, in a recent publication from the data in the Dunedin (New Zealand) cohort, of 58 subjects in their mid-teens with remission of childhood asthma and negative methacholine challenge testing, 33% subsequently relapsed by age 26, consistent with historical rates of relapse.  (Those with positive bronchoprovocation testing showed a slightly greater risk of relapse, but that group numbered only six individuals, of whom three relapsed.)  Bronchoprovocation testing appears to be of no value in predicting relapse in remitted childhood asthmatics.

 

A number of modalities are available to treat asthma.  Treatment of suspected etiologic factors such as allergic rhinitis was alluded to earlier.  In the absence of significant rhinitis, the use of immunotherapy in an attempt to treat asthma is usually disappointing.  Medications employed to treat asthma are generally classified as controller, rescue, or, in the case of EIB, prophylactic therapy.  Rescue therapy primarily consists of a variety of short-acting beta-agonists (SABA) delivered via inhalation; in addition to the fact that these agents have a number of cardiac and neurologic adverse effects, the need for a SABA generally signifies asthma that is not under control.  However, prophylactic use prior to exercising in those with solitary EIB does not indicate a similar lack of control.  Use of albuterol fifteen minutes before exertion generally confers protection for about four hours.  Among controller medications, inhaled corticosteroids (ICS) are the mainstay of asthma therapy.  They have been shown to control disease and reduce the number of exacerbations.  There exists a common misperception among patients that inhalers should give immediate relief; as a result, patients routinely overuse SABA inhalers, and grossly underuse ICS.  It is very important that patients understand that the latter are slow-acting medications; while some benefit is apparent as early as a week or two, continued improvement may be seen for up to twelve months.  Adverse effects of ICS are usually local, consisting of pharyngeal candidiasis (thrush), which is generally avoidable by rinsing and gargling after inhalation, and a smaller risk of dysphonia.  At high doses, some suppression of the hypothalamic-pituitary-adrenal (HPA) axis may occur.  Montelukast, a leukotriene receptor antagonist, has very few adverse effects, though it is generally less effective than inhaled steroids.  Nonetheless, some patients respond well, and it can be useful as add-on therapy to allow reduction of inhaled steroid dose to avoid HPA axis suppression.  It reaches maximal effect within about a day of therapy, and doses higher than 10 mg are of no additional value.  Cromolyn sodium is nearly devoid of adverse effects, but is rarely efficacious in adults.

 

Other medications are less satisfactory.  Long-acting beta-agonists (LABA) such as salmeterol (Serevent® , also contained in Advair®) and formoterol (Foradil®, also contained in Combivent®) have been in vogue in recent years.  They are often classified as controllers, though suppressor is a better term, since they fail to address the underlying inflammatory process.  Administering a LABA twice a day differs little, if at all, from plying a patient every four hours with a SABA.  As with chronic use of SABAs, tolerance with LABAs is a real problem, and concerns about cardiac and neurologic adverse effects are similar.  The tolerance problem is best illustrated with EIB; not only does regular use of a SABA or LABA result in less prophylactic efficacy prior to exercise, and a sluggish response to rescue bronchodilation, but such use also typically results in the occurrence of more severe EIB.  Furthermore, recent prospective data have shown use of salmeterol is associated with increased mortality, echoing the experience with isoproterenol and fenoterol in previous decades.  As a result, the Food and Drug Administration has published an advisory, and salmeterol is no longer recommended as first-line therapy.  While the study cited was performed using salmeterol, there is little reason to assume other LABAs would be any different.  Theophylline has a very narrow therapeutic window, and is associated with highly significant adverse effects such as cardiac arrhythmias and seizures.  Systemic steroid therapy is complicated by serious adverse effects with either acute or chronic use, and within a few weeks of therapy the HPA axis is effectively suppressed.  Furthermore, the fact that the individual needs systemic steroid therapy denotes a severe degree of asthma.

 

Aeromedical Concerns: Severity of obstruction and presence/absence of symptoms are clearly important, but the principal aeromedical concern is the risk of serious bronchospasm in response to minor insults.  Since breathing cold or dry air, or exposure to smoke, fumes or pressure breathing can provoke asthma attacks, the danger of incapacitating bronchospasm is real.  In military aviation, the combination of exercise and cold, dry air is routinely encountered in high-performance aviation.  Additionally, military aviation concerns include lack of available care in austere locations. 

 

Medical Work-up: Internal or pulmonary medicine and, where indicated, allergy/immunology are the pertinent disciplines to consult.  The note from the treating physician should address severity and frequency of attacks, provocative factors, necessity for emergency room visits, and current treatment.  Abnormal results on spirometry should be followed by bronchodilator challenge.  A post-bronchodilator study may also be useful in those with low-normal airflows who have a suspicious history; even if the FEV1/FVC is inside the normal range, a 15% improvement or more in FEV1 indicates reversible obstruction.  Though not commonly employed in clinical practice because of issues with cost efficiency, bronchoprovocation testing to assess sufficiency of therapy is an established use of that modality. In the aviator, it can give valuable insight into the degree of asthma control achieved.

 

Aeromedical Disposition (military): A history of childhood asthma may be disqualifying for entry into the military, as about a third of such individuals will have recurrences in adulthood.  Trained aircrew who have an identifiable and avoidable precipitating cause for their asthma may fully remit following control of their environment; the classic example is asthma attributable to cat exposure, which resolves after cessation of exposure.  However, most triggers are difficult to entirely avoid.  Waiver can be considered for those who are well controlled by inhaled steroids, montelukast, immunotherapy, or any combination of those.  Deployment considerations remain a significant limitation for those requiring ongoing therapy.

 

Aeromedical Disposition (civilian): In civilian aviation, medical certification for any class should not be issued to an individual with severe, acute or chronic asthma with frequent exacerbations.  For further consideration airmen will be required to submit a current status report from their treating physician.  In the report of evaluation, the treating physician should describe the cause of the asthma, severity of the condition and prognosis.  This includes the type, dosage and frequency of medication, and any adverse effects.  If the symptoms are frequent, severe, or recurrent then pulmonary function testing will be required.  All medications to include immunotherapy are permitted, with the exception of prednisone or equivalent steroid dose greater than 20 mg daily.  If the airman is found to be eligible for certification, follow-up should be performed annually and results submitted in a written report.  Some cases may be forwarded to a FAA pulmonary consultant for review and recommendations. 

 

Waiver Experience (military): A review of recent USAF waiver records through February 2007 showed 202 cases of asthma including history of asthma in flying training applicants, pilots/navigators and non-pilot aircrew.  The aeromedical summaries (155) for all disqualified (67) and 88 randomly selected cases were reviewed.  Of the 67 asthma cases disqualified, 14 were flying training applicants, 16 were pilots or navigators and 37 were non-pilot aircrew.  Of the 67 disqualified asthma cases, 63 were disqualified for the asthma and the other three were disqualified for other medical conditions [ophthalmologic (3), syncope (1)].  Of the 88 randomly selected approved waivers, 62 were for history of childhood asthma, the other 26 were for asthma controlled on medications (17), exercise induced asthma (5), and asthma induced by preventable triggers [cat, dog, horse] (4).  US Air Force policy was recently changed to allow non-high performance waiver for asthma controlled with ICS, montelukast, and/or immunotherapy; inhaled SABA is allowed for prophylaxis of solitary EIB.

 

 

Waiver Experience (civilian): Civilian airmen do not receive medical certification if they have been having frequent ER visits for asthma symptoms.  In addition, they are not allowed to fly if they are taking greater than 20 mg equivalent of prednisone.  There were 2,848 First-class airmen, 2,506 Second-class and 6,272 Third-class airmen granted medical certification for asthma by the FAA as of July 2007.

 

 

References:

 

Kardon EM. Acute asthma. Emergency Medicine Clinics of North America, Feb 1996; 14(1):93-114.

 

Li JT, O’Connell EJ. Clinical evaluation of asthma. Annals of Allergy, Asthma, & Immunology, Jan 1996; 76:1-10.

 

Rayman RB. Clinical Aviation Medicine, Third edition, New York, Castle Connolly Graduate Medical Publishing, LLS, 2000, pp. 23-24.

 

 

7/22/07