Partners Asthma Center Grand Rounds
Christopher H. Fanta, M.D.
Steroid Dependent Asthma
At an asthma referral center one is often asked to evaluate patients with unusually difficult-to-control asthma. Such patients typcially have daily or nearly daily asthmatic symptoms, functional limitations due to asthma with interrupted work, school, or recreational schedules, and a requirement for daily or every-other-day corticosteroids. The following brief example highlights the clinical challenge:
This 48 year-old woman had asthma since early childhood. Over the last several years it became particularly difficult to control. She was on continuous daily oral corticosteroids for more than two years, unable to reduce the dose of prednisone to less than 20 mg/day. She was also taking a complicated regimen of high-dose inhaled corticosteroids and multiple oral and inhaled bronchodilators, including frequent treatments with nebulized beta agonists. She reported having been intubated twice for severe asthmatic attacks.
On the day of her office visit, she had taken 30 mg of prednisone. She had loud expiratory wheezing audible without a stethoscope. She also had grossly Cushingoid features, including obesity, moon facies, striae, ecchymoses, and a dorsal "buffalo hump."
I would like to return to the specifics of her history and case management later in my talk. When faced with an unusually challenging patient with difficult-to-control asthma such as hers, one needs to ask oneself — in a systematic fashion — why this patient is different from the vast majority of other asthmatic patients under one's care. This systematic approach should encompass consideration of four general categories: inciting agents, aggravating factors, patient non-compliance, and alternative diagnoses. Using a systematic analysis and current, highly-effective antiasthmatic therapies, most patients can be successfully withdrawn from oral corticosteroids. Although alternative immunosuppressive agenst, such as methotrexate and cyclosporin, have been used for their steroid-sparing effect, in my opinion these experimental agents are of modest benefit, potentially toxic, and generally unnecessary in the care of these patients.
The importance of inciting agents, particularly inhaled allergens, in causing asthma to be more severe was emphatically demonstrated by the results of the National Cooperative Inner-City Asthma Study. Several hundred asthmatic children aged 4-9 years living in one of eight inner-city urban environments across the United States were enrolled in this study. It examined the children's sensitivity (skin test reactivity) to household allergens, their exposure to these allergens in their homes, and the severity of their asthma. Attention was focused on cockroach, dust mite, and cat antigen, as retrieved in dust samples vacuumed from the children's bedrooms. The children could be categorized into one of four groups according to their allergic sensitivities and allergic exposures: Group 1: negative skin tests and low concentrations of antigens in the home; Group 2: negative skin tests but high levels of antigen exposure in the home; Group 3: positive skin test sensitivity to one or more allergens, but low levels of exposure in the home; and Group 4: positive skin test(s) combined with high levels of antigen exposure in the home.
Asthma severity was measured in terms of whether the child was hospitalized for asthma within the past year, how many unscheduled medical visits for asthma were necessary within the past year, how many days the child had wheezing over the preceding two weeks, and how often within the past year the caregiver had to change his or her plans because of the child's asthmatic symptoms. By each measure children in Group 4 had more severe asthma. In atopic children high allergen exposure in the home is a risk factor for more severe asthma. In this particular study 21% of the children had both skin test sensitivity and high-level antigen exposure, with the predominant antigen being cockroaches.
The same observations undoubtedly pertain to adults as well as to children and to other home and workplace antigenic exposures. The combination of allergic sensitivity and intense allergen exposure may make asthma refractory to conventional therapies. The first step in managing steroid-dependent asthma is thorough detective work in identifying potential allergenic or irritant exposures and eliminating or at least minimizing the patient's exposure to them.
Table 1 presents a list of potential aggravating conditions that may contribute to difficult-to-control asthma. In 1993 Dr. Richard Irwin and colleagues reported on a series of 42 steroid-dependent asthmatic patients. In considering potentially modifiable factors contributing to the severity of their asthma, and to the success of interventions that helped eliminate their steroid dependence, they identified as particularly common aggravating conditions gastroesophageal reflux disease, chronic sinusitis, and illicit drug use or alcoholism.
Medication noncompliance can exacerbate any chronic illness and is a potential contributing factor to difficult-to-control asthma. Complicated, multidrug regimens that require dosing several times each day are particularly conducive to poor patient adherence. Improper use of medications delivered by metered-dose inhalers is rampant, and it is not at all surprising that patients fail to improve when their medication is delivered to their tongue and uvula more than to their bronchi. It is worthwhile repeatedly reviewing with your patients their technique for inhaler use, emphasizing proper timing of the inhalation, slow inspiration, brief breathhold after inspiration, and, where appropriate, use of a spacer device.
Medication non-compliance can be more complicated than poor inhalational technique, however, as illustrated by the following case example.
This 35 year-old housewife and mother of two came to our
Asthma Center from Lowell with difficult-to-control asthma and a
history of frequent recent hospitalizations for her asthma. A
variety of stimuli seemed to trigger her attacks, and sometimes
the attacks seemed to come on without identifiable precipitant.
She was taking an appropriate preventative regimen of
medications, and at the Asthma Center we worked hard to teach her
asthma co-management skills and an effective "action plan" that
would help her to manage early exacerbations of her asthma at
home. We specifically emphasized home peak flow monitoring,
recording of her peak flows in an asthma diary, and initiation of
oral corticosteroids at the first evidence of significant
On one occasion she called to report worsening symptoms
and peak flow and was advised to begin prednisone 60 mg once
daily. The following day she worsened, and she was advised to
take a second, evening dose of prednisone 60 mg. Despite these
interventions she remained symptomatic, and the next day came to
our emergency department with an asthma attack. She improved only
partially with frequent nebulized bronchodilator treatments and
was hospitalized overnight. She received intravenous solumedrol
in the hospital, with dramatic improvement.
Of interest was the observation that her admission peripheral white blood cell differential had 8% eosinophils. The following morning, after observed administration of systemic corticosteroids, her eosinophils were 0%.
We had strong suspicion that she was not absorbing — or more likely, not taking — the prescribed oral corticosteroids. This observation also helped to explain her lack of Cushingoid features despite frequently prescribed courses of systemic steroids. We suspected that her social situation was such that she received secondary gain from her frequent illnesses and hospitalizations, motivating medication non-compliance.
In this patient we began directly observed treatments with intramuscular corticosteroids, initially giving depotriamcinolone 40 mg every two weeks. This intervention proved highly effective in eliminating her frequent severe asthmatic attacks, and she was not hospitalized for asthma over the ensuing 6 months. Thereafter, she dropped out of our care at the Asthma Center.
Finally, a surprising number of patients referred for management of refractory, steroid-dependent asthma prove not to have asthma but rather an alternative diagnosis that had been misconstrued as asthma. Consider the patient whom I described at the beginning of this presentation, with loudly audible wheezing even without a stethoscope despite daily prednisone.
Her history included a psychiatric disorder said to be multiple personality syndrome. Chest examination was striking in that when one listened over her chest with a stethoscope, wheezing was soft and sounded distant. The wheezing was heard best over the upper chest and neck. Additional information was subsequently obtained from her outside medical records, including an emergency department note at the time of one of her intubations. It described loud wheezing, labored beathing, and arterial blood gases (breathing air) as follows: PO2 98 mm Hg, PCO2 29 mm Hg, pH 7.47. She was treated with frequent nebulized bronchodilators and intravenous corticosteroids in high doses. She was described as "tiring" and was intubated in the emergency department. Prior to intubation repeat arterial blood gases gave the following results: PO2 102 mm Hg, PCO2 24 mm Hg, pH 7.52.
Her arterial blood gases demonstrated hyperventilation, not the hypercapnic respiratory failure of life-threatening asthma. With loud upper airway expiratory wheezing (that would have resolved with intubation), a diagnosis of vocal cord dysfunction might be suspected. This condition, in this instance a form of Munchausen's syndrome, is a functional abnormality of the upper airway mimicking asthma. No structural abnormality of the upper airway exists. The vocal cords are inappropriately adducted during exhalation, leaving only a narrow opening through which air can flow and wheezes are generated. Vocal cord dysfunction is associated with various psychiatric conditions and may accompany true asthma. It is to be distinguished from other causes of extrathoracic upper airway obstruction, which typically present with an inspiratory wheeze or stridor. The clinical suspicion of vocal cord dysfunction syndrome can usually be confirmed by direct laryngoscopy performed during wheezing.
Many other conditions may mimic severe asthma refractory to usual treatments (Table 2). Before exploring experimental, steroid-sparing therapies, it is always appropriate to step back and consider whether the initial diagnosis of asthma is correct.
In most reported series, patients with aspirin-sensitive asthma make up a disproportionate percentage of those patients categorized as having steroid-dependent asthma. Although fewer than 5% of adult asthmatics have aspirin intolerance, approximately 20% of patients identified as steroid-dependent will have aspirin intolerance. With the introduction of leukotriene-modifying drugs, new hope is available for this subcategory of patients. Patients with aspirin-sensitive asthma produce abnormally high concentrations of the sulfidopeptide leukotrienes and are likely to benefit from pharmacologic inhibition of the production or action these leukotrienes. From my own experience, other subgroups of patients identified with steroid-dependent asthma are those with persistently elevated peripheral blood eosinophilia (despite allergy avoidance interventions) and those with very high levels of IgE antibody (in the absence of allergic bronchopulmonary aspergillosis).
Approach to treatment
The standard elements of care for all patient with asthma, as listed in Table 3, need to be meticulously applied to patients with steroid-dependent asthma. Part of the focus of care is in helping patients prevent severe and potentially life-threating exacerbations. Effective strategies include home peak flow monitoring, a clear-cut plan enabling patients to respond to deteriorating symptoms and/or peak flow (asthma "action plan"), appropropriate escalation of treatment in response to clinical worsening (often including a short course or increased dose of oral corticosteroids), and rapid access to emergency care. The other focus of care is helping patients achieve asthma control on a daily basis without systemic sterioids. Thearpies newly available within the past 5-10 years have made this latter goal achievable in the vast majority of patients.
Evidence strongly supports the use of high-dose inhaled corticosteroids in combination with long-acting inhaled beta-agonist bronchodilators in severe persistent asthma. One randomized, controlled trial, published in the New England Journal of Medicine, compared outcomes in four parallel groups of patients followed for 12 months. The groups used the inhaled corticosteroid, budesonide, at a low or intermediate dose with and without the long-acting inhaled beta agonist, formoterol. (Formoterol is not approved for use in the United States; salmeterol is currently the only FDA-approved long-acting inhaled beta agonist). The outcomes assessed included improvement in lung function and freedom from both mild and severe exacerbations. For each of these outcome measures, patients randomized to receive both intermediate-dose budesonide (800 μg/day) and formoterol had the most favorable results, significantly better than intermediate-dose inhaled steroids alone or low-dose inhaled steroids plus formoterol.
In addition, selected patients will benefit from the addition of a leukotriene modifying drug. Patients with steroid-dependent asthma are appropriate for a therapeutic trial of a leukotriene modifier. In some patients blocking the leukotriene pathway makes possible withdrawal from oral steroids after months or years of steroid dependence. As discussed in a recent Asthma Grand Rounds presentation (Asthma Grand Rounds Bulletin, Winter 2000), asthmatic patients in whom chronic oral steroids are being withdrawn because of the recent initiation of new, highly effective anti-asthmatic medications should be observed closely for the unmasking of a systemic eosinophilic vasculitis, Churg-Strauss syndrome. I have made it my practice to monitor the erythrocyte sedimentation rate and peripheral blood eosinophil percent as long-term oral steroids are being tapered off.
In 1993 Dr. Richard Irwin published the results of his application of a systematic approach similar to the one described above to the treatment of 42 patients with steroid-dependent asthma. At the end of one year, only 11 patients (26%) remained steroid-dependent. He attributed his success to: 1) application of a systematic approach; 2) routine use of inhaled corticosteroids; 3) treatment of associated gastroesophageal reflux disease; and 4) commitment to detail and perseverance on the part of both the patient and the physician. I would note that his success antedated the availability of high-potency inhaled steroids, long-acting inhaled beta agonists, and leukotriene modifying drugs.
A number of experimental "steroid-sparing" therapies have been explored in the treatment of steroid-dependent asthma. They include once-weekly methotrexate, cyclosporin, troleandomycin, intravenous gammaglobulin, and inhaled lidocaine. They all remain unproven in their efficacy and potentially toxic. Their use in any patient with steroid-dependent asthma should be considered a clinical experiment. Fortunately, careful medical care with use of currently available anti-asthmatic therapies makes it very rarely necessary to resort to such experimentation outside of controlled clinical trials.
There is both good news and bad news in considering the prognosis for persons with difficult-to-control asthma. The bad news comes from studies of fatal asthma, in which the requirement for daily oral corticosteroids and recent withdrawal from oral corticosteroids have been identified as risk factors for asthma deaths. The good news derives from published outcomes of specialist care for high-risk asthmatics. The Allergy Service at Northwestern University reported on their one-year follow-up of 15 patients with potentially fatal asthma: they had no deaths, no bouts of respiratory failure, and significant improvement in an asthma severity index that they devised. In another study conducted at the chest clinic at Bellevue Hospital in inner-city New York City, using only conventional medications for asthma, ten of fourteen patients (71%) with steroid-dependent asthma were successfully withdrawn from daily prednisone. At the same time, this group of patients required significantly fewer hospitalizations for asthmatic exacerbations. The success described in these two studies is testimony to the value of applying a systematic approach to difficult-to-control asthma, with intensive medical treatment and close medical follow-up. No experimental, steroid-sparing agents were needed in either of these case studies. And both were reported before 1994, prior to the availability of high-potency inhaled steroids, long-acting inhaled beta agonists, and leukotriene modifying drugs.
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