This case presents a patient with poorly controlled asthma that remains refractory to

treatment despite use of standard-of-care therapeutic options. For patients such as this, one
needs to embark on an extensive work-up to confirm the diagnosis, assess for comorbidities,
and finally, to consider different therapeutic options.

Take Note

Approximately 10% to 15% of asthma patients have severe asthma refractory to commonly
available medications.
A key aspect of care for these patients is a careful workup to exclude other comorbidities that
could be contributing to their uncontrolled asthma symptoms.
Once underlying conditions are ruled out, there are several treatment options to consider.

Case presentation and patient history

Mr. T is a 40-year-old recreational athlete with a medical history significant for asthma, for
which he has been using an albuterol rescue inhaler approximately 3 times per week for the
past year. During this time, he has also been waking up with asthma symptoms
approximately twice a month, and has had three unscheduled asthma visits for mild flares.
Based on the National Asthma Education and Prevention Program guidelines, Mr. T has
asthma that is not well controlled.

As a result of these symptoms, spirometry was performed revealing a forced expiratory

volume in the first second (FEV1) of 78% predicted. Mr. T then was prescribed treatment with
a low-dose corticosteroid, fluticasone 44 mcg at two puffs twice per day. However, he
remained symptomatic and continued to use his rescue inhaler 3 times per week. Therefore,
he was switched to a combination inhaled steroid and long-acting beta-agonist (LABA)
(fluticasone propionate 250 mcg and salmeterol 50 mcg, one puff twice a day) by his primary
care doctor.

Initial pulmonary assessment Even with this step up in his medication, Mr. T continued to
be symptomatic and require rescue inhaler use. Therefore, he was referred to a
pulmonologist, who performed the initial work-up shown here:

Spirometry, pre-albuterol: FEV1 79%, post-albuterol: 12% improvement

Methacholine challenge: PC20: 1.0 mg/mL
Chest X-ray: Within normal limits

Continued pulmonary assessment His dose of inhaled corticosteroid (ICS) and LABA was
increased to fluticasone 500 mcg/salmeterol 50 mcg, one puff twice daily. However, he
continued to have symptoms and returned to the pulmonologist for further work-up, shown
here:

Chest computed tomography (CT): Normal lung parenchyma with no scarring or

bronchiectasis
Sinus CT: Mild mucosal thickening
Complete blood count (CBC): Within normal limits, white blood cells (WBC) 10.0 K/mcL, 3%
eosinophils
Immunoglobulin E (IgE): 25 IU/mL
Allergy-skin test: Positive for dust, trees
Exhaled NO: Fractional exhaled nitric oxide (FeNO) 53 parts per billion (pbb)

Assessment for comorbidities contributing to asthma symptoms After this work-up,

tiotropium was added to his medication regimen. However, he remained symptomatic and
had two more flares over the next 3 months. He was assessed for comorbid conditions that
might be affecting his symptoms, and results showed:

Esophagram/barium swallow: Negative

Esophageal manometry: Negative
Esophageal impedance: Within normal limits
ECG: Within normal limits
Genetic testing: Negative for cystic fibrosis, alpha1 anti-trypsin deficiency
The ear, nose, and throat specialist to whom he was referred recommended only nasal
inhaled steroids for his mild sinus disease and noted that he had a normal vocal cord
evaluation.

Following this extensive work-up that transpired over the course of a year, Mr. T continued to
have symptoms. He returned to the pulmonologist to discuss further treatment options for his
refractory asthma.

Diagnosis

Mr. T has refractory asthma. Work-up for this condition should include consideration of other
causes for the symptoms, including allergies, gastroesophageal reflux disease, cardiac
disease, sinus disease, vocal cord dysfunction, or genetic diseases, such as cystic fibrosis or
alpha1 antitrypsin deficiency, as was performed for Mr. T by his pulmonary team.

Treatment options

When a patient has refractory asthma, treatment options to consider include anticholinergics
(tiotropium, aclidinium), leukotriene modifiers (montelukast, zafirlukast), theophylline,
anti-immunoglobulin E (IgE) antibody therapy with omalizumab, antibiotics, bronchial
thermoplasty, or enrollment in a clinical trial evaluating the use of agents that modulate the
cell signaling and immunologic responses seen in asthma.

Treatment outcome

Mr. T underwent bronchial thermoplasty for his asthma. One year after the procedure, he
reports feeling great. He has not taken systemic steroids for the past year, and his asthma
remains controlled on a moderate dose of ICS and a LABA. He has also been able to resume
exercising on a regular basis.
Discussion

Approximately 10% to 15% of asthma patients have severe asthma refractory to the
commonly available medications. One key aspect of care for this patient population is a
careful workup to exclude other comorbidities that could be contributing to their symptoms.
Following this, there are several treatment options to consider, as in recent years there have
been several advances in the development of asthma therapeutics.

Treatment options for refractory asthma There are a number of currently approved
therapies for severe, refractory asthma. In addition to therapy with ICS or combination
therapies with ICS and LABAs, leukotriene antagonists have good efficacy in asthma,
especially in patients with prominent allergic or exercise symptoms. The anticholinergics,
such as tiotropium, which was approved for asthma in 2015, enhance bronchodilation and
are useful adjuncts to ICS.3-5 Omalizumab is a monoclonal antibody against IgE
recommended for use in severe treatment-refractory allergic asthma in patients with atopy. A
non medication therapeutic option to consider is bronchial thermoplasty, a bronchoscopic
procedure that uses thermal energy to disrupt bronchial smooth muscle.

Personalizing treatment for each patient It is important to personalize treatment based on

individual characteristics or phenotypes that predict the patient's likely response to treatment,
as well as the patient's preferences and practical issues, such as adherence and cost.

In this case, tiotropium had already been added to Mr. T's medications and his symptoms
continued. Although addition of a leukotriene modifier was an option for him, he did not wish
to add another medication to his care regimen. Omalizumab was not added partly for this
reason, and also because of his low IgE level. As his bronchoscopy was negative, it was
determined that a course of antibiotics would not be an effective treatment option for this
patient. While vitamin D insufficiency has been associated with adverse outcomes in asthma,
T's vitamin D level was tested and found to be sufficient.

We discussed the possibility of Mr. T's enrollment in a clinical trial. However, because this did
not guarantee placement within a treatment arm and thus there was the possibility of
receiving placebo, he opted to undergo bronchial thermoplasty.

Bronchial thermoplasty Bronchial thermoplasty is effective for many patients with severe
persistent asthma, such as Mr. T. This procedure may provide additional benefits to, but does
not replace, standard asthma medications. During the procedure, thermal energy is delivered
to the airways via a bronchoscope to reduce excess airway smooth muscle and limit its ability
to constrict the airways. It is an outpatient procedure performed over three sessions by a
trained physician.

The effects of bronchial thermoplasty have been studied in several trials. The first large-scale
multicenter randomized controlled study was the Asthma Intervention Research (AIR) Trial,
which enrolled patients with moderate to severe asthma. In this trial, patients who underwent
the procedure had a significant improvement in asthma symptoms as measured by
symptom-free days and scores on asthma control and quality of life questionnaires, as well
as reductions in mild exacerbations and increases in morning peak expiratory flow.10 Shortly
after the AIR trial, the Research in Severe Asthma (RISA) trial was conducted to evaluate
bronchial thermoplasty in patients with more severe, symptomatic asthma. In this population,
bronchial thermoplasty resulted in a transient worsening of asthma symptoms, with a higher
rate of hospitalizations during the treatment period. Hospitalization rate equalized between
the treatment and control groups in the posttreatment period, however, and the treatment
group showed significant improvements in rescue medication use, prebronchodilator forced
expiratory volume in the first second (FEV1) % predicted, and asthma control questionnaire
scores.

The AIR-2 trial followed, which was a multicenter, randomized, double-blind, sham-controlled
study of 288 patients with severe asthma. Similar to the RISA trial, patients in the treatment
arm of this trial experienced an increase in adverse respiratory effects during the treatment
period, the most common being airway irritation (including wheezing, chest discomfort,
cough, and chest pain) and upper respiratory tract infections.

The majority of adverse effects occurred within 1 day of the procedure and resolved within 7
days. In this study, bronchial thermoplasty was found to significantly improve quality of life, as
well as reduce the rate of severe exacerbations by 32%. Patients who underwent the
procedure also reported fewer adverse respiratory effects, fewer days lost from work, school,
or other activities due to asthma, and an 84% risk reduction in emergency department visits.

Long-term (5-year) follow-up studies have been conducted for patients in both the AIR and
the AIR-2 trials. In patients who underwent bronchial thermoplasty in either study, the rate of
adverse respiratory effects remained stable in years 2 to 5 following the procedure, with no
increase in hospitalizations or emergency department visits.Additionally, FEV1 remained
stable throughout the 5-year follow-up period. This finding was maintained in patients
enrolled in the AIR-2 trial despite decreased use of daily ICS.

Bronchial thermoplasty is an important addition to the asthma treatment armamentarium.

This treatment is currently approved for individuals with severe persistent asthma who remain
uncontrolled despite the use of an ICS and LABA. Several clinical trials with long-term
follow-up have now demonstrated its safety and ability to improve quality of life in patients
with severe asthma, such as Mr. T.

Conclusion

Severe asthma can be a challenge to manage. Patients with this condition require an
extensive workup, but there are several treatments currently available to help manage these
patients, and new treatments are continuing to emerge. Managing severe asthma thus
requires knowledge of the options available as well as consideration of a patient's personal
situation-both in terms of disease phenotype and individual preference. In this case, the
patient expressed a strong desire to not add any additional medications to his asthma
regimen, which explained the rationale for choosing to treat with bronchial thermoplasty.
Personalized treatment necessitates exploring which of the available or emerging options is
best for each individual patient.