board review

A 14-year-old female with a history of asthma presents to your office for follow-up. Her mother reports that the patient has become increasingly agitated during the day and has frequent nightmares, which she never had before. When asking about any other changes to her routine, family stressors, or medication changes you learn that she was seen by an allergy specialist 2 months ago and was given a new prescription to help with her asthma management. Her mother cannot recall the name of this new medication and it is not in your electronic medical record.

Which one of the following asthma medications is most likely to have precipitated these symptoms?

• Budesonide (Pulmicort)

• Cromolyn

• Fluticasone propionate/salmeterol (Advair Diskus

• Montelukast (Singulair)

• Omalizumab (Xolair)

Answer explanation

Published studies have reported on an increased risk of neuropsychiatric events associated with the use of montelukast. The FDA first added product labeling to include information about neuropsychiatric events with this drug in 2008. These events included agitation, depression, sleeping problems, and suicidal thoughts and actions. Continued reports of adverse events prompted a 2020 boxed warning. While the overall incidence of neuropsychiatric events is low, the reports of events were severe enough to prompt this new warning after the FDA determined that the risk may outweigh the benefits in some patients, especially those who have mild disease that can be treated with alternative therapies. In addition to the boxed warning, the FDA also now requires that a new medication guide be given to patients with each montelukast prescription. Side effects from this drug should be reported by physicians to the FDA’s MedWatch program.

In 2016, parents of 223 children 1–7 years of age were surveyed regarding neuropsychiatric effects of montelukast. The 106 parents who responded were comparable to the nonresponders with the exception that responders were more likely to be white. The median age of the patients was 5 years, with 75% being ≤8 years old. The outcome of interest was neuropsychiatric adverse drug reactions that were definitely or probably related to montelukast and were serious enough to stop therapy, and this outcome was reported by 12% of responders. The adverse reactions reported were irritability, aggressiveness, and sleep disturbances, with no report of suicidal ideation. All occurred soon after initiation of therapy (median 7 days), resolved quickly after the medication was stopped (median 2 days), and were judged to be mild or very mild, with cessation of therapy the only management needed.

Chronic low- to medium-dose inhaled corticosteroid use in children is associated with

• a permanent reduction in vertical growth

• a significant reduction in bone mineral density

• cataract formation later in life

• glaucoma

• no long-term adverse effects

Answer explanation

Clinical trial data suggests that the use of inhaled corticosteroids (ICSs) in children does not have clinically significant long-term adverse effects. Asthma itself has been associated with a deceleration of growth velocity, which is most pronounced with severe disease. Available cumulative evidence suggests that while low- to medium-dose ICSs may have the potential for mild reductions in growth velocity (0.5 cm per year), the effect lessens after the first year of use and is unrelated to age, type of ICS, dosage, or delivery method. The impact on adult height appears to be small, if any, with mean adult height differences being only 1.2 cm lower in the treatment group than in the placebo group.

Low to medium doses of ICSs do not appear to have a serious adverse effect on bone mineral density in children. The Pediatric Endocrine Society Drugs and Therapeutics Committee recommends against routine testing of bone mineral density in children on ICSs, as decreases in bone density are generally not clinically significant. They do recommend ensuring a daily dietary intake of 400–800 IU of vitamin D and 1000–1300 mg of calcium.

There is no evidence that ICSs have a significant effect on the incidence of glaucoma or cataracts. The available evidence indicates that low- to medium-dose ICSs do not exert a clinically significant effect on the hypothalamic-pituitary-adrenal axis in children.

Which one of the following is known to be an adverse effect associated with the use of β-agonists?

• Bradycardia

• Hyperkalemia

• Hypoglycemia

• Tremor

Answer explanation

β-Agonists replicate the functions of catecholamines such as epinephrine, norepinephrine, and dopamine in acting on the smooth muscle of the airway to produce bronchodilation. The most common side effect of β-agonists is tremor. Common cardiac side effects are tachycardia and palpitations due to the vasodilatory effect of these agents on peripheral vessels, resulting in decreased venous return.

Epinephrine, acting via the β-adrenergic receptors, causes hyperglycemia by stimulating both glycogenolysis and gluconeogenesis from amino acids, glycerol, and pyruvate. β-Agonists cause an inward shift of potassium into cells by stimulating a cell-membrane–associated potassium-sodium pump, resulting in a potential for hypokalemia.

The use of long-acting β-agonists as monotherapy in asthma has been associated with an increased risk for

• cataracts

• hyperkalemia

• hypoglycemia

• pulmonary fibrosis

• severe asthma exacerbations

Answer explanation

Long-acting β-agonists (LABAs) are not recommended for use as monotherapy for long-term control of persistent asthma (SOR A). A meta-analysis of 60,954 patients that compared LABA monotherapy to no LABA therapy showed an increased risk of hospitalization, intubation, and death, particularly among patients younger than 11 years of age. As a result, the FDA issued an alert in 2005 advising that these agents be used only as additional therapy in patients who have not adequately responded to other asthma-controller medications, such as low- to medium-dose inhaled corticosteroids (ICSs).

In contrast, combination therapy with LABAs and ICSs has been shown to decrease the risk of severe exacerbations in subsequent meta-analyses, with no change in the risk of hospitalization and no apparent increase in the risk of intubation or death. As a result, in 2017 the FDA concluded that ICS/LABA combination inhalers do not significantly increase the risk of serious asthma-related side effects compared with ICSs alone, and they removed their earlier boxed warning on combination ICS/LABA medications that had warned of an increased risk of severe exacerbations of asthma leading to hospitalization or death. Patients should be instructed not to stop ICS therapy while taking a LABA, even though their symptoms may significantly improve.

A 47-year-old female with moderate severe asthma presents with a recent history of more frequent exacerbations now accompanied by expectoration of brown mucus plugs, intermittent fever, and increasing fatigue. She is afebrile today and her wheezing is minimal. A chest radiograph shows opacities in the parenchyma of the upper lobes, with evidence of atelectasis.

Which one of the following is true regarding the diagnosis of this condition?

• Aspergillus skin test positivity is not required for this diagnosis

• Laboratory evaluation will show a total serum IgE concentration >1000 ng/mL (N 0–430)

• Chest radiograph findings are pathognomonic for this condition

• Pulmonary function testing will show a reduced FEV₁ with a consistently positive bronchodilator response

Answer explanation

Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic disorder caused by hypersensitivity to Aspergillus fumigatus, characterized by recurrent episodes of wheezing, recurrent pulmonary infiltrates, and bronchiectasis.

Early recognition of ABPA is important to both relieve symptoms and prevent or delay development of bronchiectasis, which is associated with poorer outcomes. There is no individual test to establish the diagnosis of ABPA. The diagnosis is usually confirmed by use of a combination of clinical, radiographic, and immunologic criteria. Minimum criteria include a history of asthma or cystic fibrosis, a positive immediate Aspergillus skin test, and an elevated total serum IgE level, typically >1000 ng/mL. At least two other minor criteria must be present, including elevated serum Aspergillus (>27 mg/L), pulmonary opacities on a chest radiograph consistent with ABPA, or a total eosinophil count >500 cells/µL in patients with no history of glucocorticoid use. High-resolution chest CT is the preferred modality for diagnosis of bronchiectasis because of its sensitivity compared to a chest radiograph.