Allergic Bronchopulmonary

Aspergillus is a ubiquitous genus of saprophytic fungi that has been shown to cause disease in humans. While several species may be pathogenic, the majority of infections develop due to A. fumigatus. This is due to its ability to grow in a wide range of temperatures and soil pH, as well as the size of its conidia (2-3 microns in diameter), which allows it to be easily aerosolized, evade mucociliary clearance and reach the respiratory bronchioles and alveoli.¹

While humans have frequent exposure to Aspergillus, disease is uncommon and is determined by host-pathogen interactions. Broadly, lung disease from Aspergillus can be divided into three categories: allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA) and invasive pulmonary aspergillosis.²Â This review will address the first of these.

ABPA is diagnosed almost exclusively in patients with asthma or cystic fibrosis (CF). A few cases have been reported in patients who have pre-existing airway disease, such as chronic obstructive pulmonary disease (COPD), a history of tuberculosis and lung transplant recipients.³Â Notably, all three conditions can develop areas of bronchiectasis, and this may be the important risk factor in these patients.

ABPA develops when A. fumigatus conidia are inhaled into the small airways and, likely due to abnormal airways and inflammatory response, evade the typical immune response and trigger an allergic one. This process is called Aspergillus sensitization (AS).³

ABPA may be hard to recognize as symptoms tend to be similar to the underlying lung disease of the patient. Most patients will note cough, often productive, and wheezing. About half of patients will expectorate brownish mucus plugs. Fever, hemoptysis, chest pain, night sweats and weight loss can also occur.^2,3 Peripheral eosinophilia may be seen, and Aspergillus can be grown from sputum culture in about half of patients.³

A diagnostic pathway for ABPA in asthmatics was suggested by a mycology society working group in 2013.⁴ (See Figure 1.) This recommends screening asthmatic patients for A. fumigatus-specific IgE, or, alternatively, Aspergillus skin prick test.

If negative, ABPA is ruled out, though a patient may have allergic bronchopulmonary mycosis (ABPM). This condition is a similar pathology as ABPA but is due to sensitization to a fungus other than A. fumigatus. While there is little research on non-Aspergillus species, further workup and treatment is typically similar to that for ABPA.⁵

If this initial test is positive, a total IgE level should be checked when a patient is neither taking nor recently has taken systemic steroids. When total IgE is >1000 IU/ml, further testing must be done, including: Aspergillus precipitins or A. fumigatus IgG, absolute blood eosinophil count > 500 cells/L, and findings on high-resolution chest CT (HRCT) that are suggestive of ABPA.

A patient with two out of the three additional criteria can be diagnosed with ABPA. A patient with IgE <1000 IU/ml and controlled asthma is described as having Aspergillus sensitization, while a patient with similar laboratory findings and uncontrolled asthma is considered to have severe asthma with fungal sensitization.⁴ Of note, a patient with asthma who is found to meet the additional diagnostic criteria but has a total IgE level of less than 1000 IU/ml can also be diagnosed with ABPA.³

A consensus opinion for the diagnosis of ABPA in CF patients was published in 2003 and used similar criteria. However, some CF patients may only have a total IgE level greater than or equal to 500 IU/ml and still have ABPA. There is a recommendation that an IgE level between 200 and 500 IU/ml warrants repeat in 2-3 months if ABPA is suspected.⁶ Given a prevalence of almost 10% in the CF population,³Â care guidelines recommend annual screening with total IgE for all CF patients.

HRCT findings in ABPA can include bronchiectasis (usually central), mucoceles (mucus plugging dilated airways with resultant “finger-in-glove” appearance), centrilobular nodules, mosaic attenuation suggestive of air trapping, consolidation, fibrosis and high attenuation mucus (HAM), which is a mucus plug that is visibly denser than the paraspinal muscles.⁷ HAM is pathognomonic for ABPA.³

A study of asthmatic patients who met criteria for ABPA and underwent HRCT noted that about 20% of patients had a normal chest CT, while the most common abnormalities were bronchiectasis (78%) and centrilobular nodules (82%). HAM was noted in slightly more than a third of patients.⁷

While systemic glucocorticoids are considered first-line therapy for ABPA, there are no randomized controlled trials (RCT) proving their efficacy. Given the years of anecdotal evidence for this treatment, though, it has become standard of care and it would be difficult to get approval to do a placebo-controlled trial.

However, an RCT was performed to compare the efficacy of a medium-dose versus high-dose steroid regimen. The medium-dose regimen consisted of 0.5 mg/kg/day of prednisolone orally for 1-2 weeks, followed by the same dose every other day for 6-8 weeks, then a taper with decrease of 5-10 mg per day every 2 weeks until discontinuation.

This lower-dose regimen was no different than the higher dose one in regards to percentage of patients with exacerbations after the first year of treatment and steroid-dependent ABPA after two years.⁸ Secondary endpoints of improvement in lung function and time to first exacerbation were also not significantly different. Glucocorticoid side effects were more common in the high-dose regimen.⁸

As exacerbation rate and glucocorticoid dependence in ABPA are high (up to 50% and 15%, respectively),⁸ antifungals have been used to increase response to steroids and to reduce use of chronic steroids.²Â Traditionally, itraconazole has been the agent of choice, though data is sparse and usually in the form of case reports.⁹

A small RCT was done looking at 200 mg of itraconazole twice daily versus a placebo for 16 weeks in steroid-dependent ABPA patients. This showed a positive response, defined as 1) decrease in steroid dose of 50% or more, 2) decrease in total IgE level of 25% or more, and 3) improvement in either pulmonary function tests or radiographic findings, in 46% of itraconazole group versus 13% of placebo group. Adverse effects were similar in both groups.⁹

While Aspergillus has similar in vitro susceptibility to itraconazole and voriconazole,¹⁰ itraconazole has been shown to be inferior to newer triazoles in invasive Aspergillus infections, and the Infectious Diseases Society of America recommends voriconazole for invasive aspergillosis.¹¹

Given this data, an argument can be made for using a newer triazole when antifungal therapy is elected. Anecdotally, this author has had good responses in treating patients with ABPA and bronchiectasis with medium-dose steroids and voriconazole as initial treatment with rare need for chronic steroids. Optimal length of antifungal therapy is unknown, but therapeutic drug monitoring may be beneficial.¹¹

Omalizumab, a humanized monoclonal antibody targeting the Fc region of IgE, has been shown to improve symptoms and exacerbation rate in severe allergic asthma, as well as chronic idiopathic urticaria.¹²Â This has been used as a steroid-sparing agent in patients with ABPA, but the published reports have been case reports or small case series.

A synthesis review of these reports was done and showed a decrease in IgE, decrease in exacerbation rate, increase in forced expiratory volume in the first second, and decrease in symptoms as measured by Asthma Control Test scores. Patients on omalizumab had a decrease in systemic steroid dose – 30% were able to discontinue steroids entirely, while the remaining patients were able to reduce their daily steroid dose by 90% or more.¹²

Interestingly, about half of patients in this synthesis review had CF. Smaller case reports and series have been reported in asthmatics with ABPA who had clinical and biochemical improvement after use of mepolizumab, a humanized monoclonal antibody against interleukin-5, and dupilumab, a human monoclonal antibody that inhibits signaling from interleukins 4 and 13. Unfortunately, most of the reports do not note exacerbation rate before and after treatment or have less follow-up time after treatment than the reports of omalizumab.¹³

ABPA is almost always seen as a complication in patients with asthma and CF. An algorithmic approach to diagnosis is recommended, understanding that some patients, especially those with CF, may have total IgE levels that are elevated but below 1000 IU/mL and still meet criteria for ABPA. Treatment historically is based around systemic glucocorticoids, but antifungal and biologic agents may be helpful in reducing steroid dose or eliminating need for prolonged steroids. 

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