Hospital Medicine

Allergic bronchopulmonary aspergillosis

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Allergic bronchopulmonary aspergillosis

I. What every physician needs to know.

Allergic bronchopulmonary aspergillosis (ABPA) is a type of hypersensitivity lung disease caused by an allergic response to Aspergillus fumigatus. Aspergillus lives ubiquitously in the environment as thermotolerant spore forming fungi, found in moisture rich areas such as ceilings, compost piles and household produce and bread.

Of the 250 known species of Aspergillus, A. fumigatus generally accounts for up to 90% of infections. Pulmonary disease patterns depend on exposure history, pathogenicity of the organism and the level of the human immune response causing a broad variation of clinical diseases, including invasive pulmonary aspergillosis, aspergillomas and allergic or hypersensitivity reactions.

ABPA is characteristically found in asthmatic or cystic fibrosis patients and diagnosed by its clinical, radiographic and laboratory features. Common features include the presence of asthma, central bronchiectasis, recurrent pulmonary infiltrates, peripheral eosinophilia, elevated serum immunoglobulin (Ig) E, IgM and IgA antibodies to A. fumigatus and immediate cutaneous reaction to Aspergillus.

Patients often describe a worsening of their chronic asthmatic symptoms with a new steroid dependence, malaise, fever, and productive sputum while having bronchiectasis or recurrent pulmonary infiltrates on imaging. Treatment is based on response to systemic corticosteroids over several months with some benefit of antifungals.

The pathophysiology of ABPA is dependant on the recurrent exposure to Aspergillus coupled with an altered immune response. Genetic predisposition is believed to explain the increase in susceptibility of a hypersensitivity reaction among asthmatics or cystic fibrosis patients despite similar environments.

Inhalation of Aspergillus spores allows for the growth of hyphae in the mucosal lining of the bronchial tree. The hyphae's proteolytic enzymes alter mucociliary clearance and damage epithelial airway cells, prompting antigenic activation of local proinflammatory cytokines and chemokines. A prominent T helper cell type 2 (Th2) cluster of differentiation 4 (CD4+) T-cell response is induced with resultant generation of IgE and IgG antibodies against Aspergillus. Tissue damage mediated by eosinophils in combination with local cytokines and chemokines results in chronic airway inflammation and bronchiectatic remodeling.

ABPA in asthmatics can be divided into five stages. Each stage is not a phase of the disease and does not necessarily mean a progression.

- Stage I is the acute stage, noted by infiltrates on chest x-rays, elevated total serum IgE and eosinophilia.

- Stage II is referred to as the remission stage, with patients who have had no chest x-ray infiltrates or prednisone need for at least 6 months.

- Stage III is defined by recurrent exacerbation noted by findings on imaging and elevated serum IgE levels. Patients in this stage respond to steroid therapy and have limited scarring on high-resolution computed tomography (CT) scan.

- Stage IV is steroid dependent stage, with/without chest x-ray findings

- Stage V is fibrotic disease seen on chest x-ray or chest CT in addition to irreversible impairment on pulmonary function and poor response to prednisone therapy.

II. Diagnostic Confirmation: Are you sure your patient has allergic bronchopulmonary aspergillosis?

ABPA is characteristically found in asthmatic or cystic fibrosis patients and diagnosed by its clinical, radiographic and laboratory features. Patients can be subdivided based on the presence of bronchiectasis on imaging. Those without bronchiectasis are considered seropositive ABPA. All criteria are not required for the diagnosis.

Criteria for the diagnosis of allergic bronchopulmonary aspergillosis - central bronchiectasis

1. Asthma (required)

2. Central bronchiectasis (required)

3. Immediate cutaneous reactivity to Aspergillus species or A. fumigatus (required)

4. Total serum IgE concentration greater than 1000 international units/millilitre (IU/ml) (required)

5. Elevated serum IgE or IgG to A. fumigatus (required)

6. Chest roentgenographic infiltrates (optional)

7. Serum precipitating antibodies to A. fumigatus (optional)

Criteria for the diagnosis of allergic bronchopulmonary aspergillosis - seropositive

1. Asthma (required)

2. Immediate cutaneous reactivity to Aspergillus species or A. fumigatus (required)

3. Total serum IgE concentration greater than 1000IU/ml (required)

4. Elevated serum IgE or IgG to A. fumigatus (required)

5. Chest roentgenographic infiltrates (optional)

Suggested criteria for diagnosing allergic bronchopulmonary aspergillosis in cystic fibrosis patients

1. Clinical deterioration (increased cough, wheeze, exercise intolerance, increased sputum, decreased pulmonary function tests (PFTs))

2. Immediate cutaneous reactivity to Aspergillus species or presence of serum IgE - A. fumigatus

3. Total serum IgE concentration greater than 1000 IU/ml (required)

4. Precipitating antibodies to A. fumigatus or serum IgE or IgG - A. fumigatus

5. Chest roentgenographic infiltrates

A. History Part I: Pattern Recognition:

Patients afflicted with ABPA may note worsening of their chronic asthmatic or cystic fibrosis symptoms with a new steroid dependence and increased inhaler usage, malaise, low-grade fever, and productive sputum which can be tenacious and resistant to suctioning. Expectoration of brownish black mucus plugs is described by 31-69% of patients. Many present following multiple treatments for pneumonia based on imaging findings.

B. History Part 2: Prevalence:

ABPA is predominantly found in patients afflicted with asthma or cystic fibrosis, peaking in the 3rd or 4th decade of life but beginning as early as adolescence. The prevalence of ABPA is 1-2% in asthmatics and 2-15% in cystic fibrosis patients, although some studies have suggested rates up to 13% in asthmatic clinics and 39% of intensive care unit (ICU) patients admitted with acute severe asthma exacerbations. Gender and race have not been found to play a role.

C. History Part 3: Competing diagnoses that can mimic allergic bronchopulmonary aspergillosis

While many of the diagnoses below have imaging changes similar to ABPA, distinguishing the diagnosis is based on serologic elevations of Aspergillus antibodies and IgE levels. In the absence of radiographic changes and significant symptoms but positive Aspergillus antibodies, clinicians should be aware of Aspergillus hypersensitivity.

  1. Acute asthma exacerbation

  2. Atypical or community-acquired pneumonia

  3. Non-ABPA hypersensitivity pneumonitis

  4. Pulmonary tuberculosis

  5. Eosinophilic pneumonia

  6. Churg-Strauss syndrome

  7. Bronchocentric granulomatosis

D. Physical Examination Findings.

Physical examination may be normal or include the following pulmonary findings: wheezing, coarse crackles, focal consolidation, and productive cough.

E. What diagnostic tests should be performed?

Diagnostic testing should include multiple laboratory tests to confirm the diagnosis and pulmonary imaging by chest x-ray or CT scan.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The initial diagnosis should entail a skin prick with A. fumigatus antigen to evaluate an immediate cutaneous reaction and a total serum IgE level. Type I immediate reactions should reach a maximum wheal or edema after 10-20 minutes to be diagnostic. A delayed or type III reaction after 6-8 hours may occur but is not diagnostic for ABPA and suggests the possibility of Aspergillus hypersensitivity. A total serum IgE level is utilized both for initial diagnosis and disease activity long term.

Levels greater than 1000IU/ml of total serum IgE strongly support the diagnosis of ABPA. Patients found to have IgE levels in this range and a positive cutaneous reaction have a high probability of ABPA and should have serum IgG and IgE for A. fumigatus and serum precipitants sent in addition to imaging. Total serum IgE levels of 500-1000 IU/ml warrant serum IgG and IgE for A. fumigatus levels and close monitoring with IgE levels every several months. Total IgE levels less than 500 IU/ml should be followed yearly.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiographic studies for ABPA should include a chest roentgenographic imaging and a chest CT, preferably high resolution. Findings may be transient, such as pulmonary infiltrates or segmental collapse secondary to mucous plugging, or be permanent with bronchiectasis. Typical findings on CT scan include central bronchiectasis involving multiple lobes with varicose and cystic changes, high-attenuation mucoid impaction, centrilobular nodules, tree-in-bud opacification, and fibrosis in late stages.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Sputum culture for A. fumigatus is of limited value and not necessary for diagnosis. Similarly, bronchoscopic evaluation for fungal culture (positive culture may reflect colonization than active disease) and histology is not required for diagnosis.

III. Default Management.

N/A

A. Immediate management.

Management of ABPA utilizes oral corticosteroid therapy as treatment of choice. Prednisolone 0.5 milligrams/kilogram/day (mg/kg/day) for 1-2 weeks is given at diagnosis, then on alternate days for 6-8 weeks. Total serum IgE levels are repeated at this time and a decline of greater than 35% is suggested as a marker for successful treatment. Discontinue steroids with tapering by 5-10 milligrams every 2 weeks.

An alternative regimen has been described with a higher initial dose followed by 6-12 months of therapy. Two randomized trials have evaluated itraconazole therapy in ABPA. While serum IgE levels declined by more than 25% and decreased steroid use was noted, lung function did not significantly change and thus antifungal therapy is not commonly utilized as first line therapy. Itraconazole may have a role as an adjunct therapy if prednisone therapy has not been sufficient.

Patients should be continued on bronchodilator therapy for their underlying airway disease in addition to use of mucolytics for sputum clearance. In-exsufflation and respiratory suctioning may be of benefit.

B. Physical Examination Tips to Guide Management.

Patients should be monitored for signs of acute respiratory failure, including tachypnea, accessory muscle use or mental status changes from hypoxia or hypercapnea. The use of supplemental oxygen is recommended to keep saturation greater than 92%, and frequent bronchodilator therapies by respiratory therapy if wheezing is evident. Non-invasive positive pressure ventilation can be utilized in patients with acute respiratory failure as a means to delay or avoid intubation.

Lung examination should slowly improve on treatment with decreased wheezing and sputum production prior to discharge.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Repeat serum IgE levels every 6-8 weeks as previously described. Total IgE level will decline by at least 35% over 6 weeks period with prednisone, however, indefinite administration of prednisone to normalize the total serum IgE level is not advised. Pulmonary function testing can also be obtained to monitor pulmonary function long term.

D. Long-term management.

Following the initial treatment with steroids, patients are evaluated for disease activity with serial serum IgE levels and CT scans. Evidence of any of the following is concerning for exacerbation: increased cough or wheezing with or without sputum production, unexplained decline in expiratory flow rates, a greater than 100% increase in serum IgE, or new infiltrates on imaging.

IgE levels should be re-evaluated and steroids should be either restarted or increased to a higher dose. If IgE levels remain elevated and steroid tapering cannot be done, then evolution to stage IV has occurred.

E. Common Pitfalls and Side-Effects of Management

N/A

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

Long-term steroid use during treatment elevates the risk of increased hyperglycemia in the diabetic and non-diabetic patient. Further titration of diabetes medications and close follow-up every 4-6 weeks should be utilized. Additionally, patients should be weaned off steroid treatment to avoid adrenal insufficiency.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.).

There is an increased risk for infection and impaired wound healing while being treated with steroid therapy.

H. Primary Lung Disease (COPD, Asthma, ILD)

ABPA will induce worsening of asthma or cystic fibrosis symptoms.

I. Gastrointestinal or Nutrition Issues

There is an increased risk for gastric erosion while on steroid therapy.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

Treatment with steroid therapy may induce delirium or worsen alterations in mentation.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Monitor for evidence of acute respiratory failure.

B. Anticipated Length of Stay.

There is no defined length of stay in this population given the low prevalence.

C. When is the Patient Ready for Discharge.

Patients diagnosed with ABPA while hospitalized likely have an acute asthma or cystic fibrosis exacerbation. Discharge will be dictated by resolution of wheezing, dyspnea and decreased dependence on respiratory bronchodilator therapies. Patients should return to oxygen requirements similar to preadmission or acute illness levels.

D. Arranging for Clinic Follow-up

Follow-up in pulmonary clinic within 2-4 weeks after hospitalization is recommended.

1. When should clinic follow up be arranged and with whom.

N/A

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Monitor total serum IgE levels every 6-8 weeks over the course of a year to ensure treatment success. Increases over 100% of baseline indicate an exacerbation of ABPA. Repeating chest x-ray or chest CT after 6-7 weeks to evaluate resolution of infiltrates is recommended.

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

Prognosis for cystic fibrosis patients is unchanged by the diagnosis of ABPA.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients treated with more than 3 months of steroid therapy should be evaluated for therapies to prevent osteoporosis and be monitored for various other side effects of chronic steroid use. These individuals should also receive pneumococcal and influenza vaccinations.

VII. What's the evidence?

Greenberger, PA. "Allergic bronchopulmonary Aspergillosis". J Allergy Clin Immunol. vol. 110. 2002. pp. 685-92.

Patterson, K, Strek, ME. "Allergic Bronchopulmonary Aspergillosis". Proc Am Thorac Soc.. vol. 7. 2010. pp. 237-44.

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