Allergic bronchopulmonary aspergillosis (ABPA)

Allergic bronchopulmonary aspergillosis – 8 Interesting Facts

1. Aspergillus species are ubiquitous in soil, water, and air
2. Aspergillus spores are inhaled routinely and normally are cleared without harmful consequences; however, in some patients, colonization or saprophytic growth occurs without tissue invasion
3. Aspergillus can trigger an allergic response; this is seen almost exclusively in patients with asthma and cystic fibrosis
4. Treat symptomatic patients who have allergic bronchopulmonary aspergillosis with oral corticosteroids and possibly antifungal azoles
5. It is recommended to monitor patients receiving corticosteroids at 2-month intervals until they are stabilized. Monitoring includes physical examination, serum IgE concentrations, and a chest radiograph
6. Patients taking azole therapy also require therapeutic drug monitoring and liver function tests
7. A steroid-sparing agent such as omalizumab (a monoclonal antibody against IgE) may also be added
8. Response to therapy is determined by clinical manifestations, radiographic improvement, and a decline in serum IgE concentrations of 25% or more ¹

Pitfalls

• Aspergillus is a ubiquitous mold; it may be difficult to avoid environmental exposure and clinical exacerbation

Introduction

• Allergic bronchopulmonary aspergillosis is a pulmonary disease triggered by an allergic response to Aspergillus, a ubiquitous mold ^2 3
• Most commonly occurs in patients with asthma and cystic fibrosis ^2 3
• Typically progresses through a series of remissions and exacerbations; may result in bronchiectasis ¹
• ABPA is a noninvasive form of pulmonary aspergillosis that occurs almost exclusively in asthmatics, usually younger than 40 years of age. Patients often will have peripheral eosinophilia and IgE specific antibodies against Aspergillus .
• ABPA is the result of an IgE mediated hypersensitivity reaction to Aspergillus within the bronchial lumen. Repeated episodes of inflammation lead to bronchial wall breakdown and eventually bronchiectasis. Secretions, containing eosinophils and fungal hyphae, fill and can obstruct the affected airways.
• This manifests radiographically as central and upper lobe predominant bronchiectasis, bronchial wall thickening, and mucoid impaction, findings that could mimic cystic fibrosis. The mucoid impactions on CT can sometimes have high attenuation, which is a suggestive sign of ABPA.

Urgent Action

Patients with extensive atelectasis may require therapeutic bronchoscopy to prevent or reverse respiratory compromise

Classification

• Aspergillus infection (aspergillosis) is classified by anatomic location, presence (and degree) or absence of tissue invasion, and presence or absence of an allergic response
• Allergic bronchopulmonary aspergillosis is classified as a saprophytic (noninvasive) condition in which Aspergillus species triggers an allergic reaction; it is distinct from other pulmonary aspergillosis syndromes (eg, invasive pulmonary aspergillosis, chronic pulmonary aspergillosis) ¹
  • Usually occurs in patients with an underlying chronic pulmonary condition (eg, asthma, cystic fibrosis)
  • Characterized by:
    • Superimposition or exacerbation of pulmonary (and sometimes constitutional) symptoms; expectoration of golden brown mucus plugs is common
    • Radiographic abnormalities, primarily in the upper and right middle lobes
    • Immediate skin reactivity to Aspergillus fumigatus
    • Peripheral eosinophilia
    • Elevated total serum IgE concentrations and or IgE specific for Aspergillus fumigatus
    • Anti-IgG precipitins against Aspergillus

Diagnosis

Clinical Presentation

History

• Medical history may reveal underlying conditions that foster colonization or allergic response
  • Allergic bronchopulmonary aspergillosis occurs almost exclusively in patients with asthma or cystic fibrosis ^4 5
• Symptoms are that of new-onset asthma or of exacerbation of baseline asthma
  • Coughing, wheezing, and shortness of breath
  • Expectoration of golden brown mucus plugs (characteristic)

Physical examination

• Patient may have the following:
  • Edema and erythema of the nasal turbinates
  • Thick and discolored nasal drainage
  • Percussion tenderness over the sinuses
• Pulmonary examination may reveal:
  • Wheezing
  • Decreased air movement
  • Normal findings

Causes

• Most common cause is inhalation of the mold ³
  • Aspergillus species are ubiquitous in air, water, food, and soil and are regularly inhaled without ill effect
  • Marijuana has been shown to contain Aspergillus spores

Risk factors and/or associations

Other risk factors/associations

• Asthma
  • Incidence of allergic bronchopulmonary aspergillosis in patients with persistent asthma is estimated to be approximately 2.5% ⁴
• Cystic fibrosis
  • Incidence of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis is approximately 7% ⁶

Diagnostic Procedures

Primary diagnostic tools

• Various criteria are used to diagnose allergic bronchopulmonary aspergillosis. The International Society for Human and Animal Mycology criteria are as follows: ⁷
  • Predisposing condition: asthma or cystic fibrosis plus
  • Positive Aspergillus skin test result or elevated Aspergillus fumigatus–specific IgE concentration (more than 0.35 kUA/L) plus
  • Elevated total IgE concentration (more than 1000 units/mL) plus 2 of the following:
    • Positive result on testing of serum precipitins or IgG against Aspergillus fumigatus
    • Total eosinophil count higher than 500 cells/L (in patients who have not been treated with systemic corticosteroids)
    • Chest radiograph or CT scan findings consistent with allergic bronchopulmonary aspergillosis
• Some experts recognize severe asthma with fungal sensitization as an asthma syndrome that requires multiple medications (including high-dose inhaled corticosteroid) in patients with positive Aspergillus skin test result or elevated Aspergillus IgE concentrations who do not meet full diagnostic criteria for allergic bronchopulmonary aspergillosis ^1 4
• Have patients with allergic bronchopulmonary aspergillosis undergo pulmonary function testing to guide management of airway disease and to provide a baseline for yearly monitoring ⁸

Laboratory

• Skin testing (allergic bronchopulmonary aspergillosis)
  • Intradermal testing is more sensitive than skin prick ⁹
• Aspergillus fumigatus–specific IgE concentration ⁹
  • May be more sensitive than skin test for allergic bronchopulmonary aspergillosis
  • Most sensitive single test for allergic bronchopulmonary aspergillosis
• Combination of serum Aspergillus-specific IgE concentration and skin test is more sensitive than either alone for diagnosing allergic bronchopulmonary aspergillosis
• Total IgE concentration and eosinophil count are nonspecific indicators of allergic hypersensitivity; response may wax and wane with disease activity, and may be blunted by corticosteroid treatment ^3 9

Imaging

• Chest radiograph may be normal early in disease, and findings may wax and wane with clinical disease activity. Characteristic findings, when present, include pulmonary infiltrates, bronchial wall thickening (so-called tram tracks or finger-in-glove signs), and mucus plugs (so-called toothpaste shadow) ¹
• High resolution CT is more sensitive than plain films and may show central bronchiectasis, centrilobular nodules, and high attenuation mucus (pathognomonic for allergic bronchopulmonary aspergillosis) ¹⁰
  • Presence of high attenuation mucus and extent of bronchiectasis correlate with disease severity

Differential Diagnosis

Most common

• Exacerbation or progression of chronic lung disease (especially asthma or cystic fibrosis)
  • Clinically difficult to distinguish from exacerbation, often presenting with wheeze, cough, dyspnea, and worsening pulmonary function
  • Can be particularly challenging in patients with cystic fibrosis as many are colonized with Aspergillus or have sensitivity to it but do not fulfill criteria for allergic bronchopulmonary aspergillosis
  • Suspect allergic bronchopulmonary aspergillosis:
    • In patients who have worsening disease despite conventional therapy
    • In patients with asthma if they require chronic oral corticosteroids
  • Distinction is based on presence or absence of diagnostic criteria for allergic bronchopulmonary aspergillosis, particularly total and Aspergillus-specific IgE concentrations
• Viral or bacterial pneumonia
  • In addition to similar pulmonary symptoms, allergic bronchopulmonary aspergillosis may present with pulmonary infiltrates, which look the same as pneumonia
  • Unlike in pneumonia, fever is lacking; unlike in bacterial pneumonia, there is no clinical response to antibiotics
  • Can make diagnosis of bacterial or viral pneumonia in some patients by identifying the causative organism using culture, antigen testing, or molecular technology; other laboratory indicators also may provide support (eg, elevated WBC count)
  • Clinical resolution without recurrence also suggests an interim infectious disease

Treatment Goals

• To control the symptoms and inflammation caused by the organism

Disposition

Recommendations for specialist referral

• Suspected or proven allergic bronchopulmonary aspergillosis may be referred to pulmonologist or allergist-immunologist

Treatment Options

Treatment is aimed primarily at mitigating the allergic response, reducing the Aspergillus load, and preventing bronchiectasis development ⁸

• Oral corticosteroids are the first line agents. Impact of inhaled corticosteroids is uncertain, but they appear to be inadequate when used alone ⁷
• May add antifungal therapy for patients who do not respond adequately to corticosteroids
  • Itraconazole is the recommended first line antifungal agent
  • Voriconazole, posaconazole, or inhaled amphotericin B may be helpful in patients who do not respond to itraconazole
  • 16-week treatment course has been used in trials ^11 12
• A steroid-sparing agent such as omalizumab (a monoclonal antibody against IgE) may be added
  • A 2018 Cochrane review found scant efficacy data; however, a 2023 systematic review suggested that omalizumab reduced exacerbations and use of oral corticosteroids, and resulted in improved lung function and control of asthma ¹³
• Nebulized hypertonic saline may help loosen and clear secretions in patients with secondary bronchiectasis ⁴
• Standard bronchodilator therapy (as for asthma) may help clear secretions
• Patients should avoid activities that increase likelihood of exposure to Aspergillus (eg, composting, leaf raking, farming, cleaning out or renovating buildings); if such activities are unavoidable, advise patient to wear a surgical face mask ⁷

Drug therapy

• Corticosteroids
  • Prednisone
    • Prednisone Oral tablet; Infants, Children, and Adolescents: 0.5 mg/kg/dose PO once daily for 1 to 2 weeks, then 0.5 mg/kg/dose PO every other day for 6 to 8 weeks before tapering dose by 5 to 10 mg every 2 weeks to discontinue. Alternatively, 0.75 mg/kg/dose PO once daily for 6 weeks, then 0.5 mg/kg/dose PO once daily for 6 weeks before tapering dose by 5 mg every 6 weeks for a total duration of at least 6 to 12 months.
    • Prednisone Oral tablet; Adults: 0.5 mg/kg/dose PO once daily for 1 to 2 weeks, then 0.5 mg/kg/dose PO every other day for 6 to 8 weeks before tapering dose by 5 to 10 mg every 2 weeks to discontinue. Alternatively, 0.75 mg/kg/dose PO once daily for 6 weeks, then 0.5 mg/kg/dose PO once daily for 6 weeks before tapering dose by 5 mg every 6 weeks for a total duration of at least 6 to 12 months.
  • Pulse therapy
    • Methylprednisolone ¹⁴
      • Methylprednisolone Sodium Succinate Solution for injection; Children and Adolescents: 10 to 20 mg/kg/dose IV once daily for 3 consecutive days every 3 to 4 weeks until clinical and laboratory resolution.
      • Methylprednisolone Sodium Succinate Solution for injection; Adults: 10 to 20 mg/kg/dose IV once daily for 3 consecutive days every 3 to 4 weeks until clinical and laboratory resolution.
• Antifungal agents
  • Itraconazole
    • Itraconazole Oral solution; Infants, Children, and Adolescents: 5 mg/kg/dose (Max: 200 mg/dose) PO every 12 hours.
    • Itraconazole Oral solution; Adults: 200 mg PO every 12 hours.
  • Voriconazole
    • Voriconazole Oral suspension; Infants and Children younger than 2 years: Optimal dosing not established; limited data available. 9 mg/kg/dose PO every 12 hours has been shown to provide comparable exposure in children 2 to 11 years to adults receiving 200 mg PO every 12 hours. Varying doses of 8 to 40 mg/kg/day PO divided every 8 to 12 hours have been reported. Adjust dose as needed based on monitoring of voriconazole serum concentrations. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Voriconazole Oral suspension; Children 2 to 11 years: 9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Voriconazole Oral suspension; Children and Adolescents 12 to 14 years weighing less than 50 kg: 9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Voriconazole Oral suspension; Children and Adolescents 12 to 14 years weighing 50 kg or more: 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Voriconazole Oral suspension; Adolescents 15 to 17 years: 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Voriconazole Oral tablet; Adults: 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
  • Posaconazole
    • Oral dosage (suspension)
      • Posaconazole Oral suspension; Children weighing less than 25 kg: 18 to 24 mg/kg/day PO divided 4 times daily.
      • Posaconazole Oral suspension; Children and Adolescents weighing 25 to 35 kg: 300 mg PO twice daily.
      • Posaconazole Oral suspension; Children and Adolescents weighing more than 35 kg: 400 mg PO twice daily.
      • Posaconazole Oral suspension; Adults: 200 mg PO 3 times daily.
    • Oral dosage (tablet)
      • Posaconazole Gastro-resistant tablet; Children and Adolescents weighing more than 35 kg: 300 mg PO twice daily on day 1, followed by 300 mg PO once daily.
      • Posaconazole Gastro-resistant tablet; Adults: 300 mg PO twice daily on day 1, followed by 300 mg PO once daily.
  • Nebulized amphotericin B
    • Amphotericin B Solution for injection; Children and Adolescents: 5 to 10 mg inhaled by nebulizer twice daily, or alternatively, 25 mg inhaled by nebulizer 3 times weekly.
    • Amphotericin B Solution for injection; Adults: 10 mg inhaled by nebulizer twice daily.
• Monoclonal antibody
  • Omalizumab
    • Omalizumab (Hamster) Solution for injection; Children and Adolescents: 75 to 600 mg subcutaneously every 2 to 4 weeks. Dose range: 150 to 1,200 mg/month. Dosing varies based on age, weight, and baseline serum IgE.
    • Omalizumab (Hamster) Solution for injection; Adults: 75 to 600 mg subcutaneously every 2 to 4 weeks. Dose range: 150 to 1,200 mg/month. Dosing varies based on age, weight, and baseline serum IgE.
• Nebulized hypertonic saline (7% solution)
  • Sodium Chloride Nebulizer solution; Children and Adolescents 6 to 17 years: 4 mL/dose inhaled by nebulizer twice daily.
  • Sodium Chloride Nebulizer solution; Adults: 4 mL/dose inhaled by nebulizer twice daily.

Nondrug and supportive care

Ways to thin and clear secretions include administering nebulized saline and, for significant or persistent atelectasis, performing therapeutic bronchoscopy ⁷

• First dose of nebulized saline is preceded by a dose of a short-acting β₂-agonist to avert bronchospasm; observe the patient for wheezing ⁴

Procedures

Therapeutic bronchoscopy

General explanation

• In select patients, consider using fiberoptic bronchoscopy to loosen thick or inspissated secretions with saline and to remove these secretions with suction

Indication

• Complete atelectasis (acute) ¹
• Persistent (3 weeks) mucoid impaction of proximal bronchial branches despite standard efforts to loosen and expel secretions ⁷

Monitoring

• Therapeutic drug monitoring
  • Recommended for patients taking itraconazole
    • Measure serum concentrations at steady state (4-7 days after starting treatment)
    • Definition of optimal trough level varies depending on guideline used
  • Monitor liver function test results in patients taking azoles
• Serial biomarker monitoring
  • In patients with allergic bronchopulmonary aspergillosis, serial serum IgE concentrations help guide treatment. Measure IgE concentration every 2 months until patient is clinically stable. A 25% drop in IgE concentration indicates response to therapy ¹
• Follow-up radiologic studies
  • Until patient stabilizes, monitor chest radiographs every 2 months ¹
• Serial pulmonary function tests
  • Experts recommend that these tests be performed annually, when symptomatic exacerbations occur, and after a treatment course
  • Change in pulmonary function can add information regarding success of treatment or stability of disease ⁸

Complications

• Mucus plugging may lead to severe and extensive atelectasis (eg, lobar, total lung)
• Progressive bronchiectasis
• Asthma or cystic fibrosis exacerbations associated with allergic bronchopulmonary aspergillosis may lead to acute respiratory failure

Prognosis

• No good long-term prognostic studies exist
• Good prognosis when treated early ¹⁵
• Estimated that up to 45% of patients will be steroid-dependent ¹⁶
• When left untreated for long periods, bronchiectasis develops ¹⁵
• Most patients with central bronchiectasis do not respond to antifungal medication ¹⁶

Screening

At-risk populations

• Infectious Diseases Society of America guidelines recommend annually screening with Aspergillus fumigatus–specific IgE for allergic bronchopulmonary aspergillosis in patients who have asthma and cystic fibrosis, especially those aged 6 years or older and those who experience frequent exacerbations ⁸

Screening tests

• Total IgE concentration annually ²
  • If total is greater than 500 units/mL, consider a skin test or Aspergillus-specific IgE concentration
  • If total is 200 to 500 units/mL, repeat test if suspicion is high; consider repeat testing with exacerbation and/or performance of additional tests (skin test or Aspergillus-specific IgE)

Prevention

• There are no guidelines for primary prevention
• Prudent for patients with established disease to avoid airborne dust and contaminated materials to prevent exacerbations ⁷⁸
  • Materials and areas to avoid include construction sites, soil, compost, and mulch
  • Avoidance may require modifying occupation or hobbies (eg, construction, landscaping, gardening)
  • Marijuana is commonly contaminated with Aspergillus ¹⁷
• Immunization against respiratory pathogens (eg, Streptococcus pneumoniae, Haemophilus influenzae, influenza virus) may help patient avoid exacerbations ⁸

References

1.Kanj A et al: The spectrum of pulmonary aspergillosis. Respir Med. 141:121-31, 2018

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3.Patterson TF: Aspergillus species. In: Bennett JE et al, eds: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Elsevier; 2015:2895-908.e4

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4.Muldoon EG et al: Allergic and noninvasive infectious pulmonary aspergillosis syndromes. Clin Chest Med. 38(3):521-34, 2017

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6.Stevens DA et al: Allergic bronchopulmonary aspergillosis in cystic fibrosis–state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 37 Suppl 3:S225-64, 2003

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7.Agarwal R et al: Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 43(8):850-73, 2013

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8.Patterson TF et al: Executive summary: practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 63(4):433-42, 2016

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9.Patterson KC et al: Diagnosis and treatment of pulmonary aspergillosis syndromes. Chest. 146(5):1358-68, 2014

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10.Chabi ML et al: Pulmonary aspergillosis. Diagn Interv Imaging. 96(5):435-42, 2015

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11.Stevens DA et al: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 342(11):756-62, 2000

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12.Wark PA et al: Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. J Allergy Clin Immunol. 111(5):952-7, 2003

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13.Jin M et al: Omalizumab in allergic bronchopulmonary aspergillosis: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 11(3):896-905, 2023

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14.Cohen-Cymberknoh M et al: Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros. 8(4):253-7, 2009

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15.Kosmidis C et al: The clinical spectrum of pulmonary aspergillosis. Thorax. 70(3):270-7, 2015

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16.Evans MO 2nd et al: Omalizumab, an additional therapy for allergic bronchopulmonary aspergillosis. Ann Allergy Asthma Immunol. 115(3):250-1, 2015

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17.Sipsas NV et al: Occupation, lifestyle, diet, and invasive fungal infections. Infection. 36(6):515-25, 2008

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