Pediatrics

Allergic Bronchopulmonary Aspergillosis

Overview: What every practitioner needs to know

Are you sure your patient has allergic bronchopulmonary aspergillosis? What are the typical findings for this disease?

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to bronchial colonization by Aspergillus fumigatus that occurs in susceptible patients with asthma and cystic fibrosis (CF). ABPA affects approximately 1-2% of asthmatic patients and 7-9 % of CF patients. If unrecognized or poorly treated, ABPA leads to airway destruction, bronchiectasis and/or pulmonary fibrosis, resulting in significant morbidity and mortality. The clinician should note that the development of ABPA is not dependent on asthma severity.

The minimal criteria required for the diagnosis of ABPA is: (1) asthma with deterioration of lung function, e.g., wheezing, (2) immediate Aspergillus skin test reactivity, (3) total serum IgE =1000 IU/ml, (4) elevated Aspergillus specific IgE and IgG antibodies, and (5) chest radiographic infiltrates. Some groups recommend IgE =1000 ng/ml (416 IU/ml).

Additional criteria may include peripheral blood eosinophilia, Aspergillus serum precipitating antibodies, central bronchiectasis, and Aspergillus containing mucus plug production. The designation of ABPA-seropositive (ABPA-S) may be used to classify asthmatic patients who meet the required criteria but lack the proximal or central bronchiectasis (ABPA-CB).

Clinical symptoms of ABPA include increased coughing, episodes of wheezing, anorexia, malaise, fever, and expectoration of brown plugs. ABPA can present acutely with acute symptoms and signs associated with transient pulmonary infiltrates and eosinophilia or with mucoid impaction; it may also present as an exacerbation of a chronic disease characterized by proximal bronchiectasis.

In chronic ABPA, the acute episodes are superimposed on a background of chronic cough and sputum production. Physical examination shows the signs of chronic lung disease from CF or asthma, such as hyperaeration of the lungs, expiratory wheezing, a chronic productive cough, and crackles or wheezes. The chronically ill patient with bronchiectasis may have coarse crackles, weight loss, and digital clubbing.

In pediatrics, ABPA rarely affects children with asthma, and it is usually seen in children with CF, who may simply appear to have a worsening of their pulmonary status or an acute pulmonary exacerbation of CF. The diagnosis of ABPA in CF is more complicated and disagreement exists in the literature regarding the diagnostic criteria. The difficulty lies in the fact that the usual criteria for ABPA and the common signs and symptoms of CF overlap.

The most recent Cystic Fibrosis Foundation Consensus Conference proposed the following diagnostic criteria: (1) acute or subacute pulmonary deterioration not attributable to another etiology, (2) total serum IgE >1000 IU/mL, (3) immediate cutaneous reactivity to Aspergillus or in vitro specific IgE antibodies to Aspergillus, and (4) one of the following: Aspergillus serum precipitins, elevated specific IgG anti-Aspergillus antibodies, new or recent chest radiographic or chest CT abnormalities that have not cleared with antibiotics and chest physiotherapy.

Clinical staging

The spectrum of ABPA varies widely, from individuals with mild asthma and occasional episodes of pulmonary eosinophilia with no long-term sequelae, to patients with fibrosis, honey-comb lung, and respiratory failure.

Patterson and colleagues have suggested a clinical classification with five clinical stages of ABPA in asthmatics:

Stage I is the initial acute stage of ABPA with many of the typical features of the disease.

Stage II, the disease goes into remission; the infiltrates clear, symptoms are reduced, and the serum IgE value will decline by up to 35% within 6 weeks.

Stage III is an exacerbation associated with the recurrence of the initial symptoms and a twofold increase in serum IgE levels.

Stage IV is reached when patients need continuous corticosteroids either to control their asthma or to prevent a recurrence of ABPA.

Stage V is the fibrotic stage, which is present when there is severe upper lobe fibrosis present on the chest radiograph, and it may be associated with honeycombing. The stage V lesions may not respond to corticosteroids, although steroids are often necessary to maintain a bronchodilator response, and severe wheezing may develop if steroids are discontinued. Pulmonary fibrosis is an advanced complication that can lead to pulmonary hypertension and cor pulmonale.

What other disease/condition shares some of these symptoms?

Asthmatic patients may develop IgE sensitivity to molds including A. fumigatus. A number of investigators have reported that onset, persistence, and severity of asthma are associated with sensitivity to fungus. David Denning’s group coined the term severe asthma associated with fungal sensitivity (SAFS). Sensitivity to A. fumigatus was the most common fungus causing sensitization. Furthermore, treatment with the anti-fungal agent itraconazole improved their asthma.

Another series of studies by Andrew Wardlaw’s group also demonstrated that sensitivity to A. fumigatus was associated with severe asthma. In those studies, A. fumigatus could be cultured from sputum specimens. FEV-1 was decreased and total IgE levels were elevated.

The asthmatic patients in both Denning’s and Wardlaw’s studies did not fulfill criteria for ABPA. Colonization with A. fumigatus and development of ABPA also occurs in cystic fibrosis patients. A number of investigators have reported that colonization with A. fumigatus in CF is associated with decreased FEV-1 and more rapid pulmonary function decline even when not diagnosed as ABPA. These studies suggest that there is a spectrum of pulmonary disease states due to A. fumigatus sensitization in asthmatic and CF patients from severe asthma to ABPA.

ABPA and Cystic Fibrosis

There are a number of findings in CF that are characteristic of ABPA. These include, reactive airway disease, pulmonary infiltrates, central bronchiectasis, and bronchial colonization with A. fumigatus. IgG anti-A. fumigatus are commonly present in CF patients.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

In ABPA, total serum IgE =1000 IU/ml. Some groups recommend IgE =1000 ng/ml (416 IU/ml). An increased total serum IgE level is very characteristic of ABPA, and values may reach as high as 30,000 IU/mL.

Skin prick test is a useful screening test, as ABPA is very unlikely in patients with a negative reaction.

Elevated Aspergillus specific IgE and IgG antibodies are present in ABPA. Aspergillus-sensitive asthma will have elevated Aspergillus specific IgE antibody, but patients with ABPA will have quantitatively greater increases in Aspergillus specific IgE levels. Aspergillus specific IgE and IgG antibodies increase during flares of ABPA and decrease during remission.

Aspergillus serum precipitating antibodies also measure IgG antibodies to A. fumigatus. They are elevated during flares of ABPA and decrease during periods of remission.

Peripheral blood eosinophilia is frequent in asthmatic ABPA patients but may not be present in CF ABPA patients. Sputum eosinophilia is also present in flares of ABPA.

Plasma levels of thymus- and activation-regulated chemokines (TARC) may be a better marker for ABPA than IgE levels, especially for exacerbations. However, measurement of plasma TARC levels is not commercially available and can be obtained only in research laboratories at the present time.

Would imaging studies be helpful? If so, which ones?

Chest radiograph

There are several characteristic radiographic abnormalities associated with ABPA. The most common lesion is a large, homogeneous shadow in one of the upper lobes with no change in volume. The shadow may be triangular, lobar, or patchy, and it frequently moves to another site. “Tram line” shadows are fine parallel lines radiating from the hila that represent inflammation of airway walls. Mucoid impaction causes toothpaste shadows or gloved-finger shadows.

Chest computerized tomography (CT)

Patients have been reported with normal chest radiographs so radiographic abnormalities are not invariably present. In these individuals, cylindrical bronchiectasis and mucoid impaction has been demonstrated by CT scan.

Confirming the diagnosis

- Development of ABPA occurs in genetically susceptible asthmatic and CF patients.

- Deterioration of pulmonary function and pulmonary infiltrates.

- Elevated total serum IgE =1000 ng/ml (416 IU/ml).

- IgE sensitivity to A. fumigatus determined by either allergy prick skin test or by ImmunoCAP/RAST to A. fumigatus.

- Complete blood count to examine for eosinophilia.

- IgG antibodies or precipitins to A. fumigatus.

- Sputum culture for A. fumigatus.

- Chest CT scan to examine for bronchiectasis.

In ABPA, the total serum IgE level is not always >1000 ng/ml, and the IgE level may be elevated in asthmatic patients who do not have ABPA. IgE sensitivity to A. fumigatus is a sine quo non for the diagnosis of ABPA; thus determination of allergic sensitivity by skin test or in vitro testing must be present.

Peripheral blood eosinophilia is not always present, especially in CF patients with ABPA. Identification of A. fumigatus hyphae from sputum specimens is helpful but not always present. Central bronchiectasis in asthmatic patients is invariably associated with ABPA. However, central bronchiectasis is frequently present in CF patients without ABPA.

If you are able to confirm that the patient has allergic bronchopulmonary aspergillosis, what treatment should be initiated?

Corticosteroids

Most cases of ABPA require treatment with systemic corticosteroids, and the treatment of choice is prednisone. Steroid therapy rapidly clears the eosinophilic infiltrates and the associated symptoms, although it is less effective at treating mucus impaction. In asthmatic ABPA patients, the usual starting dose is 0.5 mg/kg/day, taken each morning, and this dose is maintained for 2 to 4 weeks while following the patient clinically and checking the chest radiograph for resolution of the acute process.

After this induction treatment, the dose of prednisone should be reduced to 0.5 mg/kg given on alternate days. Following resolution of the acute process, the dose of prednisone should be reduced over 1 to 3 months.

Bronchoscopy

If mucus impaction persists and is associated with atelectasis, bronchoscopy should be performed to confirm the diagnosis and to attempt to remove the mucus plugs.

Antifungal therapy

The antifungal agent itraconazole has been used to reduce the doses of steroids that are required. A double-blind, randomized, placebo-controlled trial of itraconazole 200 mg twice daily dose resulted in decreased IgE levels and an increase in pulmonary function and exercise tolerance. Another randomized, controlled trial showed that treatment of stable ABPA in adults with 400 mg/day itraconazole resulted in a significant reduction in sputum eosinophil count, sputum eosinophilic cationic protein levels, serum IgE concentrations, and Aspergillus-specific IgG. There was also a reduction in episodes of exacerbation requiring treatment with systemic steroids.

In the treatment of children with ABPA, we have used a dose of 10 mg/kg/day of itraconazole. The duration of itraconazole therapy is not clear, but should not be less than 6 months, in those who tolerate it, and may be extended safely, with benefit, for years. Two retrospective series of voriconazole in ABPA in cystic fibrosis suggest benefit and our experience in non-CF patients is similar or better.

Omalizumab

There have a number of case series of patients reporting the benefit of omalizumab in the therapy of ABPA.

What are the adverse effects associated with each treatment option?

Corticosteroids

Acute administration of corticosteroids produce central nervous system effects which may include changes in mood ranging from euphoria, psychosis, irritability, depressions, and increased appeitite. In addition, the HPA axis is suppressed. These symptoms reverse after discontinuation of corticosteroids.

Prolonged corticosteroid administration may cause deposition of fatty tissue in the back, cheek and abdominal areas, increased brusability, osteoporosis, hypertension, acne, thinning of the skin, striae, delayed wound healing, muscle wasting of the extremities with proximal muscle weakness, cataracts, and glaucoma. Induction of diabetes mellitus may occur, especially in patients with cystic fibrosis.

Antifungal medications

Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure. Liver function studies should be routinely monitored. Voriconazole has caused photosensitivity dermatitis.

Omalizumab

The most common reaction is swelling and redness at the injection site. Anaphylaxis has occurred in approximately 0.2% of asthmatics receiving omalizumab. Health care professionals who administer omalizumab should be prepared to manage life-threatening anaphylaxis and should observe their omalizumab-treated patients for at least 2 hours after omalizumab is given. Omalizumab should be discontinued if anaphylaxix occurs.

Oncologic side effects have included malignancies in 0.5% of patients (n=4127) compared with 0.2% of control patients (n=2236). The types of malignancies in omalizumab-treated patients included breast, skin (nonmelanoma), prostate, melanoma, and parotid. Other side effects have included viral infections (23%), pain (7%), fatigue (3%), and earache (2%). Three cases of Churg-Strauss syndrome have also been reported.

What are the possible outcomes of allergic bronchopulmonary aspergillosis?

The prognosis of ABPA is good if the disease is detected early and treatment started promptly. It is important that the diagnosis is made and treatment commenced before there is permanent lung damage from bronchiectasis. In such patients, there should be no progression of the disease, although relapses can occur many years later, and long-term follow-up is recommended.

In children with CF, the relapses seem to be more frequent than they are in patients with asthma, and careful surveillance is necessary to ensure resolution of the disease process. In some CF patients, it is difficult to wean the steroids without an increase in symptoms, such as dyspnea and wheezing; whether this is due to the underlying CF lung disease or due to patients going from stage II to stage III ABPA on withdrawal of steroids is unclear.

What causes this disease and how frequent is it?

ABPA affects approximately 1-2% of asthmatic patients and 7-9 % of CF patients.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to bronchial colonization by Aspergillus fumigatus that occurs in susceptible patients with asthma and cystic fibrosis (CF).

Aspergillus fumigatus is a ubiquitous, saprophytic mold found in both outdoor and indoor air, in potting soil, crawl spaces, compost piles, mulches, freshly cut grass, decaying vegetation, and sewage treatment facilities. A. fumigatus is found worldwide including the United States, where it is especially prevalent in the Midwest and East coast. Aspergillus spores are common indoors and outdoors. Aspergillus species are thermo-tolerant growing at 15o to 53o C temperatures and particularly grows well at 37° to 40°C which allows for sporulation in human bronchi.

ABPA in susceptible persons begins with the inhalation of A. fumigatus spores that germinate into hyphae deep within the bronchi. Fragments of hyphae have also been found within the lung parenchyma, potentially resulting in high concentrations of Aspergillus allergens exposed to the respiratory epithelium and immune system.

A. fumigatus releases a variety of proteins, including superoxide dismutases, catalases, proteases, ribotoxin, phospholipases, hemolysin, gliotoxin, phthioic acid and other toxins. Aspergillus proteins have a direct effect on the pulmonary epithelia and macrophage inflammation. Aspergillus proteases induce epithelial cell detachment and induce bronchial epithelia to produce proinflammatory chemokines and cytokines, such as IL-8, IL-6, and MCP-1.

The immune response to Aspergillus antigens in ABPA patients, as well as allergic asthmatic and CF patients, is characterized by a Th2 CD4+ T lymphocyte response.

How do these pathogens/genes/exposures cause the disease?

Several genetic susceptibility factors have been proposed in the development of ABPA:

Chauhan and colleagues (160-162) observed that asthmatic and CF patients who expressed HLA-DR2 and/or DR5 and lacked HLA-DQ2 were at increased risk to develop ABPA after exposure to A. fumigatus. Furthermore, within HLA-DR2 and HLA-DR5, there are restricted genotypes. In particular, HLA-DRB1*1501 and HLA-DRB1*1503 were reported to produce high relative risk. On the other hand, 40% to 44% of non-ABPA atopic Aspergillus-sensitive individuals have the HLA-DR2 and/or HLA-DR5 genotype. Additional studies indicated that the presence of HLA-DQ2 (especially HLA-DQB1*0201) provided protection from the development of ABPA.

In ABPA, Knutsen et al reported that IL-4RA SNPs and in particular the ile75val SNP in the IL-4 binding region was another risk factor. This results in increased sensitivity to in vitro IL-4 stimulation.

Brouard et al reported a third genetic risk, the association of the -1082GG genotype of the IL-10 promoter with colonization with A. fumigatus and the development of ABPA in CF.

Saxena et al reported that ABPA patients with polymorphisms (ala91pro, arg94arg) in the collagen region of pulmonary surfactant protein A2 (SP-A2) had more elevated total IgE levels and higher percentages of eosinophilia than patients who lacked the SNPs.

Miller et al reported that mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) in subjects without CF were present at a higher frequency in asthmatic patients who developed ABPA, 6 of 21 (28.5%), versus control asthmatics, 2 of 43 (4.6%). These ABPA patients were heterozygous for these mutations.

What complications might you expect from the disease or treatment of the disease?

Bronchiectasis is the most common complication of ABPA. Stage IV of ABPA is steroid resistence when patients need continuous corticosteroids either to control their asthma or to prevent a recurrence of ABPA. Stage V of ABPA is the fibrotic stage. This is associated with severe upper lobe fibrosis present on the chest radiograph and may be associated with honeycombing.

Are additional laboratory studies available; even some that are not widely available?

Plasma levels of thymus- and activation-regulated chemokines (TARC) may be a better marker for ABPA than IgE levels, especially for exacerbations.

How can allergic bronchopulmonary aspergillosis be prevented?

Once ABPA develops, long-term itraconazole may be beneficial. Omalizumab also may be beneficial in recurrence of exacerbations of ABPA. However, there are no controlled trials examining itraconazole and omalizumab in preventing exacerbations of ABPA.

What is the evidence?

Greenberger, PA, Patterson, R. "Allergic bronchopulmonary aspergillosis and the evaluation of the patient with asthma". J Allergy Clin Immunol. vol. 81. 1988. pp. 646-650.

Patterson, R, Greenberger, PA, Radin, RC, Roberts, M. "Allergic bronchopulmonary aspergillosis. Staging as an aid to management". Ann Intern Med. vol. 96. 1982. pp. 286-291.

Stevens, DA, Moss, R, Kurup, VP, Knutsen, AP, Greenberger, P, Judson, MA. "Allergic bronchopulmonary aspergillosis in cystic fibrosis: Cystic Fibrosis Foundation Consensus Conference". Clin Infect Dis. vol. 37. 2003. pp. S225-S264.

Latzin, P, Hartl, D, Regamey, N, Frey, U, Schoeni, MH, Casaulta, C. "Comparison of serum markers for allergic bronchopulmonary aspergillosis in cystic fibrosis". Eur Respir J.. vol. 31. 2008. pp. 36-42.

Knutsen, AP, Kariuki, B, Santigo, L, Bellone, C, Slavin, RG, Shah, MR. "HLA-DR, IL-4RA, and IL-10: Genetic risk factors in allergic bronchopulmonary aspergillosis". Pediatr Asthma Allergy Immunol. vol. 21. 2009. pp. 185-190.

Knutsen, AP, Hutcheson, PS, Albers, GM, Consolino, J, Smick, J, Kurup, VP. "Increased sensitivity to IL-4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis". Allergy. vol. 58. 2004. pp. 81-87.

Knutsen, AP, Kariuki, B, Consolino, JD, Warrier, MR. "IL-4 alpha chain receptor (IL-4Ra) polymorphisms in allergic bronchopulmonary aspergillosis". Clin Mol Allergy. vol. 3. 2006. pp. 1-6.

Crameri, R, Hemmann, S, Ismail, C, Menz, G, Blaser, K. "Disease-specific recombinant allergens for the diagnosis of allergic bronchopulmonary aspergillosis". Int Immunol. vol. 10. 1998. pp. 1211-1216.

Chauhan, BA, Knutsen, AP, Hutcheson, PS, Slavin, RG, Bellone, CJ. "T cell subsets, epitope mapping, and HLA-restriction in patients with allergic bronchopulmonary aspergillosis". J Clin Invest. vol. 97. 1996. pp. 2324-3231.

Chauhan, B, Santiago, L, Hutcheson, PS, Schwartz, HJ, Spitznagel, E, Castro, M. "Evidence for the involvement of two different MHC class II regions in susceptibility or protection in allergic bronchopulmonary aspergillosis". J Allergy Clin Immunol. vol. 106. 2000. pp. 723-729.

Brourad, J, Knauer, N, Boelle, P-Y, Corvol, H, Henrion-Caude, A, Flamant, C. "Influence of interleukin-10 on airways colonization by Aspergillus fumigatus in cystic fibrosis patients". J Infect Dis. vol. 191. 2005. pp. 1988-1991.

Saxena, S, Madan, T, Shah, A, Muralidhar, K, Sarma, PA. "Association of polymorphisms in the collagen region of SP-A2 with increased levels of total IgE antibodies and eosinophilia in patients with allergic bronchopulmonary aspergillosis". J Allergy Clin Immunol. vol. 111. 2003. pp. 1001-1007.

Stevens, DA, Schwartz, HJ, Lee, JY, Moskovitz, BL, Jerome, DC, Catanzaro, A. "A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis". N Engl J Med. vol. 342. 2000. pp. 756-762.

Wark, PA, Hensley, MJ, Saltos, N, Boyle, MJ, Toneguzzi, RC, Epid, GD. "Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis. A randomized controlled trial". J Allergy Clin Immunol. vol. 111. 2003. pp. 952-957.

Ongoing controversies regarding etiology, diagnosis, treatment

Diagnosis

ABPA probably represents the extreme in a spectrum of A. fumigatus sensitive lung diseases in asthmatic and CF patients. In patients with SAFS, sensitivity to A. fumigatus in severe asthmatic patients is present and the patients improved with antifungal itraconazole treatment. In severe asthmatic patients, Wardlaw's group reported that A. fumigatus colonization was frequent, bronchiectasis was present in 68% of Aspergillus sensitive patients. However, the patients did not have elevated total IgE levels.

Treatment

Antifungal treatment is typically used in conjunction with corticosteroid therapy. Some groups recommend prolonged, e.g., more than 6 months or continuous, antifungal therapy. There are no studies demonstrating that this will prevent an acute exacerbation of ABPA. There is a need for controlled trial of anti-IgE therapy, omalizumab, in the treatment of ABPA. There are a few case series that demonstrate that omalizumab is beneficial in the treatment of ABPA.

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