Review
Diagnosing allergic bronchopulmonary aspergillosis in children with cystic fibrosis

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Summary

Allergic bronchopulmonary aspergillosis (ABPA) is an important complication of cystic fibrosis. It is a hypersensitivity reaction to Aspergillus fumigatus, leading to a Th2 CD4 response mediated by the release of specific IgE. If ABPA is not treated early, it can cause severe impairment in lung function and long-term lung damage. Hence, early recognition with a prompt diagnosis is important. Due to clinical and radiological features of ABPA overlapping with those of bacterial or viral pulmonary exacerbations in cystic fibrosis, diagnosis can sometimes be difficult. Specific criteria for making the diagnosis of ABPA have been suggested. Newer serological tests, such as specific IgE to recombinant allergens and the detection of thymus- and activation-regulated chemokine, are being developed to improve early detection and monitoring of ABPA with greater sensitivity and specificity.

Introduction

Aspergillus is a common spore-bearing fungus that is readily found in organic waste, dust, compost and rotted plants. There are many different species, but Aspergillus fumigatus is responsible for 80% of clinical infections in humans.1 These can include an aspergilloma in those with pre-existing lung cavities; chronic necrotizing aspergillosis in those with mild immunocompromise or chronic lung disease; invasive aspergillosis in severe immunocompromise; and finally allergic bronchopulmonary aspergillosis (ABPA) in those with cystic fibrosis (CF) or adults with asthma. ABPA is a lung disease resulting from hypersensitivity to aspergillus species, clinically characterized by impaired mucociliary clearance, mucoid impaction and airway obstruction, and pulmonary infiltrates. This review is concerned with the diagnosis of ABPA in patients with CF.

Section snippets

Prevalence

The prevalence of ABPA ranges from 1−8% in patients with asthma, and it occurs primarily in adults.2 In CF, it occurs mainly in older children and adults, with a prevalence rate of 6−25%.3 The overall prevalence in Europe is 7.8%,4 with a lower reported prevalence in the USA (2%).5 In the North American Epidemiologic Study of Cystic Fibrosis (ESCF)5 and the European Epidemiologic Registry of Cystic Fibrosis (ERCF),4 there was increased prevalence of ABPA in those over 6 years of age,

Pathogenesis/stages

Inhalation of the A. fumigatus spores leads to a Th2 CD4 cellular response, with an IgG and IgE antigen-specific humoral immune response. Interaction of these antibodies with A. fumigatus antigens in the bronchial tree leads to activation of complement and mast cells, resulting in mediator release and cytokine production [interleukin (IL)-4 and IL-5]. Due to increased mucus in CF airways, inhaled spores are ‘trapped’. The continued presence of the allergen leads to persistent airway

Clinical impact

The relationship between sensitization to A. fumigatus and progression of pulmonary function is not clear as there are conflicting studies and few that are longitudinal.4, 5 Wojnarowski et al studied CF children with A. fumigatus sensitization and found an association with lower lung function, but only in those with elevated total IgE.10 Kraemer et al showed that children with ABPA demonstrated more severe decline in multiple lung function parameters than those with chronic Pseudomonas

Diagnostic criteria

If ABPA is diagnosed early and treated promptly, respiratory symptoms may be reduced, lung function improved and unnecessary treatments reduced, such as intravenous antibiotics. It is hoped this may also prevent long-term damage such as bronchiectasis and fibrosis. However, due to clinical and radiological features of ABPA overlapping with those of infective exacerbations in CF, the diagnosis of ABPA can be difficult. Maintaining a high level of clinical suspicion and then investigating for

Diagnostic difficulties

Despite clearly defined diagnostic criteria for the diagnosis of ABPA, making a definitive diagnosis in CF can be difficult. This is due to clinical, radiological, serological and microbiological features of ABPA overlapping with those seen in CF without ABPA, particularly during infective bacterial exacerbations (Table 4). The differential diagnosis for the clinical picture that may be seen in a child with CF and ABPA is outlined in Table 5, and needs to be considered while waiting for the

Clinical features

Symptoms of ABPA include worsening or new-onset wheeze, dyspnoea, fevers, malaise and expectoration of brown or black mucous plugs. Not infrequently, patients may be asymptomatic.16 Suspicion should also be raised if a patient fails to respond to a course of intravenous antibiotics given for chest symptoms. Physical examination of ABPA in CF can often be normal or non-specific with the presence of wheeze and crackles.

Chest radiograph

Transient or persistent pulmonary infiltrates may be seen. They are usually distributed in the mid-lung zones and sometimes in the upper lobes.17, 18 These changes can also be seen in a CF patient in the absence of ABPA. However, with a positive clinical context for ABPA in a CF child, new pulmonary infiltrates on a chest radiograph are suggestive. It is suggested that the clearing of pulmonary infiltrates, either partially or completely with oral corticosteroid therapy, may be a useful way of

CT chest scan

CT of the chest is considered more sensitive in detecting changes seen in CF and ABPA. High attenuation mucous plugs have been described as a feature of ABPA but not regular CF.19, 20 However, mucoid impaction with normal attenuation and centrilobular nodules seen in CT scans can be found in CF, both with and without ABPA. Mucoid impaction on CT is seen in > 80% of adults with CF, and centrilobular nodules can be found in 50% of asymptomatic CF patients, so these CT findings are less specific

Microbiology

Reports of the prevalence of A. fumigatus in the sputum of CF patients range from 10% to 60%. The wide variation in prevalence is related to the degree of exposure to its spores; people living in rural areas and inadequately ventilated houses have higher rates of colonization.5 As expected, there is a higher rate of aspergillus colonization in CF patients with ABPA. In the ERCF, A. fumigatus colonization occurs in 45% of patients with ABPA, compared to 16% without ABPA.25 Studies have suggested

Skin prick testing

Skin prick testing for sensitization to aspergillus can be carried out cheaply, easily and quickly in patients suspected of ABPA. Those with severe eczema may have a false-positive or an exaggerated response to the allergen on skin prick testing, while those taking antihistamines within 24−48 h may have a false-negative test. In most circumstances, the skin prick test to aspergillus is sensitive enough that the absence of a positive skin test reduces the likelihood of an ABPA diagnosis. However,

Serological tests

Serological testing plays an integral part in diagnosing ABPA.

Newer serological tests

There are a number of newer tests that may prove useful. Mostly, these are not yet generally available in CF centres, other than as research tools. This means that costs for their clinical use are not known.

Conclusion

ABPA is a recognized complication of CF which occurs with variable prevalence. Due to some overlap between features seen clinically and radiologically in ABPA and pulmonary exacerbations of CF, the diagnosis remains a challenge despite guidelines. Confirmation is necessary through serological testing and newer tests involving the detection of specific immunity against recombinant aspergillus antigens and TARC level may eventually improve the diagnostic accuracy for ABPA. CF centres should

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