Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of theimmune system (ahypersensitivity response) to thefungusAspergillus (most commonlyAspergillus fumigatus). It occurs most often in people withasthma orcystic fibrosis.[1]Aspergillusspores are ubiquitous in soil and are commonly found in thesputum of healthy individuals.A. fumigatus is responsible for a spectrum of lung diseases known asaspergilloses.[4]
ABPA causesairwayinflammation, leading tobronchiectasis—a condition marked by abnormal dilation of the airways. Left untreated, theimmune system and fungal spores can damage sensitive lung tissues and lead to scarring.[5]
The exact criteria for the diagnosis of ABPA are not agreed upon.Chest X-rays andCT scans, raised blood levels ofIgE andeosinophils, immunological tests forAspergillus together with sputumstaining andsputum cultures can be useful. Treatment consists ofcorticosteroids andantifungal medications.[2]
Almost all patients have clinically diagnosedasthma,[1] and present withwheezing (usually episodic in nature),coughing,shortness of breath andexercise intolerance (especially in patients withcystic fibrosis).[1][6] Moderate and severe cases have symptoms suggestive ofbronchiectasis, in particular thicksputum production (often containing brownmucus plugs), as well as symptoms mirroring recurrent infection such aspleuriticchest pain andfever. Patients with asthma and symptoms of ongoing infection, who do not respond to antibiotic treatment, should be suspected of ABPA.[1]
Aspergillusspores are small (2–3 μm in diameter) and can penetrate deep into the respiratory system to thealveolar level.[7][8] In healthy people,innate andadaptive immune responses are triggered by various immune cells (notablyneutrophils, resident alveolarmacrophages anddendritic cells) drawn to the site of infection by numerousinflammatorycytokines and neutrophilic attractants (such asCXCR2 receptor ligands).[9] In this situation,mucociliary clearance is initiated and spores are successfullyphagocytosed, clearing the infection from the host.[7][10]
In people with predisposing lung diseases—such as persistentasthma orcystic fibrosis (or rarer diseases such aschronic granulomatous disease orHyper-IgE syndrome)—several factors lead to an increased risk of ABPA.[11] These include immune factors (such asatopy or immunogenicHLA-restrictedphenotypes),[12][13] as well asgenetic factors (such asCFTR gene mutations in both asthmatics and cystic fibrosis patients and a ZNF77 mutation resulting in apremature stop codon in asthmatics and ABPA patients).[14][10][15] By allowingAspergillus spores to persist in pulmonary tissues, it permits successfulgermination which leads tohyphae growing in mucus plugs.
There arehypersensitivity responses, both a type I response (atopic, with the formation ofimmunoglobulin E, or IgE) and a type III hypersensitivity response (with the formation ofimmunoglobulin G, or IgG).[10][16] The reaction of IgE withAspergillusantigens results inmast cell degranulation withbronchoconstriction and increasedcapillary permeability.[17]Immune complexes (a type III reaction) and inflammatory cells are deposited within themucous membranes of the airways, leading tonecrosis (tissue death) andeosinophilic infiltration.[10] Type 2T helper cells appear to play an important role in ABPA due to an increased sensitivity tointerleukin (IL) 4 andIL-5. These cytokines up-regulate mast cell degranulation, exacerbating the respiratory decline.[18][19][20]
Aspergillus also uses several factors to continue evading host responses, notably the use ofproteolytic enzymes that interrupt IgG antibodies aimed towards it. Another important feature is its ability to interact and integrate withepithelial surfaces, which results in massive pro-inflammatory counter-response by the immune system involvingIL-6,IL-8 and MCP-1 (aCCL2 receptor ligand). Proteases released by both the fungus and neutrophils induce further injury to the respiratory epithelium, leading to initiation of repair mechanisms (such as an influx ofserum andextracellular matrix (ECM) proteins) at the site of infection. Aspergillus spores and hyphae can interact with ECM proteins, and it is hypothesised that this process facilitates the binding of spores to damaged respiratory sites.[10][21]
As concentrations ofAspergillus proteases increase, the immunological effect switches from pro-inflammatory to inhibitory, and further reduces phagocytic ability to clearAspergillus. Ultimately, repeated acute episodes lead to wider-scale damage of pulmonary structures (parenchyma) and function via irreversible lung remodelling. Left untreated, this manifests as progressivebronchiectasis andpulmonary fibrosis that is often seen in theupper lobes, and can give rise to a similarradiological appearance to that produced bytuberculosis.[21][22]
The exact criteria for the diagnosis of ABPA are not yet universally agreed upon, though working groups have proposed specific guidelines.[11][23] Minimal criteria include five factors: the presence of asthma and/or cystic fibrosis, a positive skin test toAspergillus sp., total serum IgE > 416 IU/mL (or kU/L), an increasedAspergillus species–specific IgE and IgG antibodies, and the presence of infiltrates on a chest X-ray.[24][25]
ABPA should be suspected in patients with a predisposinglung disease—most commonlyasthma orcystic fibrosis— and is often associated with chronic airway limitation (CAL). Patients generally present with symptoms of recurrent infection such asfever, but do not respond to conventional antibiotic therapy. Poorly controlled asthma is a common finding, with a case series only finding 19% of ABPA patients with well-controlled asthma.Wheezing andhemoptysis (coughing up blood) are common features, andmucus plugging is seen in 31–69% of patients.[11]
The first stage involves exposing the skin to Aspergillus fumigatus antigens; an immediate reaction is the hallmark of ABPA.[26] The test should be performed first by skin prick testing, and if negative followed with an intradermal injection. The overall sensitivity of the procedure is around 90%, though up to 40% of asthmatic patients without ABPA can still show some sensitivity to Aspergillus antigens (a phenomenon likely linked to a less severe form of ABPA termed severe asthma with fungal sensitization (SAFS)).[11]
Serum blood tests are an importantmarker of disease severity and are also useful for the primary diagnosis of ABPA. When serum IgE is normal (and patients are not being treated byglucocorticoid medications), ABPA is excluded as the cause of symptoms. A raised IgE increases suspicion, though there is no universally accepted cut-off value. Values can be stated ininternational units (IU/mL) or ng/mL, where 1 IU is equal to 2.4 ng/mL. Since studies began documenting IgE levels in ABPA during the 1970s, various cut-offs between 833 and 1000 IU/mL have been employed to both exclude ABPA and to warrant further serological testing. The current consensus is that a cut-off of 1000 IU/mL should be employed, as lower values are encountered in SAFS and asthmaticsensitization.[11]
IgG antibodyprecipitin testing from serum is useful, as positive results are found in between 69 and 90% of patients, though also in 10% of asthmatics with and without SAFS. Therefore, it must be used in conjunction with other tests. Various forms exist, includingenzyme-linked immunosorbent assay (ELISA) and fluorescent enzymeimmunoassay (FEIA). Both are more sensitive than conventionalcounterimmunoelectrophoresis. IgG may not be entirely specific for ABPA, as high levels are also found inchronic pulmonary aspergillosis (CPA) alongside more severe radiological findings.[11][27]
Until recently, peripheraleosinophilia (higheosinophil counts) was considered partly indicative of ABPA. More recent studies show that only 40% of people with ABPA present with eosinophilia, and hence a low eosinophil count does not necessarily exclude ABPA; for example, patients undergoing steroid therapy have lower eosinophil counts.[11]
Consolidation and mucoid impaction are the most commonly described radiological features described in ABPA literature, though much of the evidence for consolidation comes from before the development of computed tomography (CT) scans. Tramline shadowing, finger-in-glove opacities, and 'toothpaste shadows' are also prevalent findings.[28]
When using high-resolution CT scans, there can be a better assessment of the distribution and pattern of bronchiectasis within the lungs, and hence this is the tool of choice in the radiological diagnosis of ABPA. Central (confined to medial two-thirds of the medial half of the lung) bronchiectasis that peripherally tapers bronchi is considered a requirement for ABPA pathophysiology, though in up to 43% of cases, there is a considerable extension to the periphery of the lung.[1]
Mucoid impaction of the upper and lower airways is a common finding.[1] Plugs are hypodense but appear on CT with high attenuation (over 70Hounsfield units[29]) in up to 20% of patients. Where present it is a strong diagnostic factor of ABPA and distinguishes symptoms from other causes of bronchiectasis.[11]
CT scans may more rarely reveal mosaic-appearanceattenuation, centrilobularlung nodules, tree-in-bud opacities, and pleuropulmonaryfibrosis (a finding consistent with CPA, a disease with ABPA as a known precursor).[1] Rarely other manifestations can be seen on CT scans, including military nodular opacities, perihilar opacities (that mimichilar lymphadenopathy),pleural effusions and pulmonary masses.Cavitation andaspergilloma are rarer findings, not exceeding 20% of patients, and likely represent a shift from ABPA to CPA if accompanied bypleural thickening or fibrocavitary disease.[11]
Culturingfungi from sputum is a supportive test in the diagnosis of ABPA, but is not 100%specific for ABPA asA. fumigatus is ubiquitous and commonly isolated from lung expectorant in other diseases. Nevertheless, between 40 and 60% of patients do have positive cultures depending on the number of samples taken.[11]
New criteria by the ABPA Complicated Asthma ISHAM Working Group suggest 6-stage criteria for the diagnosis of ABPA, though this is yet to be formalised into official guidelines.[11] This would replace the current gold standard staging protocol devised by Patterson and colleagues.[23] Stage 0 would represent an asymptomatic form of ABPA, with controlled asthma but still fulfilling the fundamental diagnostic requirements of a positive skin test with elevated total IgE (>1000 IU/mL). Stage 6 is an advanced ABPA, with the presence of type II respiratory failure orpulmonary heart disease, with radiological evidence of severe fibrosis consistent with ABPA on a high-resolution CT scan. It must be diagnosed after excluding the other, reversible causes ofacute respiratory failure.[11]
The underlying disease must be controlled to prevent exacerbation and worsening of ABPA, and in most patients, this consists of managing their asthma or CF. Any other co-morbidities, such as sinusitis or rhinitis, should also be addressed.[30]
Hypersensitivity mechanisms,as described above, contribute to the progression of the disease over time and, when left untreated, result in extensivefibrosis of lung tissue. To reduce this,corticosteroid therapy is the mainstay of treatment (for example withprednisone); however, studies involving corticosteroids in ABPA are limited by smallcohorts and are often notdouble-blinded. Despite this, there is evidence that acute-onset ABPA is improved by corticosteroid treatment as it reduces episodes ofconsolidation. There are challenges involved in long-term therapy with corticosteroids—which can induce severeimmune dysfunction when used chronically, as well asmetabolic disorders—and approaches have been developed to manage ABPA alongside potentialadverse effects from corticosteroids.[30][31]
The most commonly described technique, known as sparing, involves using anantifungal agent to clear spores from airways adjacent to corticosteroid therapy. The antifungal aspect aims to reduce fungal causes of bronchial inflammation, while also minimising the dose of corticosteroid required to reduce the immune system's input to disease progression. The strongest evidence (double-blinded,randomized,placebo-controlled trials) is foritraconazole twice daily for four months, which resulted in significant clinical improvement compared to placebo, and was mirrored in CF patients. Using itraconazole appears to outweigh the risk from long-term and high-dose prednisone. Newertriazole drugs—such asposaconazole orvoriconazole—have not yet been studied in-depth throughclinical trials in this context.[30][31]
While the benefits of using corticosteroids in the short term are notable, and improvequality of life scores, there are cases of ABPA converting toinvasive aspergillosis while undergoing corticosteroid treatment. Furthermore, in concurrent use with itraconazole, there is potential fordrug interaction and the induction ofCushing syndrome in rare instances. Metabolic disorders, such asdiabetes mellitus andosteoporosis, can also be induced.[30][31]
To mitigate these risks, corticosteroid doses are decreased biweekly assuming no further progression of disease after each reduction. When noexacerbations from the disease are seen within three months after discontinuing corticosteroids, the patient is considered to be in completeremission. The exception to this rule is patients who are diagnosed with advanced ABPA; in this case, removing corticosteroids almost always results in exacerbation and these patients are continued on low-dose corticosteroids (preferably on an alternate-day schedule).[30][31]
Serum IgE can be used to guide treatment, and levels are checked every 6–8 weeks after steroid treatment commences, followed by every 8 weeks for one year. This allows for a determination of baseline IgE levels, though it's important to note that most patients do not entirely reduce IgE levels to baseline.Chest X-ray or CT scans are performed after 1–2 months of treatment to ensureinfiltrates are resolving.[30][31]
There are limited national and international studies into the burden of ABPA, made more difficult by non-standardized diagnostic criteria. Estimates of between 0.5 and 3.5% have been made for ABPA burden in asthma,[32][33] and 1–17.7% in CF.[32][34] Five national cohorts, detecting ABPA prevalence in asthma (based onGINA estimates),[35] were used in a recent meta-analysis to produce an estimate of the global burden of ABPA complicating asthma. From 193 million people with asthma worldwide, ABPA prevalence in asthma is estimated to be between 1.35 and 6.77 million people, using 0.7–3.5% attrition rates. A compromise at 2.5% attrition has also been proposed, placing the global burden at around 4.8 million people affected. The Eastern Mediterranean region had the lowest estimated prevalence, with a predicted case burden of 351,000; collectively, the Americas had the highest predicted burden at 1,461,000 cases. These are likely underestimates of total prevalence, given the exclusion of CF patients and children from the study, as well as diagnostic testing being limited in less developed regions.[33]
