Allergic bronchopulmonary aspergillosis 1

Allergic bronchopulmonary aspergillosis

Allergicbronchopulmonary

aspergillosisClassification and external resources

ICD-9 518.6 [1]

OMIM 103920 [2]

DiseasesDB 956 [3]

MedlinePlus 000070 [4]

eMedicine radio/55 [5]

MeSH D001229 [6]

Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of theimmune system (a hypersensitivity response) to the fungus Aspergillus (most commonly Aspergillus fumigatus). Itoccurs most often in patients with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and arecommonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseasesknown as aspergilloses.ABPA causes airway inflammation, leading to bronchiectasis—a condition marked by abnormal dilation of theairways. Left untreated, the immune system and fungal spores can damage sensitive lung tissues and lead to scarring.The exact criteria for the diagnosis of ABPA are not agreed upon. Chest X-rays and CT scans, raised blood levels ofIgE and eosinophils, immunological tests for Aspergillus together with sputum staining and sputum cultures can beuseful. Treatment consists of corticosteroids and antifungal medications.

Signs and symptomsAlmost all patients have clinically diagnosed asthma, and present with wheezing (usually episodic in nature),coughing, shortness of breath and exercise intolerance (especially in patients with cystic fibrosis). Moderate andsevere cases have symptoms suggestive of bronchiectasis, in particular thick sputum production (often containingbrown mucus plugs), as well as symptoms mirroring recurrent infection such as pleuritic chest pain and fever.Patients with asthma and symptoms of ongoing infection, who do not respond to antibiotic treatment, should besuspected of ABPA.

PathophysiologyAspergillus spores are small (2–3 μm in diameter) and can penetrate deep into the respiratory system to the alveolarlevel. In healthy people, innate and adaptive immune responses are triggered by various immune cells (notablyneutrophils, resident alveolar macrophages and dendritic cells) drawn to the site of infection by numerousinflammatory cytokines and neutrophilic attractants (such as CXCR2 receptor ligands). In this situation, mucociliaryclearance is initiated and spores are successfully phagocytosed, clearing the infection from the host.In people with predisposing lung diseases—such as persistent asthma or cystic fibrosis (or rarer diseases such as chronic granulomatous disease or Hyper-IgE syndrome)—several factors lead to an increased risk of ABPA. These include immune factors (such as atopy or immunogenic HLA-restricted phenotypes), as well as genetic factors (such as CFTR gene mutations in both asthmatics and cystic fibrosis patients). By allowing Aspergillus spores to persist in

Allergic bronchopulmonary aspergillosis 2

pulmonary tissues, it permits successful germination which leads to hyphae growing in mucus plugs.There are hypersensitivity responses, both a type I response (atopic, with formation of immunoglobulin E, or IgE)and a type III hypersensitivity response (with formation of immunoglobulin G, or IgG). The reaction of IgE withAspergillus antigens results in mast cell degranulation with bronchoconstriction and increased capillary permeability.Immune complexes (a type III reaction) and inflammatory cells are deposited within the mucous membranes of theairways, leading to necrosis (tissue death) and eosinophilic infiltration. Type 2 T helper cells appear to play animportant role in ABPA due to an increased sensitivity to interleukin (IL) 4 and IL-5. These cytokines up-regulatemast cell degranulation, exacerbating respiratory decline.Aspergillus also utilises a number of factors to continue evading host responses, notably the use of proteolyticenzymes that interrupt IgG antibodies aimed towards it. Another important feature is its ability to interact andintegrate with epithelial surfaces, which results in massive pro-inflammatory counter-response by the immunesystem involving IL-6, IL-8 and MCP-1 (a CCL2 receptor ligand). Proteases released by both the fungus andneutrophils induce further injury to the respiratory epithelium, leading to initiation of repair mechanisms (such asinflux of serum and extracellular matrix (ECM) proteins) at the site of infection. Aspergillus spores and hyphae caninteract with ECM proteins, and it is hypothesised that this process facilitates the binding of spores to damagedrespiratory sites.As concentrations of Aspergillus proteases increase, the immunological effect switches from pro-inflammatory toinhibitory, and further reduces phagocytic ability to clear Aspergillus. Ultimately, repeated acute episodes lead towider scale damage of pulmonary structures (parenchyma) and function via irreversible lung remodelling. Leftuntreated, this manifests as progressive bronchiectasis and pulmonary fibrosis that is often seen in the upper lobes,and can give rise to a similar radiological appearance to that produced by tuberculosis.

DiagnosisThe exact criteria for the diagnosis of ABPA are not yet universally agreed upon, though working groups haveproposed specific guidelines.ABPA should be suspected in patients with a predisposing lung disease—most commonly asthma or cysticfibrosis—presenting with symptoms of recurrent infection such as fever, but who do not respond to conventionalantibiotic therapy. Poorly-controlled asthma is a common finding, with a case series only finding 19% of ABPApatients with well-controlled asthma. Wheezing and hemoptysis (coughing up blood) are common features, andmucus plugging is seen in 31–69% of patients.

Blood tests and serologyThe first stage involves exposing the skin to Aspergillus fumigatus antigens; an immediate reaction is hallmark ofABPA. The test should be performed first by skin prick testing, and if negative followed with an intradermalinjection. Overall sensitivity of the procedure is around 90%, though up to 40% of asthmatic patients without ABPAcan still show some sensitivity to Aspergillus antigens (a phenomenon likely linked to a less severe form of ABPAtermed severe asthma with fungal sensitization (SAFS)).Serum blood tests are an important marker of disease severity, and are also useful for the primary diagnosis ofABPA. When serum IgE is normal (and patients are not being treated by glucocorticoid medications), ABPA isexcluded as the cause of symptoms. A raised IgE increases suspicion, though there is no universally accepted cut-offvalue. Values can be stated in international units (IU/mL) or ng/mL, where 1 IU is equal to 2.4 ng/mL. Since studiesbegan documenting IgE levels in ABPA during the 1970s, various cut-offs between 833–1000 IU/mL have beenemployed to both exclude ABPA and to warrant further serological testing. Current consensus is that a cut-off of1000 IU/mL should be employed, as lower values are encountered in SAFS and asthmatic sensitization.

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IgG antibody precipitin testing from serum is useful, as positive results are found in between 69–90% 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, including enzyme-linked immunosorbent assay (ELISA) andfluorescent enzyme immunoassay(FEIA). Both are more sensitive than conventional counterimmunoelectrophoresis. IgG may not be entirely specificfor ABPA, as high levels are also found in chronic pulmonary aspergillosis (CPA) alongside more severeradiological findings.Until recently, peripheral eosinophilia (high eosinophil counts) was considered partly indicative of ABPA. Morerecent studies show that only 40% of ABPA sufferers present with eosinophilia, and hence a low eosinophil countdoes not necessary exclude ABPA; for example patients undergoing steroid therapy have lower eosinophil counts.

Radiological investigationConsolidation and mucoid impaction are the most commonly described radiological features described in ABPAliterature, though much of the evidence for consolidation comes from before the development of computedtomography (CT) scans. Tramline shadowing, finger-in-glove opacities and ‘toothpaste shadows’ are also prevalentfindings.When utilising high resolution CT scans, there can be better assessment of the distribution and pattern ofbronchiectasis within the lungs, and hence this is the tool of choice in the radiological diagnosis of ABPA. Central(confined to medial two-thirds of medial half of the lung) bronchiectasis that peripherally tapers bronchi isconsidered a requirement for ABPA pathophysiology, though in up to 43% of cases there is considerable extensionto the periphery of the lung.Mucoid impaction of the upper and lower airways is a common finding. Plugs are hypodense but appear on CT withhigh attenuation in up to 20% of patients. Where present it is a strong diagnostic factor of ABPA and distinguishessymptoms from other causes of bronchiectasis.CT scans may more rarely reveal mosaic-appearance attenuation, centrilobular nodules, tree-in-bud opacities andpleuropulmonary fibrosis (a finding consistent with CPA, a disease with ABPA as a known precursor). Rarely othermanifestations can be seen on CT scans, including military nodular opacities, perihilar opacities (that mimic hilarlymphadenopathy), pleural effusions and pulmonary masses. Cavitation and aspergilloma are rarer findings, notexceeding 20% of patients, and likely represent a shift from ABPA to CPA if accompanied by pleural thickening orfibrocavitary disease.

CultureCulturing fungi from sputum is a supportive test in the diagnosis of ABPA, but is not 100% specific for ABPA as A.fumigatus is ubiquitous and commonly isolated from lung expectorant in other diseases. Nevertheless, between40–60% of patients do have positive cultures depending on the number of samples taken.

StagingNew criteria by the ABPA Complicated Asthma ISHAM Working Group suggests a 6-stage criteria for the diagnosisof ABPA, though this is yet to be formalised into official guidelines. This would replace the current gold standardstaging protocol devised by Patterson and colleagues. Stage 0 would represent an asymptomatic form of ABPA, withcontrolled asthma but still fulfilling the fundamental diagnostic requirements of a positive skin test with elevatedtotal 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-resolutionCT scan. It must be diagnosed after excluding the other, reversible causes of acute respiratory failure.

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TreatmentUnderlying disease must be controlled to prevent exacerbation and worsening of ABPA, and in most patients thisconsists of managing their asthma or CF. Any other co-morbidities, such as sinusitis or rhinitis, should also beaddressed.Hypersensitivity mechanisms, as described above, contribute to progression of the disease over time and, when leftuntreated, result in extensive fibrosis of lung tissue. In order to reduce this, corticosteroid therapy is the mainstay oftreatment (for example with prednisone); however, studies involving corticosteroids in ABPA are limited by smallcohorts and are often not double-blinded. Despite this, there is evidence that acute-onset ABPA is improved bycorticosteroid treatment as it reduces episodes of consolidation. There are challenges involved in long-term therapywith corticosteroids—which can induce severe immune dysfunction when used chronically, as well as metabolicdisorders—and approaches have been developed to manage ABPA alongside potential adverse effects fromcorticosteroids.The most commonly described technique, known as sparing, involves using an antifungal agent to clear spores fromairways adjacent to corticosteroid therapy. The antifungal aspect aims to reduce fungal causes of bronchialinflammation, whilst also minimising the dose of corticosteroid required to reduce the immune system’s input todisease 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-doseprednisone. Newer triazole drugs—such as posaconazole or voriconazole—have not yet been studied in-depththrough clinical trials in this context.Whilst the benefits of using corticosteroids in the short term are notable, and improve quality of life scores, there arecases of ABPA converting to invasive aspergillosis whilst undergoing corticosteroid treatment. Furthermore, inconcurrent use with itraconazole, there is potential for drug interaction and the induction of Cushing syndrome inrare instances. Metabolic disorders, such as diabetes mellitus and osteoporosis, can also be induced.In order to mitigate these risks, corticosteroid doses are decreased biweekly assuming no further progression ofdisease after each reduction. When no exacerbations from the disease are seen within three months afterdiscontinuing corticosteroids, the patient is considered to be in complete remission. The exception to this rule ispatients who are diagnosed with advanced ABPA; in this case removing corticosteroids almost always results inexacerbation and these patients are continued on low-dose corticosteroids (preferably on an alternate-day schedule).Serum IgE can be used to guide treatment, and levels are checked every 6–8 week after steroid treatmentcommences, followed by every 8 weeks for one year. This allows for determination of baseline IgE levels, thoughit’s important to note that most patients do not entirely reduce IgE levels to baseline. Chest X-ray or CT scans areperformed after 1–2 months of treatment to ensure infiltrates are resolving.

EpidemiologyThere are limited national and international studies into the burden of ABPA, made more difficult by anon-standardized diagnostic criteria. Estimates of between 0.5–3.5% have been made for ABPA burden in asthma,and 1–15% in CF. Five national cohorts, detecting ABPA prevalence in asthma (based on GINA estimates), wereused in a recent meta-analysis to produce an estimate of the global burden of ABPA complicating asthma. From 193million asthma sufferers worldwide, ABPA prevalence in asthma is estimated between the extremes of 1.35–6.77million sufferers, using 0.7–3.5% attrition rates. A compromise at 2.5% attrition has also been proposed, placingglobal burden at around 4.8 million people affected. The Eastern Mediterranean region had the lowest estimatedprevalence, with a predicted case burden of 351,000; collectively, the Americas had the highest predicted burden at1,461,000 cases. These are likely underestimates of total prevalence, given the exclusion of CF patients and childrenfrom the study, as well as diagnostic testing being limited in less developed regions.

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References[1] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=518. 6[2] http:/ / omim. org/ entry/ 103920[3] http:/ / www. diseasesdatabase. com/ ddb956. htm[4] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000070. htm[5] http:/ / www. emedicine. com/ radio/ topic55. htm#[6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2014/ MB_cgi?field=uid& term=D001229

External links• The Fungal Research Trust (http:/ / www. fungalresearchtrust. org) funded Aspergillus Website (http:/ / www.

aspergillus. org. uk) provides patient support at Aspergillosis Patients Support Website (http:/ / www. aspergillus.org. uk/ newpatients) and a highly active support group at Aspergillus Support (http:/ / uk. groups. yahoo. com/group/ AspergillusSupport/ ).

• Allergic Bronchopulmonary Aspergillosis (http:/ / www. gpnotebook. co. uk/ simplepage. cfm?ID=1100611584)— GP Notebook

• Allergic Bronchopulmonary Aspergillosis (http:/ / www. merckmanuals. com/ home/ lung_and_airway_disorders/allergic_and_autoimmune_diseases_of_the_lungs/ allergic_bronchopulmonary_aspergillosis. html) — The MerckManuals Online Medical Library

• Medpix. ABPA radiology pictures (http:/ / rad. usuhs. mil/ medpix/ medpix. html?mode=caption_search&srchstr=allergic+ bronchopulmonary+ aspergillosis#top/ )

• The Aspergillus Website Treatment Section. (http:/ / www. aspergillus. org. uk/ secure/ treatmentindex/ index.php)

• Aspergillus (http:/ / www. aspergillus. org. uk/ ) — Aspergillus Website (Diagnosis, Treatment, Cases, Images,Educational video)

• Aspergillus Patients Support (http:/ / www. aspergillus. org. uk/ patients/ New/ welcomepages. php) —Aspergillus Patients (Questions & Answers, Support Group)

Article Sources and Contributors 6

Article Sources and ContributorsAllergic bronchopulmonary aspergillosis  Source: http://en.wikipedia.org/w/index.php?oldid=597438163  Contributors: Angelito7, Arcadian, Axl, Aytrus, AzseicsoK, Baggy75, Cekahn, Ciar,Countincr, Cyberdave03, Cyclonenim, Davidruben, Eras-mus, Ewulp, Freetrashbox, Headbomb, Hordaland, InvictaHOG, Jfdwolff, Jmh649, John of Reading, Jscollin, LT910001, Lesion,Michael Devore, Nick Number, Ohnoitsjamie, Rich Farmbrough, Rjwilmsi, Sacshort, Serephine, Stevenfruitsmaak, Terry2x3, Trappist the monk, Wouterstomp, Xenny's, 23 anonymous edits

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