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Allergic bronchopulmonary aspergillosis

allergic bronchopulmonary aspergillosis, allergic bronchopulmonary aspergillosis abpa
Allergic bronchopulmonary aspergillosis ABPA is a condition characterised by an exaggerated response of the immune system a hypersensitivity response to the fungus Aspergillus most commonly Aspergillus fumigatus It occurs most often in patients with asthma or cystic fibrosis Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals A fumigatus is responsible for a spectrum of lung diseases known as aspergilloses

ABPA causes airway inflammation, leading to bronchiectasis—a condition marked by abnormal dilation of the airways 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 of IgE and eosinophils, immunological tests for Aspergillus together with sputum staining and sputum cultures can be useful Treatment consists of corticosteroids and antifungal medications


  • 1 Signs and symptoms
  • 2 Pathophysiology
  • 3 Diagnosis
    • 31 Blood tests and serology
    • 32 Radiological investigation
    • 33 Culture
    • 34 Staging
  • 4 Treatment
  • 5 Epidemiology
  • 6 References
  • 7 External links

Signs and symptomsedit

Almost all patients have clinically diagnosed asthma,1 and present with wheezing usually episodic in nature, coughing, shortness of breath and exercise intolerance especially in patients with cystic fibrosis23 Moderate and severe cases have symptoms suggestive of bronchiectasis, in particular thick sputum production often containing brown 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 be suspected of ABPA2


Aspergillus spores are small 2–3 μm in diameter and can penetrate deep into the respiratory system to the alveolar level45 In healthy people, innate and adaptive immune responses are triggered by various immune cells notably neutrophils, resident alveolar macrophages and dendritic cells drawn to the site of infection by numerous inflammatory cytokines and neutrophilic attractants such as CXCR2 receptor ligands6 In this situation, mucociliary clearance is initiated and spores are successfully phagocytosed, clearing the infection from the host47

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 ABPA8 These include immune factors such as atopy or immunogenic HLA-restricted phenotypes,910 as well as genetic factors such as CFTR gene mutations in both asthmatics and cystic fibrosis patients11 By allowing Aspergillus spores to persist in pulmonary tissues, it permits successful germination which leads to hyphae growing in mucus plugs7

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 IgG712 The reaction of IgE with Aspergillus antigens results in mast cell degranulation with bronchoconstriction and increased capillary permeability13 Immune complexes a type III reaction and inflammatory cells are deposited within the mucous membranes of the airways, leading to necrosis tissue death and eosinophilic infiltration7 Type 2 T helper cells appear to play an important role in ABPA due to an increased sensitivity to interleukin IL 4 and IL-5 These cytokines up-regulate mast cell degranulation, exacerbating respiratory decline141516

Aspergillus also utilises a number of factors to continue evading host responses, notably the use of proteolytic enzymes that interrupt IgG antibodies aimed towards it Another important feature is its ability to interact and integrate with epithelial surfaces, which results in massive pro-inflammatory counter-response by the immune system involving IL-6, IL-8 and MCP-1 a CCL2 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 influx of serum and extracellular 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 sites717

As concentrations of Aspergillus proteases increase, the immunological effect switches from pro-inflammatory to inhibitory, and further reduces phagocytic ability to clear Aspergillus Ultimately, repeated acute episodes lead to wider scale damage of pulmonary structures parenchyma and function via irreversible lung remodelling Left untreated, 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 tuberculosis1718


The exact criteria for the diagnosis of ABPA are not yet universally agreed upon, though working groups have proposed specific guidelines819

ABPA should be suspected in patients with a predisposing lung disease—most commonly asthma or cystic fibrosis— and is often associated with chronic airway limitation CAL Patients generally present with symptoms of recurrent infection such as fever, 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 and hemoptysis coughing up blood are common features, and mucus plugging is seen in 31–69% of patients8

Blood tests and serologyedit

The first stage involves exposing the skin to Aspergillus fumigatus antigens; an immediate reaction is hallmark of ABPA20 The test should be performed first by skin prick testing, and if negative followed with an intradermal injection 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 SAFS8

Serum blood tests are an important marker of disease severity, and are also useful for the primary diagnosis of ABPA When serum IgE is normal and patients are not being treated by glucocorticoid 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 in international units IU/mL or ng/mL, where 1 IU is equal to 24 ng/mL Since studies began documenting IgE levels in ABPA during the 1970s, various cut-offs between 833–1000 IU/mL have been employed to both exclude ABPA and to warrant further serological testing Current consensus is that a cut-off of 1000 IU/mL should be employed, as lower values are encountered in SAFS and asthmatic sensitization8

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 and fluorescent enzyme immunoassay FEIA Both are more sensitive than conventional counterimmunoelectrophoresis IgG may not be entirely specific for ABPA, as high levels are also found in chronic pulmonary aspergillosis CPA alongside more severe radiological findings821

Until recently, peripheral eosinophilia high eosinophil counts was considered partly indicative of ABPA More recent studies show that only 40% of ABPA sufferers present with eosinophilia, and hence a low eosinophil count does not necessary exclude ABPA; for example patients undergoing steroid therapy have lower eosinophil counts8

Radiological investigationedit

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 findings22

When utilising high resolution CT scans, there can be 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 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 considerable extension to the periphery of the lung2

Mucoid impaction of the upper and lower airways is a common finding2 Plugs are hypodense but appear on CT with high attenuation over 70 Hounsfield units23 in up to 20% of patients Where present it is a strong diagnostic factor of ABPA and distinguishes symptoms from other causes of bronchiectasis8

CT scans may more rarely reveal mosaic-appearance attenuation, centrilobular nodules, tree-in-bud opacities and pleuropulmonary fibrosis a finding consistent with CPA, a disease with ABPA as a known precursor2 Rarely other manifestations can be seen on CT scans, including military nodular opacities, perihilar opacities that mimic hilar lymphadenopathy, pleural effusions and pulmonary masses Cavitation and aspergilloma are rarer findings, not exceeding 20% of patients, and likely represent a shift from ABPA to CPA if accompanied by pleural thickening or fibrocavitary disease8


Culturing 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, between 40–60% of patients do have positive cultures depending on the number of samples taken8


New criteria by the ABPA Complicated Asthma ISHAM Working Group suggests a 6-stage criteria for the diagnosis of ABPA, though this is yet to be formalised into official guidelines8 This would replace the current gold standard staging protocol devised by Patterson and colleagues19 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 or pulmonary 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 of acute respiratory failure8


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 addressed24

Hypersensitivity mechanisms, as described above, contribute to progression of the disease over time and, when left untreated, result in extensive fibrosis of lung tissue In order to reduce this, corticosteroid therapy is the mainstay of treatment for example with prednisone; however, studies involving corticosteroids in ABPA are limited by small cohorts and are often not double-blinded Despite this, there is evidence that acute-onset ABPA is improved by corticosteroid treatment as it reduces episodes of consolidation There are challenges involved in long-term therapy with corticosteroids—which can induce severe immune dysfunction when used chronically, as well as metabolic disorders—and approaches have been developed to manage ABPA alongside potential adverse effects from corticosteroids2425

The most commonly described technique, known as sparing, involves using an antifungal agent to clear spores from airways adjacent to corticosteroid therapy The antifungal aspect aims to reduce fungal causes of bronchial inflammation, whilst 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 for itraconazole 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 Newer triazole drugs—such as posaconazole or voriconazole—have not yet been studied in-depth through clinical trials in this context2425

Whilst the benefits of using corticosteroids in the short term are notable, and improve quality of life scores, there are cases of ABPA converting to invasive aspergillosis whilst undergoing corticosteroid treatment Furthermore, in concurrent use with itraconazole, there is potential for drug interaction and the induction of Cushing syndrome in rare instances Metabolic disorders, such as diabetes mellitus and osteoporosis, can also be induced2425

In order to mitigate these risks, corticosteroid doses are decreased biweekly assuming no further progression of disease after each reduction When no exacerbations from the disease are seen within three months after discontinuing corticosteroids, the patient is considered to be in complete remission 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 schedule2425

Serum IgE can be used to guide treatment, and levels are checked every 6–8 week after steroid treatment commences, followed by every 8 weeks for one year This allows for 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 ensure infiltrates are resolving2425


There are limited national and international studies into the burden of ABPA, made more difficult by a non-standardized diagnostic criteria Estimates of between 05–35% have been made for ABPA burden in asthma,2627 and 1–177% in CF2628 Five national cohorts, detecting ABPA prevalence in asthma based on GINA estimates,29 were used in a recent meta-analysis to produce an estimate of the global burden of ABPA complicating asthma From 193 million asthma sufferers worldwide, ABPA prevalence in asthma is estimated between the extremes of 135–677 million sufferers, using 07–35% attrition rates A compromise at 25% attrition has also been proposed, placing global burden at around 48 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 regions27


  1. ^ Rosenberg, M; Patterson, R; Mintzer, R; Cooper, BJ; Roberts, M; Harris, KE April 1977 "Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis" Annals of Internal Medicine 86 4: 405–14 PMID 848802 doi:107326/0003-4819-86-4-405 
  2. ^ a b c d e Kousha, M; Tadi, R; Soubani, AO 1 September 2011 "Pulmonary aspergillosis: a clinical review" European respiratory review : an official journal of the European Respiratory Society 20 121: 156–74 PMID 21881144 doi:101183/0905918000001011 
  3. ^ Greenberger, PA November 2002 "Allergic bronchopulmonary aspergillosis" The Journal of allergy and clinical immunology 110 5: 685–92 PMID 12417875 doi:101067/mai2002130179 
  4. ^ a b Hohl, TM; Feldmesser, M November 2007 "Aspergillus fumigatus: principles of pathogenesis and host defense" Eukaryotic cell 6 11: 1953–63 PMC 2168400  PMID 17890370 doi:101128/EC00274-07 
  5. ^ Deacon, LJ; Pankhurst, LJ; Drew, GH; Hayes, ET; Jackson, S; Longhurst, PJ; Longhurst, JWS; Liu, J; Pollard, SJT; Tyrrel, SF November 2009 "Particle size distribution of airborne Aspergillus fumigatus spores emitted from compost using membrane filtration" Atmospheric Environment 43 35: 5698–5701 Bibcode:2009AtmEn435698D doi:101016/jatmosenv200907042 
  6. ^ Brown, Gordon D; Netea, Mihai G, eds 2007 Immunology of fungal infections Online-Ausg ed Dordrecht: Springer pp 5–148 ISBN 978-1-4020-5492-1 
  7. ^ a b c d e Moss, RB May 2005 "Pathophysiology and immunology of allergic bronchopulmonary aspergillosis" Medical Mycology 43 Suppl 1: S203–6 PMID 16110813 
  8. ^ a b c d e f g h i j k l Agarwal, R; Chakrabarti, A; Shah, A; Gupta, D; Meis, JF; Guleria, R; Moss, R; Denning, DW; ABPA complicating asthma ISHAM working, group August 2013 "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria" Clinical and Experimental Allergy 43 8: 850–73 PMID 23889240 doi:101111/cea12141 
  9. ^ Antunes, J; Fernandes, A; Borrego, LM; Leiria-Pinto, P; Cavaco, J September–October 2010 "Cystic fibrosis, atopy, asthma and ABPA" Allergologia et immunopathologia 38 5: 278–84 PMID 20675033 doi:101016/jaller201006002 
  10. ^ Muro, M; Mondejar-López, P; Moya-Quiles, MR; Salgado, G; Pastor-Vivero, MD; Lopez-Hernandez, R; Boix, F; Campillo, JA; Minguela, A; Garcia-Alonso, A; Sánchez-Solís, M; Álvarez-López, MR March 2013 "HLA-DRB1 and HLA-DQB1 genes on susceptibility to and protection from allergic bronchopulmonary aspergillosis in patients with cystic fibrosis" Microbiology and immunology 57 3: 193–7 PMID 23278646 doi:101111/1348-042112020 
  11. ^ Marchand, E; Verellen-Dumoulin, C; Mairesse, M; Delaunois, L; Brancaleone, P; Rahier, JF; Vandenplas, O March 2001 "Frequency of cystic fibrosis transmembrane conductance regulator gene mutations and 5T allele in patients with allergic bronchopulmonary aspergillosis" Chest 119 3: 762–7 PMID 11243954 doi:101378/chest1193762 
  12. ^ Chitkara, RK; Sarinas, PS; Fick RB Jr December 2001 "Immunoglobulin-E and anti-IgE treatment in lung disease" Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS and Istituto di clinica tisiologica e malattie apparato respiratorio, Universita di Napoli, Secondo ateneo 56 6: 514–20 PMID 11980283 
  13. ^ Mathias, CB; Freyschmidt, EJ; Caplan, B; Jones, T; Poddighe, D; Xing, W; Harrison, KL; Gurish, MF; Oettgen, HC 15 February 2009 "IgE influences the number and function of mature mast cells, but not progenitor recruitment in allergic pulmonary inflammation" Journal of Immunology Baltimore, Md : 1950 182 4: 2416–24 PMC 2653867  PMID 19201896 doi:104049/jimmunol0801569 
  14. ^ Knutsen, AP; Hutchinson PS; Albers GM; Consolino J; Smick J; Kurup VP Jan 2004 "Increased sensitivity to IL-4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis" Allergy 59 1: 81–87 PMID 14674938 doi:101046/j1398-9995200300129x 
  15. ^ Müller, U; Piehler D; Stenzel W; Köhler G; Frey O; Held J; Grahnert A; Richter T; Eschke M; Kamradt T; Brombacher F; Alber G 2012 "Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis" Mucosal Immunology 5 3: 299–310 PMID 22333910 doi:101038/mi20129 
  16. ^ Skov, M; Poulsen LK; Koch C Feb 1999 "Increased antigen-specific Th-2 response in allergic bronchopulmonary aspergillosis ABPA in patients with cystic fibrosis" Pediatr Pulmonol 27 2: 74–79 PMID 10088929 doi:101002/sici1099-049619990227:2<74::aid-ppul2>30co;2-l 
  17. ^ a b Kauffman, HF 1 January 2003 "Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling" Frontiers in Bioscience 8: e190–6 PMID 12456379 doi:102741/990 
  18. ^ Collins, J November 2001 "CT signs and patterns of lung disease" Radiologic clinics of North America 39 6: 1115–35 PMID 11699664 doi:101016/s0033-83890570334-1 
  19. ^ a b Patterson, R; Greenberger, PA; Radin, RC; Roberts, M March 1982 "Allergic bronchopulmonary aspergillosis: staging as an aid to management" Annals of Internal Medicine 96 3: 286–91 PMID 7059089 doi:107326/0003-4819-96-3-286 
  20. ^ Hogan, C; Denning, DW December 2011 "Allergic bronchopulmonary aspergillosis and related allergic syndromes" Seminars in respiratory and critical care medicine 32 6: 682–92 PMID 22167396 doi:101055/s-0031-1295716 
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  22. ^ Greenberger, PA May–June 2012 "Chapter 18: Allergic bronchopulmonary aspergillosis" Allergy and Asthma Proceedings 33 Suppl 1 3: S61–3 PMID 22794691 doi:102500/aap2012333551 
  23. ^ Agarwal, Ritesh; Sehgal, Inderpaul Singh; Dhooria, Sahajal; Aggarwal, Ashutosh 2016 "Radiologic Criteria for the Diagnosis of High-Attenuation Mucus in Allergic Bronchopulmonary Aspergillosis" Chest 149 4: 1109–1110 ISSN 0012-3692 doi:101016/jchest201512043 
  24. ^ a b c d e f Walsh, TJ; Anaissie, EJ; Denning, DW; Herbrecht, R; Kontoyiannis, DP; Marr, KA; Morrison, VA; Segal, BH; Steinbach, WJ; Stevens, DA; van Burik, JA; Wingard, JR; Patterson, TF; Infectious Diseases Society of America 1 February 2008 "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America" Clinical Infectious Diseases 46 3: 327–60 PMID 18177225 doi:101086/525258 
  25. ^ a b c d e Mahdavinia, M; Grammer, LC June 2012 "Management of allergic bronchopulmonary aspergillosis: a review and update" Therapeutic advances in respiratory disease 6 3: 173–87 PMID 22547692 doi:101177/1753465812443094 
  26. ^ a b Stevens DA, Moss RB, Kurup VP, et al October 2003 "Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference" Clin Infect Dis 37 Suppl 3: S225–64 PMID 12975753 doi:101086/376525 
  27. ^ a b Denning, DW; Pleuvry, A; Cole, DC May 2013 "Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults" Medical mycology 51 4: 361–70 PMID 23210682 doi:103109/136937862012738312 
  28. ^ Armstead, J; Morris, J; Denning, DW 10 June 2014 "Multi-Country Estimate of Different Manifestations of Aspergillosis in Cystic Fibrosis" PLoS ONE 9 6: e98502 PMC 4051580  PMID 24914809 doi:101371/journalpone0098502 
  29. ^ "GINA" PDF Global Burden of Asthma Global Initiative for Asthma Retrieved February 5, 2014 

External linksedit

  • Fungal Research Trust
  • Aspergillus Website
  • Allergic Bronchopulmonary Aspergillosis — GP Notebook
  • Medpix ABPA radiology pictures

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