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 ) . the first published description of abpa as an entity came from the united kingdom in 1952 , while the first cases in the united states were reported a decade later [ 2 , 3 ] . abpa affects approximately 1%2% of asthmatic patients and 7%9% of cf patients [ 46 ] . if unrecognized or poorly treated , abpa leads to airway destruction , bronchiectasis , and/or pulmonary fibrosis , resulting in significant morbidity and mortality . the minimal criteria required for the diagnosis of abpa are : ( 1 ) asthma or cystic fibrosis with deterioration of lung function , for example , 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 . additional criteria may include peripheral blood eosinophilia , aspergillus serum precipitating antibodies , central bronchiectasis , and aspergillus containing mucus plug production [ 711 ] . 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 ) . high - resolution computed tomography ( hrct ) may demonstrate central bronchiectasis in the inner two thirds of the field even in the absence of chest radiograph lesions . the clinician should note that the development of abpa is not dependent on asthma severity . 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 . 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 , which can be seen on plain radiograph . adult patients have been reported with normal chest radiographs so radiographic abnormalities are not invariably present . in these individuals , hrct scan may reveal central cylindrical bronchiectasis even in the absence of chest radiograph abnormalities . sometimes , tree - in - bud pattern  may been seen on hrct scan that indicates some degree of airway mucus plugging . it is more commonly considered evidence of atypical mycobacterial infection and may be seen in cystic fibrosis . however , central bronchiectasis is a common complication and finding in all cf patients . laboratory tests that support the diagnosis of abpa are those that demonstrate allergy to the a. fumigatus , such as elevated specific ige anti - aspergillus antibodies and positive aspergillus precipitins [ 711 ] . culture of a. fumigatus from the sputum is only a secondary criterion for the diagnosis of abpa , because a large proportion of individuals with cf without abpa have aspergillus on sputum cultures . some normal individuals and many individuals with lung diseases have small numbers of spores in their sputum ; these are probably present because of passive inhalation . the presence of hyphae is more specific , and the presence of eosinophils in association with hyphal elements is suggestive of the diagnosis . at the time of radiographic exacerbation , the presence of eosinophilia in sputum or blood is suggestive of abpa in asthmatics and is a primary diagnostic criterion . the peripheral blood eosinophil count is usually greater than 1000/mm , and values greater than 3000/mm are common . eosinophilia is not a diagnostic criteria of abpa in cf patients . in the authors ' experience an increased total serum ige level is very characteristic of abpa , and values may reach as high as 30,000  iu / ml . usually , the level is greater than 1000  iu / ml . much of the ige is not specific to aspergillus but is the result of polyclonal b - cell activation . the ige level is a very useful marker of disease activity , and it can be used to follow outpatients for  flares  . the simple skin - prick test is a useful screening test , as abpa is very unlikely in patients with a negative reaction . a dual - reaction skin test with an immediate ( 1015 minutes ) and a late ( 48 hours ) reaction may occur but is uncommon in abpa . alternatively , serum may be measured for the presence of specific ige and igg antibodies . patients with aspergillus - sensitive asthma will generally have elevated aspergillus - specific ige antibodies , but patients with abpa will have much higher aspergillus - specific ige levels . reported that abpa and aspergillus - sensitive patients have elevated ige antibodies to recombinant aspergillus asp f1 , asp f3 , asp f4 , and asp f6 allergens and that ige levels to asp f4 and asp f6 is highly specific for abpa in cf patients . differentiating between a bacterial flare versus an abpa flare in cf patients may be difficult . a useful serum biologic marker may be thymus and activation - regulated chemokine ( tarc ) or ccl17 . .   reported that tarc was elevated in cf patients with abpa and was further elevated during acute flares of abpa . tarc is a chemokine whose ligand is ccr4 receptor on cd4 th2 cells . in abpa , immunoelectrophoresis generally shows one to three precipitin lines , often to only one extract [ 711 ] . patients with aspergilloma will have multiple precipitin lines to all antigen extracts . extracts of a. fumigatus contain a complex mixture of proteins that are mainly derived from the hyphae . antigenic composition varies between batches according to the culture conditions even within the same laboratory . there is , therefore , a lack of standardization that makes it difficult to compare results between laboratories . there are 22 recognized recombinant allergens by the international union of immunological societies . with purification of these major antigenic components , the gross pathology of abpa demonstrates cylindrical bronchiectasis of the central airways , particularly those to the upper lobes [ 711 ] . mucoid impaction ,  a condition in which large airways are occluded by impacted mucus and hyphae . airway occlusion may lead to atelectasis of a segment or lobe and , if the atelectasis is long - standing , saccular bronchiectasis may result . typically , abpa is worse in the upper lobes than in the lower lobes . microscopic examination of the airways shows infiltration of the airway wall with eosinophils , lymphocytes , and plasma cells . the airway lumen may be occluded by mucus containing hyphal elements and inflammatory cells , especially eosinophils . as seen in figure 1 , the pathogenesis of 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 [ 1619 ] . these allergens are processed by hla - dr2 or hla - dr5 bearing antigen presenting cells ( apcs ) and presented to t cells within bronchoalveolar lymphoid tissue ( balt ) . the resulting cd4 t cell responses to aspergillus are skewed toward th2 response with the production of il-4 , il-5 , and il-13 cytokines . a. fumigatus spores 3 to 5  m in size are inhaled and germinate deep within the bronchi into hyphae . in addition , fragments of the hyphae can be identified within the interstitial of the pulmonary parenchyma . the implication of this is that there is the potential for high concentrations of a. fumigatus 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 . the first line of defense against aspergillus colonization in the lungs is macrophage and neutrophil killing of the conidia and the hyphae . in the development of abpa , kauffman 's group proposed that aspergillus proteins have a direct effect on the pulmonary epithelia and macrophage inflammation [ 20 , 21 ] . in addition , protease - containing culture filtrates of aspergillus induce human bronchial cell lines to produce proinflammatory chemokines and cytokines , such as il-8 , il-6 , and mcp-1 . thus , various aspergillus proteins have significant biologic activity that disrupts the epithelial integrity and induces a monokine inflammatory response . this protease activity is thought to allow for enhanced allergen exposure to the bronchoalveolar lymphoid tissue immune system . this is evident by the bronchoalveolar lymphoid tissue synthesis of aspergillus - specific ige and iga antibodies . an important pathogenic feature of aspergillus and other microbes is their ability to interact with epithelial cells on the mucosal surface . macrophage and neutrophil killing of the conidia and hyphae is the first line of defense against colonization in the lungs [ 12 , 2224 ] . this is evidenced by an increased susceptibility to invasive pulmonary aspergillosis in patients with chronic granulomatous disease , a disorder of phagocyte killing . a. fumigatus has several virulence factors , including proteolytic enzymes that can interfere with humoral and cellular defense in the airways [ 25 , 26 ] . proteases from aspergillus and other fungi , including alternaria and cladosporium , have been shown to cause epithelial cell detachment though aspergillus proteases demonstrated more activity at lower concentrations [ 2528 ] . in addition to damaging the integrity of the epithelial cell layer , kauffman 's group demonstrated that protease containing culture infiltrates of a. fumigatus induced human bronchial cell lines to produce proinflammatory chemokines and cytokines , such as monocyte chemoattractant protein ( mcp)-1 , il-8 , and il-6 . the cytokine - release activity could be ascribed to the proteolytic activities of these extracts [ 20 , 27 ] . these observations suggested that proteolytic enzymes released by aspergillus , growing on and between epithelial cells , were responsible for the induction of chemoattractive cytokines by epithelial cells and the corresponding inflammation . it was proposed that the induction of the severe inflammatory responses by the direct activation of epithelial cells may cause additional harm to the epithelial cell layer . destruction of the epithelial cell barrier either by fungal proteases or eosinophilic and neutrophilic inflammation was followed by repair mechanisms , resulting in the influx of serum proteins and extracellular matrix proteins to the luminal side of the epithelium . because spores and mycelium of a. fumigatus have surface structures that are able to interact with extracellular matrix molecules , damage and repair mechanisms of the airway mucosa may facilitate the binding of aspergillus to the damaged sites of the airways . the enhanced release of proteolytic enzymes and allergens on the epithelial surface would induce a continuous inflammatory response and mast cell degranulation , resulting in severe and long - lasting periods of exacerbations of abpa . 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 [ 17 , 3135 ] . skin test reactivity to aspergillus is found in 20%25% of asthmatic patients [ 5 , 36 , 37 ] and 31%59% of cf patients [ 13 , 38 ] . although sensitization is common in these populations , only a small percentage of patients develop abpa . several groups have observed t cell lymphoproliferative responses to crude aspergillus extracts [ 31 , 3941 ] . subsequently , aspergillus - specific t cell responses were examined and shown to enhance b cell ige synthesis . in addition , asp f1 t cell lines were generated , and the phenotypes were found to be cd4 cd25 t cells with the cytokine profile il-4 and ifn , indicating th2 cd4 t cells . subsequently developed t cell clones from asthmatic abpa patients and demonstrated either th2 ( il-4 , ifn- ) or th0 ( il-4 , ifn- ) patterns . we demonstrated that abpa subjects have increased frequency of il-4 cd3 t cells from asp f2/f3/f4-stimulated peripheral blood lymphocytes compared to aspergillus sensitive non - abpa subjects . il-4 produced by t lymphocytes binds to the il-4 receptor ( il-4r ) on b cells and in association with the cd40l / cd40 signals , results in ige isotype switching and b cell proliferation . il-4 also increases the expression of cd86 , which has been linked to eosinophilic airway inflammation and airway hyperresponsiveness after allergen challenge . a central question then is how abpa patients differ from aspergillus - sensitive atopic asthmatic and cf patients . we hypothesize that abpa develops in genetically susceptible individuals with asthma and cf because of increased frequency and/or activity of a. fumigatus - specific th2 cd4 cells . we further propose that polymorphisms of the interleukin-4 receptor alpha chain ( il-4ra ) subunit and hla - dr2/dr5 are the genetic susceptibility risk factors responsible for the development of abpa . human studies and murine models have shown that cd4 th2 cells and their cytokines are central to the development of abpa [ 4 , 3235 , 39 , 44 ] . in particular , il-4 has a key role in the allergic inflammatory response with effects on various cell populations . its functions include increasing vcam-1 expression on endothelial cells , which enhances the recruitment of other immune cells , particularly eosinophils , stimulating proliferation of fibroblasts , important in airway remodeling , and increasing th2 differentiation while decreasing th1 differentiation and the production of ifn- [ 45 , 46 ] . il-4 also has a myriad of effects on b lymphocytes including the stimulation of growth and activation , increasing hla - dr class ii expression important for antigen presentation and inducing cell surface expression of cd23 and soluble cd23 . this cell surface molecule is the low affinity ige receptor ( fcrii ) and an activation marker present on a number of cells including b cells , activated t cells , monocytes , and eosinophils . cd23 plays a role in augmenting b cell ige synthesis through its interactions with cd21 [ 47 , 48 ] . recently , in 2003 , anti - cd23 monoclonal antibody was administered to atopic asthmatic subjects and resulted in decreased serum ige levels . in addition , il-4 has a more direct role in ige isotype switching by b - cells . it should be noted that il-13 may also stimulate the synthesis of ige and is the only other cytokine that has this capability [ 5052 ] . recently , in 2000 and 2004 , increased sensitivity to in   vitro il-4 stimulation as measured by enhanced expression of the low - affinity ige receptor ( cd23 ) on b cells was observed in abpa patients [ 32 , 33 ] . this was associated with single - nucleotide polymorphisms of the il-4 receptor alpha chain ( il-4ra ) in 92% of abpa subjects , principally the il-4-binding single - nucleotide polymorphism ile75val [ 19 , 34 , 35 ] . this increased sensitivity to il-4 is demonstrated by increased expression of cd23 and cd86 on b cells of abpa subjects and increased cd23 expression during flares of abpa . cd23 is expressed on a variety of cells , including b cells , natural killer cells , subpopulations of t cells , and a subpopulation of dendritic cells . t - cell cd28 , b - cells cd80 , and cd86 costimulatory pathways activate both t and b cells , and cd28:cd86 is important in ige synthesis . cd86 is also found on dendritic cells that have the histamine receptor 2 , which skews antigen - specific t cells to a th2 response . we have also observed increased cd86 expression on monocyte - derived dendritic cells of abpa subjects . thus , antigen - presenting cells such as monocytes and dendritic cells bearing hla - dr2 and/or hla - dr5 and increased sensitivity to il-4 stimulation probably play a critical role in skewing a. fumigatus - specific th2 responses in abpa . hla - dr restriction has been shown to be a risk factor for the development of abpa ( table 1 ) . [ 42 , 53 ] observed that asthmatic and cf patients who expressed hla - dr2 and/or dr5 but lacked hla - dq2 were at increased risk for abpa after exposure to a. fumigatus . within hla - dr2 and hla - dr5 , there are restricted genotypes . in particular , hla - dr2 hla - drb1 * 1501 and hla - drb1 * 1503 genotypes were reported to provide high relative risk . on the other hand , 40% to 44% of non - abpa atopic aspergillus - sensitive individuals have the hla - dr2 and/or dr5 type . further studies indicated that the presence of hla - dq2 , especially dqb1 * 0201 , provided protection from the development of abpa . furthermore , chauhan et al .   demonstrated that asp f l allergen has a low - affinity of binding to hla - dr . this is consistent with th2 t cell response previously reported by others in that strong antigen hla - dr - ag - tcr affinity binding favored a th1 cellular response , whereas low affinity binding favored a th2 humoral response [ 5458 ] . four major v chains , v 3 , 6 , 13 , and 14 , reacted to asp f1 .   the il-4 receptor is a type i cytokine receptor and exists as a heterodimer that shares a subunit , il-4 receptor alpha chain ( il-4ra ) , with the il-13 receptor alpha ( il-13ra ) . type i receptors , found on all lymphohematopoietic cells , are composed of the il-4ra and the common gamma chain ( c ) , which is also a component of il-2 , il-7 , il-9 , il-15 , and il-21 cytokine receptors . il-4 receptor type ii , also known as the il-13 receptor , is formed by the association of il-4ra with the il-13ra subunits and is located on immune cells , bronchial epithelium , and vascular endothelium . il-4 stimulates both type i and type ii receptors , while il-13 signals through type ii receptors . a potential gain - of - function in the il-4ra subunit may be responsible for b cell hyperreactivity in abpa . as a consequence of increased il-4r activity , proinflammatory cytokines skew t cell responses to a dominant th2 pattern which ultimately contributes to the pathophysiology and progression of abpa . there are eight naturally occurring single nucleotide polymorphisms ( snps ) of the il4ra gene : ile75val , glu400ala , cys431arg , ser436leu , ser503pro , gln576arg , ser752ala , and ser786pro reported thus far [ 6171 ] . studies have identified a number of these snps to be associated with atopy prevalence and asthma severity . in 1997 , hershey et al .   initially reported on a high prevalence of atopy and a gain - of - function in the il-4ra as measured by increased cd23 expression in patients with gln576arg and a later study found that this allele correlated with asthma severity . hershey 's group found that the presence of two variants , val75 and arg576 together , resulted in elevated il-4 dependent cd23 expression which was not observed when these snps were present alone . in our studies , the presence of the val75 allele , located within the il-4 binding region , was found in 87.5% of abpa subjects examined , while the cytoplasmic snps were present much less frequently at 27.3% for ala400 , 27.3% pro503 , 27.3% arg576 , and 9.1% arg431 . although these alleles , particularly val75 , appear to be common in the general population , their high prevalence in abpa suggests that they may be a risk factor in the development of the disease ( table 1 ) . brouard and coworkers   recently in 2005 reported another 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 ( table 1 ) . the 1082gg polymorphism has been associated with increased il-10 synthesis , whereas the 1082a allele has lower il-10 synthesis . thus , dendritic cells expressing hla - dr2/dr5 , increased il-10 synthesis and increased sensitivity to il-4 stimulation due to il-4ra polymorphisms , may be responsible for skewing aspergillus - specific th2 responses in abpa . recently , in 2003 , saxena et al . reported that abpa patients with polymorphisms ( ala91pro and arg94arg ) in the collagen region of pulmonary surfactant protein a2 ( sp - a2 ) had more elevated total ige levels and higher percentages of eosinophilia than observed in those patients who lacked the snps ( table 1 ) . they also found that 80% of patients carrying both alleles had abpa ( p = 0.0079 , or = 10.4 ) , while only 50% and 60% of patients carrying each allele , individually , were abpa subjects , suggesting an additive effect . how these snps affect sp - a has not yet been elucidated , but the collagen region spanning both snps has been shown to associate with receptors of alveolar macrophages , which are important in protecting against aspergillus colonization . it is theorized that changes in conformation or affinity of sp - a2 may decrease these interactions and compromise host defense . because abpa is found in highest incidence among atopic patients with cf , miller et al . examined mutations in the cystic fibrosis transmembrane conductance regulator gene ( cftr ) in subjects without cf ( table 1 ) . their group reported that mutations 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 the mutations ( 1 patient was compound heterozygote and reclassified as atypical cf ) , did not have a clinical diagnosis of cf , and had sweat chlorides < 60  meq / l . although the abnormal airway mucus in cf is thought to be a susceptibility factor for abpa due to enhanced trapping of aspergillus spores , it is unclear what effect heterozygous cftr mutations may have on mucus quality in asthmatic airways . examined toll - like receptor ( tlr ) polymorphisms of tlr2 , tlr4 , and tlr9 in cavitary pulmonary aspergillosis ( ccpa ) and severe asthma associated with fungal sensitization ( safs ) . tlr-4 is among the major receptors for aspergillus hyphae and plays an important part in innate host defense as tlr-4-deficient mice have increased susceptibility to invasive aspergillosis . in ccpa patients , there was significantly increased frequency of the g allele of tlr4 on asp299gly . abpa patients had increased frequency of allele c for the tlr9 t-1237c polymorphism compared to control patients . however , in safs patients who are predominantly aspergillus sensitive , there was no association of polymorphisms of tlr2 , tlr4 , or tlr9 . in addition , lazarus et al .   reported that tlr9 polymorphisms have been associated with increased risk of asthma . novak et al .   reported that the tlr9 c allele of t-1237c decreases expression . thus , decreased tlr-9 protective function may be an underlying susceptibility in the development of abpa . 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 followup 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 . symptoms are not a reliable guide to therapy ; therefore , it is important to reevaluate the chest radiograph and the serum ige at regular intervals until a long - term remission is established . abpa occurs with a worldwide distribution in a significant number of patients with cf and less frequently in those with asthma . the development of abpa is probably the combination of many genetic susceptibility factors , gene - gene interactions , and environmental exposure which work together . understanding of the genetic risks and immunopathogenesis of abpa hopefully will lead to improved early diagnosis and improved treatment of abpa .
allergic bronchopulmonary aspergillosis ( abpa ) is a th2 hypersensitivity lung disease in response to aspergillus fumigatus that affects asthmatic and cystic fibrosis ( cf ) patients . 
 sensitization to a. fumigatus is common in both atopic asthmatic and cf patients , yet only 1%2% of asthmatic and 7%9% of cf patients develop abpa . 
 abpa is characterized by wheezing and pulmonary infiltrates which may lead to pulmonary fibrosis and/or bronchiectasis . 
 the inflammatory response is characterized by th2 responses to aspergillus allergens , increased serum ige , and eosinophilia . 
 a number of genetic risks have recently been identified in the development of abpa . 
 these include hla - dr and hla - dq , il-4 receptor alpha chain ( il-4ra ) polymorphisms , il-10 1082ga promoter polymorphisms , surfactant protein a2 ( sp - a2 ) polymorphisms , and cystic fibrosis transmembrane conductance regulator gene ( cftr ) mutations . 
 the studies indicate that abpa patients are genetically at risk to develop skewed and heightened th2 responses to a. fumigatus antigens . 
 these genetic risk studies and their consequences of elevated biologic markers may aid in identifying asthmatic and cf patients who are at risk to the development of abpa . 
 furthermore , these studies suggest that immune modulation with medications such as anti - ige , anti - il-4 , and/or il-13 monoclonal antibodies may be helpful in the treatment of abpa .