Allergic bronchopulmonary aspergillosis

Allergic Bronchopulmonary Aspergillosis

Yoavanit Srivaro M.D.

OUTLINE

• HISTORICAL PERSPECTIVE• EPIDEMIOLOGY• PATHOGENESIS AND ETIOLOGY• CLINICAL FEATURES• DIAGNOSIS• TREATMENT

HISTORICAL PERSPECTIVE

• Asthma and “aspergillosis” were first associated by Renon in 1897

• 1st report of ABPA was published in 1952 by Hinson and colleagues described 3 pts with

-recurrent episodes of “wheezy bronchitis” -serum eosinophilia -sputum production -fever -infiltrates on chest x-ray films.

JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13


Hinson KFW, Moon A Broncho pulmonary aspergillosis. Thorax 1952;7:317-33.


Hinson KFW, Moon A Broncho pulmonary aspergillosis. Thorax 1952;7:317-33



EPIDEMIOLOGY

• Later, Agarwal and associates estimated overall prevalence of ABPA in asthmatic populations at 12.9% (95% confidence interval [CI] 7.9 to 18.9)

• Most authors appear to agree that approximately 2% of asthmatic patients

• And 1% to 15% of CF patients develop ABPA


EPIDEMIOLOGY

• Usually manifesting between the third and fourth decades of life.

• No gender predilection.


-Aspergillus is a ubiquitous fungus-Widely in nature-Decaying vegetable matter-An opportunistic pathogen

Pathogenesis And Etiology



(above diagrams from MycoAlbum CD by George Barron)


Aspergillus species• Saprobic habitat -Soil -Plants -Water -Pepper -Air

Dr. Patrick R. Murray et al Medical Microbiology;7 th edition 2012


Aspergillus species• Mode of infection -Inhalation of conidia -Transfer to wound via contaminate tape

/bandages



• Aspergillus species• Growth at 37 C• Binding to fibrinogen and laminin• Secretion of elastase and proteases• Catalase• Gliotoxin(?)



• Aspergillus species• ABPA• Sinusitis• Aspergilloma• Invasive aspergillosis• Lung• Brain• Skin• GI• Heart


Oppotunistic mycosisAspergillus fumigatusAspergillus flavusAspergillus nigerAspergillus terreus


Figure 3.1 Life cycle of Aspergillus (2013 Atsu)

the colonies of Aspergillus

may be black, brown, green, yellow, white,

or other colors, depending upon the species

Original uploader was Jankaan at nl.wikipedia

http://nl.wikipedia.org/

Aspergillus fumigatus. Lactophenol cotton blue

preparation show conidial head


Aspergillus terreus. Lactophenol cotton

blue preparation show conidial head


Aspergillus niger.in lung lesion showing

both hyphae and conidial head


Aspergillus in tissue showing acute angle branching

septate hyphae


•Fungal spors(conidia) 2.5-3.5mm are inhale in to the lower airway & alveoli• Aspergillus grows through the product of hyphae from sprout conidiophores• Aspergillus secrete proteolytic enz.•Adherence of conidia to resp. epith. cells




Adherence of conidia to respiratory epithelial cells

Cellular dysfunction

Initially cilial disruption The fungal colony grows, Hyphae are produced invade between & through epithelial cells

Leading to substantial tissue disruption• JO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13

Schematic representation of components of the host response to inhaled Aspergillus conidia.

Park S J , and Mehrad B Clin. Microbiol. Rev. 2009;22:535-551


• Inhalation of fungal spores is ubiquitous• Aspergillus colonization and infection only occur in some

patients• Predisposing factors must enable Aspergillus proliferation up to

a high antigen burden.• First, the breakdown of local nonspecific immunity (e.g.,

mucociliary clearance mechanisms) will likely render an individual more susceptible to the adherence of spores to the airway epithelium.

• Preexisting lung disease such as bronchiectasis, as occurs in CF• Other factors may include the viscous mucus layer present in the

airways of these patients.


Figure 61-1 Pathogenesis of allergic bronchopulmonary aspergillosisJO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13

Luigina Romani,Nature Reviews Immunology 4, 11-24 (January) 2004)

Figure 3 | Balancing protection and immunopathology in fungal infections: a cooperative effort of the innate and adaptive immune systems


Luigina Romani,Nature Reviews Immunology 4, 11-24 (January 2004)

Immune responses:Innate immune response

• TLRs2, 4, and 9 are considered important for immunity to Aspergillus species

• Chronic fungal sensitization model:mouse• Human studies comparing ABPA patients with

healthy controls and asthma with fungal infection did not support a TLR2 allele

• A single-nucleotide polymorphism (SNP) in TLR9, a receptor-binding nonmethylated CpG motif, was associated with an odds ratio of 2.5 for ABPA


Luigina Romani,Nature Reviews Immunology 4, 11-24 (January 2004)







Chronic fungal sensitization model

Wild type TLR2-def

delayed and attenuated bronchial hyperresponsiveness to Aspergillus airway colonization,

with persistence of fungi longer than

delayed and attenuated bronchial hyperresponsiveness to Aspergillus airway

colonization, with persistence of fungi shorter than








SNP in TLR9, a receptor-binding

nonmethylated CpG motif, was associated with an odds ratio of

2.5 for ABPA

Abul K. Abbas et al.Cellular&Molecular immunology;9 edition2012:55-88


-Responses to fungi may also be influenced by certain serum acute phase reactants, the pentraxins.

-In particular in a mouse model of fungal asthma

“ in vitro stimulation of macrophages by serum amyloid protein (SAP) & reinfusion”

“improved pulmonary outcomes ”

“modulation of macrophage function may be achieved by regulation through SAP”

improved outcomes of Aspergillus infections.



Table 4-3 Pattern Recognition Molecules of the Innate Immune System

Immune responses

• Some results suggest this may translate to humans where specific SNPs in surfactant proteins and mannose-binding lectin (MBL) have been associated with both presence of and protection from ABPA

• Depending on the distinct alleles and genotype combinations of surfactant protein A2 and MBL



Table 4-3 Pattern Recognition Molecules of the Innate Immune System

Immune responses:Cellular immune response

Luigina Romani,Nature Reviews Immunology 4, 11-24 (January) 2004)

Figure 3 | Balancing protection and immunopathology in fungal infections: a cooperative effort of the innate and adaptive immune systems

Figure 61-1 Pathogenesis of allergic bronchopulmonary aspergillosis

Immune responses:Cellular immune response

Garcia and colleagues-Demonstrated different patterns of T cell

chemokine receptor expression ABPA allergic asthmatic

patientsNon-ABPA allergic asthmatic patients

After Aspergillus antigen exposure

After Aspergillus antigen exposure

Proliferating allergen-specific CD4+ T cellsdownregulated the expression of CCR4 and

CXCR3 in vitro

T cell chemokine receptor were upregulated in stimulated allergen-

specific T cellsJO A. DOUGLASS et al .Middleton’s allergy ; 8th edition 2013:1000-13

Immune responses: Specific antibody responses

• Gautum and associates used proteomics to identify 16 allergens associated with Aspergillus infection

• Another study demonstrated the relevance of the Aspergillus antigen Asp f 34, showing that

#94% of the ABPA #46% of the A. fumigatus–sensitized individuals ***Asp f 34–specific serum IgE.***


Genetic associations with ABPA

Miller and coworkers #demonstrated a higher prevalence of cystic

fibrosis transmembrane conductance regulator (CFTR) mutations in ABPA patients than healthy controls.

• In transgenic mice models the HLA-DR2 genotype, particularly DRB1 1503, appears to convey enhanced susceptibility to the pulmonary eosinophilic inflammation associated with ABPA


Genetic associations with ABPA

• Other specific associations with ABPA have been found in

-IL-4 receptor polymorphisms -IL-13 polymorphisms -tumor necrosis factor-α polymorphisms -IL-10 polymorphisms


CLINICAL FEATURES

• The first descriptions of the clinical presentation of ABPA were of patients with

-severe asthma -radiographic findings of pulmonary

consolidation or segmental lung collapse - fever, malaise, and cough productive of

brown sputum.


CLINICAL FEATURES• Diagnosis of asthma is reported to occur in more than 90%

of patients with ABPA, most with asthma for over a decade• Not all patients with ABPA will have asthma• ABPA being highly prevalent in CF patients. • Overall, ABPA occurs most often in patients with -difficult-to-control asthma -CF and atopy. • Patients with asthma or CF who develop ABPA will present

with deterioration of the disease with worsening of wheezing.


CLINICAL FEATURES

• Typically, cough occurs with thick,brown sputum or plugs of mucus with histologic evidence of eosinophilic debris and Aspergillus hyphae.

• Although rarely severe, hemoptysis is also described.


CLINICAL FEATURES


CLINICAL FEATURES

• Fever, weight loss, and fatigue are common in individuals who develop ABPA

• Fever, weight loss, and fatigue should raise suspicion of its presence when seen in patients with asthma and CF.


CLINICAL FEATURES

• Clinical picture is often accompanied by typical radiologic findings

****central bronchiectasis****• Not all patients develop permanent

pulmonary lesions• Pulmonary parenchymal infiltrates on chest

radiography may disappear with treatment


CLINICAL FEATURES

• ABPA serologic (ABPA-S) #milder form of the disease #diagnosed in the absence of radiologic

abnormalities• The range of lung features vary from the presence #clinical features with no pulmonary opacities #clinical features with classic, dominantly central

bronchiectasis or end-stage fibrosis with associated respiratory failure


DIAGNOSIS

a.Rosenberg M, Patterson R,

Mintzer R, et al1977

b.Schwartz HJ, Greenberger PA

1991 c.Greenberger

PA. 1994

d.Agarwal R, Khan A, Gupta

D, et al2010

BOX 61-1 DIAGNOSTIC CLASSIFICATIONS FOR ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)

PRIMARY AND SECONDARY CRITERIA Primary Asthma Serum eosinophilia Immediate skin reactivity to Aspergillus Precipitins to Aspergillus Elevated IgE Pulmonary infiltrates (transient or fixed) Central bronchiectasis • Secondary Aspergillus fumigatus in sputum Expectoration of brown plugs Late skin reactivity to AspergillusRosenberg M, Patterson R, Mintzer R, et al. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14;


ABPA-CB/-S CLASSIFICATIONABPA-CB: Minimal Essential Criteria ABPA-S: Minimal Essential Criteria Asthma Asthma Immediate skin test reactivity to Aspergillus Immediate skin test reactivity to Aspergillus Elevated total IgE (1000 ng/mL) Elevated total IgE (1000 ng/mL) Proximal bronchiectasis Elevated Aspergillus-specific IgE and/or IgG Additional Criteria Current or previous pulmonary infiltrates Mucus plugs Presence of Aspergillus in sputum Precipitins to Aspergillus Delayed skin test positive Eosinophilia (>1000/μL)

Schwartz HJ, Greenberger PA. The prevalence of allergic bronchopulmonary aspergillosis in patients with asthma, determined by serologic and radiologic criteria in patients at risk. J Lab Clin Med 1991;117:138-42; Greenberger PA. Diagnosis and management of allergic bronchopulmonary aspergillosis. Allergy Proc 1994;15:335-9;


AGARWAL CLASSIFICATION Patients Diagnosed with ABPA if They Meet Both of the Following Criteria: 1. Total IgE levels >1000 ng/mL 2. Aspergillus fumigatus–specific IgE levels >0.35 kUA/L And Two of the Following Criteria: 1. Presence of serum precipitins against A. fumigatus 2. Radiographic pulmonary opacities (fixed/transient) 3. Absolute blood eosinophil count >1000 cells/μL 4. Central bronchiectasis on HRCT

Agarwal R, Khan A, Gupta D, et al. An alternate method of classifying allergic bronchopulmonary aspergillosis based on high-attenuation mucus. PLoS One 2010;5

DIAGNOSIS

-Fungal airways disease caused by Aspergillus may represent a continuum

colonization of the airway severe fibrosis

airway immunologic reactions to the fungus


DIAGNOSIS

Differential Diagnosis• Severe asthma with fungal sensitization”

(SAFS)• Pulmonary infiltrates from bacterial or viral

pneumonia in the setting of SAFS• Impaired lung function in those with severe

asthma who have coexistent fungal sensitization

DIAGNOSIS

Differential Diagnosis• Serum total IgE is higher than 1000 ng/mL

(417 IU/mL) in ABPA patients.• The levels between 500 and 1000 ng/mL

should be closely monitored for development of ABPA, with follow-up IgE levels monitored every 6 weeks.


DIAGNOSIS

Cystic fibrosis -Recognition of ABPA is complicated by the usual

concomitant bronchiectasis, with variable presence of asthma.

-Frequent colonization of airways with Aspergillus species elevation of serum total IgE and problems with coexistent fungal sensitization



Skin Testing&Laboratory Investigations

• Absence of sensitivity to Aspergillus effectively excludes ABPA, except in rare individuals

• Absence of reactivity to Aspergillus antigens makes a diagnosis of ABPA extremely unlikely,

• Prevalence of fungal sensitization has been reported as high as 66% in severely asthmatic patients, with sensitivity to Aspergillus of 45%.

• Indicating that both blood and skin testing should be performed to ascertain fungal sensitization.



Aspergillus Skin Test: • The Aspergillus skin test is performed using

an A fumigatus antigen -Commercial (eg, Aspergillin; Hollister-Stier

Laboratories; Spokane, WA) -Locally prepared.

Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009


Aspergillus Skin Test: The test is read every 15 min for 1 h, and then after 6 to 8 h. ** The reactions are classified as** Type I reaction if a wheal and erythema developed within 1 min, reaches a

maximum after 10 to 20 min, and resolves within 1 to 2 h. Type III reaction read after 6 h, and any amount of subcutaneous edema is

considered a positive result. Ritesh Agarwal, CHEST / 135 / 3 / MARCH, 2009


Aspergillus Skin Test: An immediate cutaneous hypersensitivity to A fumigatus antigens

“ is a characteristic finding of ABPA and represents the presence A fumigatus specific IgE antibodies”

A type III skin reaction

“probably represents the immune complex hypersensitivity reaction, although its exact significance remains unclear. “



• More than 80 allergens of Aspergillus have been identified in humans.

• Asthma & CF, reactivity to the antigens Asp f 1, 3, 4 & 6 • Pts with asthma appear to recognize Asp f 1 and 3,• Both asthma & CF Pts, the presence of antibodies to

either Asp f 4 or Asp f 6 has been associated with high sensitivity and specificity for ABPA.

• The use of recombinant antigens for testing #not currently routine #but may improved diagnostic rigor.



• ABPA is highly elevated serum total IgE level. • Agawal and coworkers proposed a threshold

of 1000 IU/mL as a criterion for ABPA diagnosis.

• Not all agree with such a high threshold• Total IgE may be even lower in some patients,

(being treated with corticosteroids.)



• Many patients have very high levels of total IgE, (>10,000 IU/mL).

• The most sensitive indicator of disease progression is serial measurements of total IgE showing increasing levels of IgE.

• A decline in serum total IgE of 35% is considered diagnostic of achieving remission of ABPA.

• A doubling of serum total IgE is considered diagnostic of relapse of ABPA, especially in CF patients.

• Oral corticosteroids will reduce blood IgE levels and also need consideration.


• Precipitating antibodies to Aspergillus by gel diffusion

#Predominantly of the IgG class #Occasionally IgE and IgA• Precipitating antibodies may also be

detectable in several fungal pulmonary dis.:Aspergilloma


Eosinophilia• Not a specific test• Asthma & allergic disease • Suppressed in pts taking oral corticosteroids


• The presence of Aspergillus, particularly hyphae in the sputum, also suggests ABPA.

• Aspergillus colonization of the airways may occur without sufficient criteria to diagnose ABPA and is also present in invasive fungal infections in the lung.

• Curschmann spirals and eosinophilic debris (e.g., Charcot- Leyden crystals) may be found in the sputum of ABPA patients, indicating inflammatory airway response

• These findings can be seen in asthmatic patients without ABPA as well.


Curschmann spirals

Wikipedia,the free encyclopedia

http://en.wikipedia.org/wiki/Wikipedia

http://en.wikipedia.org/wiki/Free_content

http://en.wikipedia.org/wiki/Encyclopedia

Charcot- Leyden crystals

Wikipedia,the free encyclopedia

http://en.wikipedia.org/wiki/Wikipedia

http://en.wikipedia.org/wiki/Free_content

http://en.wikipedia.org/wiki/Encyclopedia

Radiologic Findings

**Fleeting parenchymal pulmonary opacities***Pulmonary opacities frequently manifest in

those with ABPA-S but without overt evidence of symptoms*

*May be confused with persistent pneumonia*


Radiologic Findings

•Once large airways are involved• Transitory opacities•Thickened airway walls •Central bronchiectasis •Mucus plugging atelectasis•More significant pulmonary collapse



Radiologic Findings

HRCT:Lung Parenchymal Changes

Transient parenchymal lung opacity Lung collapse Parenchymal

scaring


Radiologic FindingsHRCT:Airways Changes

Bronchiectasis involving large central airways with a predilection for the upper lobes are diagnostic of ABPA.


Radiologic Findings

-Bronchiectasis at lobar & segmental levels and involving the majority of airways is characteristic.

-Severe asthma can also be associated with bronchiectasis on CT

( not exceed two lobes, as typically occurs in ABPA)-Mucoid impaction leading to airway collapse -“Tree-in-bud” opacities is also described. -Severe central bronchectasis will also give rise to more

peripheral bronchiectasis & the fibrosis associated with end-stage disease.



Histopathologic Findings

• Inflammatory infiltration of the airways by eosinophils and lymphocytes

• Globlet cell hyperplasia • Granulomas with distal exudative bronchiolitis• Mucoid impaction• End-stage disease:fibrosis


Histopathologic Findings

• Pathologic samples are not required for the diagnosis of ABPA

• The detection of Aspergillus in lung tissue when lung biopsy is performed is useful because it supports the diagnosis.


The bronchi of this resected lobe are markedly distended with mucous. This is a manifestation of allergic bronchopulmonary aspergillosis

Mucin admixed with degenerating eosinophiles (allergic mucin) with multiple Charcot-Leyden crystals. This is a manifestation of allergic bronchopulmonary aspergillosis

The bronchi are markedly distended with mucous. This is a manifestation of allergic bronchopulmonary aspergillosis

This bronchus is markedly distended with mucous. This is a manifestation of allergic bronchopulmonary aspergillosis

Ritesh Agarwal et al, Clinical & Experimental Allergy,2013; 43 : 850–873

Fig. 6. Protocol for investigating allergic bronchopulmonary aspergillosis(ABPA) in patients with asthma.

Ritesh Agarwal et al, Clinical & Experimental Allergy, 43 : 850–873


TREATMENT

TREATMENT

• Corticosteroid• Antifungal Agents• Anti-IgE Biologics


AIM

• Improve clinical symptoms of disease• Reduce exacerbations• Prevent progression of disease to central

bronchiectasis.


CORTICOSTEROID

• Oral corticosteroids are the basis of therapy for patients with ABPA.

• Serum total IgE is used to monitor disease activity.

• Initial recommended treatments for ABPA were at least 3 months.


Prednisone 0.5 mg/kg every day for 2 weeks

Prednisone 0.5 mg/kg alternate days for 3 months

Staging of disease &Repeat level of serum total IgE for monitor disease activity

CORTICOSTEROID


CORTICOSTEROID

• Larger cohorts indicated use of higher doses of corticosteroids for longer duration to prevent disease relapse.

• No controlled data compare dosage regimens.• More recent studies -higher-dose regimens -with duration of treatment determined by serologic

and clinical response -in particular aiming for a 35% reduction in serum

total IgE to reduce the risk of relapse


CORTICOSTEROID

0.75 mg/kg/day for 6 weeks

0.5 mg/kg/day for 6 weeks

then reduction of 5 mg/day every 6 weeks, with 6 to 12 mnth of tx


CORTICOSTEROID

• Lung damage can occur even in the absence of symptoms.Monitor serum total IgE levels every 1 to 2 months

• Increase corticosteroid dosing if IgE levels double from the baseline values obtained after stability on the maintenance dose.

• Alternate-day regimens may be an option for subjects who cannot be tapered off corticosteroids completely.


CORTICOSTEROID

• Acute exacerbations should be treated with

Prednisone 0.5 to 1.0 mg/kg/day for 1 to 2 weeks

Prednisolone 0.5 mg/kg/day for 6 to 12 weeks on clinical remission


CORTICOSTEROID

*Monthly pulsed methylprednisolone regimen*

3 days of 10 to 15 mg/kg/day repeated every month


CORTICOSTEROID

• Methyl prednisolone with itraconazole demonstrated effective reduction of serum total IgE and improvement in symptoms.

• Methylprednisolone with itraconazole has been used in patients with CF as well.

• High-dose intravenous corticosteroid treatments have also been used in life-threatening situations involving ABPA


CORTICOSTEROID

• A study of budesonide and formoterol inhalation therapy in 21 patients with ABPA-S

ABPA-s with Progressive elevation of serum IgE

Responded to oral corticosteroids, with reduction in total IgE levels

no pt used antifungal therapy

budesonide &formoterol6 months


Antifungal Agents

Steven DA,et al N Engl J Med 2000;342:756-62

Stevens and associates showed symptomatic improvement decreased corticosteroid requirement in 46% of those receiving 200 mg of itraconazole twice dailyversus 19% in the placebo group.

19%46%

Itraconazole

Placebo

Wark and colleaguesshowed reduced sputum eosinophil counts in both patients with ABPA-S and patients with ABPA-CB in remission, using daily itraconazole(400 mg/day for 16 wks)

Wark PAB et al, J Allergy Clin Immunol 2003;111:952-7

Limper AH et al .An offi cial American Thoracic Society statement: treat ment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128






The apparent consensus is that itraconazole, 200 mg twice daily for 6 months, should be offered for these patients

Antifungal Agents

• Voriconazole has been used as an alternative antifungal agent and was effective in a case series.


Antifungal Agents

• Azoles are strong inhibitors of the cytochrome P450–dependent CYP3A4 enzyme involved in the metabolism of budesonide and other corticosteroids.

• Adrenal suppression has been demonstrated by the ACTH stimulation test in pts receiving inhaled corticosteroids and itraconazole.

• Some of the benefit of adjunctive azole therapy in ABPA might be caused by the relatively higher dose of bioavailable corticosteroid.


Anti-IgE Biologics

• Key role of IgE in the pathology of ABPA• Effectiveness of anti-IgE treatments in asthma• Anti-IgE therapy has been tried in ABPA. • Recommended dose range of IgE for which

omalizumab has proved effective is frequently exceeded in patients with ABPA


Anti-IgE Biologics

• Uncontrolled case series report effective use of omalizumab in

#ABPA patients #Corticosteroid-dependent CF patients • Others report the effective use of omalizumab

with corticosteroids in life-threatening respiratory failure caused by ABPA.

• Second-line option for ABPA in patients with and without CF.


Take home message

• Patients with well-treated but uncontrolled asthma should be screened for allergic bronchopulmonary aspergillosis.

• Diagnostic criteria for ABPA include asthma, increased total IgE levels, positive skin testing to Aspergillus fumigatus, increased specific IgE to Aspergillus, and central bronchiectasis (may be absent in ABPA serologic).

• First-line therapy for ABPA is systemic corticosteroids; the antifungal itraconazole or voriconazole may be considered as an alternative, corticosteroid-sparing agent.

THANK YOU

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Allergic bronchopulmonary aspergillosis