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 Bronchopulmonary aspergillosis. Thorax 1952;7:317-33.

Hinson KFW, Moon A Bronchopulmonary 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.

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

(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 mycosis
Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus 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

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 aspergillosis

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)

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

Immune responses:Innate immune
response
-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
Abul K. Abbas et al.Cellular&Molecular immunology;9 edition2012:55-88

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

Immune responses:Cellular immune response

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
patients
Non-ABPA allergic asthmatic
patients
After Aspergillus antigen
exposure
After Aspergillus antigen
exposure
Proliferating allergen-specific CD4+ T cells
downregulated the expression of CCR4 and
CXCR3 in vitro
T cell chemokine receptor were
upregulated in stimulated allergen-specific
T cells

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

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

a.Rosenberg M,
Patterson R,
Mintzer R, et al
1977
b.Schwartz HJ,
Greenberger PA
1991
c.Greenberger PA.
1994
d.Agarwal R,
Khan A, Gupta
D, et al
2010

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 Aspergillus
Rosenberg 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 CLASSIFICATION
ABPA-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

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.

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

Charcot- Leyden crystals
Wikipedia,the free 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
lung opacity Lung collapse Parenchymal
Transient parenchymal
scaring

Radiologic Findings
HRCT: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

Fig. 6. Protocol for investigating allergic bronchopulmonary aspergillosis(ABPA) in patients with asthma.
Ritesh Agarwal et al, Clinical & Experimental Allergy,2013; 43 : 850–873

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

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.

CORTICOSTEROID
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
• 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
budesonide &formoterol
6 months
no pt used
antifungal therapy

19%
46%
Stevens and associates showed symptomatic improvement
decreased corticosteroid requirement in 46% of those receiving 200 mg of itraconazole
twice daily
versus 19% in the placebo group.
Steven DA,et al N Engl J Med 2000;342:756-62

Placebo
Itraconazole
Wark and colleagues
showed 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 official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-12
Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary Limper AH et al .An official American Thoracic Society statement: treatment of fungal
infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med
2011;183:96-128

Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-12
The apparent consensus is that itraconazole, 200 mg twice
daily for 6 months, should be offered for these patients
Limper AH et al .An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary Limper AH et al .An official American Thoracic Society statement: treatment of fungal
infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med
2011;183:96-128

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.

Allergic bronchopulmonary aspergillosis

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