Fungi and allergic lower respiratory tract diseases.
ABSTRACT Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain T(H)2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.
Article: Asthma cases attributable to atopy: results from the Third National Health and Nutrition Examination Survey.[show abstract] [hide abstract]
ABSTRACT: The percentage of asthma cases attributable to atopy is the subject of debate. The objectives were to estimate the percentage of asthma cases in the US population attributable to atopy and to examine associations between allergen-specific skin tests and asthma. Data were obtained from the Third National Health and Nutrition Examination Survey, in which subjects age 6 to 59 years were skin tested with 10 allergens. Atopy was defined as at least 1 positive allergen-specific test. Doctor-diagnosed current asthma was assessed by questionnaire. In the United States, 56.3% of the asthma cases were attributable to atopy, and that percentage was greater among males than females, among persons in the highest education category than in lower education categories, and among persons living in highly populated metropolitan areas than in all other areas. Each allergen-specific test was strongly associated with asthma before adjustment (odds ratios varied from 2.1 to 4.5); however, after adjustment by all the allergens, only tests to cat, Alternaria, white oak, and perennial rye were independently associated with asthma. Perennial rye was inversely associated with asthma. Of the 10 allergens, a positive response to cat accounted for the highest percentage of asthma cases (29.3%). About half of the current asthma cases in the US population represented by the Third National Health and Nutrition Examination Survey were attributable to atopy. Some allergen-specific skin tests were not independently associated with asthma. If atopy could be prevented or reversed, or its effect on asthma blocked, then a large percentage of asthma cases in the US population could be prevented.The Journal of allergy and clinical immunology 12/2007; 120(5):1139-45. · 9.17 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Atopy is known to be important for childhood asthma, but this is to our knowledge the first study on its relation with development of asthma in adulthood. We addressed the role of atopy, measured as total IgE and Phadiatop, and of specific IgE antibodies to mites and molds in development of adult-onset asthma. A population-based incident case-control study was conducted in the Pirkanmaa District in Southern Finland. All new clinically diagnosed cases of asthma 21-63 years of age were recruited 1997-2000 in the study district. A random sample of the source population formed the controls. A total of 485 cases and 665 controls provided a serum sample. Diagnosis of asthma was based on demonstration of reversibility in lung function investigations. Subjects with previous asthma were excluded. Phadiatop score and IgE antibodies were analyzed with the UniCAP system. The adjusted odds ratio of asthma increased with total IgE and Phadiatop score in a dose-dependent pattern. IgE antibodies to house dust mite and storage mite were significantly related to an increased risk of asthma. Among molds, increased risk of asthma was seen in relation to IgE antibodies to Aspergillus fumigatus and Cladosporium herbarum. Population attributable fraction due to sensitization to common aeroallergens was 30% (95% CI, 23-41). Atopy is a strong determinant of asthma in adulthood. Specific IgE antibodies to mites and some molds are significantly related to increased risk of adult-onset asthma. A considerable fraction of adult asthma could be prevented by measures to reduce atopy.Journal of Allergy and Clinical Immunology 04/2006; 117(3):642-8. · 11.00 Impact Factor
Article: Fungi and pollen exposure in the first months of life and risk of early childhood wheezing.[show abstract] [hide abstract]
ABSTRACT: Many studies have found that the risk of childhood asthma varies by month of birth, but few have examined ambient aeroallergens as an explanatory factor. A study was undertaken to examine whether birth during seasons of elevated ambient fungal spore or pollen concentrations is associated with risk of early wheezing or blood levels of Th1 and Th2 type cells at 24 months of age. 514 children were enrolled before birth and followed to 24 months of age. Early wheezing was determined from medical records, and Th1 and Th2 type cells were measured in peripheral blood using flow cytometry. Ambient aeroallergen concentrations were measured throughout the study period and discrete seasons of high spore and pollen concentrations were defined. A seasonal pattern was observed, with birth in autumn to winter (the spore season) associated with increased odds of early wheezing (adjusted odds ratio 3.1; 95% confidence interval 1.3 to 7.4). Increasing mean daily concentrations of basidiospores and ascospores in the first 3 months of life were associated with increased odds of wheeze, as were increasing mean daily concentrations of total and specific pollen types. Levels of Th1 cells at age 24 months were positively associated with mean spore concentrations and negatively associated with mean pollen concentrations in the first 3 months of life. Children with higher exposure to spores and pollen in the first 3 months of life are at increased risk of early wheezing. This association is independent of other seasonal factors including ambient levels of particulate matter of aerodynamic diameter <or=2.5 microm and lower respiratory infections.Thorax 03/2009; 64(4):353-8. · 6.84 Impact Factor
Clinical reviews in allergy and immunology
Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD
Fungi and allergic lower respiratory tract diseases
Alan P. Knutsen, MD,aRobert K. Bush, MD,bJeffrey G. Demain, MD,cDavid W. Denning, FRCP, FMedSci,d
Anupma Dixit, PhD, MPH,eAbbie Fairs, MD,fPaul A. Greenberger, MD,gBarbara Kariuki, BS, MPH,aHirohito Kita, MD,h
Viswanath P. Kurup, PhD,iRichard B. Moss, MD,jRobert M. Niven, MD,dCatherine H. Pashley, MD,f
Raymond G. Slavin, MD,eHari M. Vijay, PhD, MPH,kand Andrew J. Wardlaw, MDf
Anchorage, Alaska, Manchesterand Leicester,United Kingdom, Chicago, Ill, Rochester, Minn, Palo Alto, Calif, and Ottawa, Ontario, Canada
St Louis, Mo, Madison and Milwaukee, Wis,
Asthma is a common disorder that in 2009 afflicted 8.2% of
adults and children, 24.6 million persons, in the United States.
In patients with moderate and severe persistent asthma, there is
significantly increased morbidity, use of health care support,
and health care costs. Epidemiologic studies in the United States
and Europe have associated mold sensitivity, particularly to
Alternaria alternata and Cladosporium herbarum, with the
development, persistence, and severity of asthma. In addition,
sensitivity to Aspergillus fumigatus has been associated with
severe persistent asthma in adults. Allergic bronchopulmonary
aspergillosis (ABPA) is caused by A fumigatus and is
characterized by exacerbations of asthma, recurrent transient
chest radiographic infiltrates, coughing up thick mucus plugs,
peripheral and pulmonary eosinophilia, and increased total
serum IgE and fungus-specific IgE levels, especially during
exacerbation. The airways appear to be chronically or
INFORMATION FOR CATEGORY 1 CME CREDIT
Credit can now be obtained,free for a limited time, by reading the review
articles in this issue. Please note the following instructions.
Method of Physician Participation in Learning Process: The core ma-
terial for these activities can be read in this issue of the Journal or online at
the JACI Web site: www.jacionline.org. The accompanying tests may only
be submitted online at www.jacionline.org. Fax or other copies will not be
Date of Original Release: February 2012. Credit may be obtained for
these courses until January 31, 2014.
Copyright Statement: Copyright ? 2012-2014. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects
of allergic disease to those who research, treat, or manage allergic
Target Audience: Physicians and researchers within the field of allergic
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is ac-
credited by the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians. The
AAAAI designates these educational activities for a maximum of 1 AMA
PRA Category 1 Credit?. Physicians should only claim credit commensu-
rate with the extent of their participation in the activity.
List of Design Committee Members: Alan P. Knutsen, MD, Robert K.
Bush, MD, Jeffrey G. Demain, MD, David W. Denning, FRCP FMedSci,
Anupma Dixit, PhD, MPH, Abbie Fairs, MD, Paul A. Greenberger, MD,
Barbara Kariuki, BS, MPH, Hirohito Kita, MD, Viswanath P. Kurup,
PhD, Richard B. Moss, MD, Robert M. Niven, MD, Catherine H. Pashley,
MD, Raymond G. Slavin, MD, Hari M. Vijay, PhD, MPH, and Andrew J.
1. To describe the most common environmental factors affecting fungal
spore dispersal .
2. To list the diagnostic criteria for allergic bronchopulmonary aspergil-
3. To identify the genetic characteristics that might increase suscepti-
bility to fungal diseases of the lower airway.
4. To formulate a treatment plan for ABPA and other fungal diseases of
the lower airway.
Recognition of Commercial Support: This CME activity has not re-
ceived external commercial support.
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: J. G. Demain is a fellow with the ACAAI
for the University of Washington and an adjunct clinical professor for the
University of Alaska. D. W. Denning is founder and shareholder of F2G
Ltd. P. A. Greenberger has provided expert witness testimony on the topic
visory board and given paid advice to Vecture Limited and has received re-
search support from The Moulten Foundation. A. J. Wardlaw has received
research support from Pfizer. The rest of the authors declare that they
have no relevant conflicts of interest.
tion of Allergy, Immunology, Pulmonary, Critical Care, and Sleep Medicine, Depart-
ment of Medicine, University of Wisconsin–Madison;
Immunology Center of Alaska, Anchorage;dthe National Aspergillosis Centre, Uni-
versity Hospital of South Manchester, University of Manchester, Manchester Aca-
demic Health Sciences Centre;ethe Department of Internal Medicine, Division of
Immunobiology, Section of Allergy and Immunology, Saint Louis University;fthe In-
sity ofLeicester,GlenfieldHospital, Leicester;gthe Department ofMedicine,Division
of Allergy-Immunology, Northwestern University Feinberg School of Medicine;hthe
Department of Medicine, Allergy and Immunology, Mayo Clinic, Rochester;ithe
cthe Allergy Asthma &
Section of Allergy and Immunology, Medical College of Wisconsin, Milwaukee;
jthe Department of Pediatrics, Stanford University, Palo Alto; andkthe Environmental
Health Directorate, Health Canada, Ottawa.
Received for publication December 8, 2011; accepted for publication December 12,
St Louis, MO 63104-1095. E-mail: firstname.lastname@example.org.
? 2012 American Academy of Allergy, Asthma & Immunology
intermittently colonized by A fumigatus in patients with ABPA.
ABPA is the most common form of allergic bronchopulmonary
mycosis (ABPM); other fungi, including Candida, Penicillium,
and Curvularia species, are implicated. The characteristics of
ABPM include severe asthma, eosinophilia, markedly increased
total IgE and specific IgE levels, bronchiectasis, and mold
colonization of the airways. The term severe asthma associated
with fungal sensitization (SAFS) has been coined to illustrate the
high rate of fungal sensitivity in patients with persistent severe
asthma and improvement with antifungal treatment. The
immunopathology of ABPA, ABPM, and SAFS is incompletely
understood. Genetic risks identified in patients with ABPA
include HLA association and certain TH2-prominent and cystic
fibrosis variants, but these have not been studied in patients with
ABPM and SAFS. Oral corticosteroid and antifungal therapies
appear to be partially successful in patients with ABPA.
However, the role of antifungal and immunomodulating
therapies in patients with ABPA, ABPM, and SAFS requires
additional larger studies. (J Allergy Clin Immunol
Key words: Allergic bronchopulmonary aspergillosis, allergic bron-
chopulmonary mycosis, Aspergillus fumigatus, Alternaria alternata,
Cladosporium herbarum, severe asthma with fungal sensitivity
Discuss this article on the JACI Journal Club blog: www.jaci-
Asthma is a common disorder that in 2009 afflicted 8.2% of
adults and children, 24.6 million persons, in the United States.1
Sensitization to fungi is an important factor in patients with aller-
gic respiratory tract diseases, playing a major role in the develop-
ment, persistence, and severity of lower airway disease,
exposure and loss of asthma control are numerous,2but only re-
cently have direct causal associations with the development of
asthma become apparent. Arbes et al3demonstrated that Alter-
et al4showed that fungal sensitivity, particularly to Aspergillus
and Cladosporium species, increases the risk of adult-onset
and ascospores in the first 3 years of life had an increased risk of
Fungal sensitization might also contribute to the persistence of
activesymptoms of asthma. In a large survey of US housing, Salo
et al6reported that exposure to A alternata antigens correlated
with active asthma symptoms. Stern et al7showed that sensitiza-
tion to Alternaria species at age 6 years correlated with persistent
asthma at age 22 years (odds ratio, 7.4). Sensitization to Alter-
naria and other species has been associated with severe and po-
tentially fatal episodes of asthma.2,8,9Epidemics of asthma
caused by increased airborne Alternaria spores that occur during
thunderstorms further illustrate this association.10
PREVALENCE OF FUNGAL SENSITIVITY
The precise prevalence of fungal sensitivity is unclear. The
National Health and Nutrition Examination Survey III study11re-
ported that among US citizens aged 6 to 59 years, 12.9% have
positive skin prick test (SPT) responses to Alternaria species,
whereas in another US study 21% of 102 atopic subjects had
positive skin test results to 1 or more fungal allergens.12In Euro-
though various studies report that 12% to 42% of atopic patients
are mold sensitive,13-16others are as high as 80%.17Newer diag-
nostic approaches, such as fungal enzyme microarrays,18fluores-
for a more accurate assessment of fungal sensitization.
DEVELOPMENT OF SENSITIZATION
Sensitization arises from a combination of genetic factors and
exposure. Sensitization to Alternaria species has been associated
to this allergen, although the risk of asthma is unknown.20Envi-
ronmental exposure to fungi occurs both indoors and outdoors.
A recent study showed that in fungus-sensitized asthmatic chil-
dren, outdoor mold exposure rather than indoor mold exposure
ies report an association between indoor mold exposures and
lower airway symptoms. A Finnish cohort study reported a corre-
lation between visible mold growth in homes and wheezing epi-
sodes in children.22Bundy et al23demonstrated that indoor
Penicillium species levels correlated with peak expiratory flow
rate variability in asthmatic children.
Allergic rhinitis and asthma both have been associated with
50% in adverse respiratory health outcomes in occupants because
States,26Europe,27and the World Health Organization28affirm
Fungi in water-damaged homes of asthmatic children have been
found to differ from fungi in control homes without visible water
damage. The dominant fungi in the dust of water-damaged homes
fluctuated with the geographic location.29-31
ROLE OF CLIMATE CHANGE IN FUNGUS-RELATED
RESPIRATORY TRACT DISEASES
Further factors that might influence the frequency of fungal
sensitization and lower respiratory tract disease in the future are
the effects of global climate change.30,31There is growing evi-
dence of the effect of climate change on other aeroallergens, in-
cluding mold sporulation.32-36The plant response to increasing
ABPA: Allergic bronchopulmonary aspergillosis
ABPM: Allergic bronchopulmonary mycosis
CF: Cystic fibrosis
IL-4RA: IL-4 receptor a chain
ITGB3: Integrin b3
IUIS: International Union of Immunological Societies
MBL: Mannose-binding lectin
PAR: Protease-activated receptor
SAFS: Severe asthma with fungal sensitivity
sIgE: Specific IgE
SNP: Single nucleotide polymorphism
SPT: Skin prick test
TLR: Toll-like receptor
J ALLERGY CLIN IMMUNOL
VOLUME 129, NUMBER 2
KNUTSEN ET AL 281
CO2concentrations includes greater biomass and a greater car-
bon/nitrogen ratio of plant tissues; thus fungi growing on plant
materials encounter changes in substrate. When grown on plant
material in higher CO2environments, A alternata exhibits in-
creased spore production, as well as increased antigen levels
per plant.37Lake and Wade38demonstrated an acceleration of
pathogenic plant fungal growth in increased CO2environments;
tablished mycelia colonies by 40%. Increases in regional temper-
ature at 2 sites in the United Kingdom over a 27-year period
correlated with an increased number of days in which Cladospo-
rium species spore counts exceeded 4000/m3.39In a prospective
study of patients with mild-to-moderate asthma (60% atopic), a
positive relationship was established between high basidiospore
levels and asthma symptom scores, with a modest but significant
risk ratio of 1.19. Days with high basidiospore levels also
correlated with nocturnal awakening and increased medication
use.40Studies directly linking increases in CO2concentrations
with increases in fungi formation and sporulation are limited.
Klironomos et al41,42demonstrated a 4-fold increase in airborne
fungal spores in response to increasing CO2 concentration.
Thus climate change joins the ranks of potential contributing fac-
tors to the increase in the prevalence and severity of respiratory
FUNGI ASSOCIATED WITH LOWER AIRWAY
Aerobiological studies have shown the majority of fungal
spores in outdoor air to be from the phyla Ascomycota and
Basidiomycota (Table I).43The most commonly studied aller-
genic fungi are conidia-producing anamorphs of ascomycetes,
such as Alternaria, Aspergillus, Botrytis, Cladosporium, Epicoc-
cum, Fusarium, and Penicillium species. Asexually produced co-
nidia represent 30% to 60% of the spores present in outdoor air,
the remainder being comprised mostly of teleomorphic (sexual)
spores of the Ascomycota and Basidiomycota, which are referred
to as ascospores and basidiospores, respectively. Studies have
suggested that the prevalence of hypersensitivity to basidiospores
and conidial allergens might be comparable, although little is
known about the allergenicity of ascospores.43Exposure to air-
borne fungi can occur in both outdoor and indoor environments.
Spores are usually present in outdoor air throughout the year, fre-
quently exceeding the pollen population by 100- to 1000-fold or
more, depending on environmental factors, such as water, nutri-
ents, temperature, and wind.44,45Spores and fungal fragments
found indoors originate from fungi present outdoors and from
fungi that might have grown inside the buildings on moist
Precipitation is required for the discharge of basidiospores,
with concentrations increasing during and after rainstorms.48The
resultant airborne concentrations of actively wet spores discharg-
precipitation withminimal effectof windspeed onairbornespore
counts.49During extended periods of rainfall, productivity might
become a limiting factor, with re-establishment of spore concen-
trations dependent on replenishment of spores. Rainfall can also
dislodge spores from surfaces, an effect heightened with larger
Many airborne conidia (asexual spores) are from fungal plant
known for all; however, light might be an important factor in
spore discharge.50The duration of sporulation is largely deter-
mined by temperature, humidity, and moisture, partly explaining
why fungal spore counts are subject to seasonal periodicity.51
Alternatively, dry discharged spores from fungi, such as Alter-
naria, Aspergillus, Cladosporium, and Penicillium species, are
mostly emitted when dry, warm, and windy conditions prevail.49
Wind velocity required for detachment varies between fungi.50,52
A minimum of 1.0 m/s is required for detachment of Cladospo-
rium species, and 0.5 m/s is required for Aspergillus and Penicil-
lium species.51,52Dry discharged spores are easily dispersed and
can be carried long distances by the wind. Nonspherical spores
fall slower and therefore have the potential to be carried farther
by the wind than spherical spores, and similarly, spores released
wind speed and drier air result in enhanced spore liberation.
Aspergillus fumigatus and related species are distributed
widely in the environment.53Aspergillus and Penicillium species
are closely related genera, the spores of which cannot be readily
distinguished in studies relying solely on microscopy. They are
present in outdoor air and are also considered major indoor
fungi.54They are often present in the outdoor air throughout the
year, although they might show seasonal fluctuations dependent
on geographic region. In the United Kingdom they are the domi-
nant spore type in the air in autumn and winter, but levels reach
their peak in the autumn,55with levels higher outdoors during
Penicillium species are prevalent indoor fungi.43Inhalation of
asthma in sensitive persons. Among more than 100 known Peni-
cillium species, Penicillium citrinum, Penicillium chrysogenum
(Penicillium notatum), Penicillium oxalicum, Penicillium brevi-
compactum, and Penicillium spinulosum, are considered the
TABLE I. Taxonomic distribution of allergenic fungi
Kingdom Chromista Ascomycota
J ALLERGY CLIN IMMUNOL
282 KNUTSEN ET AL
Cladosporium species spores are released during both wet and
dry conditions and dispersed by rain splash. Spore release is de-
pendent on fluctuations in humidity triggered particularly by
rapid decreases in humidity.57Outdoor counts tend to be higher
in warmer weather and during thunderstorms.58Cladosporium
species spores occur abundantly worldwide and are the dominant
airbornesporesinmanyareas, especiallyintemperate climates.59
Cladosporium herbarum frequently dominates indoor and out-
door air and is a major source of inhalant allergens.60
Alternaria species exhibits diurnal periodicity, with counts
peaking during daylight hours.49Sporulation is induced by light
rain or heavy dew, with sudden humidity changes stimulating re-
lease.61,62Although rainfall is required for sporulation, airborne
levels are shown to decrease with precipitation.63Intermittent
rainfall is more beneficial in the formation and dispersal of Alter-
naria species spores.63Temperature also affects concentrations,
with counts higher in warmer weather.58Harvesting increases
the concentration of airborne Alternaria species spores because
are observed in air samples during periods of harvest, which is
likely problematic for allergic patients because the particles
will be of more inhalable size and internal allergens will be ex-
posed.10,63Alternaria species is a predominant outdoor fungus
but has been reported in house dust samples.64
Another fungal spore of interest with regard to asthma and
allergy is Didymella species, which is often observed in routine
counts during the summer months, particularly during rainfall.
Didymella species concentrations have been associated with
asthma morbidity after thunderstorms65and positively correlate
with humidity, with temperature being less important. Under fa-
vorable meteorological conditions, concentrations can reach ex-
plosive peaks of up to 30,000 spores/m3air.66
Most fungi possess multiple and diverse allergens. Some are
metabolic products secreted outside the organism; others are
cytoplasmic and structural components released on lysis or autol-
approved by the Allergen Nomenclature Sub-committee of the
that are fully characterized are listed in Table II. This listing in-
cludes isoallergens and variants from 25 fungal species belonging
vidual sensitization to multiple fungi. IgE-binding allergens of A
fumigatus, Penicillium species, A alternata, and C herbarum
have been obtained by using molecular cloning techniques.68-74
Genomic analysis of Aspergillus species and homology compari-
sons with allergen sequences from other fungi have identified a
core set of allergen-like proteins occurring across fungi. The
IUIS listing includes 30 allergens from 5 species of Aspergillus
(Table II), including proteins, polysaccharides and glycoproteins,
cleases, catalases, and superoxide dismutases.53,75The most com-
Aspergillus niger, Aspergillus oryzae, Aspergillus flavus, and As-
pergillus terreus. Several of these enzymes have been attributed
to the pathogenesis of Aspergillus species–induced diseases.
A number of these antigens demonstrate reactivity with specific
wall and cytoplasm also showed reactivity with sera of patients
with ABPA. However, these allergens frequently show cross-
rinum and 11 antigens from P chrysogenum have been shown to
react with IgE from patients’ sera by means of immunoblotting.77
Sixteen Penicillium species allergens have also been characterized
from 4 species (Table II). Ten allergens (Table II) have been char-
of the 10 allergens is a fungal conidial allergen (Cla h HCh-1); the
remainder are hyphal. Allergenic cross-reactivity between Clado-
sporium cladosporioides, C herbarum, and Cladosporium sphaer-
ospermum has been reported.78Alternaria species possess both
mycelial and metabolic antigens capable of causing allergy. The
IUIS database recognizes 9 Alternaria species allergens, of which
Alt a 1 is the most significant (Table II). Major fungal allergens,
such as Asp f 1 and Alt a 1, are unique and have not been found
to share sequence homology with any other known allergen.79
ALLERGIC FUNGAL LUNG DISEASES
ABPA and related conditions
First described in 1952, ABPA is commonly caused by A fumi-
gatus, an ubiquitous mold common indoors and frequently found
around farm buildings and compost heaps.80-85ABPA is charac-
terized by exacerbations of asthma, recurrent transient chest ra-
eosinophilia, especially during an exacerbation. ABPA is a TH2
hypersensitivity lung disease caused by bronchial colonization
matic patients and 7% to 9% of patients with cystic fibrosis
(CF).80-85The diagnosis of ABPA is based on clinical and immu-
nologic reactivity to A fumigatus. The minimal criteria required
for the diagnosis of ABPA are as follows: (1) asthma or CF
with deterioration of lung function, (2) immediate Aspergillus
species skin test reactivity, (3) total serum IgE level of 1000 ng/
mL (416 IU/mL) or greater, (4) increased Aspergillus species–
specific IgE and IgG antibodies, and (5) chest radiographic infil-
trates. Additional criteria might include peripheral blood eosino-
philia, Aspergillus species serum precipitating antibodies, central
plugs.80-85Designation of ABPA-seropositive (ABPA-S) can be
used to classify asthmatic patients who meet required criteria
but lack proximal or central bronchiectasis (ABPA-CB). High-
resolution computed tomography can demonstrate central bron-
chiectasis in the inner two thirds of the field, even in the absence
of chest radiographic lesions.86PCR for detecting Aspergillus
species in sputum is more sensitive than culture in ABPA but
needs to be interpreted with other clinical and laboratory fea-
tures.87At the time of radiographic exacerbation, the presence
if the total IgE concentration has increased compared with base-
line concentrations. Plasma levels of thymus and activation-
regulated chemokines (CCL17) might be a better marker for
ABPA than IgE levels, especially for exacerbations.88
mycosis (ABPM). Other fungi, including Candida, Penicillium,
and Curvularia species, are occasionally responsible for a similar
syndrome.83Recently, L€ otvall et al89proposed endotype classifi-
cation of asthma syndromes, which included ABPM. The charac-
teristics of ABPM included severe asthma, blood and pulmonary
eosinophilia, markedly increased IgE and specific IgE levels,
J ALLERGY CLIN IMMUNOL
VOLUME 129, NUMBER 2
KNUTSEN ET AL 283
TABLE II. Fungal allergens approved by the Nomenclature Sub-
committee of the IUIS*
weight (kd) Biological activity
Alt a 1 28
Alt a 3
Alt a 4
Alt a 5
Alt a 6
Alt a 7
Alt a 8
Heat Shock Protein 70
Ribosomal protein P2
Alt a 1053
Alt a 12 11Acid ribosomal protein
Alt a 326
Asp fl 13
Asp f 1
Alkaline serine protease
Asp f 2
Asp f 3
Asp f 4
Asp f 5
Asp f 6
Asp f 7
Asp f 8
Asp f 9
Asp f 10
Asp f 11
Ribosomal protein P2
Asp f 12
Asp f 13
Asp f 15
Asp f 16
Asp f 17
Asp f 18
Heat Shock protein P90
Alkaline serine protease
Asp f 22
Asp f 23
Asp f 27
Asp f 28
Asp f 29
Asp f 34
Asp n 14
Asp n 18
Ribosomal protein L3
PhiA cell wall protein
Asp n 25
Asp o 13
Asp o 21
Asp v 13
66-100 3-phytase B
Alkaline serine protease
Candida albicansCand a 1
Cand a 3
Cand b 2
Cla c 9 36
TABLE II. (Continued)
Fungal species Allergen
weight (kd)Biological activity
Cla c 14
Cla h 2
Cla h 511Acid ribosomal protein
Cla h 6
Cla h 7
Cla h 8
Cla h 9Vacuolar serine
Cla h 10 53
Cla h 1211Acid ribosomal protein
Curvlaria lunata Cur l 1
Cur l 2
Cur l 3
Cur l 4
Epi p 130
Fus c 111Ribosomal protein P2
Fus c 213 Thioredoxin-like
Pen b 1333 Alkaline serine protease
Pen b 2611Acidic ribosomal
Pen ch 1334 Alkaline serine protease
Pen ch 18 32 Vacuolar serine
Pen ch 20 68N-acetyl
CalreticulinPen ch 31
Pen ch 33
Pen ch 35
Pen c 3
Alkaline serine protease
Heat shock protein P70
Elongation factor 1 beta
Pen c 13
Pen c 19
Pen c 22
Pen c 24
Pen c 30
Pen c 32
Pen o 18
Sta c 321Extracellular alkaline
Tri r 2
Tri r 4
Tri t 1
Tri t 283 Serine protease
J ALLERGY CLIN IMMUNOL
284 KNUTSEN ET AL
bronchiectasis, and mold colonization of the airways. Genetic
risks of ABPM can include CF variants and HLA association.
Sensitization to A fumigatus is common, particularly in patients
with more severe airway disease,90although few fulfill all the cri-
teria for ABPA. The term severe asthma associated with fungal
sensitivity (SAFS) has been coined to illustrate the high rate of
fungal sensitivity in patients with severe asthma and response to
oral antifungal therapy with itraconazole.91It is speculative
whether ABPA represents one florid manifestation of a spectrum
of fungus-associated airway disease.
Fungal sensitivity in patients with severe asthma
The human lungis notsterile froma fungal perspectivein most
persons. The conidia of A fumigatus, Penicillium and Cladospo-
ducing an immune response when germination is initiated.92
Excess mucus and airway architecture distortion can allow
fungal germination and protection from immune attack, with a
consequent inflammatory reaction. Although A fumigatus is the
most common fungus found in the airways, much of which is
not culturable,87other fungi can be cultured from sputum in asth-
matic patients. In a study of 126 patients with severe asthma, 24
sociation with A fumigatus. In approximately 50% of these
patients, cultures were positive without evidence of IgE fungal
sensitization, suggesting that fungal colonization of the airways
is common, even in the absence of an allergic component. In pa-
tients with severe asthma, Fairs et al93reported that there was a
significant association between A fumigatus IgE sensitization,
colonization, and impaired postbronchodilator FEV1. This obser-
tients with SAFS respond to antifungal therapy.
Diagnosis of fungal sensitization
SPTs and specific serum IgE tests are used to determine
sensitization to various fungi.95Common fungi tested included A
num (P notatum), C herbarum, and Saccharomyces cerevisiae.
ton species, Malassezia species, Aureobasidium pullulans, Hel-
minthosporium halodes, Epicoccum species, Fusarium species,
Mucor species, Rhizopus species, and Coprinus species. The ac-
curacy of SPTs for positive results is approximately 50% to
60%, with variations dependent on the reagent and manufacturer,
dictive result has a 95% accuracy.96-99Major geographic and age
variations in the frequency of sensitization to fungi are seen.97,98
patients who cannot undergo SPTs.96-99Smits et al96found that
only 43% of patients reacted to both SPTs and serum specific
O’Driscoll et al99described a general lack of concordance be-
tween positive SPT responses and serum sIgE testing in patients
species (56%) and the worst in Botrytis species (14%). Both au-
thors recommended the use of both tests for a definitive diagnosis
because not all sensitivities will be identified with the use of one
alone. It has been reported that SPTs are more sensitive but less
specific than serum sIgE tests to diagnose allergic sensitization
in subjects with asthma or rhinitis.98O’Driscoll et al99prospec-
tively examined SPT and serum sIgE test results to individual
fungi together and separately in patients with severe asthma in
the United Kingdom. Among 121 patients, 66% demonstrated
sensitization to 1 or more fungi on either test. Nine of these pa-
tients had a total serum IgE level of greater than 1000 IU/mL: 6
likely had ABPA, and 3 had ABPM to other fungi (1 to Candida
species and 2 to Trichophyton species). Sensitization to multiple
fungi or sensitization to cross-reacting allergens can occur.100
Others have demonstrated relatively high rates of sensitization
to other fungi in asthmatic patients, including Rhizopus and
PATHOPHYSIOLOGY OF FUNGAL DISEASES OF
THE LOWER AIRWAYS
b-Glucan and dectin receptors
(1/3)-b-D-glucans are part of the carbohydrate structures in
dry weight of the cell wall of fungi might be glucans.102An asso-
ciation between high b-glucan levels and increased peak expira-
tory flow variability has been observed in children with
TABLE II. (Continued)
Fungal species Allergen
weight (kd)Biological activity
Coprinus comatusCop c 1
Cop c 2
Cop c 3
Cop c 5
Cop c 7
Mala f 2
11 Leucine zipper protein
Malassezia furfur 21Peroxysomal membrane
Mala f 320 Peroxysomal membrane
Mala f 435
Mala s 1
Mala s 5
Mala s 6
Mala s 7
Mala s 8
Mala s 9
Mala s 10
Mala s 11
Heat shock protein 70
Mala s 12 67Glucose-methanol-
Thioredoxin Mala s 3
Psi c 1
Psi c 2
Rho m 1
Rho m 247Vacuolar serine
*Current as of April 29, 2010 (http://www.allergen.org).
J ALLERGY CLIN IMMUNOL
VOLUME 129, NUMBER 2
KNUTSEN ET AL 285
in infancy appear to be risk factors for asthma by age 3 years.104
opposite effect on asthma risk compared with visible mold. In-
door fungal species vary widely in their content of b-glucan,
and although Aspergillus and Alternaria species are highly aller-
genic, they have relatively low levels of b-glucan. Of the 36 in-
door fungal species tested, Cladosporium and Aspergillus
genera were the most important contributors to the indoor
b-glucan levels105; A alternata did not seem to be an important
contributor to indoor b-glucan levels.
Dectin-1 is a receptor for b-glucan on macrophages, neutro-
phils, and dendritic cells that transduces signals for vigorous cell
response with phagocytosis, oxidative burst, and production of
inflammatory mediators, including IL-8, IL-6, IL-12, IL-18, and
TNF-a.106,107In mice dectin-1 and Toll-like receptor (TLR)
2–mediated neutrophil recruitment and TNF-a and macrophage
inflammatory protein 2 secretion when germinating conidia of
A fumigatus were administered into murine trachea.108,109The
tive immune responses, including the regulation of the TH17 re-
sponse and generation of regulatory T cells.107,109
Fungal proteases and protease-activated receptors
Fungi contain many proteases that are required for growth and
are also fungal allergens.2,110It is possible that the proteolytic
activity of fungal proteases contributes to their own immunoge-
nicity orthatofotherfungus-derived proteins.Invitro fungalpro-
teases damage an epithelial layer system with shrinkage,
desquamation, and disruption of intercellular adhesion.2,110
Once the epithelial layer is damaged, proteases/allergens have
flammatory cytokines could lead to an exacerbation of asthma.
ologic changes analogous to that of asthma.110Protease activities
can be recognized by unique receptors, protease-activated recep-
in the immune response in the airways. PAR-1, PAR-2, PAR-3,
imens from asthmatic patients and healthy subjects.111PAR-2 is
overexpressed on epithelial cells from asthmatic patients com-
pared with that seen in healthy control subjects, suggesting in-
creased vulnerability of asthmatic patients to proteases from
fungi or other sources.
Chitin is a major structural component of the outer coatings of
many organisms, such as fungi, parasitic nematodes, and arthro-
anallergicresponse,characterized byabuild-up ofIL-4–express-
ing innate immune cells. Shuhui et al115proposed that chitin-
also stimulate airway smooth muscle. Increased chitinase levels
have been associated with asthma and increased IgE levels, per-
haps through an IL-13 pathway.116,117Furthermore, polymor-
phisms in the promoter of acidic mammalian chitinase have
been associated with atopic asthma and increased IgE levels.117
Mycotoxins and volatile organic compounds
Patients with asthma tend to be more readily symptomatic by
respiratory exposure to airborne irritants, such as perfume and
smoke, than healthy subjects. Fungi produce mycotoxins as
nonvolatile secondary metabolites and volatile organic com-
pounds as byproducts of metabolism.118The volatile organic
and duration of exposure to mycotoxins are difficult to quantify.
HLA class II antigens
In patients with ABPA, HLA-DR2 (HLA-DRB1*15 and
B1*16)/HLA-DR5 (HLA-DRB1*11 and HLA-DRB1*12) re-
striction was reported as a risk factor for the development of
ABPA.120Furthermore,HLA-DQB1*02 wasprotective inthede-
velopment of ABPA. Similarly, DQB1*03 appeared to be protec-
moderate-to-severe asthma in children.121The HLA-DQB1*03
genotypewas associatedwith decreased Alternariaspecies–stim-
ulated IL-5 and IL-13 synthesis.
IL4RA and IL13 polymorphisms
Single nucleotide polymorphisms (SNPs) of IL-4 receptor a
chain (IL4RA), IL4, IL10, IL13, and CD14 have been described in
ciatedwithatopy prevalenceand asthmaseverity.123Increased fre-
quency of the ser503pro IL4RA polymorphism was observed in
adults with severe asthma.124IL13 110gln was associated with
increased IgE levels and increased asthma severity125; the 110gln
polymorphism is significantly more active than wild-type IL13 in
stimulating signal transducer and activator of transcription 6 phos-
In studies of Alternaria species–sensitive patients with moderate-
to-severe asthma, the presence and allele frequency of the IL4RA
ile75val SNP was also significantly increased.
Polymorphisms in innate immune receptors
Carvalho et al127examined TLR polymorphisms of TLR2,
TLR4, and TLR9 in patients with cavitary pulmonary aspergillo-
sis, ABPA, and SAFS. No association of TLR2, TLR4, or TLR9
polymorphisms was found in SAFS. Patients with ABPA had in-
creased frequency of allele C for the TLR9 T-1237C polymor-
phism compared with control subjects. Novak et al128reported
that the mechanism might be that the TLR9 C allele of T-1237C
decreases expression of TLR9. Decreased TLR9 protective func-
tion might be an underlying susceptibility in the development of
ABPA and asthma.
the platelet- and monocyte-specific heterodimeric receptor for fi-
brinogen and the receptor for vitronectin. Polymorphisms of
ITGB3 have been associated with asthma and mold sensitiza-
tion.129Smit et al130reported that the TLR2/1596 C polymor-
phism was associated with asthma. Furthermore, they identified
that ITGB3 SNPs are associated with mold sensitization in pa-
tients with asthma and hypothesized that an association of the
TLR2/1596 genotype and ITGB3 SNPs might influence the asso-
ciation of mold sensitization in adults with asthma.
J ALLERGY CLIN IMMUNOL
286 KNUTSEN ET AL
TABLE III. Possible treatments of ABPA
TherapyTypical doseTypical durationObjectives of therapyMonitoringComments
Adults: 40-50 mg qd
10 d-6 wk, depending
convert to alternate-
after 1-2 wk for
wheeze and allows
Chest radiograph and
clinical. IgE level
slow to decrease,
decrease by 33% in
6 wk; blood glucose
Attempt to stop in all
VariableAsthma control; of no
proved value for
Reduce viscosity of
sputum to ease
PF, FEV1, symptomsInteractions with
4 mL, 7% unit dose
Always challenge first
issue; beware those
with FEV1<1.0 L/s.
Itraconazole Adults: 300-400 mg
qd or 500 mg bid in
patients with CF
5-10 mg/kg/d, divided
bid if > _200 mg
Itraconazole levels to
cortisol and total
Fungal cultures and
species PCR in
sputum if available;
Voriconazole levels to
fungal cultures and
species PCR in
Toxicity minimized if
blood levels in
occur, PCR positive
an indication of
infiltrates can occur
with elevation of
total serum IgE
For those intolerant or
limiting in some
Voriconazole Adults: 200-600
<40 kg 100 mg bid
> _40 kg 200 mg bid
Months or yearsSame as itraconazole
800 mg qd
> _13 y
400 mg bid
Long-term Same as itraconazole Fungal cultures and
species PCR in
if adverse events to
dose can be
Cough frequency and
For those intolerant or
250 mg qd or 33
5 mg/kg/d qd or in CF
<40 kg 250 33
> _40 kg 500 33
75-600 mg SC 2-4
Long-term Airway anti-
If no effect after
mo, should be
Omalizumab Long-term, if effective
at 16 wk
Reduction in IgE-
Asthma controlLimited experience in
bid, Twice daily; MIC, minimum inhibitory concentration; PF, peak flow; qd, once daily; SC, subcutaneously.
J ALLERGY CLIN IMMUNOL
VOLUME 129, NUMBER 2
KNUTSEN ET AL 287
Molecules in the collectin family, such as mannose-binding
lectin (MBL), pentraxin 3, and surfactant proteins, have all been
demonstrated to bind Aspergillus species. Polymorphism of
MBL2 at G11011 in intron 1 results in increased MBL levels
and has been associated with development of ABPA. Saxena
et al131reported that patients with ABPA with polymorphisms
(ala91pro and arg94arg) in the collagen region of pulmonary sur-
factant protein A2 had more increased total IgE levels and higher
percentages of eosinophilia than patients who lacked the SNPs.
They found that 80% of patients carrying both SNPs had
ABPA, suggesting an additive effect.
TREATMENT OF ALLERGIC FUNGAL LUNG
Exacerbations of ABPA are best treated with a course of oral
steroids over 3 to 6 weeks (Table III).132No prospective studies
with corticosteroids have been conducted to evaluate efficacy
rates, optimum dose, and duration or relapse rates. There are con-
flicting data concerning the clinical utility of inhaled corticoste-
roids in reducing exacerbation frequency, but they are important
in controlling underlying asthma (Table III).133,134The potential
utility ofsystemic antifungaltherapyfor ABPAwasfirstshownin
the early 1990s.135Two placebo-controlled randomized studies
demonstrated benefit from itraconazole treatment (200 mg twice
daily initially).136,137The outcomes that were assessed in the first
study were as follows: reduction in corticosteroid oral dose, re-
duction in total IgE levels, and increases in exercise tolerance
or pulmonary function on testing.136In the second study eosino-
and exacerbations requiring corticosteroid courses were signifi-
cantly reduced in itraconazole-treated subjects (P 5 .03).137
Overall,about 60% of patients benefitfrom itraconazole (number
needed to treat 5 3.58). Itraconazole levels should be monitored
to optimize exposure. Sufficient exposure to itraconazole is prob-
ably important to ensure efficacy, and low plasma levels (ie, <5
mg/L [bioassay] or <1.0 mg/L [HPLC]) might require switching
between capsules and oral solution and sometimes increasing the
dose. Proton-pump inhibitors and H2blockers reduce absorption
in bioavailability. Excessive itraconazole concentrations often re-
of itraconazole therapy is not clear but should not be less than 6
months in those who tolerate it and might be extended safely
with benefit for years. In patients who cannot tolerate itracona-
zole, voriconazole or posaconazole might be helpful (Table III).
Two retrospective series of voriconazole in patients with ABPA
and CF suggest benefit, and our experience in patients without
CF is similar or better. There are a number of case series of pa-
tients reporting the benefit of omalizumab in the therapy of
ABPA138-140but no randomized studies, and therefore efficacy
is uncertain. Exacerbations of ABPA or difficult-to-treat asthma
(with fungal sensitization) necessitate considering the home and
ing with fungus-laden mulches, that might be subject to change.
Bronchiectasis is a common sequela of ABPA. Sometimes
patients with bronchiectasis do better with long-term macrolide
treatment (ie, azithromycin) if they are highly symptomatic; no
large randomized controlled studies have been done, but clinical
experience is positive for many patients.141-143Initiation of
azithromycin therapy should immediately follow a different class
of antibiotic in those with purulent sputum to ‘‘clean out the air-
ways’’ to minimize the immediate acquisition of macrolide
SAFS and ABPM
Patients with SAFS usually have severe asthma requiring
of oral corticosteroids usually control patients’ worst symptoms
ing a major effect on pulmonary and nasal symptoms in 60% of
suggests that omalizumab might also be beneficial.138-140
Reductions in asthma morbidity subsequent to interventions
for improvingoverall indoor airquality,decreasinghumidity,and
Fungal allergen immunotherapy
allergen immunotherapy are wanting, in part because of the lack
of standardized therapeutic reagents. A limited number of con-
trolled trials with A alternata and C herbarum have shown some
ommended; however, patients might receive or continue allergen
immunotherapy for treatment of allergic rhinitis or asthma. His-
torically, fungal (mold) extracts are not included in the treatment
What do we know?
d Sensitivity to molds, especially Alternaria and Cladospo-
rium species, is associated with the development, persis-
tence, and severity of allergic asthma.
d ABPA is the most common form of ABPM. ABPA might
represent an extreme manifestation of a spectrum of im-
munologically mediated fungus-associated airway disease.
d Sensitization to A fumigatus is common in asthmatic pa-
tients with more severe airway disease (ie, so-called
d Both ABPA and SAFS might respond to antifungal ther-
apy, as well as corticosteroids. What is still unknown?
d The pathophysiology and genetic risks of mold sensitivity
in patients with severe asthma remain to be fully
d The diagnostic criteria of ABPA, ABPM, and SAFS need
to be better defined.
d The role of antifungal and immunomodulating therapies
in the treatment of ABPA, ABPM, and SAFS requires fur-
ther controlled clinical trials for validation and determi-
nation of the role in overall management.
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