Clinical Commentary Review
Clinical Evaluation and Management of Patients With
Suspected Fungus Sensitivity
Desiree Larenas-Linnemann, MDa, Sachin Baxi, MDb, Wanda Phipatanakul, MD, MSb, and Jay M. Portnoy, MDc; on behalf
of the Environmental Allergens Workgroup* Mexico City, Mexico; Boston, Mass; Kansas City, Mo
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
material for these activities can be read in this issue of the Journal or
online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The
accompanying tests may only be submitted online at www.jaci-
inpractice.org/. Fax or other copies will not be accepted.
Date of Original Release: March 1, 2016. Credit may be obtained for
these courses until February 28, 2017.
Copyright Statement: Copyright 2016-2018. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects
of allergic disease to those who research, treat, or manage allergic
disease.
Target Audience: Physicians and researchers within the field of
allergic disease.
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is
accredited by the Accreditation Council for Continuing Medical Edu-
cation (ACCME) to provide continuing medical education for physi-
cians. The AAAAI designates these educational activities for a
maximum of 1 AMA PRA Category 1 Credit. Physicians should only
Fungus-sensitized patients usually present with symptoms that
are similar to symptoms presented by those who are sensitized
to other aeroallergens. Therefore, diagnosis and management
should follow the same pathways used for patients with allergic
conditions in general. The physician should consider that a
relationship between fungal exposure and symptoms is not
necessarily caused by an IgE-mediated mechanism, even when
a medical management, and, when appropriate, specific
Hospital Medica Sur, Mexico City, Mexico
b
Boston Children’s Hospital, Boston, Mass
c
Division of Allergy/Immunology, Children’s Mercy Hospital, Kansas City, Mo
Conflicts of interest: The authors declare that they have no relevant conflicts of
interest.
Received for publication August 18, 2015; revised September 25, 2015; accepted for
publication October 15, 2015.
Corresponding author: Jay M. Portnoy, MD, Division of Allergy, Asthma &
Immunology, Children’s Mercy Hospital, 2401 Gillham Rd, Kansas City,
MO 64108. E-mail: jportnoy@cmh.edu.
* The complete list of Environmental Allergens Workgroup members appears in the
Acknowledgments.
2213-2198
Ó 2015 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaip.2015.10.015
claim credit commensurate with the extent of their participation in the
activity.
Activity Objectives
Learning objectives:
1. To ask appropriate questions to identify patients who are likely to be
sensitive to mold.
2. To determine whether a patient is likely to be experiencing harm
from fungus exposure and if so by what mechanism.
3. To perform appropriate tests for IgE sensitization to fungi.
4. To recommend appropriate immunotherapy, when indicated, to
mold-sensitive patients.
Recognition of Commercial Support: This CME has not received
external commercial support.
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: CME authors’ COI statement: The exam
authors disclosed no relevant financial relationships.
Acknowledgement: The Editors thank the Children’s Mercy Hospital
Allergy/Immunology training program for developing this CME ex-
amination. The individuals who contributed to its preparation were Jill
Hanson, MD, Neha Patel, MD, Brooke Polk, MD, and Hani Hadi, MD,
under the direction of Paul Dowling, MD.
specific fungal IgE is detected. Until recently, IgE-mediated
allergy has been documented only for a limited number of
fungi. We propose a series of questions to be used to identify
symptoms that occur in situations with high fungal exposure
and a limited skin-prick-test panel (Alternaria, Cladosporium,
Penicillium, Aspergillus, Candida) that can be amplified only
in cases of high suspicion of other fungal exposure
(eg, postfloods). We also review in vitro testing for fungi-
specific IgE. Treatment includes environmental control,
immunotherapy. Low-quality evidence exists supporting the
use of subcutaneous immunotherapy for Alternaria to treat
allergic rhinitis and asthma, and very low quality evidence
supports the use of subcutaneous immunotherapy for
Cladosporium and sublingual immunotherapy for Alternaria.
As is the case for many allergens, evidence for immunotherapy
with other fungal extracts is lacking. The so-called toxic mold
syndrome is also briefly discussed. Ó 2015 American
Academy of Allergy, Asthma & Immunology ( J Allergy Clin
Immunol Pract 2015;-:---)
Key words: Mold allergy; Toxic mold; Alternaria; Cladosporium
1
2 LARENAS-LINNEMANN ET AL
Abbreviations used
LR- likelihood ratio (given that a test is either positive or
negative, the LR is the ratio of the pretest odds that the
patient has a given condition divided by the posttest odds
that the patient has that condition)
SCIT- subcutaneous immunotherapy
SLIT- sublingual immunotherapy
SPT- skin prick test
Patients with concerns about mold allergy are commonly seen
by allergists in clinical practice. Such individuals might be spe-
cifically concerned about possible adverse health effects from
exposure to mold that they have observed in their house, or they
may be seeking care for medical conditions that subsequently
turn out to be triggered, at least in part, by fungi. There is a clear
relationship between exposure to fungi and asthma (and rhinitis)
symptom exacerbations,1 but part of these reactions might be
due to mechanisms other than fungal allergy,2 even if TH2-
skewed reactions are found in these individuals and even if
fungus-specific IgE is reported. Thus, the presence of IgE to
fungus in a patient with asthma does not necessarily mean that
fungal allergy is the cause. Even when we take into account the
fact that not all IgE-sensitized patients have allergy, mold allergy
does appear to be a relatively common condition, because the
prevalence of sensitization to fungi, as determined by skin prick
test (SPT), is estimated to be as high as 19% of the allergic
population.3 In addition, because the prevalence of sensitization
among various fungal genera is highly variable, with some taxa
eliciting an IgE response more frequently than do others, the
spectrum of mold allergy is also likely to be variable depending
on the genera to which the patient is exposed.
Fungus-sensitized patients usually present with symptoms that
are similar to symptoms presented by those who are sensitized to
other aeroallergens. Clear links have been reported between
sensitization to Alternaria and Cladosporium and seasonal res-
piratory allergy symptoms. As outdoor allergens these fungi
behave similarly to pollen allergens, with particular seasons/
conditions that elevate their concentration in air (end-summer/
autumn, thunderstorms, etc) eliciting at that particular moment
symptom exacerbations. Alternatively, Penicillium sensitization
has been linked to indoor allergen exposure, especially in humid
moldy environments and after floods.1 There are data related to
Aspergillus and Candida that suggest a possible role as allergens.3
Thus, some fungi do seem to cause direct allergy with respiratory
allergic symptoms. Convincing data for other allergy-causing
fungi apart from these 5 (Alternaria, Cladosporium, Penicil-
lium, Aspergillus and Candida) are lacking, which does not mean
that they do not exist. Therefore, methods for the diagnosis and
management of fungus-allergic patients should follow the same
clinical pathways that are used for patients with allergic condi-
tions in general. This includes eliciting a history consistent with
respiratory diseases that are likely to be triggered by exposure to
fungi, identifying plausible mechanisms for the observed adverse
health effects given the history of exposure, detecting the pres-
ence of fungus-specific IgE, and treatment with appropriate
environmental controls, medical management, and, when
appropriate, specific immunotherapy. This review will consider
each of these components as they pertain to identifying and
treating patients who have fungal allergy.
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2015
MECHANISMS OF ADVERSE HEALTH EFFECTS
Fungal contaminants (allergens and irritants) are produced by
actively growing fungi and become incorporated into a building’s
reservoirs over time. Reservoirs then periodically release these
contaminants back into the environment when disturbed, which
can lead to long-term intermittent or continuous exposure to a
building’s occupants. The presence of dampness (defined as
sufficient moisture to support fungal growth on available sub-
strates) tends to augment the production of fungal and other
microbial contaminants, which is why dampness has been asso-
ciated with adverse health effects.4
The specific adverse health effects triggered by fungal exposure
depend on the fungal products to which the patient is exposed.
An extensive discussion of fungal products that are capable of
triggering health effects and their mechanisms appears elsewhere
in this issue.2 For the current discussion, primary exposures
include fungal allergens, volatile organic compounds, and various
other substances that serve as either proinflammatory molecules
or irritants. The possible effect of other substances on health,
such as mycotoxins, will be addressed later. The mechanisms of
adverse health effects from fungal exposure therefore are as fol-
lows: (1) the patient could be allergic to the fungus; (2) the
patient could be experiencing an irritant effect from exposure; (3)
the patient could be infected by the fungus; (4) the patient could
be allergic to other allergens, and coexposure to fungi acts as an
adjuvant stimulating a TH2 response via nonspecific routes of the
innate immune system; and (5) there could be other mechanisms
that are unknown.
CLINICAL EVALUATION
Fungal exposure has been associated with increased symptoms
in patients with allergic rhinitis, asthma, and atopic dermatitis.5
The clinical evaluation of a patient with one of these conditions,
therefore, is the same regardless of the patient’s fungus sensitivity
status. It begins by eliciting a history consistent with increased
symptoms that are triggered by exposure to the suspected
allergen.6
Indoor environments with high fungal exposure generally
include those with increased moisture content as is found in a
basement or other damp environment. Old buildings often
experience moisture problems that result in fungal growth. It
therefore helps to ask whether symptoms increase in the presence
of dampness, visible mold in the home, and a moldy odor. This
type of question necessarily is nonspecific because old buildings
often have multiple air quality issues such as rodent or cockroach
infestations, lack of ventilation, and increased particle counts due
to decaying organic material that can trigger symptoms. Ques-
tions that have been shown to correspond to health effects from
fungi are whether there is visible mold and whether there is a
moldy smell.5
Outdoor situations in which increased moisture may be
associated with fungal exposure include storms or prolonged
periods of damp weather, cut grass, raking leaves, which stirs up
fungal spores, and work with organic materials such as compost.
The sexual state of Alternaria produces ascospores for a brief
period in the late spring followed by increasing concentrations as
the growing season progresses into early fall. Alternaria conidia
tends to peak on dry days at midday with increasing concen-
tration as a function of wind turbulence. Table I includes specific
questions the physician might ask to determine whether there is
J ALLERGY CLIN IMMUNOL PRACT
VOLUME -, NUMBER -
TABLE I. Questions that can be asked to identify an association
between fungus exposure and increased symptoms*

Do your symptoms get worse when you are in an environment with
visible mold?

Do your symptoms get worse when you visit an old house or
building?

Do your symptoms get worse when you enter a basement or other
damp environment?

Do your symptoms get worse after rain storms?

Do your symptoms get worse after you mow the lawn, rake leaves,
or work with compost or hay?

Do your symptoms get worse when you are in buildings with a moldy
or musty smell?

Do your symptoms get worse during the late summer and fall?
*While the predictive value of these questions has not been validated in clinical
trials, they do make sense given our knowledge of fungus exposure in certain types
of environments.
an association between exposure to environments likely to have
increased fungus exposure and increased symptoms.
Clinicians may have a tendency to overestimate the likelihood
of fungal allergy. In one study, allergists were asked to predict
whether patients were allergic to mold (Alternaria) on the basis of
history alone before an SPT or specific-IgE test to Alternaria was
performed.7 The history accurately predicted sensitization in
24% and lack of sensitization in 10% and falsely predicted
sensitization in 19%. The rest were indeterminate in that the
clinicians did not feel that they could predict the patient’s fungus
sensitization. Of those, 24% were negative and 9% were positive.
In another study,8 the question “do molds increase your
symptoms?” was associated with a positive likelihood ratio (LR)
of 2.09 and a negative LR of 0.73. These values are only
marginally useful for helping to make a clinical decision about
fungal allergy. The problem with such questions is that patients
may not know whether they are exposed to molds when they
have symptoms. In addition, there may be other exposures
involved besides fungi when patients do have symptoms. Patients
who have a preexisting belief that fungi are a cause of their
symptoms may overestimate or overstate the association between
fungus exposure and symptoms.
Patients who have observed fungi in their home and conse-
quently believe that they have symptoms that must be caused by
fungus exposure will in many cases display confirmatory bias in
their history. It is therefore important to determine whether the
patient had symptoms first and then concluded that fungi in the
home must be causing them or whether the patient first observed
the fungi and then looked for symptoms that have occurred as a
result. This temporal ordering can provide an insight into the
role of psychological bias in the development of clinical symp-
toms. It may be helpful to ask such patients why they believe that
fungi are causing the symptoms and how they came to such a
belief. It is important in the initial stages of evaluation to simply
accept patients’ statements and not to contradict their beliefs
until a more trusting relationship has been established.
Symptoms that are consistent with fungal exposure primarily
include respiratory conditions such as rhinitis and asthma. There
is evidence that atopic dermatitis can also be exacerbated by fungi
such as Malassezia.9 Other symptoms such as fatigue, behavior
changes, and vague constitutional symptoms are unlikely to be
LARENAS-LINNEMANN ET AL 3
caused by exposure to fungi. Patients who experience those
symptoms often have other conditions that are a more likely
cause. Insistence on fungi as a cause of health problems can, at
times, lead to litigation. Such individuals have a vested interest in
maintaining a belief that fungi have harmed them, making it
unlikely that any evidence elicited in the clinical evaluation
would change their minds. It is therefore helpful to determine
whether legal action is contemplated or in progress because that
may affect how the evaluation is performed.
DETECTION OF SENSITIZATION (FUNGUS-
SPECIFIC IgE)
There are currently 19 standardized allergenic extracts in the
United States, none of which is a fungal extract. Extracts for
which there are no US reference standards are referred to as
unstandardized extracts. All registered fungal extracts in the
United States as of October 2013 are nonstandardized extracts.10
Recently, the Food and Drug Administration has reviewed
nonstandardized extracts with the intent of eliminating any that
lack documented evidence for either their clinical utility or
diagnosis or treatment. Most fungal extracts were felt to have
inadequate evidence to support their use either for diagnosis or
for treatment.
Improvement in the diagnosis and treatment of fungal allergy
has been hampered, in part, by the fact that fungal extracts are
highly variable in their protein and major allergen composition.11
This variability is due to strain differences, batch-to-batch vari-
ations, and the fact that extracts may be derived from spores and/
or mycelia.12 According to allergen databases (http://www.
meduniwien.ac.at/allergens/allfam/), 189 fungal species are
thought to produce allergens and these consist of 61 protein
families containing approximately 132 allergens.13 Studies with
recombinant fungal allergens have demonstrated their utility for
clinical diagnosis.14,15
SPTs and in vitro tests are commonly used to detect the
presence of fungus-specific IgE. The primary limitation of these
tests is that their performance characteristics including specificity,
sensitivity, and LRs are not known—except for Alternaria—and
vary according to the quality of the specific extract used. This is
largely due to the lack of high-quality fungal extracts, the pres-
ence of extensive, taxonomically related cross-reactivity among
fungi, and the lack of well-designed studies with a relevant cri-
terion standard for fungi other than Alternaria. Even so, tests that
currently are available can be used to identify evidence of fungal
sensitization as long as their limitations are kept in mind.
The decision as to whether to use an SPT or an in vitro test
depends on the clinical judgment of the provider taking into
account patient preference. Because certain fungal taxa are
available only by one technique, sensitization to those taxa needs
to be identified using the available method.
Skin prick tests
Skin prick testing is a diagnostic procedure that provokes a
wheal and flare response following the introduction of a minute
amount of an allergen extract through the skin using a pricking
device. The diagnostic utility of the test depends on its clinical
reliability in terms of sensitivity and specificity, and its repeat-
ability as measured by coefficient of variance. The procedure for
performing SPTs and variables that can affect the results have
been described previously.16 Currently available extracts for
performing percutaneous tests for fungi are listed in Table II.
4 LARENAS-LINNEMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
MONTH 2015

TABLE II. Extracts and in vitro tests currently available for the fungi to test for; however, the quality of the extracts used in most
diagnosis of fungal sensitization studies is unknown, and it is unclear which fungi were used as
Genus Species Extract iCAP source materials for the extracts. In addition, many studies are
decades old. Furthermore, results come from differing groups of
Acremonium kiliense Yes
subjects from different parts of the world with different genetic
Aerobasidium pullulans Yes Yes
backgrounds.17 So although many fungal extracts have been
Alternaria alternata Yes Yes shown to produce a wheal and flare response in some fungus-
Aspergillus flavus Yes sensitized individuals, their ability to identify patients with
Aspergillus fumigatus Yes Yes clinical allergy is not known with the exception of Alternaria.
Aspergillus niger Yes One study of SPT with an Alternaria extract18 using nasal
Aspergillus sp mixture Yes challenge as a criterion standard found that the positive LR for
Aspergillus terreus Yes SPTs was 11.75 and the negative LR was 0.05 with a sensitivity
Botrytis cinerea Yes Yes of 95.2 and a specificity of 91.9. More recently, a study
Candida albicans Yes compared Alternaria prick and intradermal skin testing and
Chaetomium globosum Yes Yes in vitro testing to bronchial challenges in 74 Alternaria-sensitized
Cladosporium herbarum Yes patients with asthma.19 Bronchial challenge results were analyzed
Cladosporium sphaerospermum Yes by receiver operating characteristic curves and logistic regression.
Curvularia lunata Yes The positive LR for SPTs was 9.45 and the negative LR was
Curvularia spicifera Yes 0.02. These 2 studies suggest that skin testing with Alternaria
Epicoccum nigrum Yes effectively identifies patients with fungal sensitivity both for
Epicoccum purpurascens Yes rhinitis and for asthma.
Epidermophyton floccosum Yes Another question that commonly arises is which fungi should
Fusarium moniliforme Yes Yes be tested. In one study, SPTs among patients with any allergy
Geotrichum candidum Yes
were most frequently positive for Alternaria (12.6%) and Candida
Helminthosporium halodes Yes
(8.5%). When patients with a positive SPT result to a fungus
were considered separately (19% of allergic patients), positive test
Helminthosporium solani Yes
results were found for Alternaria (66.1%), Candida (13.1%),
Malassezia orbiculare Yes
Cladosporium (13.1%), Aspergillus (12.6%), and Trichophyton
Malassezia spp Yes
(10.2%). Patients who were sensitized to 1 or 2 fungi were
Mucor plumbeus Yes
consistently skin-reactive to Alternaria and Candida. In patients
Mucor racemosus Yes
sensitized to multiple fungi, skin tests were positive in descending
Penicillium chrysogenum Yes order of frequency to Alternaria, Candida, Cladosporium,
Penicillium glabrum Yes Aspergillus, Saccharomyces, Penicillium, and Trychophyton.3
Penicillium mixture Yes This suggests that patients could be screened for fungal
Phoma betae Yes Yes sensitization using a limited number of skin tests (Alternaria and
Rhizopus nigricans Yes Yes Cladosporium to represent outdoor fungi, Aspergillus and
Rhizopus oryzae Penicillium to represent indoor fungi, and possibly Candida as a
Rhodotorula mucilaginosa Yes marker for fungal sensitization). It would be reasonable for pa-
Saccharomyces cerevisiae Yes tients to be tested with this limited panel if fungal sensitization is
Stachybotrys chartarum Yes not anticipated on the basis of history as was proposed in a recent
Stemphylium herbarum Yes review.20 Patients could be tested with a more extensive panel if
Stemphylium solani Yes it is important to identify their specific sensitization pattern as
Trichophyton mentagrophytes Yes would be the case if immunotherapy is being considered or if
Trichophyton rubrum Yes Yes evidence for an association between exposure and symptoms due
Trichosporon pullulans Yes to specific fungi identified in a patient’s environment is needed.
Tricoderma harzianum Yes The extensive panel includes most of the different fungal speci-
Tricoderma viride Yes ficities from the various taxa keeping in mind that a few are not
Ulocladium chartarum Yes available for testing. Table IV has suggestions for a limited panel
Ustilago sp Yes and an extensive panel that could be used for this purpose.
rAsp f 1 Yes
The use of intradermal tests for aeroallergens is controversial
largely because of its low specificity, which can lead to false-
rAsp f 2 Yes
positive tests as has been demonstrated for timothy grass.21 A
rAsp f 3 Yes
study of patients who were prick negative and intradermal pos-
rAsp f 4 Yes
itive to 5 extracts including Alternaria22 used nasal challenges to
rAsp f 6 Yes
determine whether these tests were clinically significant. The 2
rAlt a 1 Yes
patients who had a positive intradermal test for Alternaria had a
iCAP, ImmunoCAP. negative nasal challenge to Alternaria, suggesting that the test had
a substantial false-positive rate. Another study18—already dis-
Compiled sensitization rates from publications on skin testing cussed above—using nasal challenges as the criterion standard
with fungi can be found in Table III. The frequency of sensiti- found that for Alternaria, the positive LR was 8.8 and the
zation to various extracts can provide evidence concerning which negative LR was 0.05 with a sensitivity of 95.2 and a specificity
 VOLUME -, NUMBER -
J ALLERGY CLIN IMMUNOL PRACT
TABLE III. Frequency of SPT reactions to various fungal taxa
Study Acremonium Aureobasidium Alternaria Aspergillus Botrytis Candida Cephalosporium Cladosporium Curvularia Epicoccum

Open population, nonselected subjects

NHANES III (61) N ¼ 10,508 subjects 12.9%
ECRHS-I (62) N ¼ 15,160 3.3% 1.7%
Post-Katrina (63) N ¼ 529 0.8% 2.6% 1.1% 1.8% 0.0% 11.0% 0.9% 3.8% 1.9%
Patients with symptoms of allergic conjunctivitis, rhinitis, or asthma
Bogotá (64) N ¼ 540 16.7% 21.7%
Greece (65) N ¼ 284 11.3%
Finland (24) N ¼ 121 22.0% 14.0% 24.0% 28.0% 28.0% 18.0% 7.0%
Netherlands (66) N ¼ 833 6.8% 1.1% 4.7% 6.1% 2.3% 3.0%
Saudi Arabia, Saudi Arabs (16) N ¼ 806 13.0% 6.8% 7.1% 7.9%
Saudi Arabia, Western expatriates (16) N ¼ 241 36.0% 16.2% 17.8% 21.9%
China (67) N ¼ 63 26.4% 24.9% 22.0%
Mexico (68) N ¼ 101 15.0% 13.0% 11.0% 16.0%

Fusarium Helminthosporium Mucor Penicillium Phoma Rhizopus Stemphyllium Comment

6-59-y-old US open population

20-44-y-old, pan-European open population
0.9% 2.8% 0.4% 1.8% 2.5% 0.0% 0.6% After an important flood in the United States
14.3% 9.4% 19.0% 26.7% Of 2000 patients in Bogotá visiting the Allergy Department with AR/asthma, 540 had at least 1
positive ID test. Testing done with extracts made from colonies. 1000 PNU
Allergic conjunctivitis
22.0% 26.0% 19.0% 21.0% 18.0% 8.0% 22.0% Phadebas. Children with perennial and seasonal asthma
3.8%
9.4% Patients with AR symptoms living in Saudi Arabia, divided into Saudi Arabs (results on this

LARENAS-LINNEMANN ET AL
line) and Western expatriates (next line)
23.6%
20.1% 29.6% Subjects who suffered from AR and/or asthma living in the Chinese province of Guangxi. ID
tests were done
11.0% 11.0% 13.0% Patients with asthma living in the dry north of Mexico. ID skin testing was done with extracts
from the laboratory. Freeman

AR, Allergic rhinitis; ECRHS, European Community Respiratory Health Survey in Adults; ID, intradermal; NHANES, National Health and Nutrition Examination Survey; PNU, protein nitrogen unit.

5
6 LARENAS-LINNEMANN ET AL J ALLERGY CLIN IMMUNOL PRACT
MONTH 2015

TABLE IV. Fungi that could be used to test for sensitization using
either a limited (screening) panel or an extensive panel taking into
account cross-reactivities among genera. This table only includes
taxa for which commercial extracts are currently available for di-
agnostics. There are others (eg: Malassezia spp) for which there
are no readily available diagnostics. The screening panel could be
supplemented with additional fungi. Positive results may be due to
cross-reactivity
Limited Panel for Fungal Sensitization (can be used for screening).

Alternaria

Cladosproium

Aspergillus

Penicillium

Candida
Extensitve Panel for Fungal Sensitization (can be used if fungal
sensitization is strongly suspected)

Mucor or Rhizopus

Candida or Saccharomyces

Geotrichum

Cladosporium

Alternaria or Stemphyllium

Curvularia

Helminthosporium

Phoma or Epicoccum

Aerobasidium

Aspergillus

Penicillium

Trichophyton

Fusarium

Stachybotrys

Chaetomium

Botrytis

Rhodotorula

Ustilago
of 89.2. A different study found that intradermal tests in 45
prick-negative patients with asthma who underwent bronchial
challenge had a positive LR of 1.04 and a negative LR of 0.04
with a sensitivity of 100% and a specificity of 3.8%. So for nasal
allergies it is possible that intradermal tests might be useful;
however, for asthma they do not appear to be of any use.
Intradermal tests of Aspergillus fumigatus used to diagnose
allergic bronchopulmonary aspergillosus in one study had a
sensitivity of 88% and a specificity of 85.9%; however, this was
performed on all patients with allergic bronchopulmonary
aspergillosus rather than on those with negative SPT results.23
The performance characteristics of intradermal tests in SPT
negative patients with allergic bronchopulmonary aspergillosus is
not known.
In vitro tests
In vitro tests for fungi are available in a number of different
formats but generally rely on binding of specific IgE to fungal
proteins with subsequent detection using labeled anti-IgE. Fungi
currently available for in vitro tests are listed in Table II. The
only fungal components available are recombinant Aspergillus
components and Alternaria Alt a 1.
In one study, sera from patients with suspected fungal allergy
were tested for specific IgE antibodies to 16 different fungi using
the Phadebas RAST technique. Specific IgE was detected in 73%
of the patients to at least 1 of the 16 fungi. The highest frequency
of IgE antibodies was directed to Cladosporium, Botrytis, Hel-
minthosporium, and Phoma.24 In another study using Phadebas
RAST, the most frequently detected fungi were Cladosporium,
Candida, and Helminthosporium.25 Most of these are old studies
that used technologies no longer in use. A more recent study
compared percentages of positive fungal tests by SPT with
ImmunoCAP in vitro test. SPT detected 100% of the patients
who were sensitized to only 1 fungus, either Alternaria, Candida,
or Trichophyton, whereas ImmunoCAP detected 89%, 75%,
and 61% of the patients, respectively. When multiply fungus-
sensitized patients were evaluated, the in vitro tests generally
detected a higher percentage of patients than did the SPT.3 None
of these studies compared in vitro tests with a “criterion stan-
dard” test to determine whether the detected specific IgEs were
clinically relevant.
One study of Alternaria that did use nasal challenge as a cri-
terion standard found that in vitro testing for Alternaria had a
positive LR of 14 and a negative LR of 0.46.18 This means that a
positive test result likely indicates clinically relevant rhinitis
whereas a negative test result does not effectively rule it out.
Microarray tests
Results of microarray testing of sera of 23,077 allergic patients
in Italy (allergic rhinitis, asthma, atopic dermatitis, food allergy)
showed positivity to at least 1 allergen molecule in 16,408
subjects (71.1%). The most frequent fungal allergen was Alt a 1,
found to be positive in 1569 subjects (9.6%), followed by Pen i 1
and Pen m 1, positive in 2% and 1.9% of the subjects, respec-
tively. Positivity to Alt a 6 and Asp f 1 was less frequent.26
At this moment, an extended study is ongoing in European
children using the MeDALL allergen-chip, based on the allergen-
microarray technology, for the diagnosis and monitoring of al-
lergy. This might show in the near future whether certain fungal
allergens play a role in the development of allergic diseases.27
IgG as an exposure marker
Mold-specific IgG in patient serum also has been proposed for
use as a biomarker to indicate fungal exposure. Unfortunately,
the few studies that have been performed are not sufficient to
indicate the sensitivity or specificity of the test, particularly
because antibody measurements were not compared with actual
mold exposure.28,29 In addition, the tests do not indicate when
the exposure took place, nor do they take into account potential
cross-reactivity among different fungal taxa. For that reason, it
has no proven clinical diagnostic utility.
TREATMENT OF FUNGUS-SENSITIVE PATIENTS
Environmental assessment and interventions
Treatment of fungus-sensitive patients is similar in many ways
to treatment for any patient who is allergic to an aeroallergen.
This first involves recommendations for environmental control
with the aim to reduce exposure sufficiently to improve symp-
toms. Such interventions have been shown to be effective in a
recent Cochrane systematic review5 and are discussed in detail
elsewhere in this issue.1 Recommendations should focus on
removing sources of moisture that facilitate fungal growth,
eliminating or cleaning reservoirs, and blocking pathways from
J ALLERGY CLIN IMMUNOL PRACT
VOLUME -, NUMBER -
sources of fungal contamination to a home’s occupants. Because
it is impossible to completely avoid exposure to fungi, particu-
larly in the outdoor environment, realistic recommendations for
fungal avoidance should be provided to the patient.30
Patients who have extreme concerns about fungal contami-
nation in their home are possible candidates for referral to a
reputable indoor environmental professional. It is helpful to
establish a relationship with an indoor environmental profes-
sional to facilitate such referrals and to ensure that the quality of
the assessment is reliable. A recently published questionnaire
found elsewhere in this issue can be used to help determine
whether a home is likely to be contaminated with fungi.31
When litigation is involved, the patients often already had
their home assessed. In many cases, this will have been done by
professionals who are not very experienced. Patients may provide
the clinician with a home assessment report. It is helpful to
understand how to interpret such reports and to be able to
determine whether the assessment was done correctly. In some
cases when the results are questionable or unclear, it may help to
suggest that the more reliable indoor environmental professional
also perform an assessment.
Immunotherapy for fungi
In addition to environmental interventions and medical
management, immunotherapy can be provided to fungus-
sensitive patients. Two methods for delivering immunotherapy
for aeroallergens have been shown to be safe and effective in
randomized clinical trials. These include subcutaneous immu-
notherapy (SCIT), in which increasing amounts of allergen are
injected subcutaneously into a patient, and sublingual immu-
notherapy (SLIT), which requires the patients to place a small
amount of allergen under their tongue for up to 1 minute. There
is limited evidence for the use of immunotherapy to treat fungal
allergy by either method. It is important to remember that
treatment for fungal allergy with SCIT is currently approved in
the United States, while treatment for fungal allergy with SLIT is
currently undergoing evaluation and therefore is not approved
for use in the United States.
Subcutaneous immunotherapy
Alternaria. SCIT with fungi has been studied using controlled
trials in patients with allergy to Alternaria and Cladosporium. A
3-year open controlled trial of SCIT in 39 Alternaria-allergic
children with asthma using the highest tolerated dose of an
Alternaria extract (>80,000 protein nitrogen unit) showed
significantly decreased symptoms in the active group.32
In another 1-year double-blind placebo-controlled clinical trial
in 28 Alternaria-allergic patients with asthma, patients were
treated with an extract that incorporated 0.1 mg of Alt a 1
administered monthly during maintenance therapy. After 6
months, improvements were found in respiratory symptoms and
peak flows; however, the severity of asthma and rhinitis symp-
toms improved in both treatment groups. The study was un-
derpowered, and the treatment might also have been poorly
effective in view of the very low maintenance dose of allergen
included in the extract.33
Another 1-year double-blind placebo-controlled study in 24
Alternaria-allergic patients was performed using a standardized
Alternaria extract.34 Patient evaluations of the treatment were
lower in the placebo group, and symptom scores (asthma and
rhinitis) were less in the active groups. Nasal challenges also were
LARENAS-LINNEMANN ET AL 7
improved in the active group, and skin tests were reduced and
Alternaria-specific IgG level increased.
Another study that used a high-dose (8 mg Alt a 1/6 weeks)
Alternaria depot extract showed convincing improvement of
asthma and rhinoconjunctivitis.35 After a baseline run-in season,
symptom and medication scores reduced progressively over the 3
years in favor of the active treatment group, accompanied by
improved quality of life.
Another study of Alternaria immunotherapy was an open,
observational trial of 99 patients who received a depot prepara-
tion of 0.2 mg Alt a 1 every 4 to 6 weeks at maintenance. Asthma,
rhinitis, and conjunctivitis scores were greatly improved from
baseline, as well as the use of asthma medication.36 The open
design and low dose of allergen used reduce the reliability of this
result.
Recombinant Alternaria allergens were studied by Twaroch
et al.15 The investigators conclude thus far that rAlt a 1 is a
highly allergenic molecule allowing sensitive diagnosis of Alter-
naria allergy. In a recent publication, they presented data on
carrier-bound nonallergenic Alt a 1 peptides that might be can-
didates for safe specific immunotherapy of Alternaria allergy.15
Cladosporium. In addition to Alternaria, Cladosporium has
been studied in trials of immunotherapy. A 1-year double-blind
placebo-controlled trial of Cladosporium herbarum in 22
Cladosporium-allergic adult patients with asthma was
performed.37 Patients in the active group had decreased
symptoms and medication use. Adverse effects (70% had large
local reactions) were more common in the active group.
Another double-blind trial of immunotherapy in children using
a purified and standardized Cladosporium herbarum allergen
showed decreased IgE and increased IgG levels.38
A 10-month double-blind placebo-controlled trial of immu-
notherapy in 30 Cladosporium-allergic children with asthma
and/or rhinitis was carried out.39 During the first 6 months,
there was no difference in eye, nose, and bronchial symptoms;
however, medication scores were lower in the active group. After
10 months, medication scores and bronchial and eye symptoms
were significantly reduced in the active group.
Sublingual immunotherapy. There currently is only very
low quality evidence for the efficacy of SLIT with Alternaria in
patients with asthma. In a randomized double-blind placebo-
controlled trial, 27 patients (14-42 years) suffering from allergic
rhinitis (plus mild asthma) caused by Alternaria were assigned to
10-month SLIT or placebo. In the active group, a significant
improvement in symptoms and a reduction in medication intake
versus placebo and versus the run-in season were confirmed,
whereas no changes were noted in the placebo group. Oral
itching and conjunctivitis were reported by 1 patient undergoing
SLIT only at the beginning of the trial. Asthma symptom score
was part of this total symptom score; however, because only 4
patients had mild asthma, 2 in each group, no separate asthma
analysis was done.40
There is 1 randomized open 3-year SLIT trial in 52 adults
with respiratory allergy (rhinoconjunctivitis and/or asthma) to
Alternaria alternata. Assessor-blinded, patient-reported outcomes
with a once-a-year evaluation of symptoms and medication use
showed positive results, but no separate asthma parameters were
reported and the design of the study makes this very low quality
evidence.41
8 LARENAS-LINNEMANN ET AL
Immunotherapy and fungi. From the above discussion, it
should be clear that evidence supporting the administration of
immunotherapy for Alternaria and Cladosporium is low quality
and for other taxa of fungi is nonexistent. Unfortunately, this
situation is true for many other allergens that currently are given
as immunotherapy in the United States, which is why the Food
and Drug Administration decided to review the various extracts
to begin with. Although there is very little evidence to support
the administration of immunotherapy for fungal extracts, there
also is no evidence that it causes significant harm. Aqueous
fungal extracts currently are available and are routinely given to
patients as immunotherapy. Clinicians therefore need to use their
best judgment when deciding whether to administer fungal ex-
tracts to patients until additional evidence in the form of well-
conducted randomized controlled trials becomes available.
If fungi are used to produce allergen extracts, it is important to
be aware that such extracts tend to have high amounts of protease
activity. For that reason, fungal extracts should not be mixed
with other extracts that might be sensitive to such activity. For
example, a significant loss of potency has been demonstrated for
extracts from grass pollen, cat, birch, white oak, box elder, dog,
and some weeds when they are mixed with fungal extracts42-45
and recently also for extracts from cockroach.46
TOXIC MOLD SYNDROME
Patients who present with concerns about fungi may refer to
having an illness caused by exposure to “toxic mold” or “black
mold.” This condition has been surrounded by a great deal of
controversy, particularly with respect to mold-related litigation,
which reached a peak in the early 2000s and has subsequently
tapered off. The term “toxic mold syndrome” was coined in a
study of 65 patients who claimed that they had rhinitis (62%),
cough (52%), headache (34%), respiratory symptoms (34%),
central nervous system symptoms (25%), and fatigue (23%) after
being exposed to indoor environments that had Stachybotrys.47
In 32 patients who reported having exposure to Stachybotrys,
Aspergillus, and Penicillium, a minority had demonstrable fungal
allergy though many had asthma-like symptoms.48 Stachybotrys is
a favorite culprit in this syndrome largely because of a report
from Cleveland that found an increased likelihood of exposure to
this fungus in a series of infants with pulmonary hemosiderosis.49
The presumed mechanism of symptoms was often believed to be
exposure to indoor mycotoxins. A subsequent analysis50 sug-
gested that exposure to environmental tobacco smoke had an
equal or greater impact.
Outside of occupational circumstances, almost all reports of
fungal toxins in buildings are based on the use of methods that
have not been validated for this purpose.51,52 Tests that claim to
measure trichothecenes in human sera or urine have not proven
to be analytically reliable.52,53 The simple trichothecenes (eg,
diacetoxyscirpenol [anguidine] deoxynivalenol, T-2 toxin) are
rapidly metabolized and cleared within hours after administra-
tion54 including in humans.55 This is also the case in relevant
animal models for macrocyclic trichothecenes.56 There is one
study in which a very high dose of satratoxin G was administered
orally in a murine model. In this model, the satratoxin G that
entered the serum was rapidly cleared and a high percentage of
the dose remained in the nasal area. The dose used (500 mg/kg
body weight) was incomparably higher than possible even under
the most extreme circumstances. There appears to be only 1
J ALLERGY CLIN IMMUNOL PRACT
MONTH 2015
report of airborne satratoxin concentrations measured by a
specialist laboratory by using a valid instrument method. A high-
volume sampler used to take a large mass of particulate in a
highly contaminated environment measured 100 to 116 pg
satratoxin/m3.57
The presence of Stachybotrys chatarum in indoor air samples
generally means that the building has or had significant moisture
problems. Sensitivity to S chartarum is potentially much more
widespread than previously appreciated. Intact spores are a small
fraction of the exposure in damp buildings. Almost all the
exposure is to spore and mycelial fragments and much smaller
particles. In 1 study, 65 of 132 (49.2%) sera contained IgG and
13 of 139 (9.4%) sera contained IgE against S chartarum. Pooled
sera identified 2 IgE-binding proteins (34 and 52 kD) from
extracts of S chartarum spores and mycelia.58 At least 2 allergenic
proteins from S chartarum have been sequenced.59 The primary
allergen is called Sta c 3 (aexodeoxyribonuclease), and epitope
mapping has been conducted.60 This species almost never occurs
by itself and the population health effects from indoor exposure
are indistinguishable from those of other species that also are
commonly found indoors.61
The Institute of Medicine report on damp spaces and health
reported that “[i]nsufficient evidence was found to determine an
association between mycotoxin exposure and a number of other
reported health effects, including gastrointestinal problems, fa-
tigue, neuro-psychiatric symptoms and skin problems.”62 This
was also the conclusion of the World Health Organization panel
on mold and dampness.4
Patients who have concerns that they or their family may have
been harmed by exposure to mycotoxins should be evaluated in
the same way as any other patient who has symptoms. Once that
is complete, provided no cause of the symptoms has been
identified, it may help to have a frank discussion about the ev-
idence (or lack thereof) for toxic mold syndrome. Patients who
honestly are seeking information about their illness will usually
respond favorably to this approach. Patients who arrived with a
fixed belief that toxic mold has caused harm, particularly if liti-
gation has already been initiated, are unlikely to accept this
discussion. There is a community of active believers in this
syndrome who promote and encourage the idea that toxic mold
causes harm and that the medical establishment is covering up
the evidence for this. Unfortunately, this “promold” belief at
times is reinforced by “antimold” experts who deny that exposure
to fungi can have any detrimental effect at all, which is also
incorrect. Clearly what is needed is an unbiased assessment of the
evidence that does exist and a reasonable interpretation of its
implications.
SUMMARY
Patients with respiratory symptoms often seek consultation
with an allergist in an attempt to identify environmental triggers.
In up to 20% of such patients, there will be evidence for sensiti-
zation to fungi based either on SPTs or in vitro tests for fungus-
specific IgE. When the history suggests that exposure to indoor
fungus-contaminated or outdoor fungus-rich environments is
associated with increased symptoms, the conclusion that the pa-
tient is allergic to fungi is as convincing as it would be for any other
aeroallergen given similar clinical evidence. Such patients should
be managed by recommending reduced exposure using effective
interventions, appropriate medical treatment, and possibly by
J ALLERGY CLIN IMMUNOL PRACT
VOLUME -, NUMBER -
fungus-specific immunotherapy recognizing that the evidence for
the effectiveness of such treatment is high (rhinitis) to low
(asthma) for Alternaria and practically absent for all other fungi.
Patients who have a preexisting belief that exposure to mold
has caused harm pose additional challenges. If they are truly
seeking advice, it may be possible to explain what is and what is
not known about the health effects of exposure to fungi. Patients
who already have a strong belief that mold has caused harm are
often unwilling to accept any conclusion other than that which
they already have. In some cases, they are merely seeking
confirmation or validation of their beliefs. The best approach in
this situation is to provide the best information that is available
and avoid causing harm by doing unnecessary tests or treatment.
By engaging in this type of discussion, it is possible that reason
will prevail.
Acknowledgments
Environmental Allergens Workgroup members: Charles
Barnes, PhD, Center for Environmental Health, The Children’s
Mercy Hospitals & Clinics, Kansas City, Mo; Sachin Baxi, MD,
Immunology, Boston Children’s Hospital, Boston, Mass; Carl
Grimes, CIEC, Healthy Habitats LLC, Denver, Colo; W. Elliott
Horner, PhD, UL Environment, Marietta, Ga; Kevin Kennedy,
MPH, CIEC, Center for Environmental Health, Children’s
Mercy Hospital, Kansas City, Mo; Desiree Larenas-Linnemann,
MD, Allergy Faculty, Hospital Medica Sur, Mexico City,
Mexico; Estelle Levetin, PhD, Faculty of Biological Science, The
University of Tulsa, Tulsa, Okla; J. David Miller, PhD, NSERC
Industrial Research Chair, Carlton, University, Ottawa, Ontario,
Canada; Wanda Phipatanakul, MD, MS, Division of Allergy and
Immunology, Harvard Medical School, Children’s Hospital,
Boston, Mass; Jay M. Portnoy, MD, Division of Allergy, Asthma
& Immunology, Children’s Mercy Hospital, U. Missouri-Kansas
City School of Medicine, Kansas City, Mo; James Scott, PhD,
ARMCCM, Division of Occupational & Environmental Health,
Dalla Lana School of Public Health, University of Toronto,
Toronto, Ontario, Canada; P. Brock Williams, PhD, Division of
Allergy, Asthma & Immunology, U. Missouri-Kansas City
School of Medicine and The Children’s Mercy Hospitals &
Clinics, Kansas City, Mo.
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