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Indoor mold exposure: epidemiology, consequences and immunothapy

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Miller JD, Day JD (1997) Indoor mold exposure: epidemiology, consequences and immunothapy.
Can J Allergy & Clinical Immunology 2:25-32

Indoor Mold Exposure: Epidemiology, Consequences, and Immunotherapy

J. David Miller, PhD, James H. Day, MD, FRCPC

J.D. Miller -- Research Branch, Agriculture Canada, Ottawa; J.H. Day -- Division of Allergy and
Immunology, Department of Medicine, Queen=s University, Kingston, Ontario

ABSTRACT
The toxic and allergenic effects of exposures to environmental filamentous fungi (mold) in
homes and the nonindustrial workplace are reviewed. The consequences of indoor mold
exposures are more serious than once thought. This has led to the development of guidelines by
the Canadian Federal-Provincial Committee on Occupational Safety and Health and the
American Industrial Hygiene Association for the management of such fungi in buildings. More
research is needed to understand the basis for some of the health effects reported.

INTRODUCTION
"Mold" is the colloquial term for Deuteromyceteus filamentous fungi. Until recently, the emphasis
has been on outdoor or agricultural exposure to fungal spores as allergens or toxins. In 1924, a
correlation was documented between the onset of asthma and the presence of fungal spores in
outdoor air. The prevalence of fungi in the atmosphere and demonstrated positive skin-test reactivity
to fungal antigens were then reported (Day 1996). Fungal spores are present in the atmosphere in
significantly greater concentrations than pollen grains, yet much less is known about this group of
outdoor air allergens. The earliest record of the relationship of fungi to asthma and hay fever in
indoor air comes from the eighteenth century, when Sir John Floyer noted asthmatic symptoms in
individuals who had visited a wine cellar.

EPIDEMIOLOGICAL STUDIES AND THE WALLACEBURG (ONTARIO) PROJECT

Since 1982, approximately 20 studies have been conducted on the association of dampness, mold,
and respiratory health in European and North American residential housing. In the Harvard
University six-cities program, the respiratory health of 4600 children was examined in relation to
mold and dampness in their homes. The outcomes were correlated to several respiratory and
nonrespiratory symptoms. The deleterious health effects on the children were demonstrated to be
similar to those found in situations of parental smoking.1
Similar conclusions were drawn from the 30-community study of the Long Range Transport of Air
Pollutants Program of Health Canada, which involved one study of 15,000 children and another of
18,000 adults.2 The authors suggested that a nonallergenic mechanism was involved. A dose effect
was also seen in that more visible mold yielded more symptoms.3,4 Data from a study of a total of
13,000 children in 24 cities in the United States and 5 cities in Canada demonstrated the same
pattern.5
All the above studies report an association between self-reported symptoms, and home dampness
and mold. Similar health effects have been reported both in children and in adults by different
investigators using different questionnaires. Examples of the health effects in relation to moisture
plus mold indicators in the American and Canadian studies are shown in Table I. The Harvard
University/Health Canada questionnaire was tested in Wallaceburg, Ontario, one of the 30
communities in the Canadian study, and was shown to be highly reproducible.6
Wallaceburg was chosen for a series of further studies because of its size and because its homes
were representative of Canadian housing. The investigation of the 400 homes for biological
contaminants included analyses of living-room dust for fungi, house dust mite antigens and mite
species, Lipopolysaccharide (LPS) endotoxin, ergosterol (a measure of fungal biomass), and cat
antigen. Endotoxin and ergosterol were measured in the air from 18-hour samples taken in the living
room and children's bedrooms. Samples of visible mold were taken in the children's bedroom and
mattress dust was sampled for dust mite allergen. In addition, night-time coughing was recorded. A
very important finding was that the pattern of biological contaminants differed from home to home.7
(Miller & Young 1997)
Over 270 species of fungi were isolated from the 400 Wallaceburg homes. While phylloplane and
wild mushroom spores were the most common findings, most of the top 10 species were xerophilic,
toxigenic molds such as Aspergillus versicolor and various Penicillium species (Table II). Analysis
of the objective data on biological contaminants allowed a comparison to be made of self-reporting
of mold (i.e., on a questionnaire) versus actual mold burdens. Self-reported mold, water damage, and
moldy odors were associated with elevated concentrations of indoor fungi. However, inaccuracy was
high and systematic bias appeared to be present; respondents with respiratory symptoms were more
likely to report the presence of fungi than respondents without symptoms.8 These homes were
subgrouped to assess the health of the index child in each home and to examine the features of the
buildings' construction. The health of children whose homes had high objective measures of mold
was compared to a group of children whose homes had low objective measures of mold and mold
products associated with a 3- to 4-fold change in visible mold, a 10-fold change in the proportion of
Aspergillus and Penicillium, and an approximate 100-fold change in viable colony-forming units per
gram of dust. The presence of other contaminants (dust mite and animal antigens, volatile organic
compounds in the air, combustion spillage, etc.) was similar between the two groups. The children's
peak flows were measured and their respiratory symptoms monitored, nasal lavage was performed,
and blood samples were taken.9
Living in more (as compared to less) contaminated homes was associated with: (1) a larger number
of CD3+ T-cells expressing CD45RO, (2) a larger number of CD20+ B-cells expressing CD5+, and
(3) a reduced CD4/CD8 ratio. The levels of statistical significance were p=0.02, 0.07, and 0.06,
respectively, after controlling for the children's= ages, dust mite antigens, and the presence of furry
or feathered pets or a humidifier.10
The engineering analysis investigated whether occupants' reports of moisture were largely accurate,
which they were. Primary sources of moisture were basements, infiltration around windows, and
condensation caused by inadequate ventilation.9
Endotoxin was present in high concentrations in indoor dust.7 Clinical studies11 have shown that the
concurrent presence of endotoxin and dust mites in homes results in an increased response to the
presence of dust mite allergens in asthmatics (more severe asthma). Endotoxin affects respiratory
function in a number of ways.12
In the past year, studies in Italy, England, and North America have shown that high concentrations
of endotoxin-producing bacteria and fungi in outdoor air provide a source for the endotoxin found in
homes.13,14 (Beckker and Miller, unpublished data). The importance of endotoxin in building
environments has been seen in large buildings. Mendell15 and Raw et al.16 report that a number of
published studies have indicated an association between the degree of cleanliness in large buildings
and sick building syndrome (SBS). Hedge et al.17 have reported that total particulate burdens are a
strong predictor of SBS symptoms. In mechanically ventilated office buildings, particulate burdens
comprise ash, mineral fibres, endotoxin, and fungi. A number of recent studies have shown that the
concentrations of endotoxin and fungi in office and residential dusts are very high.7,18,19 In these
studies, the concentrations of endotoxin and/or fungi in dust are the best predictors of SBS.

EXPOSURES TO FUNGAL TOXINS

New research suggests that relatively low exposures to the spores of indoor molds have nonallergic
consequences due to beta 1,3 glucan (a component of fungal cell walls) and other toxins, reflecting
the epidemiological data.20 Pulmonary alveolar macrophage function and the immune system
response to beta 1,3 glucans are only partially understood. It appears that exposure causes
inflammatory reactions in lymphocytes, decreases lymphocyte mitogenicity and interleukin-I (IL-1)
secretion (via T-cells), and stimulates bacterial and tumor defences. Fungal glucan decreases
phagocytosis and decreases pulmonary alveolar macrophage numbers.21,22 Fogelmark et al.23 report
that in guinea pigs, inhalation exposure to beta 1,3 glucan resulted in a decrease in macrophages and
lymphocytes. A prolonged decrease of inflammatory cells, particularly lymphocytes, was seen -- the
opposite response to that caused by LPS endotoxin.
Human volunteers were exposed to beta 1,3 glucan (curdulan), endotoxin, and saline in an
environmental chamber. The subjects experienced throat and nose irritations and headache. Curdulan
alone caused headaches (Rylander 1993) A field study was performed and tiredness , nose and throat
irritation and cough could be related to airborne beta 1,3 glucan concentrations (Rylander et al.
1993). These Aneurological@ responses were ascribed to the effects of disregulating pulmonary
alveolar macrophage cells. Various neurotransmitters can be released by such cells.
The spores of many species of toxigenic molds have been demonstrated to contain mixtures of the
toxins associated with the species in concentrations from 1 to 650 microg/g. These include:
Fusarium graminearum (deoxynivalenol), F. sporotrichioides (T-2), F. moniliforme (fumonisin),
Stachybotrys atra (= S. chartarum, satratoxins), Penicillium expansum (citrinin), P. chrysogenum
(roquefortine C), P. brevicompactum (mycophenolic acid), Aspergillus versicolor (sterigmatocystin),
A flavus/parasiticus (aflatoxins), and A. fumigatus (fumitremorgen B, verruclogen.7 These toxins
have been shown to affect macrophage function in vitro and in vivo.26,27
Sorenson and Lewis28 reported variability in the effects of fungal spores on rat pulmonary alveolar
macrophage cells; this variability probably was mediated by spore-borne toxins. Sorenson et al.29
reported that exposure to spores of five species of Aspergillus, Penicillium spinulosum ,and
Cladosporium cladosporioides resulted in the release of leukotriene B4, increased superoxide anion
production, and activation of complement. Several species of Aspergillus inhibited LPS-stimulated
IL-1 production, whereas the other species had no effect. Jakab et al.26 demonstrated that inhalation
exposure of aflatoxin in rats and mice led to persistent reductions in phagocytosis, among other
effects. Damage to clearance mechanisms affects processing of antigens and leads to accumulation
of material in granulomatous matter leading to an immunotoxic effect.30-32
In occupational settings, spore-borne mycotoxins have proven to cause disease. The mycotoxin
aflatoxin is an International Agency for Research on Cancer class I human carcinogen.33
Concentrations of aflatoxin B1 in airborne dusts from the handling of contaminated corn and peanuts
have been reported up to 612 ng/g. Retrospective studies of Danish feed-processing workers
reported elevated risks of liver and biliary tract cancers with a two- to three-fold risk after a ten-year
latency period. Inhalation exposure to aflatoxin was the most likely explanation (170 microg/d).
Serum-aflatoxin B1 adduct concentrations were later shown to correlate with the handling of
aflatoxin-contaminated feeds.34,35 A substantial fraction of the aflatoxin in grain dusts is contained in
the spores of A. flavus/parasiticus. In rats, inhalation exposure to alfatoxin has also been
demonstrated to result in systemic exposure.36
Agricultural occupational exposures to the spores of Stachybotrys atra from handling contaminated
hay have been reported for at least 50 years.37 Studies of the agricultural and occupational inhalation
exposure to the spores of S. atra done in Russia and France concluded that these exposures induced
mycotoxicosis.38,39 A wide variety of reported symptoms, including respiratory-tract bleeding, are
associated with such exposures. These symptoms are consistent with the demonstrated presence of
trichothecene mycotoxins in the conidia of S. atra.40
Stachybotrys atra is now considered the cause of a pulmonary hemosiderosis in infants, which in
some cases is fatal.41,42 This species produces the most potent members of a large family of
mycotoxins called trichothecenes. In addition to the trichothecenes, S. atra produces
phenylspirodrimanes and a cyclosporin.43,44 The toxicity of S. atra spores is likely due to a
combination of the trichothecenes and immunosuppressive compounds.43 A great deal is known
about the effects of trichothecenes in humans and animals. At high doses, exposure cause emesis,
life-threatening hypotension, and myocardial hemorrhage. Lower exposures cause immune system
damage, affect the appetite center of the brain, and alter neurotransmitters.45-48 Creasia and
Lambert49 have studied the effects of inhalation exposure of another trichothecene, T-2 toxin, in
several animal models. In general, the effects of T-2 toxin exposure by inhalation were much greater
(>10x) than intravenous dosing. The trichothecene diacetoxyscirpenol was administered to cancer
patients in an experimental chemotherapy trial; thus there are clinical data on the effects of these
compounds.45
Concern about S. atra in indoor environments surfaced in the mid-1980s. Documented case reports
in Canada and the United States in both residential and nonindustrial workplace environments
suggested that chronic indoor exposures resulted in a variety of nonrespiratory symptoms.50,51
Following reports of symptoms among workers in a New York City building who were handling
cardboard boxes that were highly contaminated with S. atra, a study of these affected individuals
was initiated by the occupational health department of Mt. Sinai Hospital in that city. These workers
described a variety of debilitating respiratory and nonrespiratory symptoms. In addition, data were
collected suggesting prolonged, exposure-dependent effects on their immune function.38,52
In the cases of infant mortality ascribed to exposure to S. atra, these infants came from houses
located in a flood plain that were subjected to flooding conditions resulting in a high prevalence of
moisture damage (up to 80%). In a case-control study, all other plausible contaminants were
examined and ruled out.53 Exposure to the fungus in the case homes was very high.54 Pulmonary
hemosiderosis was detected in approximately 24 infants leading to 9 deaths. Pulmonary
hemosiderosis is apparently caused by the inhalation of spores, mycelial fragments, and/or dusts
from the substrate likely containing S. atra toxins.
Infant lung tissues grow at a rapid rate, making them sensitive to one of the important effects of
such toxins -- inhibition of protein synthesis.55 This is the basis for the following working hypothesis
on the pathophysiology of the disease. Normal development of the blood vessels of the lungs is
impaired, making them fragile. Exposure to agents such as cigarette smoke and other irritants causes
bronchial spasm and altered blood flow in the lungs with local areas of increased capillary pressure
resulting in stress hemorrhage of the fragile capillaries. The clinical presentation of the disease is
often subtle but overt symptoms include failure to thrive, coughing up blood, nose bleeds, and
central nervous system symptoms (irritation, fatigue, etc.). A very high proportion of hemosiderin-
laden macrophages is found in the air space of the lung. Some infants have hemoglobin in their
urine, indicating hemolysis of red cells, and the blood smears from most of these patients show signs
of hemolysis.42

FUNGAL ALLERGY
All mold spores are probably allergenic.56 Allergenic differences probably exist among different
species of fungi within the same genus. Strain-to-strain and batch-to-batch variations certainly occur
in the processing of allergenic extracts. While many fungal allergens appear to be glycoproteins, the
carbohydrate component of the glycoprotein and its role in allergenic activity need further
investigation. The allergenic extracts used in the clinical diagnosis of fungal sensitivity are
characterized by their variability and are often unpredictable in their biological activity.57 Aas et al.58
compared commercial Alternaria, Cladosporium, Mucor, and Penicillium extracts by skin-prick
testing and found considerable differences of potency among the extracts. An unpublished study
done at Queens University (Kingston, Ontario) of 175 patients in Montreal and Kingston concurred
with the above finding of Aas et al. Day et al.59 report that in several cases where extracts of the
same species were purchased from different companies, there were different skin-test responses.
Phylloplane molds and xerophilic, toxigenic molds such as Aspergillus versicolor and various
Penicillium species were the common fungi in the 400 Wallaceburg homes. In the above-noted study
of skin testing done in Montreal and Kingston, there was a widespread response to Penicillium,59
echoing the responses of studies conducted elsewhere.60 A remarkable finding was that the extreme
xerophile Wallemia sebi was common in some Wallaceburg homes (Table II). This fungus had been
considered only as a contaminant of salt fish. Japanese researchers61 have reported this species from
Japanese homes. They found that a large percentage (5% by skin-prick, 18% by RAST) of Japanese
are allergic to this mold from building exposures. The lists of common molds from the 400
Wallaceburg homes as well as from a previous study of 52 homes mainly in Ontario and Quebec62 do
not correspond to the extracts of fungal species available from major companies for allergy testing.
Most of what is known about allergy to molds comes from studies of a few species. In outdoor air
worldwide, the dominant fungi are the phylloplane species (fungi that grow on the surfaces of
leaves) and mushroom spores. In Canada the phylloplane species are Alternaria alternata,
Cladosporium cladosporioides, C. sphaerospermum, Eppicoccum nigrum, and Aureobasidium
pullulans. This is reflected in the species found in the Wallaceburg study (Table II).
The major allergenic fraction of Alternaria alternata is heterogeneous and can induce allergenic
reactions at low concentrations in sensitized individuals.63 Several studies have shown the
complexity and variability in allergens among different Alternaria strains.64,65 Investigators have
characterized 32 antigens and 19 different allergens.65-67 A deliberate inhalation challenge of
Alternaria produced an attack in a person with a history of asthmatic response to damp
environments.68,69 Licorisch et al. (1987) produced immediate asthmatic responses after inhalation
challenge of Alternaria and its extracts. O=Hollaren et al.70 found that exposure to airborne spores of
A. alternata has been implicated in severe asthma attacks. They examined 11 patients with asthma
who had suffered sudden respiratory arrest.. Ten of the 11 patients (91%) who had respiratory arrest
had positive skin-puncture tests to A. alternata compared to only 31% of controls. After adjustment
for age, A. alternata skin-test reactivity was found to be associated with a 200-fold increase in the
risk of respiratory arrest. They concluded that exposure to A. alternata is a risk factor for respiratory
arrest in both children and young adults with asthma.
Although Cladosporium herbarum is less common in outdoor air than C. cladosporioides and C.
sphaerospermum, it has been studied extensively. Approximately 60 antigens have been reported
from extracts.71 Aukrust and Borch72 isolated two allergens, Cla h I known as Antigen 32 and Cla h
II known as Antigen 54, from Cladosporium herbarum. Both allergens have been found to vary
widely from strain to strain. Variability in composition is demonstrated by the finding of a 0% to
100% range in allergen content among 10 isolates of Cladosporium. Wallenbeck et al.73 were able
to isolate two clinically important allergens of A. fumigatus, Ag-10 and Ag-40. Longbottom74
similarly uncovered the major allergen Ag-3. A. fumigatus is uncommon in indoor environments.
Aspergillus species common in Canadian homes include A. versicolor, A. niger, and Eurotrium
herbariorum ( Eurotrium is the sexual state of Aspergillus).

IMMUNOTHERAPY
In order to proceed with skin testing and possibly immunotherapy, it is necessary to determine which
species of fungi an individual may be reacting to. Unfortunately, this crucial information is often
inaccurate as can be seen from the data from the Wallaceburg study. Exposure information is
therefore incomplete, making it difficult to be certain that the samples used in preparing extracts will
be sufficiently representative to be effective.
The variability and stability of routinely used extracts are also concerns. Differences in
preparation can produce widely differing arrays of allergens. As fungi also contain enzymes,
allergens may be degraded during extraction or preparation, detracting from the stability and potency
of a particular extract. Because of these inadequacies, Browning75 found that most mold extracts are
of little clinical value. Efforts have been made to introduce tighter controls on extract preparation,
but differences in allergenic potency and composition continue to exist.58 It is possible, therefore,
that past studies which have failed to demonstrate clinical efficacy of mold immunotherapy may
have been fundamentally flawed because of nonstandardized extracts. Further, it is known that
allergen materials must be dialyzed or defatted to remove toxic metabolites (mycotoxins) produced
by some fungi. As discussed above, many indoor molds are toxigenic.
The best characterized fungi for immunotherapy are Alternaria and Cladosporium, and the
therapeutic benefits of immunotherapy with these fungi have been demonstrated. Placebo-controlled,
double-blind immunotherapy trials using standardized Alternaria preparations have produced
improvement in allergic rhinitis. Immunotherapy trials using standardized preparations of C.
herbarum have demonstrated beneficial effects in both adults and children with allergic rhinitis and
asthma. No clinical trials using Aspergillus or Penicillium immunotherapy have been reported.
Although used for rhinitis, immunotherapy is rarely used in mold-induced asthma. Nevertheless,
there is, as with other specific antigens, a theoretical basis for it through reducing bronchial
sensitivity in asthmatic patients and increasing tolerance to antigen exposure.76 In a study involving
immunotherapy in 22 adults suffering from Cladosporium asthma, Malling et al.77 reported clinical
efficacy in 81% of treated patients versus 27% in the placebo group. Horst et al.78 also reported that
subjects allergic to Alternaria who received immunotherapy had greater relief of symptoms than
those in the placebo group.

CONCLUSION
Despite the important consequences of exposures to biological contaminants indoors, little is known
about the disease-causing biochemicals. This is particularly true for molds. North American studies
have suggested that between 10% and 35% of homes have serious mold contamination. The range of
fungi that are common in mold-contaminated houses represents a very different flora than
traditionally assumed. While there is information on the allergens of outdoor species of molds such
as Alternaria and Cladosporium, these do not grow to any extent indoors. The spores of indoor
species contain allergens as well as toxic metabolites. As noted, endotoxin occurs in high
concentrations in residential environments and this may also be true for other bacterial compounds
including peptidoglycan. Endotoxin causes respiratory symptoms and apparently synergizes patients'
responses to allergens, among other effects. Exposure to beta 1,3 glucan and exposure to
peptidoglycan may have similar consequences. For North American physicians treating patients with
allergy, asthma, and some other respiratory diseases, a major hindrance is the lack of knowledge of
fungal allergens and fungal and bacterial toxins.
Avoidance and environmental control are basic to the management of respiratory disease, no matter
what the cause. Because of the ubiquitous nature of fungi, this is not always possible. Mold-sensitive
patients should make efforts to avoid dense foliage in wooded areas in spring and fall. Lawn care
should be limited (raking leaves, etc.) unless a spore-filtering mask is used. Inside the home, efforts
should be made to control moisture by using ventilation and dehumidifiers, and managing water
spills, floods, and leaks. Carpets in homes and sometimes in the nonindustrial workplace are a sink
for molds.79 The Clean Air Guide80 produced by the Canada Mortgage and Housing Corporation
provides more details on appropriate strategies to eliminate mold growth in houses. Similar
information is available for the nonindustrial workplace from Health Canada.

Acknowledgments: The Wallaceburg studies were supported by Canada Mortgage and Housing
Corporation, Natural Resources Canada, and Health Canada administered by Dr. Robert Dales, Mr.
Jim White and Dr. J. David Miller. The mycological data reported in Table II were done in the
laboratory of Dr. David Malloch.

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Table I Odds ratios between dampness-mold and health indicators*

30-community Canadian study 6-U.S cities study

Current asthma 1.45 (1.23-1.71) 1.42 (1.04-1.94) Bronchitis 1.32 (1.18-1.48) 1.32 (1.05-1.6
Chest illness 1.52 (1.37-1.70) 1.52 (1.20-1.93)
Wheeze 1.58 (1.42-1.76) 1.23 (1.10-1.39)
Cough 1.89 (1.63-2.20) 2.16 (1.64-2.84)

*Adapted from Brunekreef et al.1 and Dales et al.3

Table II The most common of the 270 species in the Wallaceburg homes in ascending order

By frequency By propagule count/g dust

Penicillium brevicompactum
Penicillium viridicatum
Penicillium expansum
Cladosporium herbarum
Aspergillus niger
Trichoderma viride
Penicillium commune
Penicillium corylophilum
Penicillium spinulosum
Cladosporium herbarum
Penicillium corylophilum
Aspergillus niger
Penicillium expansum
Trichoderma viride
Aspergillus species
Penicillium spinulosum
Phoma species
Alternaria alternata
 Cladosporium cladosporioides
Eppicoccum nigrum
Eurotium herbariorum
Aspergillus versicolor
Penicillium chrysogenum
Alternaria alternata
mushroom spores
Aureobasidium pullulans
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Cladosporium cladosporioides
Aspergillus versicolor
Cladosporium sphaerospermum
Phoma herbarum
Penicillium chrysogenum
Wallemia sebi
mushroom spores
Aurebasidium pullulans