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Indoor fungal diversity and asthma: A meta-analysis and systematic review of risk factors

Published:August 23, 2014DOI:https://doi.org/10.1016/j.jaci.2014.07.002

      Background

      Indoor dampness increases the risk of indoor fungal growth. A complex interaction between occupant behaviors and the built environment are thought to affect indoor fungal concentrations and species diversity, which are believed to increase the risk of having asthma, exacerbation of asthma symptoms, or both. To date, no systematic review has investigated this relationship.

      Objective

      This review aims to assess the relationship between exposure to indoor fungi identified to the genera or species level on asthma outcomes in children and adults.

      Methods

      Ten databases were systematically searched on April 18, 2013, and limited to articles published since 1990. Reference lists were independently screened by 2 reviewers, and authors were contacted to identify relevant articles. Data were extracted from included studies meeting our eligibility criteria by 2 reviewers and quality assessed by using the Newcastle-Ottawa scale designed for assessment of case-control and cohort studies.

      Results

      Cladosporium, Alternaria, Aspergillus, and Penicillium species were found to be present in higher concentrations in homes of asthmatic participants. Exposure to Penicillium, Aspergillus, and Cladosporium species were found to be associated with increased risk of reporting asthma symptoms by a limited number of studies. The presence of Cladosporium, Alternaria, Aspergillus, and Penicillium species increased the exacerbation of current asthma symptoms by 36% to 48% compared with those exposed to lower concentrations of these fungi, as shown by using random-effect estimates. Studies were of medium quality and showed medium-high heterogeneity, but evidence concerning the specific role of fungal species was limited.

      Conclusion

      Longitudinal studies assessing increased exposure to indoor fungi before the development of asthma symptoms suggests that Penicillium, Aspergillus, and Cladosporium species pose a respiratory health risk in susceptible populations. Increased exacerbation of current asthma symptoms in children and adults were associated with increased levels of Penicillium, Aspergillus, Cladosporium, and Alternaria species, although further work should consider the role of fungal diversity and increased exposure to other fungal species.

      Key words

      Abbreviations used:

      CFU (Colony-forming unit), ERMI (Environmental Relative Moldiness Index), IAQ (Indoor air quality), MSqPCR (Mold-specific quantitative PCR), NOS (Newcastle-Ottawa Scale), OR (Odds ratio), RR (Relative risk)
      Genetic factors alone cannot explain the high asthma prevalence rates in childhood
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      This has led to a research focus on poor indoor air quality (IAQ) in the home environment. IAQ can be compounded by efforts to reduce the carbon footprint of domestic domociles
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      Environmental Protection Agency. Public health consequences and cost of climate change impacts on indoor environments. Washington: Available at: http://www.epa.gov/iaq/pdfs/mudarri.pdf. Accessed January 26, 2014.

      and the adoption of increased household energy efficiency measures to reduce the domestic carbon footprint, protect against temperature-related morbidity and mortality, and alleviate fuel poverty.
      • Wilkinson P.
      • Smith K.R.
      • Beevers S.
      • Tonne C.
      • Oreszczyn T.
      Energy, energy efficiency, and the built environment.
      Efforts to prevent heat loss by reducing ventilation lead to undesired consequences for IAQ,
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      • Van Den Bosschea N.
      • Heijmansb N.
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      increasing indoor dampness and the risk of fungal contamination,
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      Dampness and moulds in relation to respiratory and allergic symptoms in children: results from Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC Phase Two).
      Dampness and fungal contamination has been consistently shown to increase the risk of asthma
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      and asthma exacerbation.
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      Meta-analyses of the associations of respiratory health effects with dampness and mold in homes.
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      Fisk et al,
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      • Mirer A.G.
      • Cheung K.
      • Tong M.
      • Douwes J.
      Respiratory and allergic health effects of dampness, mold, and dampness-related agents: a review of the epidemiologic evidence.
      and Quansah et al
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      • Hugg T.T.
      • Heikkinen S.A.M.
      • Jaakkola J.J.K.
      Residential dampness and molds and the risk of developing asthma: a systematic review and meta-analysis.
      review the role of fungal contamination, as defined by the presence of visible fungi, a moldy musty odor, or both. We contribute to existing knowledge by investigating the role of individual fungal genera/species (as opposed to the presence of any fungi) on asthma outcomes, which has yet to be explored.
      Human behaviors, socioeconomic factors, and the built environment have been shown to increase the fungal load found in house dust.
      • Reponen T.
      • Levin L.
      • Zheng S.
      • Vesper S.
      • Ryan P.
      • Grinshpun S.A.
      • et al.
      Family and home characteristics correlate with mold in homes.
      Old terraced houses (≥90 years old) are at increased risk of higher concentrations of Penicillium and Aspergillus species propagules, exceeding outdoor spores per cubic meter of air per day in homes with no suspected damp or fungal contamination.
      • Fairs A.
      • Wardlaw A.J.
      • Thompson Jr.,
      • Pashley C.H.
      Guidelines on ambient intramural airborne fungal spores.
      These fungi are also more frequently cultured from damp indoor home environments
      • Gravesen S.
      • Nielsen P.A.
      • Iversen R.
      • Nielsen K.F.
      Microfungal contamination of damp buildings—examples of risk constructions and risk materials.
      and are of interest because they have been shown to increase the risk of asthma development in children.
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      Changes in composition of indoor air spores are complicated by the interaction with outdoor ambient levels. The indoor fungal profile is regulated by the dispersal of outdoor sources of fungi,
      • Adams R.I.
      • Miletto M.
      • Taylor J.W.
      • Bruns T.D.
      Dispersal in microbes: fungi in indoor air are dominated by outdoor air and show dispersal limitation at short distances.
      such as Cladosporium and Alternaria species.
      • Simon-Nobbe B.
      • Denk U.
      • Pöll V.
      • Rid R.
      • Breitenbach M.
      The spectrum of fungal allergy.
      The indoor fungal profile varies by geographic location,
      • Vesper S.
      • Wakefield J.
      • Ashley P.
      • Cox D.
      • Dewalt G.
      • Friedman W.
      Geographic distribution of Environmental Relative Moldiness Index molds in USA homes.
      season,
      • Ja Cho S.
      • Ramachandran G.
      • Banerjee S.
      • Ryan A.D.
      • Adgate J.L.
      Seasonal variability of culturable fungal genera in the house dust of inner-city residences.
      temperature, humidity, and air exchange rates,
      • Frankel M.
      • Bekö G.
      • Timm M.
      • Gustavsen S.
      • Hansen E.W.
      • Madsen A.M.
      Seasonal variations of indoor microbial exposures and their relation to temperature, relative humidity, and air exchange rate.
      which are modified by ventilation and occupant behaviors. Variations in concentrations and diversity of fungal propagules (hyphae and spores) regulate the risk of asthma.
      • Asher M.I.
      • Keil U.
      • Anderson H.R.
      • Beasley R.
      • Crane J.
      • Martinez F.
      • et al.
      International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.
      In a public health context we were interested in the development of new asthma-like symptoms over time and the exacerbation of symptoms. For the purpose of this review, we define asthma development as the initiation and progression of the disease to a point at which the reversible airflow obstruction and bronchospasm become common. We use the risk of asthma to describe either the development of new asthma-like symptoms, having “asthma,” or the exacerbation of current asthma symptoms, and it is defined either by wheezing episodes (eg, International Study of Asthma and Allergies in Childhood
      • Asher M.I.
      • Keil U.
      • Anderson H.R.
      • Beasley R.
      • Crane J.
      • Martinez F.
      • et al.
      International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.
      ), a doctor's diagnosis, or medical examination using protocols, such as the European Respiratory Society and American Thoracic Society.
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      • Wenzel S.E.
      • Brozek J.L.
      • Bush A.
      • Castro M.
      • Sterk P.J.
      • et al.
      International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.
      The adoption of molecular techniques is advancing our ability to identify and quantify indoor exposures. To our knowledge, there has been no systematic review exploring the role of fungal diversity identified to the genus or species level and risk of asthma in children and adult populations. This is complicated by the ubiquity of fungi and the fact more than 80 fungal genera have been shown to induce IgE-mediated type I hypersensitivity in susceptible populations. These fungi primarily belong to 3 phyla: Ascomycota (including species of Aspergillus, Penicillium, Alternaria, and Cladosporium species), Basidiomycota, and Zygomycota.
      • Simon-Nobbe B.
      • Denk U.
      • Pöll V.
      • Rid R.
      • Breitenbach M.
      The spectrum of fungal allergy.
      Fungal components have been cultured from sputum samples taken from asthmatic and nonasthmatic subjects and are associated with an impaired postbronchodilator FEV1.
      • Agbetile J.
      • Fairs A.
      • Desai D.
      • Hargadon B.
      • Bourne M.
      • Mutalithas K.
      • et al.
      Isolation of filamentous fungi from sputum in asthma is associated with reduced post-bronchodilator FEV1.
      There are several mechanisms that operate together in the pathogenesis of hypersensitivity reactions to fungi. Fungi are potent sources of allergenic molecules, including enzymes, toxins, cell-wall components, and highly conserved cross-reactive proteins.
      • Crameri R.
      • Garbani M.
      • Rhyner C.
      • Huitema C.
      Fungi: the neglected allergenic sources.
      Also, the inhalation of serine proteases of Alternaria species can also cause inflammation through stimulation of protease-activated receptor 2 of airway epithelium, which might be implicated in the development and exacerbation of airway allergic diseases.
      • Matsuwaki Y.
      • Wada K.
      • White T.
      • Moriyama H.
      • Kita H.
      Alternaria fungus induces the production of GM-CSF, interleukin-6 and interleukin-8 and calcium signaling in human airway epithelium through protease-activated receptor 2.
      Systematically reviewing studies concerning the diversity and concentrations of indoor fungi and the risk of having asthma, exacerbation of symptoms, or both provide an opportunity to assess associations and improve future health intervention work.
      This review aims to assess the role of indoor fungal diversity being identified and quantified to the genus or species level on asthma symptoms in infants, children, and adults.

      Methods

       Search strategy

      Electronic searches were conducted on April 18, 2013, and limited to studies published after 1990 in accordance with our protocol (PROSPERO reference: CRD42013004333). In addition to electronic searches, author contacts and references of included studies were conducted in August 2013. The full search strategy was used on all 10 databases (listed in Appendix E1 in this article's Online Repository at www.jacionline.org) to identify eligible articles. The screening process was managed in Endnote version X5.0 (Thomas Reuters, New York, NY)

      Thomson-Reuters. Endnote. US, 2012.

      and recorded by using the PRISMA guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      Articles were independently screened by 2 team members (R.A.S. and N.B.), and where there was disagreement, a third reviewer (N.J.O.) was consulted and any discrepancies were resolved through discussion.

       Eligibility criteria and study selection

      Included articles were those reporting associations between the home environment, indoor fungal genera/species, and risk of asthma (Fig 1). Forward and backward citation chasing was performed on all included studies, and authors were contacted for additional relevant articles.
      Figure thumbnail gr1
      Fig 1Diagram of the systematic search and included studies.
      The populations investigated encompassed all ages (infants, children [aged <18 y], and adults) and both sexes. Studies deemed eligible for the analysis comprised:
      • 1.
        original peer-reviewed articles publishing original data;
      • 2.
        cohort, case-control, and nonrandomized and randomized controlled trials (including cluster-randomized and crossover trials);
      • 3.
        studies published in 1990 or later;
      • 4.
        investigations of the indoor home environment;
      • 5.
        assessments of indoor fungi identified to the genus or species level;
      • 6.
        studies with outcomes of asthma ever and/or asthma symptoms in the last 12 months, including wheeze, whistling in the chest, or a dry cough; doctor's diagnosis or skin prick test, peak flow, or spirometric results; and asthma development requiring newly diagnosed new cases of asthma by a physician or doctor; and
      • 7.
        those that provided a measure of risk for asthma, including the relative risk (RR) or odds ratio (OR) and CI.

       Data extraction

      Relevant participant and study characteristics were recorded with a standardized data extraction template (see Appendix E2 in this article's Online Repository at www.jacionline.org), which was subsequently used to populate data synthesis tables.

       Quality assessment

      Two team members (R.A.S. and N.B.) assessed the quality of each study by using the Newcastle-Ottawa Scale (NOS)

      The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed April 11, 2013.

      modified to reflect fungal exposure (see the case-control form, Exposure point 1, Appendix E3 in this article's Online Repository at www.jacionline.org). Included studies were independently scored out of 10 and 13 for case-control and cohort studies, respectively, in accordance to the NOS standard procedure. Both team members (R.A.S. and N.B.) independently scored included articles and a final score was obtained by consensus. Journal article authors were contacted if data were missing.

      Results

       Synthesis

      We provide an overarching narrative synthesis of included studies and a meta-analysis of studies of similar design and those reporting ORs and CIs. We included 7 studies in a meta-analysis of Salo et al,
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      Araki et al,
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      Dales et al,
      • Dales R.E.
      • Miller D.
      • White J.
      Testing the association between residential fungus and health using ergosterol measures and cough recordings.
      Jones et al,
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      Li and Hsu,
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      Rosenbaum et al,
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      and Dharmage et al
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      because these met our inclusion criteria for conducting a meta-analysis; the other 10 studies were too heterogeneous to be included. We had planned to prioritize studies rated more highly on the NOS rating scale; however, the evidence located was all of a midrange quality, and therefore we did not weight studies in the analysis.
      Studies were grouped in our narrative synthesis according to those reporting risk of increased fungal concentrations in homes of asthmatic patients (analysis of indoor fungi in homes being occupied with ≥1 asthmatic patients). We then assessed fungal genera, total fungi, and risk of asthma in our meta-analyses. Meta-analyses were undertaken to explore the relationship between exposure to individual groups of fungi and current asthma by using the generic inverse variance method

      Cochrane Handbook. Chapter 9: analysing data and undertaking meta-analyses. Available at: http://hiv.cochrane.org/sites/hiv.cochrane.org/files/uploads/Ch09_Analysing.pdf. Accessed October 18, 2013.

      to conduct random-effects meta-analysis
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      in RevMan 5 (version 5.2.6; Cochrane Collaboration, Copenhagen, Denmark). Logistic regression was used to calculate ORs and CIs for adjusted and unadjusted data because of the inconsistency of reporting unadjusted data. We were unable to stratify by age, study design, or outcome because of the limited number of studies and inconsistent reporting.
      Heterogeneity was assessed by using the I2 statistic, where an I2 value of 0% to 40% was considered low heterogeneity and an I2 value of 75% or greater represented considerable heterogeneity.

      Cochrane Handbook. Chapter 9: analysing data and undertaking meta-analyses. Available at: http://hiv.cochrane.org/sites/hiv.cochrane.org/files/uploads/Ch09_Analysing.pdf. Accessed October 18, 2013.

      No further analyses were conducted because of sample size limitations.

       Participant characteristics of included studies

      The searches revealed 17 studies meeting our eligibility criteria. Included studies were from 8 countries and included case-control, nested case-control, cross-sectional, and longitudinal design methodologies (Table I).
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      • Dales R.E.
      • Miller D.
      • White J.
      Testing the association between residential fungus and health using ergosterol measures and cough recordings.
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      • Herrera A.B.
      • Rodríguez L.A.
      • Niederbacher J.
      [Biological pollution and its relationship with respiratory symptoms indicative of asthma, Bucaramanga, Colombia.].
      One author
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      provided additional analyses to be included in our results synthesis. Eight studies were based on populations living in the United States, and the remaining were from the United Kingdom, Sweden, Taiwan, Colombia, Australia, Canada, and China. Not all studies clearly reported whether they had investigated urban or rural environments. Based on the summary results (Table I), 9 studies assessed indoor fungal concentrations in homes located in predominantly urban areas, with only 1 study specifically investigating homes situated in an agricultural setting.
      Table ISummary of participant characteristics of included studies
      ReferenceCountryStudy populationUrban/rural, regionStudy designStudy sizeFollow-up yExposure measurementDefinition of asthmaFinal quality score
      Rosenbaum et al
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      United StatesInfants aged <1 yUrban; Syracuse, NYBirth cohort39 cases, 64 control subjects2Air sampling (CFU/m3)Diagnosis of wheeze during the first year of life was defined as (1) primary care provider documenting wheezing, reactive airway disease, asthma, or bronchiolitis; (2) wheeze heard on physical examination by the NP; or (3) prescription for bronchodilator, inhaled steroid, or steroid pulse prescription documented in medical records.7/13
      Matheson et al
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      AustraliaAdults aged 20-45 yUrban, MelbourneLongitudinal3602Air sampling (CFU/m3)Wheeze <12 mo, spirometry plus bronchial hyperreactivity to methacholine and clinical activity7/13
      Reponen et al
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      United StatesChildren aged 7 yCincinnati, Ohio, and northern KentuckyBirth cohort69 cases, 220 control subjects1 and 7House dust sampling (ERMI)Parental self-reports and then diagnosis of asthma based on asthma symptoms and objective measures of lung function and airway hyperresponsiveness; all children completed spirometric testing (Koko; nSpire Health, Longmont, Colo) according to ATS criteria.6/13
      Gent et al
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      United StatesInfants aged <1 yConnecticut/western MassachusettsCohort, longitudinal8193 in 1 yAir sampling (CFU/m3)Respiratory symptoms of wheeze and persistent cough defined by yearly symptom counts5/13
      Jones R et al
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      United StatesChildren aged 3-17 yBuffalo, NYNested case-control50 cases, 59 control subjectsNAAir sampling (CFU/m3)Self-reported questionnaire and clinical interview to assess medication use and asthma symptoms, including lung function and skin prick testing for allergens8/10
      Araki et al
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      JapanAll agesNot specified; study conducted across 6 regionsCase-control609NAAir sampling (CFU/m3)Self-reported questionnaire for receiving medical treatment for bronchial asthma7/10
      Holme et al
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      SwedenChildren aged 1-6 yMixed, VärmlandNested case-control198 cases, 202 control subjectsNAAir sampling (CFU/m3)Doctor-diagnosed asthma defined by medical examination6/10
      Vesper et al
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      United StatesChildren aged 9-12 yUrban, Detroit, MichCase-control28 cases, 83 control subjectsNAHouse dust by vacuum (CE/mg dust [ERMI])Parental self-reported use of asthma medication using the GINA classification system6/10
      Su et al
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      TaiwanChildren aged 10-12 yUrban, TaiwanCase-control23 cases, 12 control subjectsNAAir sampling (CFU/m3)Adult self-reported child receiving a diagnosis from a physician and re-examined by a pediatrician at the National Cheng Kung University Hospital before they were included into the year-long study6/10
      Strachan et al
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      United KingdomChildren aged 6-7 yScotlandCase-control34 cases, 54 control subjectsNAAir sampling (CFU/m3)Examination followed the ATS protocol: wheeze in <12 mo and bronchial lability >10%. Wheeze and bronchial lability were defined as the difference between the postexercise and pre-exercise FEV divided by the pre-exercise FEV.5/10
      Li and Hsu
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      ChinaChildren aged 7-15 yUrban, TaiwanCase-control46 cases, 26 control subjectsNAAir sampling (CFU/m3)Asthma status defined by ATS criteria5/10
      Vesper et al
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      United StatesChildren; mean age, 6.8 yCleveland, OhioCase-control60 cases, 22 control subjectsNAAir and dust sampling (mg/g [ERMI])Homes with an asthmatic child4/10
      Meng et al
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      United StatesChildren aged 2-18 yRural, agricultural area in the MidwestCase-control88 cases, 85 control subjectsNAAir sampling (CFU/m3)Persistent asthma defined by National Heart, Lung, and Blood Institute4/10
      Salo et al
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      United StatesAll agesMetropolitan areas, nationwideCross-sectional2456NADust sampling (mg/g)Doctor-diagnosed asthma and allergy defined at interview to obtain information on doctor-diagnosed asthma and allergies, asthma symptoms in the past year, and current asthma medication use7/10
      Dharmage et al
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      AustraliaAdults aged 20-44 yUrban, MelbourneCross-sectional485NAAir sampling (CFU/m3)Wheeze <12 mo, spirometry plus bronchial hyperreactivity to methacholine and clinical activity6/10
      Dales et al
      • Dales R.E.
      • Miller D.
      • White J.
      Testing the association between residential fungus and health using ergosterol measures and cough recordings.
      CanadaChildren aged 10 yOntarioCross-sectional400NASelf-reported and house dust samples collectedSelf-reported questionnaire of current and diagnosed asthma; cough or wheeze during the night and within the last 12 mo; asthma defined by a doctor confirming the child has asthma or regularly takes asthma medication5/10
      Herrera et al
      • Herrera A.B.
      • Rodríguez L.A.
      • Niederbacher J.
      [Biological pollution and its relationship with respiratory symptoms indicative of asthma, Bucaramanga, Colombia.].
      ColombiaChildren aged 7 yUrban, BucaramangaCross-sectional678NAAir sampling (CFU/m3)Self-reported via questionnaire, respiratory symptoms suggestive of asthma, which is measured by questionnaires from EISL and the ISAAC4/10
      ATS, American Thoracic Society; CE, cell equivalents; EISL, International Study of Wheezing in Infants; GINA, Global Initiative for Asthma; ISAAC, International Study of Asthma and Allergies in Childhood; NA, not applicable; NP, nurse practitioner.
      Thirteen included studies involved children (aged <18 years), 2 included adult populations, and the remaining 2 included all age groups. Demographic variables (ie, variations in the built environment and occupant behaviors) potentially modifying the risk of fungi, asthma, or both were not consistently reported. Reported asthma outcome measures also varied (Table I), and only 2 studies, those of Reponen et al
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      and Matheson et al,
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      examined the development of new asthma symptoms.

       Study design characteristics of included studies

      We included 4 cohort studies with follow-up periods of 1, 2, and 7 years. Thirteen studies were cross-sectional, which included 9 case-control studies. Funding, recruitment, and statistical analyses varied between studies (see Table E2 in this article's Online Repository at www.jacionline.org). The heterogeneity between study designs and the defined exposure and outcomes prevented the inclusion of all studies in our meta-analysis. The following presents results separately for both our narrative synthesis and meta-analysis.

       Results of studies included in our narrative synthesis

      We provide a narrative synthesis of 10 studies
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      • Herrera A.B.
      • Rodríguez L.A.
      • Niederbacher J.
      [Biological pollution and its relationship with respiratory symptoms indicative of asthma, Bucaramanga, Colombia.].
      that were not included in the meta-analysis because of heterogeneity between study designs, statistical analyses, and outcomes. The first part of the narrative synthesis includes 2 main elements because 7 studies
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      used 2 different sampling and analysis techniques to quantify fungal concentrations in homes of asthmatic patients (Table II, Table III).
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      These are defined by those reporting fungal species as cell equivalents per gram of house dust and fungal genera as colony-forming units (CFU) per cubic meter of air. This is followed by a review of the associated risk of asthma exacerbation assessed as rate or prevalence ratios (see Table E4, A, in this article's Online Repository at www.jacionline.org) and then ORs (Table IV
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      • Dales R.E.
      • Miller D.
      • White J.
      Testing the association between residential fungus and health using ergosterol measures and cough recordings.
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      and see Table E5 in this article's Online Repository at www.jacionline.org), which were subsequently included in the meta-analysis.
      Table IIResults synthesis: risk of fungi identified to the species level (CE) in homes of asthmatic patients
      StudyFungal analysisFungi measured as CE/g of house dust
      Aspergillus nigerPenicillium species group 2Cladosporium sphaerospermum
      Aspergillus ochraceusPenicillium spinulosumCladosporium cladosporioides 1
      Aspergillus unguisPenicillium variabileCladosporium cladosporioides 2
      CaseControl subjectP valueCaseControl subjectP valueCaseControl subjectP value
      Vesper et al
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      GM CE/gNRNRNR2,604.09654.48.084,714.398,172.98.03
      1,895.462,117.95.79710.903,600.06.01177,704.3544,160.00.00
      3,831.601,881.66.321,050.691,033.93.9216,155.3750,671.42.01
      Vesper et al
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      Median CE/mg6724.011611.49169.10
      4024.09
      Missing data.
      Missing data.
      Missing data.
      325370.59
      32.022714.39710.70
      Reponen et al
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      GM CE/g13.75.7<.05NS137.270.5NS
      6.82.0<.051.10.9NS2,099.31,349.2NS
      2.61.0<.0512.64.0<.0528.127.7NS
      Aureobasidium pullulansEpicoccum nigrumScopulariopsis brevicaulis
      Vesper et al
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      GM CE/g417,991.00727,917.30.02407,868.70920,578.1.001,179.00480.64.04
      Trichoderma virideAlternaria alternataWallemia sebi
      Vesper et al
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      GM CE/g1,602.96284.82.0116,452.4555,594.45018,954.018,442.97.05
      CE, Cell equivalents; GM, geometric mean; NR, not reported; NS, not significant.
      Missing data.
      Table IIIResults synthesis: risk of fungi identified to the genus level (CFU) in homes of asthmatic patients
      StudyFungal analysisAspergillus speciesPenicillium speciesCladosporium speciesAlternaria species
      CaseControl subjectP valueCaseControl subjectP valueCaseControl subjectP valueCaseControl subjectP value
      Strachan et al
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      GM CFU/m3NR3955−.781612.46NR
      Holme et al
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      Mean CFU/m3NR
      On DG-18113128.602104119.29892125.130
      On MEA22957.14795106.69970100.762
      Su et al
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      Total CFU/m3
      Spring306.7226.9NS839.6608.3NS4,972.93,906.10NS3,039.14,098.6NS
      Summer738.0427.0NS568.4260.7NS2,085.02,303.90NS47.44.5NS
      Fall303.1269.8NS454.0479.3NS6,469.516,726.10NS87.9178.8NS
      Winter451.2165.0NS496.8276.3<.0517,696.016,999.3NS251.0336.53NS
      Meng et al
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      Mean CFU/m33.623.33.244.123.72.095.184.43<.00013.993.60.07
      Acremonium speciesUlocladium speciesEpicoccum species
      3.320<.023.060<.0013.633.62.98
      The outcome of interest is risk of fungi in homes of asthmatic and nonasthmatic subjects.
      GM, Geometric mean; NR, not reported; NS, not significant.
      Table IVSummary table of studies reporting ORs and CIs
      StudyFungal analysisAspergillus speciesPenicillium speciesCladosporium speciesAlternaria species
      UnadjustedAdjustedUnadjustedAdjustedUnadjustedAdjustedUnadjustedAdjusted
      Salo et al
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      <3.90Not reportedNot reportedNot reported1.01.0
      3.90-6.271.60 (0.90-2.77)1.52 (0.90-2.55)
      2 fold increase in concentration≥6.28 μg/g1.84 (1.21-2.93)1.84 (1.18-2.85)
      All agesNot reported1.31 (1.05-1.64)
      Children <18 yNot reported1.47 (0.83-2.62)
      Adults >18 yNot reported1.25 (0.99-1.58)
      Araki et al
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      >GM CFU/m30.83 (0.53-1.29)0.73 (0.45-1.21)1.44 (0.89-2.33)1.43 (0.84-2.42)0.84 (0.59-1.20)0.87 (0.59-1.28)Not reported
      Dales et al
      • Dales R.E.
      • Miller D.
      • White J.
      Testing the association between residential fungus and health using ergosterol measures and cough recordings.
      Detectable limits CFU/g0.92 (0.35-2.44)Not reported0.46 (0.18-1.21)1.90 (0.55-6.59)
      Jones R et al
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      ≥85th percentileNot reported
      Viable countsCFU/m32.81 (1.00-7.90)6.1 (1.37-27.19)*0.49 (0.19-1.31)0.35 (0.11-1.17)1.37 (0.52-3.56)1.19 (0.39-3.60)
      Total countsSpores/m30.54 (0.10-2.92)†0.70 (0.27-1.82)‡0.94 (0.31-2.83)‡1.93 (0.73-5.14)2.37 (0.77-7.26)
      Li and Hsu
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      Summer1.55 (0.71-3.36)0.61 (0.21-1.81)1.88 (1.07-3.30)
      Winter0.69 (0.28-1.73)0.56 (0.17-1.84)4.14 (1.17-14.67)
      Rosenbaum et al
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      Not detected v high CFU/m33.00 (1.07-8.39)1.58 (0.43-5.79)7.88 (2.30-26.99)6.18 (1.34-28.46)2.74 (0.98-7.66)2.28 (0.41-12.67)1.18 (0.41-3.41)0.96 (0.27-3.45)
      Dharmage et al
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      Highest quartileNot reported3.9 (1.1-14.3)8.5 (1.6-44.3)Not reported
      Matheson et al
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      CFU/m3Not reportedNot reported0.96 (0.80-1.16)§Not reported
      1.11 (0.91-1.37)‖
      1.52 (1.08-2.13)¶
      The outcome of interest is risk of fungi in homes of asthmatic and nonasthmatic subjects.
      GM, Geometric mean.
      Individual analyses in studies: *without family history of asthma; †with family history of asthma; ‡model for Aspergillus and Penicillium combined (Jones et al
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      ); §effect of doubling allergen or fungal exposure on the risk of current asthma; ‖effect of doubling exposure to allergens or fungi on the remission of current asthma; and ¶effect of doubling allergen or fungal exposure on the risk of asthma attack in the last 12 months (Matheson et al
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      ).
      Adjusted models in each study:
      • Salo et al
        • Salo P.M.
        • Arbes Jr., S.J.
        • Sever M.
        • Jaramillo R.
        • Cohn R.D.
        • London S.J.
        • et al.
        Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
        adjusted for age, sex, race, education, smoking, and sampling season. Please note other adjusted models were provided, with all showing positive associations in the third quartile. Analysis for a 2-fold increase (children <18 years) has fewer observations because of missing values.
      • Araki et al
        • Araki A.
        • Kanazawa A.
        • Kawai T.
        • Eitaki Y.
        • Morimoto K.
        • Nakayama K.
        • et al.
        The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
        adjusted for sex, age, tobacco smoke exposure, renovation history, wall-to-wall carpeting, dampness index, and hay fever.
      • Dales et al
        • Dales R.E.
        • Miller D.
        • White J.
        Testing the association between residential fungus and health using ergosterol measures and cough recordings.
        adjusted for child's age, parental illness, passive smoking, and dust mites.
      • Jones et al
        • Jones R.
        • Recer G.M.
        • Hwang S.A.
        • Lin S.
        Association between indoor mold and asthma among children in Buffalo, New York.
        adjusted for age and 1 or more family members with asthma. There was a strong interaction between an increased level of Aspergillus species and 1 or more family members with asthma. Therefore separate models were generated for subjects with and without a family member with asthma.
      • Li and Hsu
        • Li C.S.
        • Hsu L.Y.
        Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
        adjusted for age, parental education, number of household smokers, and use of a gas stove for cooking.
      • Rosenbaum et al
        • Rosenbaum P.F.
        • Crawford J.A.
        • Anagnost S.E.
        • Wang C.J.K.
        • Hunt A.
        • Anbar R.D.
        • et al.
        Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
        adjusted for season of visit, maternal smoking during pregnancy, any smoker in the home, day care center or nonrelative care, and endotoxin.
      • Dharmage et al
        • Dharmage S.
        • Bailey M.
        • Raven J.
        • Mitakakis T.
        • Cheng A.
        • Guest D.
        • et al.
        Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
        adjusted for potential confounders: sociodemographic factors, current smoking, parental asthma/allergy, medication use, and season during which the participant was investigated.
      • Matheson et al
        • Matheson M.
        • Abramson M.J.
        • Dharmage S.C.
        • Forbes A.B.
        • Raven J.M.
        • Thien F.C.K.
        • et al.
        Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
        adjusted for season of sampling and smoking status. Analysis provided for asthma attack in the last 12 months, atopy, and doctor-diagnosed asthma.
      Three studies from the United States assessed the risk of increased fungal concentrations in the homes of asthmatic patients
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Neas L.
      • Hudgens E.
      • Heidenfelder B.
      • et al.
      Higher Environmental Relative Moldiness Index (ERMIsm) values measured in Detroit homes of severely asthmatic children.
      • Vesper S.J.
      • McKinstry C.
      • Yang C.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      by using house dust samples and mold-specific quantitative PCR (MSqPCR) to quantify fungal concentrations (Table II). This method has been developed to assess 36 fungi of the Environmental Relative Moldiness Index (ERMI) developed to quantify the indoor fungal load.
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Wymer L.
      • Bradham K.
      • Ashley P.
      • et al.
      Development of an Environmental Relative Moldiness Index for US Homes.
      These studies quantify 9 fungal genera at the species level that were found to be present in higher concentrations in homes of asthmatic patients, although these were not consistent, and concentrations varied considerably (see Table E3 in this article's Online Repository at www.jacionline.org). The other studies
      • Strachan D.P.
      • Flannigan B.
      • McCabe E.M.
      • McGarry F.
      Quantification of airborne moulds in the homes of children with and without wheeze.
      • Holme J.
      • Hagerhed-Engman L.
      • Mattsson J.
      • Sundell J.
      • Bornehag C.G.
      Culturable mold in indoor air and its association with moisture-related problems and asthma and allergy among Swedish children.
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      used air sampling and microscopy to quantify indoor fungus to the genus level as CFU per cubic meter of air (Table III), as opposed to MSqPCR. Studies using microscopy to define CFU per cubic meter of fungi present indoors showed that levels of Penicillium species (496.8 vs 276.3 total CFU/m3),
      • Su H.-J.
      • Wu P.-C.
      • Chen H.-L.
      • Lee F.-C.
      • Lin L.-L.
      Exposure assessment of indoor allergens, endotoxin, and airborne fungi for homes in southern Taiwan.
      Cladosporium species (5.18 vs 4.43 mean CFU/m3), Ulocladium and Acremonium species (3.32 vs 0 mean CFU/m3), and total fungi (5.92 vs 5.19 mean CFU/m3)
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      were higher in homes of asthmatic patients, although other studies did not report this relationship. Studies with molecular techniques to quantify indoor fungal concentrations reported higher concentrations of Aspergillus, Penicillium, Cladosporium, Ulocladium, Acremonium, Aureobasidium, Epicoccum, Scopulariopsis, Trichoderma, Alternaria, and Wallemia species in house dust. Not all studies found this relationship, and only higher concentrations of Aspergillus and Penicillium species were reported by 2 of the studies. The evidence reviewed here is weak and requires further investigation into variations in species diversity and the interaction between the indoor and outdoor environments.
      In an attempt to examine the role of fungi in asthma beyond exacerbation, 2 longitudinal studies have enabled the investigators to assess the effect of fungal diversity before the development of asthma symptoms. Birth cohorts at risk of atopy showed a 2-fold increased risk of higher rates of infant wheeze
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      and the onset of childhood asthma
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      associated with exposure to species of Penicillium and Aspergillus. Cladosporium species increased the risk of a new asthma attack in the last 12 months by 50% in adults.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      We were unable to include these studies
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      in a separate meta-analysis because of the limited number of studies (with varying study designs) assessing fungal concentrations and the risk of having asthma symptoms in longitudinal analyses. The longitudinal study designs also prevented them from being included in our meta-analysis of the cross-sectional and case-control studies assessing the risk of asthma exacerbation.
      Investigations into specific groups of fungi and associated risk of asthma exacerbation were not consistent and limited our syntheses, particularly with respect to variations in asthma outcome definitions (Table I). Three studies
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      • Herrera A.B.
      • Rodríguez L.A.
      • Niederbacher J.
      [Biological pollution and its relationship with respiratory symptoms indicative of asthma, Bucaramanga, Colombia.].
      assessed the potential risk of asthma by calculating prevalence or rate ratios and were omitted from our meta-analysis because of heterogeneity of study designs. In summary, Herrera et al
      • Herrera A.B.
      • Rodríguez L.A.
      • Niederbacher J.
      [Biological pollution and its relationship with respiratory symptoms indicative of asthma, Bucaramanga, Colombia.].
      reported an increased probability (>50%) of respiratory symptoms (indicative of bronchial asthma) being associated with Acremonium species (prevalence ratio, 6.2; 95% CI, 3.8-10.0). Gent et al
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      reported that the highest level of Penicillium species (≥1000 CFU/m3) was associated with higher rates of wheeze (adjusted RR, 2.2; 95% CI, 1.3-3.5) in the first year of life, although it is impossible to assess whether reported wheeze developed into asthma later in childhood. Finally, the summation of Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile were associated with the development of asthma in children aged 7 years (adjusted RR, 2.2; 95% CI, 1.8-2.7).
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.

       Results of studies included in the meta-analysis

      We identified 7 studies
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      • Araki A.
      • Kanazawa A.
      • Kawai T.
      • Eitaki Y.
      • Morimoto K.
      • Nakayama K.
      • et al.
      The relationship between exposure to microbial volatile organic compound and allergy prevalence in single-family homes.
      • Dales R.E.
      • Miller D.
      • White J.
      Testing the association between residential fungus and health using ergosterol measures and cough recordings.
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      that met our criteria for conducting a meta-analysis to assess fungal (identified to the genus level) exposure and risk of asthma exacerbation. Included studies were of case-control or cross-sectional study designs and consistently assessed increased exposure to concentrations of Aspergillus, Penicillium, Cladosporium, and Alternaria species and risk of asthma exacerbation. Included studies also assessed increased exposures to other fungi, such as Rhodotorula, Epicoccum, and Acrodontium species, as well as total fungi, ergosterol, and yeasts, although these were not consistently investigated by all studies. Reported health outcomes were defined as doctor-diagnosed asthma, self-reported use of asthma medication, wheeze plus bronchial hyperreactivity to methacholine, and medical examination according to the American Thoracic Society criteria (Table I). In some cases studies did not report unadjusted data (see Table E5), which prevented the inclusion of raw data into our meta-analysis. This meant that we used unadjusted data (when reported) and data from the adjusted models reported by each study. Included studies did not consistently adjust for potential covariates (Table III), although a number of built environment and demographic risk factors were assessed (see Tables E5 and E6 in this article's Online Repository at www.jacionline.org).
      We were unable to assess the risk associated with fungal species because identification was only made to the genus level (eg, for Aspergillus, Penicillium, Cladosporium, and Alternaria species), with the exception of 1 study.
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      Increased exposure to these fungi was associated with an increased risk of asthma in child and adult populations (Table III), although this relationship was not consistently reported. Other fungi investigated included Rhodotorula, Epicoccum, and Acrodontium species and sterile fungi (those lacking asexual or sexual spore production), which were not associated with increased risk of residents having asthma (see Table E5). Seven studies were included in random-effects meta-analysis to assess the strength and direction of association concerning exposure to Aspergillus, Penicillium, Cladosporium, and Alternaria species and risk of asthma exacerbation (Table V). We excluded data concerning the associated risk of asthma resulting from models investigating the associated level of risk with doubling fungal exposures
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      because the methodology differed from that for other included data.
      Table VSummary effect estimates and heterogeneity scores of results synthesis
      Model in subgroup analysisUnadjusted synthesis of outcome: AsthmaAdjusted synthesis of outcome: Asthma
      No. of studies included in analysisSummary effect estimates for pooled unadjusted data (95% CI)I2 valueNo. of studies included in analysisSummary effect estimates for pooled adjusted data (95% CI)I2 value
      Model 1: Total fungi30.98 (0.53-1.82)25%30.86 (0.46-1.59)1%
      Model 2: Identified and unidentified fungi (Aspergillus, Penicillium, Cladosporium, Alternaria, Rhodotorula, Acrodontium, and Epicoccum
      Only unadjusted data are available.
      species; sterile; Basidiomycetes; hyaline unknown and dark unknown)
      41.40 (1.07-1.82)54%71.29 (1.02-1.62)50%
      Model 3: Fungi, including nonsporulating (Aspergillus, Penicillium, Cladosporium, Alternaria, Rhodotorula, Acrodontium, and Epicoccum
      Only unadjusted data are available.
      species; sterile)
      41.47 (1.09-1.97)61%71.34 (1.05-1.71)54%
      Model 4: Fungi, excluding nonsporulating (Aspergillus, Penicillium, Cladosporium, Alternaria, Rhodotorula, Acrodontium, and Epicoccum
      Only unadjusted data are available.
      species)
      41.51 (1.10-2.07)64%71.34 (1.04-1.73)64%
      Model 5: Four most commonly reported fungi (Aspergillus, Penicillium, Cladosporium, and Alternaria species)41.48 (1.03-2.14)67%71.36 (1.02-1.82)61%
      Model 6: Aspergillus species31.74 (0.66-4.60)76%50.98 (0.59-1.63)54%
      Model 7: Penicillium species31.66 (0.48-5.70)83%51.19 (0.56-2.54)67%
      Model 8: Cladosporium species31.29 (0.64-2.59)61%61.96 (1.13-3.41)66%
      Model 9: Alternaria species21.71 (1.11-2.63)0%31.77 (1.22-2.56)0%
      Only unadjusted data are available.
      Random-effect estimates were calculated in combined models to investigate the role of fungal load and then individual fungal genera to further explore associations between different fungal genera. Effect estimates of each model were calculated with the number of included studies and the I2 statistic, indicating that included studies were subject to medium-high heterogeneity (Table V). No associations were reported with the total fungal load found indoors (model 1), and model 2 suggests a 29% to 40% risk. In accordance with our protocol, we omitted exposures not defined to the genera or species level, and this suggests a 34% to 51% (model 3) and 34% to 51% (model 4) increased risk of asthma symptoms. The combination of the most consistently reported fungal genera and the 4 prevalent indoor fungi Cladosporium, Alternaria, Penicillium, and Aspergillus species (model 5) increased the risk of current asthma by 48% in the unadjusted model and 36% in the adjusted model. Studies were subject to medium heterogeneity, with an I2 statistic ranging from 61% to 67% (Table V). Because of the heterogeneity, we carried out subgroup analyses of the 4 most commonly reported fungal genera to determine which genus or genera modified our combined effect estimates. This analysis suggests that the association was primarily caused by increased levels of Cladosporium and Alternaria species (models 6-9), with no significant association with exposure to Penicillium and Aspergillus species (Fig 2, Fig 3 and see Appendix E1). Further analyses showed that the findings might be driven by a single study
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      demonstrating a strong association between Alternaria alternata and asthma exacerbation. The fungal analysis of this study differed by the use of ELISA techniques to quantify concentrations of A alternata antigen in house dust. Analyses in these models excluded Rhodotorula, Acrodontium, and Epicoccum because data concerning these fungi were not consistently reported.
      Figure thumbnail gr2
      Fig 2Unadjusted model for indoor fungi and risk of asthma.
      Figure thumbnail gr3
      Fig 3Adjusted model for indoor fungi and risk of asthma.

       Risk of bias of individual studies

      The NOS for included items (Table I) indicated the studies were of medium quality, suggesting the potential inclusion of bias. There is also the potential for the inclusion of reporting bias resulting from inclusion of unadjusted and adjusted data into the random-effects models. Funnel plots present the variability between individual fungal groups (see Fig E1 in this article's Online Repository at www.jacionline.org) and the I2 statistic (Table V) suggests that there is medium-to-considerable heterogeneity, further suggesting conservative effect estimates, with the exclusion of combined models for total fungi and Alternaria species (I2 value ranging from 0 to <25).

      Discussion

      Our findings suggest that exposure to Aspergillus, Penicillium, Cladosporium, Ulocladium, Acremonium, Aureobasidium, Epicoccum, Scopulariopsis, Trichoderma, Alternaria, and Wallemia species might represent a respiratory health risk to asthmatic patients living in homes with increased fungal concentrations. These analyses do not provide sufficient detail to assess whether these fungi exacerbated asthma symptoms or potential health outcomes resulting from increased exposure to known allergenic fungal species (ie, fungi only identified to the genus level) present in higher concentrations at the time of sampling. Development of the ERMI and use of MSqPCR
      • Vesper S.
      • McKinstry C.
      • Haugland R.
      • Wymer L.
      • Bradham K.
      • Ashley P.
      • et al.
      Development of an Environmental Relative Moldiness Index for US Homes.
      enables us to more reliably quantify fungal species present indoors.
      • Vesper S.
      Traditional mould analysis compared to a DNA-based method of mould analysis.
      Aspergillus niger, A unguis, Cladosporium cladosporioides, Aureobasidium pullulans, Epicoccum nigrum, and A alternata were found in higher concentrations in homes of asthmatic patients in studies using MSqPCR. These fungi are allergenic species that might induce type I hypersensitivity.
      • Simon-Nobbe B.
      • Denk U.
      • Pöll V.
      • Rid R.
      • Breitenbach M.
      The spectrum of fungal allergy.
      It is not clear which factors regulate indoor fungal diversity and the risk of asthma at the individual level or how potential covariates might modify the outcome.
      We identified a limited number of longitudinal studies to explore the risk of new cases of asthma symptoms in populations exposed to increased concentrations of indoor fungi. Included studies highlight that exposure to species of Penicillium, Aspergillus, and Cladosporium species increases the risk of asthma in children and adults, although these studies do not embrace the full extent of indoor fungal diversity and exposure to other allergenic fungi.
      • Simon-Nobbe B.
      • Denk U.
      • Pöll V.
      • Rid R.
      • Breitenbach M.
      The spectrum of fungal allergy.
      Seven of the identified studies reviewed investigate exposure to increased fungal concentrations and increased risk of the exacerbation of asthma symptoms, which were included in our meta-analysis.

       Meta-analysis: Indoor fungal contamination and asthma exacerbation of asthma symptoms

      Our meta-analysis suggests that a number of fungal genera investigated by the included studies increase the risk of exacerbation of asthma symptoms. The associated level of risk did not appear to be significantly different when grouped by all reported fungi (model 2) versus those identified to the genera level (model 5). These findings could be affected by increased heterogeneity (I2 statistic) as we refine our meta-analysis model in accordance with our protocol. Our refined model for the 4 most consistently reported fungal genera, Penicillium and Aspergillus species,
      • Méheust D.
      • Le Cann P.
      • Reboux G.
      • Millon L.
      • Gangneux J.-P.
      Indoor fungal contamination: health risks and measurement methods in hospitals, homes and workplaces.
      Penicillium species,
      • Rosenbaum P.F.
      • Crawford J.A.
      • Anagnost S.E.
      • Wang C.J.K.
      • Hunt A.
      • Anbar R.D.
      • et al.
      Indoor airborne fungi and wheeze in the first year of life among a cohort of infants at risk for asthma.
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      Aspergillus species,
      • Jones R.
      • Recer G.M.
      • Hwang S.A.
      • Lin S.
      Association between indoor mold and asthma among children in Buffalo, New York.
      Cladosporium species,
      • Li C.S.
      • Hsu L.Y.
      Airborne fungus allergen in association with residential characteristics in atopic and control children in a subtropical region.
      • Dharmage S.
      • Bailey M.
      • Raven J.
      • Mitakakis T.
      • Cheng A.
      • Guest D.
      • et al.
      Current indoor allergen levels of fungi and cats, but not house dust mites, influence allergy and asthma in adults with high dust mite exposure.
      and Alternaria species,
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      increases the risk of the exacerbation of asthma symptoms by 36% to 48% in our effect estimates. These fungi have also been shown to be associated with an increased risk in longitudinal studies discussed in our narrative analyses
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      • Gent J.F.
      • Ping R.
      • Belanger K.
      • Triche E.
      • Bracken M.B.
      • Holford T.R.
      • et al.
      Levels of household mold associated with respiratory symptoms in the first year of life in a cohort at risk for asthma.
      and warrant further investigation in future research. Further analyses suggest that exposure to increased concentrations of Cladosporium and Alternaria species are primarily associated with increased risk of the exacerbation of asthma symptoms. However, this might be a result of the adopted study designs and limited sample sizes. For example, the strong association with Alternaria species results from the inclusion of one study
      • Salo P.M.
      • Arbes Jr., S.J.
      • Sever M.
      • Jaramillo R.
      • Cohn R.D.
      • London S.J.
      • et al.
      Exposure to Alternaria alternata in US homes is associated with asthma symptoms.
      with a large sample size (n = 2456) compared with other studies and used ELISA to quantify concentrations of A alternata antigen. This study supports the adoption of such diagnostic assays and a large sample size in future investigations into fungal exposure and asthma.
      Heterogeneity between studies explains some of the inconsistent findings, including sample size, age ranges, and outcome definitions. This is likely to be compounded by variations in the adopted sampling methodologies (air CFU per cubic meter vs dust CFU per gram sampling) because of their poor correlation in estimating potential exposures
      • Chew G.L.
      • Rogers C.
      • Burge H.A.
      • Muilenberg M.L.
      • Gold D.R.
      Dustborne and airborne fungal propagules represent a different spectrum of fungi with differing relations to home characteristics.
      and differences in fungal identification techniques.
      • Vesper S.J.
      • McKinstry C.
      • Chin Y.
      • Haugland R.A.
      • Kercsmar C.M.
      • Yike I.
      • et al.
      Specific molds associated with asthma in water-damaged homes.
      • Méheust D.
      • Le Cann P.
      • Reboux G.
      • Millon L.
      • Gangneux J.-P.
      Indoor fungal contamination: health risks and measurement methods in hospitals, homes and workplaces.
      Resultant health risks depend on the timing and extent of exposure to other groups of fungi, as well as ambient outdoor/indoor conditions, growth substrates, and levels of dampness,
      • Sharpe R.
      • Thornton C.R.
      • Osborne N.J.
      Modifiable factors governing indoor fungal diversity and risk of asthma.
      which cannot be ascertained from the included studies. Included studies did not consistently account for potential covariates, and few considered the role of indoor dampness and increased relative humidity, which increase the biological (house dust mite and fungi) and chemical load
      • Arundel A.V.
      • Sterling E.M.
      • Biggin J.H.
      • Sterling T.D.
      Indirect health effects of relative humidity in indoor environments.
      and should be considered potential covariates. Sensitization to pet allergens increases asthma exacerbation, with cat allergen being the most insidious,
      • Gaffin J.
      • Phipatanakul W.
      The role of indoor allergens in the development of asthma.
      although other work suggests that early dog ownership is associated with changes in immune development and reductions in wheezing and atopy.
      • Bufford J.D.
      • Reardon C.L.
      • Li Z.
      • Roberg K.A.
      • DaSilva D.
      • Eggleston P.A.
      • et al.
      Effects of dog ownership in early childhood on immune development and atopic diseases.
      It is also not clear from the evidence reviewed here how fungal diversity and risk of asthma might be modified by residential characteristics and the influx of outdoor fungal spores, which regulates the indoor fungal profile.
      • Sharpe R.
      • Thornton C.R.
      • Osborne N.J.
      Modifiable factors governing indoor fungal diversity and risk of asthma.
      Penicillium, Aspergillus, Cladosporium, and Alternaria species sporulation rates have considerable daily and seasonal variability and, combined with the adoption of different sampling techniques,
      • Fernández-Rodríguez S.
      • Tormo-Molina R.
      • Maya-Manzano J.M.
      • Silva-Palacios I.
      • Gonzalo-Garijo Á.
      Outdoor airborne fungi captured by viable and non-viable methods.
      • Pashley C.H.
      • Fairs A.
      • Free R.C.
      • Wardlaw A.J.
      DNA analysis of outdoor air reveals a high degree of fungal diversity, temporal variability, and genera not seen by spore morphology.
      add another level of complexity. Indoor fungal concentrations used to calculate ERMI values have also been shown to be heterogeneously distributed across the United States.
      • Vesper S.
      • Wakefield J.
      • Ashley P.
      • Cox D.
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      • Friedman W.
      Geographic distribution of Environmental Relative Moldiness Index molds in USA homes.
      These factors introduce another layer of uncertainty that cannot be explained from the evidence included in this review. The evidence reviewed suggests that exposure to increased concentrations of these 4 fungal groups represents a respiratory risk for asthmatic patients, but the evidence is not conclusive when assessing species diversity and asthma risk. It is yet unknown how exposure to fungi influences the development of new asthma-like symptoms, exacerbation of asthma symptoms, or both.

       Synthesis with existing knowledge

      Our combined random-effect estimates concerning exposures to individual fungal genera are similar to the meta-analyses of Fisk et al,
      • Fisk W.J.
      • Lei-Gomez Q.
      • Mendell M.J.
      Meta-analyses of the associations of respiratory health effects with dampness and mold in homes.
      who reported an approximate 30% to 50% increased risk of asthma outcomes. Two cohort studies have demonstrated that exposure to increased fungal contamination and risk of atopy increase the risk of asthma development in children
      • Jaakkola J.J.
      • Hwang B.F.
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      Home dampness and molds, parental atopy, and asthma in childhood: a six-year population-based cohort study.
      and adult
      • Jaakkola M.S.
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      Indoor dampness and molds and development of adult-onset asthma: a population-based incident case-control study.
      populations. A recent systematic review reported a significant association with increased exposure to fungal odor (random-effects model; effect estimate, 1.7; 95% CI, 1.2-2.5) and the development of asthma.
      • Quansah R.
      • Jaakkola M.S.
      • Hugg T.T.
      • Heikkinen S.A.M.
      • Jaakkola J.J.K.
      Residential dampness and molds and the risk of developing asthma: a systematic review and meta-analysis.
      Fungal diversity and concentrations of Penicillium, Aspergillus, Cladosporium, and Alternaria species vary considerably between different populations.
      • Meng J.
      • Barnes C.S.
      • Rosenwasser L.J.
      Identity of the fungal species present in the homes of asthmatic children.
      • Sharma R.
      • Deval R.
      • Priyadarshi V.
      • Gaur S.N.
      • Singh V.P.
      • Singh A.B.
      Indoor fungal concentration in the homes of allergic/asthmatic children in Delhi, India [published erratum appears in Allergy Rhinol (Providence) 2011;2):e62].
      • Blanc P.D.
      • Quinlan P.J.
      • Katz P.P.
      • Balmes J.R.
      • Trupin L.
      • Cisternas M.G.
      • et al.
      Higher environmental relative moldiness index values measured in homes of adults with asthma, rhinitis, or both conditions.
      This is likely to regulate asthma outcomes in different populations given that variations in residential characteristics regulate fungi found in US
      • Reponen T.
      • Levin L.
      • Zheng S.
      • Vesper S.
      • Ryan P.
      • Grinshpun S.A.
      • et al.
      Family and home characteristics correlate with mold in homes.
      and United Kingdom
      • Fairs A.
      • Wardlaw A.J.
      • Thompson Jr.,
      • Pashley C.H.
      Guidelines on ambient intramural airborne fungal spores.
      homes. Included studies in our meta-analysis used predominantly microscopy to identify and quantify the genus of fungi, which is likely to underestimate microbial exposures compared with molecular techniques.
      • Méheust D.
      • Le Cann P.
      • Reboux G.
      • Millon L.
      • Gangneux J.-P.
      Indoor fungal contamination: health risks and measurement methods in hospitals, homes and workplaces.
      Exposure to Cladosporium and Alternaria species increased the risk of asthma in our effect estimates, which might be due to asthma severity being associated with Cladosporium
      • Matheson M.
      • Abramson M.J.
      • Dharmage S.C.
      • Forbes A.B.
      • Raven J.M.
      • Thien F.C.K.
      • et al.
      Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults.
      • Hayes J.D.
      • Jhaveri M.A.
      • Mannino D.M.
      • Strawbridge H.
      • Temprano J.
      The effect of mold sensitization and humidity upon allergic asthma.
      and Alternaria species.
      • Zureik M.
      • Neukirch C.
      • Leynaert B.
      • Liard R.
      • Bousquet J.
      • Neukirch F.
      Sensitisation to airborne moulds and severity of asthma: cross sectional study from European Community respiratory health survey.
      • Pulimood T.B.
      • Corden J.M.
      • Bryden C.
      • Sharples L.
      • Nasser S.M.
      Epidemic asthma and the role of the fungal mold Alternaria alternata.
      It is not clear how the risk of asthma and severity of symptoms might be modified in sensitized populations, which is important to consider given that the development of allergic asthma (presence of IgE antibodies) in adults has been associated with Aspergillus fumigatus and Cladosporium species.
      • Jaakkola M.S.
      • Ieromnimon A.
      • Jaakkola J.J.K.
      Are atopy and specific IgE to mites and molds important for adult asthma?.
      Penicillium species is frequently cultured from damp indoor home environments and has been associated with asthma severity,
      • Pongracic J.A.
      • O'Connor G.T.
      • Muilenberg M.L.
      • Vaughn B.
      • Gold D.R.
      • Kattan M.
      • et al.
      Differential effects of outdoor versus indoor fungal spores on asthma morbidity in inner-city children.
      peak flow variability,
      • Bundy K.W.
      • Gent J.F.
      • Beckett W.
      • Bracken M.B.
      • Belanger K.
      • Triche E.
      • et al.
      Household airborne Penicillium associated with peak expiratory flow variability in asthmatic children.
      and asthma morbidity
      • Turyk M.
      • Curtis L.
      • Scheff P.
      • Contraras A.
      • Coover L.
      • Hernandez E.
      • et al.
      Environmental allergens and asthma morbidity in low-income children.
      when present in low concentrations.
      • Gent J.F.
      • Kezik J.M.
      • Hill M.E.
      • Tsai E.
      • Li D.-W.
      • Leaderer B.P.
      Household mold and dust allergens: Exposure, sensitization and childhood asthma morbidity.
      The lack of association between exposure to Penicillium and Aspergillus species and asthma in meta-analyses might be due to the limitations discussed above. These are important fungi to consider in future work because they dominate the damp indoor environment, where propagule concentrations exceed those in their natural outdoor environments,
      • Sharpe R.
      • Thornton C.R.
      • Osborne N.J.
      Modifiable factors governing indoor fungal diversity and risk of asthma.
      and have been implicated in the development of childhood asthma.
      • Reponen T.
      • Lockey J.
      • Bernstein D.I.
      • Vesper S.J.
      • Levin L.
      • Hershey G.K.K.
      • et al.
      Infant origins of childhood asthma associated with specific molds.
      Dampness appears to be a high risk for fungal growth present both in the US and European scenarios.
      There is insufficient evidence to support targeted interventions to decrease exposures to high-risk fungi in the general public and reduce symptoms or the initiation of disease. It is accepted that fungal sensitization is associated with an increased risk of asthma.
      • Agarwal R.
      • Gupta D.
      Severe asthma and fungi: current evidence.
      Fungal diversity and concentrations of different fungal groups appear to modify asthma outcomes in atopic and nonatopic subjects. However, this might also be the result of inhalation of different indoor/outdoor fungal propagules. Variations in the composition of ambient fungal spores also influence asthma episodes resulting from increased seasonal sporulation rates or those resulting from extreme weather events, such as thunderstorm-related asthma in A alternata–sensitized populations.
      • Nasser S.
      • Pulimood T.
      Allergens and thunderstorm asthma.
      For example, outdoor fungal exposure is associated with increased asthma symptoms and exacerbation in an-inner city population.
      • Pongracic J.A.
      • O'Connor G.T.
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      • Vaughn B.
      • Gold D.R.
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      • et al.
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      Thermotolerant filamentous fungi, such as Aspergillus and Penicillium species, can germinate and colonize the bronchial tree and regulate fungal sensitization and asthma severity.
      • Agbetile J.
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      • et al.
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      Allergenic proteins have been identified in 23 fungal genera, although not all are considered major allergens, such as Alt a 1 of A alternata, Cla h 8 of C herbarum, and Asp f 1 from A fumigatus.
      • Simon-Nobbe B.
      • Denk U.
      • Pöll V.
      • Rid R.
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      The spectrum of fungal allergy.
      Fungal sensitization has been reported in up to 80% of asthmatic patients, although research into fungal allergies has been compounded by high variability between their protein compositions.
      • Simon-Nobbe B.
      • Denk U.
      • Pöll V.
      • Rid R.
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      The spectrum of fungal allergy.
      In terms of asthma severity, it is thought that more than 6.5 million persons have severe asthma with fungal sensitization and up to 50% of adult asthmatic patients attending secondary care have fungal sensitization.
      • Denning D.
      • Pashley C.
      • Hartl D.
      • Wardlaw A.
      • Godet C.
      • Del Giacco S.
      • et al.
      Fungal allergy in asthma-state of the art and research needs.
      This is likely influenced by a high aeroallergen load,
      • Salo P.M.
      • Arbes Jr., S.J.
      • Crockett P.W.
      • Thorne P.S.
      • Cohn R.D.
      • Zeldin D.C.
      Exposure to multiple indoor allergens in US homes and its relationship to asthma.
      which can have opposing health effects.
      • Heederik D.
      • von Mutius E.
      Does diversity of environmental microbial exposure matter for the occurrence of allergy and asthma?.
      Work to date is inhibited by the lack of species identification. The adoption of a multidisciplinary approach and consistent sampling methodologies are required to accurately measure the timing and extent of exposures to microbial agents and other indoor/outdoor aeroallergens. This should be combined with a protocol for identifying the appropriate sampling period,
      • Crawford C.
      • Reponen T.
      • Lee T.
      • Iossifova Y.
      • Levin L.
      • Adhikari A.
      • et al.
      Temporal and spatial variation of indoor and outdoor airborne fungal spores, pollen, and (1→3)-β-D-glucan.
      along with clearly defined outcomes for developing asthma (long-term) or exacerbation (short-term) and epidemiologic techniques to investigate the cause of asthma at a population level.

       Strengths and limitations of the systematic review

      This assessment of the fungi and asthma literature has undergone a structured systematic review, with all phases of this systematic review conducted in accordance to our published protocol. A number of limitations exist, and we have tried to account for them by synthesizing our findings in Table E6 in this article's Online Repository at www.jacionline.org. Our analyses were limited by the quality, reporting inconsistencies, and limited number of peer-reviewed studies investigating the role of fungal diversity and risk of asthma exacerbation. The included studies had relatively small sample sizes, resulting in low power to our analyses, and prevented the stratification by age, exposure, and outcome definitions. This assumes that asthma in children and adults is the same disease with the same pathways of pathogenesis. They showed medium-high heterogeneity and were of medium quality, meaning that our findings might include reporting bias. We were unable to conduct further analyses to explore potential bias associated with the heterogeneity between studies because of the small number of included studies.
      The majority of the included studies used cross-sectional or case-control study designs, which reduces our confidence in these results because bias can be introduced as a result of incorrect estimation of exposures and failure to account for confounders, as evidenced by the decrease in the strength of the relationship between moisture-related risk factors and asthma in longitudinal analyses.
      • Larsson M.
      • Hägerhed-Engman L.
      • Moniruzzaman S.
      • Janson S.
      • Sundell J.
      • Bornehag C.-G.
      Can we trust cross-sectional studies when studying the risk of moisture-related problems indoor for asthma in children?.
      We identified a limited number of longitudinal study designs, which restricted our meta-analysis to assess the role of fungal exposures taken from a single sample on the exacerbation of asthma symptoms. Few studies quantified indoor fungal contamination defined to the species level by using molecular techniques, which restricted analyses to the fungal genera and potentially underestimate exposures. Potential covariates were not consistently assessed, and studies did not account for the effect of increased dampness and relative humidity on concentrations of house dust mites or volatile organic compounds or the seasonality of outdoor air spore composition. It is also not clear how fungal exposures and risk of asthma exacerbation might be modified by different occupant behaviors, such as heating and ventilation patterns, which have been shown to modify the indoor fungal profile, and this adds another layer of complexity in assessing indoor exposures.
      Longitudinal studies assessing increased exposure to indoor fungi before the development of asthma symptoms suggests that species of Penicillium, Aspergillus, and Cladosporium pose a respiratory health risk in susceptible populations. Increased exacerbation of current asthma symptoms in children and adults were associated with increased levels of Penicillium, Aspergillus, Cladosporium, and Alternaria species, although further work should consider the role of fungal diversity and increased exposure to other fungal species. Adoption of a holistic approach to the complex disease of asthma in atopic and nonatopic populations, with the understanding that multiple exposures are potentially involved and should be measured, will lead to better study design and capture of sufficient data to allow a more measured view. This remains challenging because it will be expensive to achieve at the population level. We recommend that future studies should consider the adoption of a multidisciplinary approach using both molecular and epidemiologic tools to accurately estimate the extent and timing of exposures and reliably assess potential health effects.
      Key message
      • Future studies should consider the adoption of a multidisciplinary approach using both molecular and epidemiologic tools to accurately determine the extent and timing of exposures to allergenic fungi and reliably assess potential health effects.
      We thank our colleagues at the European Centre for Environment and Human Health (part of the University of Exeter Medical School), particularly Dr Ruth Garside and the Information Services Team for their contribution to the development the review protocol. We also thank all the authors who responded to our queries, specifically contributions from the nationwide epidemiologic studies on prevalence of sick house syndrome and their risk factors and the project team of Health and Labor Sciences Research, Ministry of Health Labor and Welfare 2003-2005 and 2006-2007 (principal investigator: Reiko Kishi, Hokkaido University Centre for Environmental and Health Sciences). We would like to thank Coastline Housing and their customers for their participation in the Health and Housing project, and are particularly grateful to the Technical Services team led by Mr Mark England for their continued help and support throughout the project delivery.

      Supplementary data

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