AWMF mold guideline "Medical clinical diagnostics for indoor mold exposure" - Update 2023 AWMF Register No. 161/001.

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Abridged version of the AWMF guideline for the medical clinical diagnostics of indoor mould exposure: S2K Guideline of the German Society of Hygiene, Environmental Medicine and Preventive Medicine (GHUP) in collaboration with the German Association of Allergists (AeDA), the German Society of Dermatology (DDG), the German Society for Allergology and Clinical Immunology (DGAKI), the German Society for Occupational and Environmental Medicine (DGAUM), the German Society for Hospital Hygiene (DGKH), the German Society for Pneumology and Respiratory Medicine (DGP), the German Mycological Society (DMykG), the Society for Pediatric Allergology and Environmental Medicine (GPA), the German Federal Association of Pediatric Pneumology (BAPP), and the Austrian Society for Medical Mycology (ÖGMM).

This article is an abridged version of the AWMF mould guideline "Medical clinical diagnostics of indoor mould exposure" presented in April 2016 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin, GHUP), in collaboration with the above-mentioned scientific medical societies, German and Austrian societies, medical associations and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. Apart from allergic bronchopulmonary aspergillosis (ABPA) and mould-caused mycoses, only sufficient evidence for an association between moisture/mould damage and the following health effects has been established: allergic respiratory disease, asthma (manifestation, progression and exacerbation), allergic rhinitis, hypersensitivity pneumonitis (extrinsic allergic alveolitis), and increased likelihood of respiratory infections/bronchitis. In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitizing prevalence of 3-10% in the general population across Europe. Limited or suspected evidence for an association exist with respect to mucous membrane irritation and atopic eczema (manifestation, progression and exacerbation). Inadequate or insufficient evidence for an association exist for chronic obstructive pulmonary disease, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis and cancer. The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, above all the substrate. In the case of indoor moisture/mould damage, everyone can be affected by odour effects and/or mood disorders. However, this is not a health hazard. Predisposing factors for odour effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly with regard to an infection risk are persons on immunosuppression according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission für Krankenhaushygiene und Infektionsprävention, KRINKO) at the Robert Koch- Institute (RKI) and persons with cystic fibrosis (mucoviscidosis); with regard to an allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma should be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections the reader is referred to the AWMF guideline "Diagnosis and Therapy of Invasive Aspergillus Infections". With regard to mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medicine standpoint it is important that indoor mould infestation in relevant dimension cannot be tolerated for precautionary reasons. With regard to evaluating the extent of damage and selecting a remedial procedure, the reader is referred to the revised version of the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA).

Medical diagnostics for indoor mold exposure.

In April 2016, the German Society of Hygiene, Environmental Medicine and Preventative Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin (GHUP)) together with other scientific medical societies, German and Austrian medical societies, physician unions and experts has provided an AWMF (Association of the Scientific Medical Societies) guideline 'Medical diagnostics for indoor mold exposure'. This guideline shall help physicians to advise and treat patients exposed indoors to mold. Indoor mold growth is a potential health risk, even without a quantitative and/or causal association between the occurrence of individual mold species and health effects. Apart from the allergic bronchopulmonary aspergillosis (ABPA) and the mycoses caused by mold, there is only sufficient evidence for the following associations between moisture/mold damages and different health effects: Allergic respiratory diseases, asthma (manifestation, progression, exacerbation), allergic rhinitis, exogenous allergic alveolitis and respiratory tract infections/bronchitis. In comparison to other environmental allergens, the sensitizing potential of molds is estimated to be low. Recent studies show a prevalence of sensitization of 3-10% in the total population of Europe. The evidence for associations to mucous membrane irritation and atopic eczema (manifestation, progression, exacerbation) is classified as limited or suspected. Inadequate or insufficient evidence for an association is given for COPD, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis, and cancer. The risk of infections from indoor molds is low for healthy individuals. Only molds that are capable to form toxins can cause intoxications. The environmental and growth conditions and especially the substrate determine whether toxin formation occurs, but indoor air concentrations are always very low. In the case of indoor moisture/mold damages, everyone can be affected by odor effects and/or impairment of well-being. Predisposing factors for odor effects can be given by genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for impairment of well-being are environmental concerns, anxieties, conditioning and attributions as well as a variety of diseases. Risk groups that must be protected are patients with immunosuppression and with mucoviscidosis (cystic fibrosis) with regard to infections and individuals with mucoviscidosis and asthma with regard to allergies. If an association between mold exposure and health effects is suspected, the medical diagnosis includes medical history, physical examination, conventional allergy diagnosis, and if indicated, provocation tests. For the treatment of mold infections, it is referred to the AWMF guidelines for diagnosis and treatment of invasive Aspergillus infections. Regarding mycotoxins, there are currently no validated test methods that could be used in clinical diagnostics. From the perspective of preventive medicine, it is important that mold damages cannot be tolerated in indoor environments.

Development and application of mold antigen-specific enzyme-linked immunosorbent assays (ELISA) to quantify airborne antigen exposure.

The aim of our study was to develop specific enzyme-linked immunosorbent assays (ELISAs) and apply these to assess mold antigen exposure in composting plants. Sandwich ELISAs based on polyclonal antibodies to Aspergillus fumigatus (Af), Penicillium chrysogenum (Pc), and Cladosporium herbarum (Ch) antigens were developed and validated. Reactivity to 18 different mold species was tested. To optimize extraction procedure, inhalable dust samples taken by a parallel sampler were extracted with or without homogenization. In 31 composting plants stationary pumps were installed at 4 sites to collect 124 inhalable dust samples. The newly developed ELISAs were used in addition to an anti ß-1,3-glucan ELISA to quantify mold antigens. The Cladosporium ELISA showed less than 0.04% reactivity to extracts from other fungal genera, while the Af ELISA demonstrated a reactivity of up to 3.6% and the Pc ELISA reacted up to 11% to other mold species. Extraction of parallel sampled filters gave higher antigen amounts with homogenization. The increase was highest for Pc-antigens, followed by Af-antigens, and lowest for Ch-antigens. Mean lower detection limits of homogenized inhalable dust samples were 5 ng/m(3) (Af), 0.6 ng/m(3) (Pc), 0.2 ng/m(3) (Ch), and 0.6 ng/m(3) (ß-1,3-glucan). The ELISAs were able to detect antigens in 43% (Af), 37% (Pc), 94% (Ch), or 100% (ß-1,3-glucan) of the 124 airborne dust samples. Inhalable dust, ß-1,3-glucan, and Af-, Pc-, and Ch-antigen concentrations were significantly correlated. The newly developed mold antigen ELISAs are thus able to measure airborne exposure levels in composting plants and differentiate between distinct fungi genera.

Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

Estimating the single nucleotide polymorphism genotype misclassification from routine double measurements in a large epidemiologic sample.

Previously, estimation of genotype misclassification of single nucleotide polymorphisms (SNPs) as encountered in epidemiologic practice and involving thousands of subjects was lacking. The authors collected representative data on approximately 14,000 subjects from 8 studies and 646,558 genotypes assessed in 2005 by means of matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Overall discordance among 57,805 double genotypes from routine quality control was 0.36%. Fitting different misclassification models by maximum likelihood assuming identical misclassification for all SNPs, the estimated misclassification probabilities ranged from 0.0000 to 0.0035. When applying the misclassification simulation and extrapolation (MC-SIMEX) method for the first time to genetic data to account for the misclassification in a reanalysis of adiponectin-encoding (APM1) gene SNP associations with plasma adiponectin in 1,770 subjects, the authors found no impact of this small error on association estimates but increased estimates for a more substantial error. This study is the first to provide large-scale epidemiologic data on SNP genotype misclassification. The estimated misclassification in this example was small and negligible for association estimates, which is reassuring and essential for detecting SNP associations. In situations with more substantial error, the presented approach using duplicate genotyping and the MC-SIMEX method is practical and helpful for quantifying the genotyping error and its impact.

SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.

Analysis of airborne microorganisms, MVOC and odour in the surrounding of composting facilities and implications for future investigations.

Emission and dispersal of microorganisms and odours from composting facilities were studied in a 3-year project at nine different composting facilities in Germany. Measurements were carried out under so-called 'normal-case', i.e. typical local climate conditions and working activities within the facilities, and 'real worst-case' conditions ('drainage flow' conditions) being characterized by the translocation of cold air mostly at night, and containing large amounts of bioaerosols. Highest concentrations of microorganisms were observed during turning of compost with a maximum of 2.4x10(6)cfu m(-3) for thermophilic actinomycetes. Other groups of microorganisms were detected in concentrations of about 10(5)cfu m(-3). During shredding of fresh organic material, the concentrations of all microorganisms reached 10(4)cfu m(-3). Here, odour concentrations turned out to be highest (up to 1,367 odour units (OU)m(-3)). At facilities equipped with a biofilter (odour reduction), a decrease in OU by a factor of 10 was observed. In the surrounding of the facilities, highest concentrations ranged between 10(1)-10(3)cfu m(-3) upwind and from 10(1)-10(4)cfu m(-3) downwind. The specific local meteorological situations must be considered carefully in advance and during sampling. Especially 'drainage flow' situations can lead to high microorganism concentrations (>10(4)-10(5)cfu m(-3) of thermophilic actinomycetes and thermophilic fungi) in the surroundings of composting facilities.

Gliotoxin production by clinical and environmental Aspergillus fumigatus strains.

The mycotoxin gliotoxin is produced by fungi of the genus Aspergillus, including the important human pathogen Aspergillus fumigatus. Gliotoxin exerts a broad spectrum of immunosuppressive effects in vitro and is detectable in the sera of patients suffering from invasive aspergillosis. In order to correlate the pathogenic potential of A. fumigatus with the ability to produce gliotoxin and to investigate the taxonomic distribution of gliotoxin-producing Aspergillus strains among clinical isolates, a total of 158 Aspergillus isolates comprising four different species (A. fumigatus, n=100; A. terreus, n=27; A. niger, n=16; A. flavus, n=15) were collected from different medical centers (some originating from probable cases of aspergillosis) and from environmental samples in Germany and Austria. Remarkably, gliotoxin was detected in most culture filtrates of A. fumigatus of both clinical (98%) and environmental (96%) origin. The toxin was also detected, with decreasing frequency, in culture filtrates of A. niger (56%), A. terreus (37%), and A. flavus (13%). The highest gliotoxin concentrations were detected in A. fumigatus strains of clinical (max. 21.35 microg/ml, mean 5.75 microg/ml) and environmental (max. 26.25 microg/ml, mean 5.27 microg/ml) origin. Gliotoxin productivity of other Aspergillus species was significantly lower. Culture supernatants of A. fumigatus strains lacking gliotoxin production showed a significantly lower cytotoxicity on macrophage-like cells and T-cells in vitro. In contrast, lack of gliotoxin production in the other Aspergillus species tested had no significant influence on the cytotoxic effect of culture supernatant on these immune cells.

Recommendations for study design and sampling strategies for airborne microorganisms, MVOC and odours in the surrounding of composting facilities.

Microorganisms and odour emissions from composting plants often lead to complaints by residents, especially by people living close to such plants. Both parameters were studied in a systematic approach under specific local meteorological conditions at nine different composting plants in Germany with emphasis on dispersal of microorganisms. Measurements were done at emission points and at sampling sites in the downwind and upwind directions of the facilities under 'normal case' (i.e. weather conditions typical for the location in combination with working activities at the plants) and 'real worst case' conditions (dispersal of bioaerosols into the surroundings expected to occur with high probability). Airborne microorganisms were sampled using filtration and impingement. Subsequent cultivation on four different culture media allowed quantification and identification of the culturable microflora. It turned out that a general assessment of emissions and dispersal of bioaerosols from composting plants is not possible because of the coherences of various factors influencing the dispersal. The site-specific meteorological situations must be considered carefully, whenever sampling locations are selected and need to be recorded in any sampling protocol. Air inversions in particular can lead to high concentrations of microorganisms (>10(4)-10(5)cfu m(-3) of thermophilic actinomycetes and thermotolerant fungi) in the surroundings of composting plants. Finally, it was shown that both thermotolerant fungi and thermophilic actinomycetes can serve as indicator organisms.

FT-IR spectroscopy as a tool for rapid identification and intra-species characterization of airborne filamentous fungi.

Identification of microfungi is time-consuming due to cultivation and microscopic examination and can be influenced by the interpretation of the macro- and micro-morphological characters observed. Fungal conidia contain mycotoxins that may be present in bioaerosols and thus the capacity for production of mycotoxins (and allergens) needs to be investigated to create a basis for reliable risk assessment in environmental and occupational hygiene. The present investigation aimed to create a simple but sophisticated method for the preparation of samples and the identification of airborne fungi by FT-IR spectroscopy. The method was suited to reproducibly differentiate Aspergillus and Penicillium species on the generic, the species, and the strain level. There are strong indications that strains of one taxon differing in metabolite production can be reliably distinguished by FT-IR spectroscopy (e.g. Aspergillus parasiticus). On the other hand, species from different taxa being similar in secondary metabolite production showed comparably higher similarities. The results obtained here can serve as a basis for the development of a database for species identification and strain characterization of microfungi. The method presented here will improve and facilitate the risk assessment in case of bioaerosol exposure, as strains with different physiological properties (e.g. toxic, non-toxic) could be differentiated. Moreover, it has the potential to significantly improve the identification of microfungi in various fields of applied microbiological research, e.g. high throughput screening in view of specific physiological properties, biodiversity studies, inventories in environmental microbiology, and quality control measures.

(M)VOC and composting facilities. Part 2: (M)VOC dispersal in the environment.

BACKGROUND, AIMS AND SCOPE: Composting facilities are known to release odorous volatiles due to biodegradation of municipal waste and plant residues. Although odour perception and its grading is influenced by experience, attitude and adaptation, these emissions have created a lack of acceptance for residents in the vicinity of composting facilities. Enclosure of compost pile halls, ventilation systems and biofilters are often insufficient to minimise the burden of compost-derived compounds in the air. Moreover, economic considerations forced smaller communities to establish less sophisticated facilities with open storage areas and other relevant sources for wind-borne dispersal of bioaerosols. Aim of the present study was to characterise the immission and dispersal of microbial volatiles (MVOC) and, besides, to find coincidences between MVOC and compost odour. METHODS: In the course of this study, the surroundings of two composting facilities, differing in their type of process engineering, were investigated for emission of volatiles in the environment. Both microbially and plant-derived substances were assessed, several of which have low odour thresholds. Air samples were taken in distances ranging from 50 to 800 m in a downwind direction from each facility. RESULTS AND DISCUSSION: Compost-derived and microbial volatile organic compounds (MVOC) were found at distances of up to 800 m from the composting facilities. Terpenes like alpha-pinene, camphene and camphor were the dominant compounds and coincided with typical compost odour, whereas several typical MVOC were not found at greater distances. The terpenes in combination with certain MVOC may play an important role in the perception of compost odour. Exposure concentrations were not of toxicological relevance, but sensory irritation and psychohygienic effects due to an annoyance potential of such compounds should not be dismissed. RECOMMENDATIONS AND OUTLOOK: Although terpenes are generally associated with pleasant odour characteristics, they seemed to contribute to malodours in a mixture with other VOC, in this context of volatile waste from compost facilities. Malodorous emissions from biowaste have to be considered as sources of health complaints and the investigation of mixtures of compost-derived volatiles is still inevitable. Exposure levels have to be discussed taking VOC mixtures into account. Within composting facilities, technical devices have to be improved to minimise dispersal of volatiles to prevent residents from immissions eventually causing health complaints.

(M)VOC and composting facilities. Part 1: (M)VOC emissions from municipal biowaste and plant refuse.

GOAL, SCOPE AND BACKGROUND: Malodorous volatiles derived from the decomposition of biowaste within the process of composting might pose a risk to human health. Different techniques of process engineering have been developed to minimise the burden of malodorous compounds in air possibly affecting compost workers and residents in the vicinity. METHODS: In the present study, three different composting facilities were examined for the emission of volatiles to estimate the impact of process engineering on the dispersal of odorous compounds and to discuss its relevance for human health. RESULTS AND DISCUSSION: Concentrations of single compounds belonging to alcohols, ketones, furanes, sulfur-containing compounds and especially terpenes ranged from 10(2) up to nearly 10(6) ng/m3 depending on the sampling sites and the process engineering. The ratio of MVOC and total VOC measured changed throughout the process of biodegradation. A certain combination of volatile compounds coincided with the occurrence of typical compost odour. CONCLUSION: The type of process engineering seemed to have a major impact on the emission of volatiles, as amounts of (microbial) volatiles emitted were characteristic for the different techniques used. Thus, the MVOC emission basically depends on the degree of biodegradation. It is likely that the concentrations workers are exposed to can have an impact on human health. RECOMMENDATIONS AND OUTLOOK: It is obvious that less sophisticated types of process engineering give rise to greater amounts of bioaerosols and volatiles and, therefore, technical devices have to be improved and controlled regularly to minimise adverse health effects on workers.

Relevance of airborne fungi and their secondary metabolites for environmental, occupational and indoor hygiene.

Airborne fungal contaminants are increasingly gaining importance in view of health hazards caused by the spores themselves or by microbial metabolites. In addition to the risk for infection, the allergenic and toxigenic properties, as well as the inflammatory effects are discussed in this review as possible health impacts of bioaerosols. A major problem is the lack of threshold values for pathogenic and non-pathogenic fungi, both in the workplace and in outdoor air. While the relevance of mycotoxins has been intensely studied in connection with contamination of food and feed, the possible respiratory uptake of mycotoxins from the air has so far not been sufficiently taken into account. Toxic secondary metabolites are expected to be present in airborne spores, and may thus occur in airborne dust and bioaerosols. Potential health risks cannot be estimated reliably unless exposure to mycotoxins is determined qualitatively and quantitatively. Microbial volatile organic compounds (MVOC) have been suggested to affect human health, causing lethargy, headache, and irritation of the eyes and mucous membranes of the nose and throat. The production of MVOC by fungi has been discussed in connection with domestic indoor microbial pollution, but the relevance of fungal metabolites in working environments remains insufficiently studied.