This article is based on a presentation at the International Conference on Indoor Mold and Children held 21-24 April 1998 in Alexandria, Virginia.

Address correspondence to R. Rylander, Department of Environmental Medicine, University of Gothenburg, Box 414, 405 30 Gothenburg, Sweden. Telephone: 46 31 773 3601. Fax: 46 31 82 5004. E-mail: ragnar.rylander@envmed.gu.se

Received 3 September 1998; accepted 4 November 1998.

Background

Reactive airways disease in children is increasing in many countries. The clinical diagnosis of asthma or reactive airways disease includes a variable airflow obstruction and an increased airway responsiveness. This condition can develop after an augmented reaction to a specific agent (allergen) and may cause a life-threatening situation within a very short period of exposure. It can also develop after long-term exposure to irritating agents that cause inflammation in the airways in the absence of an allergen.

Several environmental agents are associated with exacerbations of childhood asthma. They include mite allergens, cat dander, outdoor and indoor air pollution, cooking fumes, and infections. There is, however, increasing evidence that mold growth indoors in damp buildings is an important risk factor for childhood respiratory illness. About 40 investigations from many different countries have demonstrated an association between living in damp homes or homes with mold growth, and adverse respiratory symptoms in children. Some studies show a relation between dampness/mold and objective measures of lung function or a history of respiratory infections. Apart from respiratory symptoms, some studies demonstrate the presence of general symptoms in terms of fatigue, headache, and symptoms from the central nervous system. At excessive exposures to certain toxigenic molds, an increased risk for pulmonary hemorrhage and death among infants has been documented.

The described effects may have important consequences for children in the early years of life. A child´s immune system develops from birth to adolescence and requires a natural stimulation with antigens as well as inflammatory agents. Any disturbances of this normal maturing process may increase the risk for abnormal reactions to inhaled antigens and irritants in the environment.

Knowledge about health risks due to mold exposure is not widespread among clinicians, and public health authorities in some countries may not be aware of the serious reactions mold exposure can provoke in some children. Individual physicians may have difficulties treating these children because of the lack of recognition of the relationship between the symptoms and the indoor environment.

This workshop was organized to develop a basis for risk assessment and formulation of recommendations, particularly for diagnostic purposes. The participants were all active researchers with current experience in child health, molds, and respiratory disease. During the workshop, three work groups were formed, given specific problems and questions regarding the different aspects of the relationship between molds and children's health, and asked to produce a written report. These reports were discussed in a plenary session and further revised and circulated several times to all participants.

Conclusions and Recommendations of the Workshop

Symptoms and Pathology
Children in homes with dampness and/or mold growth are at higher risk for episodic and/or persistent upper respiratory symptoms such as rhinitis, blocked nose, sneezing, eye irritation, and hoarseness, as well as lower respiratory tract symptoms such as dry or productive cough and wheezing (1-3). They may also have skin symptoms--itching and redness--that can be present both in exposed areas of the body (suggesting contact dermatitis) or in areas protected by clothing (suggesting other mechanisms).

Systemic symptoms such as headache, fever, excessive fatigue, and joint pains have been described among persons in moldy environments but are less well documented, and the underlying mechanisms are not known. Food intolerance to mold in cheese, wine, beer, and mushrooms has also been described (4). Unusual symptoms reported in high-exposure conditions, and particularly in connection with the exposure of infants to certain toxigenic fungi (e.g., Stachybotrys), are nosebleeding and hemoptysis (5,6).

It is very important that when a physician evaluates a child with these symptoms, specific questions about the home, child care setting, or school environments are asked.

The pathologic mechanisms for the respiratory symptoms can be considered to result from inflammation (7). This inflammation can be induced by the well-recognized allergic, IgE-mediated mechanisms but also by nonallergic mechanisms induced by toxic agents, where macrophages and lymphocytes play important roles. Molds contain agents able to induce all these reactions: a number of well-defined allergens, immunomodulating agents such as (13)-ß-d-glucan, and mycotoxins.

Although children with diagnosed or suspected IgE-related airway inflammation dominate the clientele at outpatient departments for pediatric lung disease or allergy, data from epidemiologic studies suggest that nonspecific inflammation may be the most common pathology among a larger group of children not selected for hospital admission.

The inflammatory response in children's airways can be both augmented and suppressed by simultaneous exposure to environmental agents. These considerations are separate from the infection concerns in immune-suppressed children. In view of the profound changes in the immune system during its development in infancy and early childhood, such environmental exposures are likely to be of importance by inducing hypersensitivity or modifying the immunologic maturation process, steering away from the allergic Th2-driven response at birth to a Th1-driven response (8). Pathologic reaction patterns induced by environmental exposure can manifest themselves throughout the remainder of childhood and adolescence as impacted by puberty.

All responses to the environment, in terms of both allergy and inflammation, are related to the genetic predisposition of the individual, particularly those with an atopic predisposition. The influences of gender and race on risk are not yet fully understood.

Children with symptoms related to mold in houses may also be more susceptible to inhaled agents in general such as particulates, smoke, and chemicals. The presence of such increased airway symptoms should be regarded as a further indication to pose questions about the housing environment in which the child lives.

Diagnostic Methods
For the clinician faced with a child with symptoms possibly related to exposure to indoor air, the initial aim is to rule out other diseases such as bronchiectasis and congenital immune deficiencies.

Diagnostic tools must be used in a focused and stepwise manner, depending on the severity of the symptoms, and their potential relationship to the indoor environment. A child may be exposed in various environments simultaneously, e.g., in the home, child care setting or school environment, and during play activities, which makes the evaluation of possible risk factors and temporal relationships quite complicated.

A history of an environment-related symptomatology is very important (i.e., child has symptoms in home/school/child care setting and does not have symptoms elsewhere). When the symptoms are suspected to have an allergic etiology, a blood eosinophil count, total IgE concentration, and skin prick tests (SPTs) should be considered. SPTs have useful predictive value when testing with standardized allergen extracts for allergy to pets, dust mites, and pollen (9,10). Fungal SPT extracts may be unreliable, often because of lack of standardization of the extracts. In addition, the panel of fungal allergen extracts available to the clinician does not accurately reflect the true mold exposure profile in most indoor enviroments. A negative SPT can, on the other hand, reflect the presence of a nonspecific inflammation. There are no published data comparing microbial-specific (radioallergosorbent tests [RAST]) tests and respective SPT results. Approximately 15 microbes account for the vast majority of positive findings.

Determination of mold-specific IgE antibodies (RAST, enzyme-linked immunosorbent assay [ELISA]) is also a useful method to identify specific IgE-mediated response, but high costs limit the use of this test in primary health care. RAST and related tests have lower sensitivity than SPTs. The finding of a high total IgE level supports a relation between exposure and allergic symptoms. If specific IgE levels are low, one may be dealing with a nonallergic inflammatory pathogenesis for the symptoms.

Further diagnostic analyses depend on the symptom complex. For example, with persistent lower respiratory tract symptoms, measures of reversible airflow obstruction and airway responsiveness should be made (11). Peak expiratory flow, flow volume, and spirometry may be used, depending on the age of the patient. The diagnosis of asthma in an infant is a clinical diagnosis based on a judgment of an experienced clinician, in most cases a pediatrician.

Only a few tests of nonallergic inflammation are currently available and they are used mainly in research. Some of these tests provide promising results and may provide additional information on the pathophysiologic mechanisms behind the symptoms associated with exposure to microorganisms. Determinations of inflammatory cytokines in nasal lavage fluid or induced sputum or nitric oxide concentrations in exhaled air are examples of such tests.

If hypersensitivity pneumonitis (allergic alveolitis), toxic pneumonitis (organic dust toxic syndrome), or pulmonary hemorrhage is suspected, leukocyte counts and neutrophil/lymphocyte ratios should be determined. More extensive tests are available such as measurements of total lung capacity and diffusion capacity and bronchoscopy with alveolar lavage, but they are to be used only in clinically severe cases or in those with diagnostic doubt. If pulmonary hemorrhage is suspected, hemosiderin-laden macrophages should be counted. Additionally, particularly in infants, possible anemia should be assessed and stools checked for occult blood (12). In toxic pneumonitis, no diagnostic tools need to be used as the disease disappears within 24 hr.

Microbe-specific IgG antibodies (precipitins, IgG, ELISA antibodies) can be determined but are useful only as markers of the exposure.

Measurement Tools for Use in Epidemiologic Studies
Questionnaires are the golden standard and are available for all age groups including children. The questionnaires should be validated and tested for sensitivity and specificity. Symptom diaries are easy to use if children are well motivated and older than about 10 years of age. Alternatively, the parents can complete the diaries, although their information may not be as accurate. Symptom diaries, together with peak flow measurements, give more precise and objective information on the spatial and temporal relationship between suspected exposure and symptoms. Spirometry before and after physical exercise among children, SPT, RAST, specific IgE, and the previously mentioned cell-related tests may be useful, but a control group of children with no indoor-related symptoms must always be included.

Environmental Measurements

Assessment of the condition of the building and measurements of the presence of molds are important activities in the process of relating a child's symptoms and clinical findings with mold exposure. Questions on the presence of molds at home or in the school/child care setting can be posed in a clinical examination or in a questionnaire (13). Important questions to be included in such investigations are the following:

• Do you notice a moldy/earthy or cellarlike odor in the home/child care setting/school?

   

• Is there a history of water damage such as leakage from water pipes or washing machines, boiler, refrigerator, freezer, or cooling of the ventilation system in the child's home/child care setting/school?

   

• Do you have, or have you previously had, visible signs of moisture damage such as damp stains or spots, deterioration or darkening of surface materials in the ceiling, walls, or floors, or signs of condensation of water on surfaces in the home/child care setting/school?

   

• Do your child's symptoms change or disappear when she/he is away from the home/child care setting/school?

   

• Is there anything in particular that aggravates your child's symptoms?

In addition, questions on the ventilation system could give important information: What kind of heating system/ventilation system do you have? Do you have air conditioning? How often are air cleaners in use? How often are air filters changed or cleaned? Are special filters such as electric precipitators used? These questions may vary or be left out according to local practices in different climatic conditions.

Important information for the diagnosis can also be obtained by paying a visit to the child's home, school, or child care setting. Observations of moisture spots, water leakage, mold spots, or mold or earthy odor support the hypothesis of a mold exposure. On wallboards, mold growth sufficient to influence the air quality extends as much as 0.5-1 m beyond visible mold cultures. There may also be hidden damage and mold growth behind the surface materials such as wallpaper, gypsum board, or carpets, which can affect indoor air quality.

The decision to remediate a structure can often be made by visual inspection and without sampling microorganisms. If water intrusion has occurred, timely action is essential because mold growth can proliferate extensively within a few days. The first step must be to eliminate the source of water. If visible mold growth is extensive, air and bulk samples for molds should be taken prior to remedial action to identify the organisms. Sampling in the absence of visible mold growth may also be merited to assure that there are no further hidden sources of mold. A difference in rank order of mold species inside when compared to outside is the gold standard for diagnosing building contamination. Identification of mold species is important because some are known to produce potent mycotoxins, e.g., tricothecenes by Stachybotrys chartarum (13,14). Extensive mold growth, especially toxigenic mold growth, also requires that the remedial workers be protected (14,15).

Accurate exposure assessment is difficult with currently available sampling and analysis methods. No single measurement technique is entirely suitable, and sampling should never be conducted alone but in conjunction with inspection. A measure of culturable molds (as colony-forming units) in an air sample is of little value because the sampling periods of traditional methods are too short to represent accurately the variability of concentrations over time. Also, the culturable portion represents only a small fraction of the total number of mold spores present in an air, dust, or bulk sample.

The analysis of settled dust can provide a time-integrated index of exposure. In settled dust samples, measures of total cell mass using ergosterol or (13)-ß-d-glucan, and cytotoxicity tests have been associated with the extent of symptoms and clinical findings. Spore trap sampling with microscopic counting of spores can also provide a measure of fungal mass but is laborious and requires considerable experience (16).

Work group members: Symptoms and pathology. Erika von Mutius, Dorr Dearborn, Peyton Eggleston, Suzanne Gravesen, Ragnar Rylander. Diagnostic methods. Tuula Husman, Robert Dales, Ruth Etzel, David Fishwick, Eckardt Johanning. Mold exposure measurements. Kenneth Dillon, Jeroen Douwes, Robert R. Jacobs, J. David Miller, W.G. Sorenson.

Appendix. Participants at the Workshop on Child Health and Mold Exposure

Robert E. Dales, Respiratory Medicine, Ottawa General Hospital, 501 Smyth, Ottawa, Ontario K1H 8L6, Canada. Tel: (613) 737-8198. Fax: (613) 737-8141. E-mail: rdales@ogh.on.ca

Dorr G. Dearborn, Pediatric Pulmonary Division, Case Western Reserve University, 11,100 Euclid Ave, Cleveland, OH 44106 USA. Tel: (216) 368-4518, Fax: (216) 368-4223. E-mail: dxd9@po.cwru.edu

Kenneth H. Dillon, University of Alabama, UAB, School of Public Health, Department of Environmental Health Sciences, 309 C Ryals Bldg, 1665 University Blvd, Birmingham, AL 35294-0022 USA. Tel: (205) 934-6089. Fax: (205) 975-6341. E-mail: dillonk@uab.edu

Jeroen Douwes, Environmental & Occupational Health, Department of Environmental Sciences, Wageningen Agricultural University, PO Box 238, 6700 AE Wageningen, The Netherlands. Tel: 31 317 48 2595. Fax: 31 317 48 2782. E-mail: jeroen.douwes@staff.eoh.wau.nl

Peyton Eggleston, Pediatric Allergy & Immunology, Johns Hopkins University Medical Center, 600 N Wolf Street, Baltimore, MD 21287 USA. Tel: (410) 955 5883. Fax: (410) 955 0229. E-mail: pegglest@welchlink. welch.jhu.edu

Ruth Etzel, Division of Epidemiology and Risk Assessment, Food Safety and Inspection Service, 1400 Independence Ave, SW, Rm 3718, Franklin Ct, Washington DC 20250-3700 USA. Tel: (202) 501-7373. Fax: (202) 501-6982. E-mail: ruth.etzel@usda.gov

David Fishwick, Health and Safety Laboratory, Broad Ln, Sheffield S3 7HQ, UK. Tel: 44 114 2892677. Fax: 44 1142892768. E-mail: david.fishwick@hsl.gov.uk

Suzanne Gravesen, Danish Bldg Research Institute, SBI, PO Box 119, Dr Neergaards Vej 5, 2970 Hørsholm, Denmark. Tel: 45 45 86 5533. Fax: 45 45 86 75 35. E-mail: sug@sbi.dk

Tuula Husman, National Public Health Institute, Dept of Environmental Medicine, PO Box 95, 70701 Kuopio, Finland. Tel: 358 17 201 325. Fax: 358 17 201 265. E-mail: tuula.husman@ktl.fi

Robert R Jacobs, University of Alabama, UAB, School of Public Health, Department of Environmental Health Sciences, 309 C Ryals Bldg, 1665 University Blvd, Birmingham, AL 35294-0022 USA. Tel: (205) 934-6089. Fax: (205) 975-6341. E-mail: jacobsr@uab.edu

Eckardt Johanning, Eastern New York Occupational and Environmental Health Center, 155 Washington Ave, Albany, New York 12210 USA. Tel: (518) 436-5511. Fax: (518) 436-9110. E-mail: johanni2@crisny.org

David Miller, Dept of Chemistry, Carleton University, Ottawa, Ontario, Canada K1S 5B6. Tel: (613) 520-2710. Fax: (613) 520-3749. E-mail: jdmiller@ccs.carleton.ca

Erika von Mutius, University Children's Hospital, Lindwurmstr 4, D 80337, Münich, Germany. Tel: 49 89 5160 2709. Fax: 49 89 5160 4452. E-mail: u7r11ad@sunmailhost.lrz-muenchen.de

Ragnar Rylander (workshop coordinator), Dept of Environmental Medicine, Box 414, 405 30 Gothenburg, Sweden. Tel: 46 31 773 3601. Fax 46 31 825004. E-mail: ragnar.rylander@envmed.gu.se

Babsahaeb Sonawane, U.S. Environmental Protection Agency, 401 M St, Washington, DC 20460 USA. Tel: (202) 564-3292. Fax: (202) 565-0078. E-mail: sonawane.bob@epamail.epa.gov

William Sorensen, Immunology Section, National Institute for Occupational Safety and Health, 1095 Willowdale Rd, MS 215, Morgantown WV 26505 USA. Tel: (304) 285- 5797. Fax: (304) 285-5861. E-mail: WGS1@cdc.gov

Yvonne Peterson (workshop secretary), Department of Environmental Medicine, Box 414, 405 30 Gothenburg, Sweden. Tel: 46 31 773 3602. Fax: 46 31 825004. E-mail: yvonne.peterson@envmed.gu.se

REFERENCES AND NOTES

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3. Dales RE, Zwanenburg H, Burnett R, Franklin CA. Respiratory health effects of home dampness and mold among Canadian children. Am J Epidemiol 134:196-203 (1991).

4. Husman T. Health effects of indoor air microorganisms. Scand J Work Environ Health 22:5-13 (1996).

5. Centers for Disease Control and Prevention. Update: Pulmonary hemorrhage/hemosiderosis among infants: Cleveland, Ohio, 1993-1996. Morb Mortal Wkly Rep 46:33-35 (1997).

6. Etzel RA, Montana E, Sorenson WG, Kullman GJ, Allan TM, Dearborn DG. Acute pulmonary hemorrhage in infants associated with exposure to Stachybotrys atra and other fungi. Arch Pediatr Adolesc Med 152:757-762 (1998).

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11. Peat JK, Britton WJ, Salome CM, Woolcock AJ. Bronchial hyperresponsiveness in two populations of Australian school children. III: Effect of exposure to environmental allergens. Clin Allergy 17:291-300 (1987).

12. Sherman JM, Winnie G, Thomassen MJ, Abdul-Karim FW, Boat TF. Time course of hemosiderin production and clearance by human pulmonary macrophages. Chest 86:409-411 (1984).

13. Health Canada. Fungal Contamination in Public Buildings: A Guide to Recognition and Management. Ottawa, Ontario:Federal Provincial Committee on Environmental and Occupational Health, 1995.

14. New York City Human Resources Administration, and Mount Sinai-Irving J. Selikoff Occupational Health Clinical Center. Guidelines on assessment and remediation of Stachybotrys atra in indoor environments. New York City Department of Health, 1993. In: Fungi and Bacteria in Indoor Air Environments. Health Effects, Detection and Remediation (Johanning E, Young CS, eds). Albany, NY:Eastern New York Occupational Health Program, 1993.

15. ISIAQ. Control of Moisture Problems Affecting Biological Indoor Air Quality. TFI-1996. Ottawa, Ontario:International Society of Indoor Air Quality and Climate, 1996.

16. Dillon HK, Heinsohn PA, Miller JD. Field Guide for the Determination of Biological Contaminants in Environmental Samples. Fairfax, VA:American Industrial Hygiene Association, 1996.