The fundamentals of mold-related illness

When to suspect the environment is making a patient sick

Frederick Fung, MD, MS; William G. Hughson, MD, PhD

WEB EXCLUSIVE / JUNE 2003 / POSTGRADUATE MEDICINE

CME learning objectives

• To review current medical evidence about the link between mold exposure and clinical illness
• To recognize the clinical implications of indoor mold exposure
• To understand the basic management of mold-related medical conditions

The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.

Preview: Disorders related to indoor air quality have become a major concern for primary care physicians, who often are asked to evaluate patients whose symptoms may be caused or aggravated by indoor exposure to mold. In this article, the authors review the common types of indoor mold and discuss the management of mold exposure and related illnesses.

The public, healthcare professionals, and engineers are becoming more aware of the possible medical consequences of indoor mold exposure (1). It is not uncommon for primary care physicians to encounter patients such as the woman cited in the following case report.

Hypothetical case

A patient has noted recent upper respiratory symptoms (eg, nasal congestion, sinus headache, episodic dyspnea). She works in an office building that has flower planters along the outside walls. Water from the planters has leaked into the building and stained the wallboard and adjacent carpet. The office smells musty, and other workers have complained of the odor.

What is the diagnosis? Has the water leak had a role in causing the symptoms? What should be done for the patient? Should the patient be considered disabled? What is the prognosis? What should be done to correct the problem in the building?

What is mold?

Mold belongs to the kingdom Fungi, one of five classifications of living organisms. The others are Monera (eg, bacteria), Protista (eg, protozoa), Plantae, and Animalia. Fungi cannot photosynthesize and therefore are described as heterotrophic; they obtain nutrients from other organisms, either living or dead (2). Fungi are regarded as decomposers, whereas plants are producers and animals are consumers.

Molds are classified into three groups: microfungi, mushrooms, and dry-rot fungi. Mold spores are analogous to plant seeds. They can remain dormant for months or years and can withstand extreme conditions. Whenever nutrients and moisture are present in sufficient amounts, spores germinate to form hyphae. Fungal growth continues as long as moisture is present.

Types of mold in indoor environments

Mold is ubiquitous in the environment. Typically, levels of viable and nonviable spores in a modern, air-conditioned structure are about 60% of those outdoors, and the distribution of mold species is similar. The number and types of molds inside homes are comparable with those outdoors because domestic structures are leakier than modern, tightly sealed office buildings.

Increased levels of mold or a distortion in the distribution of mold species in a building compared with outdoors suggests the presence of excessive moisture and possible mold amplification. In general, when the level of a mold species in a building is at least one order of magnitude greater than the outdoor concentration, a person's symptoms are probably related to indoor mold exposure.

Indoor mold can be classified into two groups. The first group requires low to moderate moisture and includes Penicillium, Cladosporium, and Alternaria. The second group requires high moisture and includes Stachybotrys, Chaetomium, Trichoderma, and Aspergillus niger. Some species of fungi are prone to growing in certain substrates. Table 1 lists the common indoor molds.

Implications for medical practice

Mucous membrane discomfort (ie, eye, nose, and throat irritation), headache, and fatigue are the most common symptoms caused by poor indoor air quality. The term sick building syndrome has been used to describe these building-related symptoms when a specific diagnosis (eg, asthma, rhinitis) cannot be established.

In contrast to sick building syndrome, the term building-related illness is used when a disease that affects one or more building occupants has been proven to be clinically and causally linked to the indoor environment. With proper therapy and avoidance, the medical condition usually resolves.

Mold-related illnesses

In general, mold can produce four types of human illness: allergy, infection, irritation, and toxic effects (table 2).

Allergy and hypersensitivity pneumonitis
Allergic reactions to mold can range from mild to severe and from transitory to chronic. Detailed descriptions of allergic diseases are available in a textbook by Middleton and associates (3). Briefly, allergic rhinitis and asthma are associated with responses mediated by immunoglobulin E (IgE); hypersensitivity pneumonitis is associated with T-cell responses and responses mediated by immunoglobulin G (IgG). Allergic rhinitis and sinusitis can be diagnosed using patient history, physical examination findings, the presence of eosinophils in nasal smears, and the results of skin prick tests and radioallergosorbent tests to detect specific IgE antibodies.

Asthma due to fungal allergens is characterized by chest tightness, wheezing, cough, and dyspnea that worsen with exposure to the allergen (4,5). Symptoms typically occur within 1 hour of exposure. Diagnosis is made on the basis of patient history, physical evidence of bronchospasm, pulmonary function tests demonstrating reversible air flow obstruction, or a positive methacholine chloride (Provocholine) challenge test.

In its early stages, hypersensitivity pneumonitis is characterized by recurrent symptoms of fever, cough, and chest tightness and the presence of pulmonary infiltrates on a chest radiograph. Chronic hypersensitivity pneumonitis features progressive dyspnea, fatigue, interstitial pneumonitis, and pulmonary fibrosis. This condition occurs mainly in farmers, pigeon breeders, cheese makers, wood processors, and mushroom growers exposed to high levels of organic dust and fungal antigens. Diagnosis is made on the basis of patient history, physical examination findings, an abnormal chest radiograph or computed tomographic (CT) scan (figure 1a), a restrictive pattern on pulmonary function tests, reduced diffusion capacity, and the presence of numerous lymphocytes on bronchoalveolar lavage. Open lung biopsy may be needed to confirm the diagnosis (figure 1b).

Infection
The most common fungal disease is a superficial mycosis, such as tinea infection, that is not linked to indoor air quality or building-related illness. Bronchopulmonary aspergillosis, or allergic bronchopulmonary aspergillosis, is an inflammatory disease caused by an immunologic response to an Aspergillus species, usually Aspergillus fumigatus, growing in the bronchi of patients with asthma. It has been reported in immunocompromised patients and in patients with chronic obstructive pulmonary disease and has been linked to building-related illness.

Systemic fungal infections such as histoplasmosis, coccidioidomycosis, and cryptococcosis have occurred after contaminated bird droppings or construction dusts were disseminated in an indoor environment. Detailed descriptions of mycoses can be found in standard textbooks, such as the publication by Mandell and colleagues on infectious diseases (6).

Irritation
Mold exposure may aggravate existing allergic rhinitis or asthma because of its irritant effects. Mold can produce a variety of organic chemicals, including alcohols and sulfur-containing compounds that exude musty and pungent odors. Irritation may cause mucous membrane symptoms such as conjunctivitis and rhinitis with trigeminal nerve stimulation. Pungent odors may initiate avoidance reactions, a generalized feeling of discomfort, breath holding, and a burning sensation on the skin.

Under unusual circumstances, volatile organic chemicals may reach levels sufficient to produce central nervous system symptoms such as headache, inability to concentrate, or dizziness. Glucans are glucose polymers that are components of most fungal cell walls, and exposure to airborne 13-beta-D-glucan has been known to cause irritation symptoms due to airway inflammation (7). However, these irritant effects are transient and self-limiting.

Mycotoxicosis
Molds produce antibiotics and mycotoxins to gain a competitive advantage over bacteria and other mold species. Mycotoxins, which typically are cytotoxic, disrupt cell membranes and interfere with the synthesis of protein, RNA, and DNA. Not all molds produce mycotoxins, however. Toxigenic molds vary in their mycotoxin production depending on the substrate, environmental factors (eg, temperature, relative humidity, light, presence of oxygen and carbon dioxide), and seasonal and life cycle stages. The presence of a toxigenic mold in an indoor environment does not prove that the occupants have been exposed to mycotoxins.

The only well-documented human mycotoxicoses have been the result of ingestion rather than inhalation. Although these cases are unrelated to indoor mold exposure, they are important to the understanding of the toxin-production mechanism, pathophysiologic factors, and clinical syndrome of mycotoxicosis.

One of the earliest documented examples of mycotoxicosis is ergotism from eating rye contaminated with Claviceps purpurea (2). The major clinical syndromes of ergotism are classified as either gangrenous or convulsive. The toxic effects of aflatoxins, which are produced by Aspergillus flavus, were collectively called turkey X disease when they were first documented in 1960 (2). Aflatoxins, which probably are the most extensively studied mycotoxins, cause such diseases as acute fatty liver syndrome, hepatic necrosis, and an encephalopathy similar to Reye's syndrome. Chronic exposure to aflatoxins can lead to hepatocellular carcinoma (8).

Stachybotrys chartarum (also called Stachybotrys atra) typically is slimy and not easily aerosolized. Stachybotrys mycotoxin had been thought to cause acute pulmonary hemorrhage and death in infants (9). However, the Centers for Disease Control and Prevention recently issued a report stating that the association has not been proved (10). The controversy over airborne Stachybotrys mycotoxins originated from extrapolation of data from case series that did not have specific medical diagnoses. About 10 ng of mycotoxins are produced for every 1 million mold spores (11). Assuming the exposure is cumulative, inhalation of 10⁹ spores per hour would be required for toxic effects. Therefore, it is unlikely that inhalation of fungal parts presumed to contain mycotoxins could produce significant human illness--particularly in a nonagricultural setting (12,13).

Identification of a serum fungal antibody means only that the patient has been exposed at one time; it does not prove that a disease was caused by the fungus or its metabolites. Interpretation of antibody tests is complicated by cross-reactivity with other fungi that have similar antigenic properties. Also, the level of antibody at any point in time is not predictable (14). Therefore, S chartarum IgG antibodies cannot be used to establish the date or source of the last exposure.

Management of mold exposure

The first step in the management of mold exposure is to establish a diagnosis using the previously described clinical tools. A medical history of the chronology of symptoms and the duration of exposure should be obtained. Open-ended questions about a building's water intrusion, leaks, musty odor, and water stains and the presence of visible mold on the walls, carpets, or clothes should be asked.

Physical examination should focus on the evaluation of rhinitis, sinusitis, asthma, and hypersensitivity pneumonitis. Laboratory studies, radioallergosorbent tests, radiographs, pulmonary function tests, cultures, and other specialized tests (eg, CT, bronchoscopy) may be indicated when clinical symptoms and signs suggest allergy, asthma, hypersensitivity pneumonitis, or sinus infection.

The issue of disability depends on the specific diagnosis. Allergy can be managed with antihistamines and avoidance of mold exposure. Asthma can be treated and controlled with a beta-agonist and a corticosteroid inhaler. Infection can be treated with antifungal medications, and recovery is usually complete. Hypersensitivity pneumonitis, however, may require prolonged prednisone therapy, and the patient may have significant disability due to pulmonary impairment.

Unfortunately, many patients have nonspecific signs and symptoms, and the diagnostic label may be imprecise. Nevertheless, the presence of similar problems in coworkers and the temporal relationship between when the patient entered the building and the onset of symptoms suggest a causal relationship, even when a specific diagnosis is not possible.

Typically, the environmental problem that caused the mold has been present for some time, and corporate management may be aware of employee complaints. To avoid creating adversarial work relationships, it is wise for the physician to discuss the situation with the patient's supervisor. In some cases, an environmental assessment already has been done and data are available for review. If not, the physician can recommend an industrial hygiene inspection to detect water intrusion and mold amplification.

Industrial hygiene evaluation is useful only when a patient has symptoms that suggest mold exposure. Without medical complaints, results of industrial hygiene assessment are too nonspecific to be useful. In general, an industrial hygienist is able to perform a visual inspection and to obtain surface, bulk, and air samples of molds and mold spores to confirm the presence and source of mold growth. Once identified, these problems usually can be corrected in a relatively straightforward manner. Currently, because of a lack of sensitivity and specificity in laboratory tests, sampling for mycotoxins is performed only in the research setting.

Patient symptoms usually improve or disappear when the mold contamination is eliminated. In rare instances, health problems (eg, asthma, hypersensitivity pneumonitis) may persist, requiring long-term healthcare, permanent work restrictions, or a determination of disability.

Summary and conclusion

Health effects of bioaerosol exposure from fungal sources include allergy, infection, irritation, and toxicity. The first three categories have well-established mechanisms, but dose-response data are lacking and the degree of individual susceptibility is highly variable.

Specific toxic effects due to inhaled mycotoxins are not well documented and therefore remain controversial. In the absence of specific illness and respiratory symptoms in the occupants of a home or office, responding to visible mold with knee-jerk advice is not advised. Such statements as "Move out of your home" or "Evacuate the building" have significant psychosocial and economic consequences.

Excessive moisture is the fundamental cause of mold proliferation. Before starting expensive and often low-yield environmental investigations, the first step is to eliminate excess moisture (15). Proper building design and construction, combined with periodic preventive maintenance to avoid water intrusion, are fundamental in preventing the adverse health effects of mold exposure.

References

1. American Society of Heating, Refrigerating and Air-Conditioning Engineers. Ventilation for acceptable indoor air quality. Atlanta: ASHRAE Standard 62-1999, 1999
2. Kendrick B. The fifth kingdom. 2nd ed. Sidney, British Columbia: Mycologue, 1992
3. Middleton E Jr, Reed CE, Ellis EF, et al, eds. Allergy: principles and practice. 5th ed. St Louis: Mosby, 1998
4. Fung F, Tappen D, Wood G. Alternaria-associated asthma. Appl Occup Environ Hyg 2000;15(12):924-7
5. Fung F, Young C. Mold-associated asthma. American Society of Heating, Refrigerating, and Air Conditioning Engineers, IAQ Moisture, Microbes and Health Effects: Indoor Air Quality and Moisture in Buildings meeting, San Francisco: 2001
6. Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Vol 2. 5th ed. Philadelphia: Churchill Livingstone, 2000
7. Rylander R. Airborne (13)-beta-D-glucan and airway disease in a day-care center before and after renovation. Arch Environ Health 1997;52(4):281-5
8. Shank RC, Siddhichai P, Subhamani B, et al. Dietary aflatoxins and human liver cancer. V. Duration of primary liver cancer and prevalence of hepatomegaly in Thailand. Food Cosmet Toxicol 1972;10(2):181-91
9. Update: pulmonary hemorrhage/hemosiderosis among infants--Cleveland, Ohio, 1993-1996. MMWR Morb Mortal Wkly Rep 1997;46(2):33-5
10. Update: pulmonary hemorrhage/hemosiderosis among infants--Cleveland, Ohio, 1993-1996. MMWR Morb Mortal Wkly Rep 2000;49(9):180-4
11. Burge HA. Fungi: toxic killers or unavoidable nuisances? Ann Allergy Asthma Immunol 2001;87(6 Suppl 3):52-6
12. Fung F, Clark R, Williams S. Stachybotrys, a mycotoxin-producing fungus of increasing toxicologic importance. J Toxicol Clin Toxicol 1998;36(1-2):79-86
13. Fung F, Clark R, Williams S. Stachybotrys: still under investigation. (Letter) J Toxicol Clin Toxicol 1998;36(6):633-4
14. Halsey J. Performance of a Stachybotrys chartarum serology panel. (Abstr) Presented at the Western Society of Allergy, Asthma and Immunology Annual Meeting. Allergy Asthma Proc 2000;21(3):174-5
15. Macher J, ed. Bioaerosols: assessment and control. Cincinnati: American Conference of Governmental Industrial Hygienists, 1999

Dr Fung is chief toxicologist, Sharp Rees-Stealy Medical Group, San Diego, and medical toxicology consultant, University of California, San Diego, School of Medicine. Dr Hughson is director and professor, Center for Occupational and Environmental Health, University of California, San Diego, School of Medicine. Correspondence: Frederick Fung, MD, MS, Sharp Rees-Stealy Medical Group, 2001 4th Ave, San Diego, CA 92101. E-mail: fred.fung@sharp.com.