Indoor mold and your patient's health: From suspicion to confirmation

The quality of indoor air is an ongoing public health concern, especially in the wake of evidence from numerous epidemiologic studies linking symptoms with damp homes and exposure to indoor molds.^1-8 Extensive media coverage of these problems and the current obsession with "tight" energy-efficient homes have further fueled interest in indoor mold-related disease (IMRD).

Each year, a significant number of patients present to their physicians with symptoms suggesting exposure to indoor molds. Yet the diagnosis of IMRD remains difficult to confirm. A major obstacle to diagnosis is the inability to standardize indoor mold testing.⁹ However, other obstacles can be overcome by maintaining both a high index of suspicion and an up-to-date knowledge of the underlying mechanisms and symptoms of IMRD.

In this article, we will summarize the health effects of exposure to indoor mold and will present our approach to the workup. We will limit our discussion to respiratory problems, which are the most common manifestation of IMRD.

HEALTH EFFECTS OF INDOOR MOLD

The health effects of exposure to indoor molds can be divided into 6 categories: irritant effects, nonspecific respiratory symptoms, allergic sensitization, infection, mycotoxicosis, and psychogenic reactions.While certain fungi, such as Alternaria,Aspergillus, and Cladosporium species, are more allergenic than others, approximately 80 species are known to be allergenic.

Irritation

Indoor fungal contamination can cause transient irritation of the respiratory and ocular mucosa. Symptoms may include tearing, conjunctivitis, rhinitis and, rarely, wheezing.⁹ A number of different fungal elements, such as glucans, proteases, ergosterol, and volatile organic compounds, may cause these symptoms.¹⁰

Glucans are a particularly important potential irritant. These cell wall constituents have inflammatory and adjuvant properties, perhaps as a result of their ability to stimulate the release of interleukin 1 and 2.¹⁰ Airway exposure to (1,3) ß-d-glucans has been associated with airway inflammation.¹⁰ However, there is a paucity of data on the presence of these fungal elements as well as other fungal products in homes, even in association with mold contamination.

It is important to remember that irritational symptoms are transient and temporally related to exposure to mold-contaminated buildings. Symptoms that persist when the person is outside the building for a prolonged period should not be attributed to "aeroirritation." It is highly doubtful that this mechanism plays a substantial role in causing respiratory symptoms, except in the most contaminated dwellings, such as those with overt flooding or other significant incursion of water. Further research is necessary to validate aeroirritation as a commonly accepted mechanism of IMRD.

Nonspecific respiratory symptoms

Several epidemiologic studies have demonstrated an association between indoor dampness/humidity and a variety of nonspecific respiratory complaints, especially in children.^1-8 Typical manifestations include nasal symptoms, phlegm production, cough, wheeze, recurrent respiratory infections, fatigue, and headache.^1-8

While the association between damp indoor environments and respiratory problems is well documented, there is insufficient evidence of a causal relationship.¹¹ Several factors contribute to this, including the inability to segregate fungal from other important indoor allergens, the difficulty of measuring mold levels in house dust and other airborne specimens, and the inability to separate the irritative effects of the (1,3) ß-d-glucans and volatile organic compounds emitted by mold from other indoor irritants (such as tobacco smoke).

Allergic sensitization and hypersensitivity

Common allergic responses to indoor molds are characterized as either an IgE-mediated immediate hypersensitivity or a humoral and cell-mediated hypersensitivity pneumonitis.

• Immediate hypersensitivity: This can trigger symptoms of asthma or allergic rhinitis, including rhinorrhea, nasal congestion, conjunctivitis, and wheezing. Persons with mold allergies typically are sensitive to other seasonal and perennial allergens. Indoor exposure to mold, especially at high concentrations, can play a significant role in their symptoms.

• Hypersensitivity pneumonitis: The interaction between activated T cells and inhalational exposure to mold proteins can result in hypersensitivity pneumonitis. Symptoms include the common triad of cough, dyspnea, and fever. Because very high levels of airborne antigen are needed to cause hypersensitivity pneumonitis, most cases occur in occupational settings, such as those of pigeon breeders or grain farmers.¹²

The diagnosis of hypersensitivity pneumonitis is based on the combination of symptoms, physical findings (basilar rales, for example), hypoxemia and reduced carbon monoxide-diffusing capacity on pulmonary function tests, pulmonary infiltrates (documented by chest imaging), the presence of serum-specific IgG antibody, and a temporal association with exposure to a known triggering antigen.

• Other hypersensitivity reactions: Occasionally, fungi can cause allergic fungal sinusitis (AFS) or aller-gic bronchopulmonary aspergillosis (ABPA). These are IgE-mediated illnesses characterized by fungal growth in the airway. Atopic persons are most at risk. ABPA causes bronchial inflammation, with wheeze, productive cough, fever, weight loss, and pulmonary infiltrates. AFS is a similar process that is characterized by recurrent rhinosinusitis and nasal polyps.

Mycosis

Indoor mold exposures are generally not considered risk factors for mycosis, especially in persons who are immunocompetent. Infections caused by fungi such as Histoplasma capsulatum and Coccidioides immitis are primarily outdoor phenomena. This is also true of Cryptococcus neoformans.

Mycotoxicosis

Mycotoxins are natural environmental contaminants produced by fungi. There are more than 400 known mycotoxins, which are produced by at least 350 fungi worldwide. The effects of these toxins in humans primarily result from ingestion of contaminated moldy foods, causing predominantly GI symptoms.^13-15

Several recent studies have attempted to link inhalation of indoor mycotoxins with a poorly defined symptom complex that can involve practically any organ system.^16-18 The pathophysiologic mechanisms underlying this "toxic mold syndrome" (TMS) are unknown.^19-26 A recent review of 50 patients showed that most had other disorders that could account for their TMS-like symptoms.²⁷ Nonetheless, this patient population tends to believe strongly that fungi are responsible for their symptoms.

Psychogenic effects

Patients who believe their symptoms are related to mold exposure may be especially concerned about their health. Strong belief systems linking subjective symptoms to poor air quality can become deeply entrenched and lead to somatization in some patients.

PATIENT EVALUATION

Most mold-related illnesses are related to outdoor exposures, and IMRD is considered to be a diagnosis of exclusion. Therefore, a primary goal of the evaluation is to identify any established disorders that can masquerade as IMRD. Six general groups of disorders have been identified in patients who present with building-related symptoms (Table 1).²⁷

General approach

A systematic approach to the workup of suspected IMRD can help avoid 3 common pitfalls:

• Failure to recognize or uncover a preexisting medical disorder that could be responsible for symptoms.

• Failure to diagnose an underlying condition of recent onset masquerading as IMRD.

• Physician support of patient claims in the absence of credible scientific substantiation.

When a patient presents with respiratory symptoms in an area in which indoor mold illnesses are prevalent, it is reasonable to immediately start evaluating for IMRD. If there is a low probability that symptoms are mold-related, we consider it equally reasonable to investigate or empirically treat the more probable disease(s). If the diagnosis remains unclear, evaluate for IMRD.

Investigating for IMRD

The approach to patient evaluation is summarized in Table 2. One of the most important components is the history. One must ask about symptoms, including those involving the upper airway, lower airway, and skin, as well as systemic symptoms. The date of onset is important, particularly if it correlates with a new exposure at a "suspect" building. Keep in mind that reactions may not be immediate if sensitization has not yet occurred. Symptom duration and exacerbating or alleviating measures should also be elicited.

Unfortunately, no single historical clue identifies IMRD. A history of symptom improvement during weekends, holidays, or other periods of extended absence from building exposure or symptom worsening on return to the suspect building suggests the diagnosis but is neither sensitive nor specific.

To further investigate whether IMRD is playing a role, you must ask about any aspect of the home or work environment that could contribute to mold growth. This includes information on dampness, humidity, evidence of leakage or flooding, and visible mold growth. Also ask about indoor pets, plants, humidifiers, and thermostat settings, as well as exposure to compost or barns. For example, a history of humidifier use, basement water leakage, or visible mold growth significantly heightens the suspicion of IMRD.

A comprehensive medical history that includes a general review of symptoms, previous illnesses, allergies, medications, and illicit drug use can help determine whether there are other causes for the patient's symptoms. Because patients' recollections of past illnesses are often inconsistent, it is useful to augment the information obtained in the personal interview with a review of all prior medical records.

A focused physical examination is unlikely to differentiate IMRD from other problems, but it can help objectively document disease. It can also reveal evidence of other diseases or disorders that may be responsible for symptoms.For example, a physical examination could reveal thyroid enlargement, indicating thyroiditis, which may explain many or all of the patient's systemic complaints. The examination also may uncover signs of pneumonia, which may be the cause of the patient's malaise or cough.

Laboratory and other tests to order include serum studies, imaging, and spirometry. The initial evaluation focuses on high-yield, low-cost procedures, including hemogram; chemistry; measurement of total immunoglobulin levels and levels of IgE, IgG, and IgA; and skin prick or in vitro testing for common indoor fungal and nonfungal aeroallergens.

IgG-specific antibodies only provide a biologic marker of past exposure and are usually not helpful.²⁸ They do, however, have limited usefulness for evaluating patients with certain mold-related hypersensitivity states, such as hypersensitivity pneumonitis, ABPA, and AFS. Some laboratories offer immunoassays to identify trichothecenes or trichothecene-specific antibodies in blood or urine; these involve procedures that have not been analytically validated and are not recommended.^29-32

If you suspect bacterial or fungal sinusitis, arrange for sinus imaging studies and nasal smears. Chest imaging (radiography or CT scanning) and spirometry can provide supportive evidence of hypersensitivity pneumonitis. Spirometry can also yield important results in fungal allergic asthma, especially if you can arrange to test the patient before and after he or she is exposed to the incriminated building.

If the results of spirometry are normal, methacholine challenge can be performed to rule out the presence of underlying bronchial hyperreactivity. If the diagnosis is still in question, the gold standard test is a specific provocation study, in which the suspect building is used as the challenge tool. Consider arranging for a specific provocation study if the patient has findings such as nasal obstruction or spirometric abnormalities that can be measured objectively.

We do not recommend environmental avoidance for patients with nonspecific symptoms, since there is no way to obtain the objective measurements necessary for determining a causal relationship between environmental trigger and symptoms.

Referral

Specialists can be helpful if the diagnosis remains in doubt. A pulmonologist, for example, should be consulted when chest imaging findings are abnormal. Symptoms suggesting upper airway obstruction or a change in the patient's larynx (suggesting, for example, vocal cord dysfunction) warrant consultation with an otolaryngologist.

We strongly encourage collaboration with an environmental hygienist. These specialists know how to perform a comprehensive indoor mold survey correctly. Assaying for indoor irritants, mycotoxins, mold, and perennial allergens (with appropriate controls) can significantly strengthen or weaken the case for IMRD. Patient history can help guide potential locations of contamination.

ASSESSING INDOOR MOLD

Of the estimated 250,000 species of fungi, fewer than 100 are known to be primary pathogens in humans or animals.³³ The most common pathogens in humans are Candida albicans and Aspergillus species.

Sampling

Because fungi are so abundant, it is challenging to sample indoor environments for pathogenic fungi. Sampling is affected by such variables as the nature and location of the sample, the manner of collection, and the selection of media.⁹

The population of mold indoors is greatly influenced by that outdoors. Simply opening a door or window permits entry of airborne molds, and molds and fungi can easily be tracked inside on shoes, clothing, pets, sporting equipment, and plants. Thus, environmental sampling needs to include specimens taken from outdoors.

Keep in mind, however, that outdoor concentrations of molds vary widely depending on geographic location, climatic conditions (such as wind), season, and time of day. Despite these limitations, the prevailing opinion is that in well-constructed homes without water contamination, the relative levels of fungi found indoors reflect those found outdoors.³⁴ Indoor levels are expected to be 40% to 80% lower than corresponding outdoor levels of similar species of mold.³⁵

The ideal approach to sampling for indoor fungi has recently been described.³⁶ When sampling, there are a few points to keep in mind. For example, the physical presence of mold is insufficient evidence of patient exposure--it is also necessary to determine how the person came in contact with the mold.

The isolation of a toxigenic mold species indoors does not necessarily confirm the presence of mycotoxins or aeroirritants unless they are measured.³⁷ Indoor air-quality studies usually focus on mold, excluding other important indoor allergens and irritants. Persons with an atopic phenotype could be reacting to one of many indoor allergens other than mold.

Indoor air-quality assessments are generally limited to a suspect home or office, ignoring such areas of potential mold exposure as automobiles, barns, greenhouses, and schools. This undermines any attempt to establish causality. Evidence indicates that persons alleging health effects from a specific source of exposure often have sensitivities that do not correlate with molds found in the suspect location.²⁷ Alternative sites of exposure could contain high levels of aeroallergens, including molds, that could account for sensitization and symptoms.

Determining biologic impact

Interpreting the biologic significance of indoor mold is just as problematic as acquiring the sampling data. There are no uniform numeric standards defining acceptable levels of indoor airborne or surface fungi.^38,39 Furthermore, there is no consistency between any of the suggested guidelines for assessing indoor molds.

One of the major impediments to establishing indoor airborne standards is the absence of scientific evidence documenting adverse health effects of molds encountered in occupational settings, where a high concentration of airborne fungi is common.^40,41 Equally significant is the lack of known dose-response relationship between a specific ambient mold concentration and health.

Because air is densely populated with fungal spores, there is no way to identify the source of a person's sensitivity precisely . Moreover, the presence of immunologic sensitivity indicates only previous exposure to a specific or antigenically similar fungal species; it does not demonstrate a symptomatic state. For example, one study found IgG- and IgE-specific antibody to Stachybotrys atra in 49.2% and 9.4% of asymptomatic Red Cross blood donors, respectively.²⁸

If indoor airborne mold spores are present at expected levels (40% to 80% of outdoor concentrations), there is no way to attribute symptoms to that specific indoor environment because there is an equal opportunity for the same exposure to occur outdoors.

INTERPRETING THE EVIDENCE

The diagnosis of IMRD depends on the following:

• No other medical condition is found to account for symptoms.

• Symptoms are consistent with an accepted pathogenic mechanism of IMRD.

• Symptoms demonstrate a temporal relationship with exposure to a building suspected of having mold contamination.

• The suspect building is documented to contain mold.

It also is important to determine the inhalational process that caused the patient's problems. Results from laboratory testing, immunologic studies, imaging, and spirometry help determine whether symptoms are related to aeroirritation, allergy, infection, or unrelated disorders.

References:

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