Objectives

1. To review evidence supporting mold spores as a cause of asthma exacerbations.
2. To understand the diagnostic criteria and a treatment algorithm for allergic bronchopulmonary aspergillosis.
3. To review the clinical, radiographic, and histopathologic features of hypersensitivity pneumonitis with a focus on occupational exposure to molds.
4. To understand the diagnostic criteria and treatment modalities for allergic fungal sinusitis.
5. To review mechanisms underlying each category of mold-related disease.

Abbreviations

ABPA = allergic bronchopulmonary aspergillosis; AFS = allergic fungal sinusitis; CF = cystic fibrosis; HP = hypersensitivity pneumonitis

Fungi are one of the largest groups of organisms on earth and may account for as much as 25% of the planet's biomass. A small number of molds cause human illness by invading an immunocompromised host. A far greater number of fungi cause human disease via immunologic mechanisms. This review will focus on disease caused by noninvasive fungi; specifically, allergic mechanisms including asthma, allergic bronchopulmonary aspergillosis (ABPA), hypersensitivity pneumonitis (HP), and allergic fungal sinusitis (AFS) will be discussed.

Asthma and Mold

Fungal spores are potential triggers for exacerbations of chronic allergic disease as both asthma and rhinitis are type I, IgE-mediated, immunologic responses. The contribution of major allergens, such as cat dander, dust mites, and cockroaches, has proven easier to assess than the role of fungi in IgE-mediated disorders. The ubiquitous and ever-changing aspects of mold in both indoor and outdoor environments, coupled with a lack of standardized, commercially available mold antigen, make scientific study problematic.¹ Several mold-specific methods are available to test for sensitization to specific organisms. Skin prick testing is a simple technique that can detect IgE towards a specific allergen. Intradermal testing is available and is more sensitive but less specific than skin prick testing.² Radioallergosorbent testing is a serologic test that measures the circulating allergen-specific IgE antibodies. Finally, in rare cases, inhalation challenge testing for bronchial reactivity is performed. Each of these tests suffers from lack of standardized mold extract and provides variable results.

Despite limitations, mold sensitization has been associated with allergic disease. Twenty-five to 33% of atopic patients in various parts of Europe and the United States have positive skin test reactions to one of the basidiomycete species.³ However, sensitization to mold can be detected in many asymptomatic individuals. Children may be particularly affected by elevated mold spore counts. In one study, symptom severity increased as much as 30% for every 1,000 spores/m³ of air.⁴ Additionally, asthma epidemics have been epidemiologically linked to times of high spore counts in the air.⁵ Recently, a group of Canadian investigators reported that increased fungal spore counts were associated with the phenomenon of thunderstorm asthma. The researchers accounted for other asthma triggers, such as increases in pollen counts, ozone, and other aeroallergens with statistical tools.⁶

Allergic Bronchopulmonary Aspergillosis

ABPA is an allergic disorder found in asthmatic patients and in individuals with cystic fibrosis (CF). The disease stems from colonization and saprophytic growth of fungus, most commonly Aspergillus fumigatus, in bronchial mucus of afflicted patients. Why some people are predisposed to this condition is unknown. The clinical features, immunopathology, and treatment of ABPA are briefly reviewed.

A diagnosis of ABPA should be considered in a patient with refractory asthma or in a CF patient with bronchospastic features, such as reversible airflow limitation or response to steroids. The diagnostic criteria differ slightly in these two groups. Originally posited by Rosenberg et al⁷ in 1977, the criteria have been modified to allow earlier diagnosis and thus earlier therapy for patients with ABPA. An asthmatic patient should fulfill five criteria: (1) asthma; (2) central bronchiectasis on chest CT; (3) immediate cutaneous reactivity to A fumigatus; (4) total serum IgE level >1,000 ng/mL; and (5) elevated specific IgE for A fumigatus.⁸ Another common feature includes infiltrates on chest radiograph, typically in the mid and upper lung zones. Classic radiographic features are the "gloved finger" of an occluded distal bronchus and "tram tracking" due to bronchial wall edema. Supportive laboratory findings include peripheral blood eosinophilia in patients not receiving corticosteroid therapy and precipitating antibodies to Aspergillus, which are present in 60 to 70% of individuals.⁸ Finally, patients may expectorate mucous plugs containing fungal hyphal elements. The estimated prevalence of ABPA varies widely, ranging from 2 to 28% of patients with asthma.⁹

CF patients fulfill many of the diagnostic criteria for ABPA as a result of their underlying disease. For example, bronchiectasis and reversible airflow obstruction are hallmarks of CF. Additionally, up to 60% of CF patients will have immediate cutaneous reactivity to A fumigatus and IgE levels are increased in up to 25% of CF patients. Yet, this group is uniquely predisposed to ABPA, and 8 to 12% of CF patients may have concomitant ABPA.¹⁰ Thus, in an effort to establish uniform guidelines, the Cystic Fibrosis Foundation convened a Consensus Conference in 2001 and established a set of diagnostic criteria.¹¹ The minimal criteria are: (1) clinical decline; (2) total serum IgE >1,200 ng/mL; and (3) immediate cutaneous sensitivity to Aspergillus or A fumigatus-specific IgE antibody. Additionally, one of two other criteria must by met: (1) A fumigatus precipitins or A fumigatus-specific IgG; or (2) abnormal chest radiograph or change from baseline chest radiograph.

The mainstay of therapy for ABPA is corticosteroids. To guide therapy, disease is staged into one of five categories. Stage I is acute disease characterized by wheezing, infiltrates, elevated IgE, eosinophilia, and specific antibodies to A fumigatus. In stage II, disease activity is decreased (remission) and the chest radiograph is normal/baseline, IgE levels are decreased, and eosinophilia is absent. In stage III disease, a patient with previously diagnosed ABPA develops recurrent signs and symptoms (exacerbation). Patients with stage IV disease are steroid-dependent, and when steroids are tapered, the signs/symptoms recur (corticosteroid-dependent). This is the stage at which most patients are diagnosed. Finally, stage V disease is end-stage pulmonary fibrosis (fibrotic stage). In this stage, many of the defining features of ABPA, such as IgE level and eosinophilia, may be absent. Fortunately, few patients progress to stage V.

ABPA is characterized by a complex immunologic response to fungus. While A fumigatus accounts for the overwhelming majority of cases, there are reports of the syndrome in association with other fungi. Curvularia sp and Candida albicans comprise the majority of these atypical cases.¹² The immunopathogenesis of ABPA is complex and incompletely understood. Both IgE-mediated (type I) and immune complex-mediated (type III) hypersensitivity reactions occur. Additionally, a T-helper type 2 CD4 + lymphocyte cellular response is induced. The spores of A fumigatus are inhaled and the hyphal forms grow within, but do not invade, the bronchial mucosa. Growth of the organism potentiates ongoing production of numerous antigens that elicit the hypersensitivity responses.⁹

Treatment of ABPA relies on suppressing the immune responses with corticosteroids. A recommended regimen for an exacerbation is prednisone 0.5 mg/kg/d for 1 to 2 weeks, followed by every-other-day dosing for 6 to 8 weeks, and then a slow taper, decreasing the dose 5 to 10 mg every 2 weeks. A total serum IgE level should be obtained 6 to 8 weeks into therapy and then periodically to establish the individual baseline. Patients who cannot taper off steroids are considered to have stage IV ABPA, and every-other-day steroid dosing is recommended rather than daily dosing. Treatment with antifungal agents has emerged as a potential therapy for patients with ABPA. Current studies indicate that itraconazole may have a role as a steroid-sparing agent. One randomized, double-blind trial comparing placebo and itraconazole showed that in 46% of patients taking itraconazole, the steroid dose could be reduced by 50%, serum IgE decreased by 25%, and improvement in either exercise tolerance or radiographic infiltrates was observed.¹³

Hypersensitivity Pneumonitis

HP, also known as extrinsic allergic alveolitis, is an inflammatory lung disease characterized by repeated exposure and ultimately sensitization to a variety of organic and chemical antigens. Diagnosis relies on combining clinical history with particular emphasis on antigen exposure and radiographic and pathologic findings. Specific focus is given to the role fungi can play in this disease. Several excellent reviews are available to provide readers with further detail regarding HP.^14,15 HP is divided into acute, subacute, and chronic stages. In clinical practice, there is often overlap, especially between subacute and chronic HP.

Systemic symptoms, such as fever, chills, and myalgias characterize the presentation of acute HP. Respiratory symptoms include cough and shortness of breath. Crackles are often heard on examination. Exacerbations occur with repeated antigen exposure. Subacute and chronic HP have more indolent clinical presentations, with cough and dyspnea the most common presenting symptoms. Fatigue and weight loss are also typical. Chest examination may reveal crackles or wheezing, or the findings can be normal. The radiographic hallmark of HP is diffuse, ill-defined, small (<5 mm), centrilobular nodules on chest CT scan.¹⁶ Chronic HP may be characterized by fibrosis, honeycombing, and volume loss on chest CT. HP histopathology is characterized by poorly formed, noncaseating granulomas, lymphocytic interstitial infiltrate, and bronchiolitis.¹⁷ The key to treatment is identification of the precipitating antigen and removal from exposure. Ongoing exposure can result in asthma, emphysema, or interstitial fibrosis. Corticosteroids are often used, although they have not been demonstrated to improve the long-term prognosis of patients with HP.

Portions of the pathway underlying the development and continuation of HP have been elucidated, yet many questions remain. Traditionally, HP was considered a typical type III immune complex-mediated illness. This has been challenged by several observations. First, while many patients with HP have precipitating antibodies to specific antigens, a large number do not have such precipitins.¹⁸ Additionally, many individuals exposed to known antigens will remain free of disease but have positive serologic tests.¹⁹ The sensitized and activated T cell (type IV immune response) now appears to be the driving immunologic force. The number of antigens capable of triggering HP is large, and, over time many colorful names have arisen, yet most precipitating antigens can be categorized as either microbial, animal, or chemical in origin.

Microbial antigens account for the majority of cases and fungi are common causes of HP. In Japan, summer-type hypersensitivity pneumonitis is the most common form of HP. The causative antigen comes from the mold Trichosporon asahii, a seasonal fungus found indoors and associated with straw mats.²⁰ In Australia, the most common causes of HP are rotting wood and dampness in the home. Many mold species have been associated with HP in this context: Penicillium sp, Alternaria tenuis, Fusarium solani , and Aspergillus sp.²¹ A variety of occupations have been associated with HP, and in many cases a mold is the etiologic agent. Aspergillus spp are associated with farmer's lung and mushroom worker's lung.^22-24 Workers utilizing esparto grass in the production of rope, baskets, and other products have also been afflicted with HP from Aspergillus sp.²⁵ Certain occupations involve working with various molds, and some of these exposures have resulted in HP; cork workers (Penicillium frequentans) and cheese workers (Penicillium casei, Penicillium roqueforti) are two examples.^26,27 Sugarcane workers have developed HP from exposure to molds in rotting sugarcane refuse.²⁸

Allergic Fungal Sinusitis

AFS is distinct from invasive fungal sinusitis and is caused by a hypersensitivity reaction to fungal antigens. The original description for this syndrome was allergic Aspergillus sinusitis because of histopathologic similarity to ABPA. However, sinus cultures of these patients have shown that non-Aspergillus strains are usually responsible. The more common fungal pathogens are members of the dematiaceous family and include Bipolaris with a prevalence of 67% of AFS,²⁹ followed in frequency by Drechslera, Alternaria, Curvularia, and Exserohilu.³⁰ The clinical presentation resembles any form of chronic sinusitis. Susceptible patients are atopic, and there is a slight predilection for younger patients. Potential clues in the clinical history are that 75% of patients expel dark, rubbery nasal casts and many will have undergone previous sinus surgeries.²⁹ Prevalence estimates are variable. Approximately 5 to 10% of patients with chronic sinusitis who undergo surgery will have pathology consistent with AFS.³¹ On physical examination, most patients with AFS demonstrate nasal polyps.

Laboratory testing during an exacerbation often reveals increased total eosinophil counts and high total IgE levels. Skin testing to fungal antigens is often positive.³⁰ Precipitating antibodies to fungal antigens often are not detected and various hypotheses have been put forth to explain this observation. Some authors believe that the lack of commercially available IgG antibodies to dematiaceous fungi make it impossible to prove the type III immunologic response that occurs in AFS. Other investigators suggest that AFS is primarily a type I IgE-mediated response and thus precipitating IgG antibodies are not formed.

The findings on sinus CT are characteristic. These notable features include heterogenous hyperattenuation within the sinus cavity, representing the thick, tenacious mucin that is characteristic of AFS. T1-weighted MRI images show hypoattenuation in the affected sinus and T2-weighted images are black. It is thought that increased levels of magnesium, manganese, and iron cause the dense T2-weighted MRI appearance.³² Additionally, bony loss and even erosions can be seen as the inflammatory mucin pushes inferiorly, posteriorly, and/or laterally.³⁰ Invasion into the soft tissue of the central nervous system does not occur in this disease.

Pathologic evaluation of mucus from patients with AFS yields findings identical to those seen in the mucus impactions of patients with ABPA: thick, dense, proteinaceous material ranging in color from brown to green. A hematoxylin-eosin stain reveals large numbers of eosinophils in a background of basophilic mucin. Charcot-Leyden crystals composed of lysophospholipase are seen. Silver staining may reveal fungal hyphae.³¹

Treatment of AFS incorporates medical and surgical therapies. Corticosteroids are the mainstay of therapy for ABPA and are useful in keeping AFS quiescent. Initially, oral steroids are necessary, but transition to nasal steroids is usually possible. Desensitization to specific molds with immunotherapy is controversial. A theoretical contraindication is that promoting increased IgG to a particular fungus for patients with already increased immunoglobulins against that allergen may worsen the disease. Alternatively, allergen immunotherapy may decrease the IgE-mediated late-phase inflammatory response and reduce chronic inflammation.³³ The utility of antifungal agents is unclear. AFS is immunologically mediated and not a result of tissue invasion, so antifungal medications lack even a hypothetical advantage. Unlike ABPA, surgical treatment of AFS is possible. However, patients treated with surgery alone will usually have a relapse. The goal of surgical treatment is removal of polyps and inflammatory material, allowing aeration of the sinuses.³⁴ Multiple surgeries are sometimes necessary. AFS is potentially curable with a combination of medical and surgical therapies.

Conclusion

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