Aspergillus is a ubiquitous saprophyte in nature found in air, soil, and organic matter. Humans normally inhale the spore form of the fungi. However, the disease is usually seen in immunocompromised patients. The immune system plays an important role not only in recognizing inhaled mold and controlling growth but also in regulating the body’s allergic and inflammatory response to the infection. This activity describes the evaluation, diagnosis, and management of aspergillus and highlights the role of team-based interprofessional care for affected patients.
Causes
The most common species responsible for infections are A. fumigatus, Aspergillus flavus, and Aspergillus terreus.
A. fumigatus is a fungus from the family of Trichocomaceae. First described by Fresenius in 1863, it is known to have a stable haploid genome of 29.4 million base pairs.
The life cycle outside of the human host is characterized by asexual reproduction which proceeds through conidiophores, structures where the infectious form known as conidia, are produced and released into the air. Conidia are responsible for fungal dispersion and preserving the fungi genome under adverse conditions.
Infections caused by Aspergillus are commonly located in the lower respiratory tract, lungs, sinuses, and skin. The central nervous system (CNS) and cardiovascular system may be affected by direct or hematogenous spread.
Human-host defense against inhaled spores begins with the mucous layer and the ciliary action (compromised in diseases such as cystic fibrosis, asthma, Kartagener) located in the respiratory tract. Macrophages normally react upon recognizing fungi key cell wall components such as beta-D-glucan, secreting inflammatory mediators that ultimately attract neutrophils to initiate cellular immunity.
Many species of Aspergillus are known to produce toxic metabolites (aflatoxins, mycotoxins 3-nitropropionic acid, and ochratoxin A) which inhibit the action of macrophage and neutrophil phagocytosis.
Underlying immunosuppression is directly proportional to neutrophil dysfunction and the reduced number of neutrophils. Patients on chronic steroid treatment also have associated macrophage and neutrophil function. In these cases, the risk of disease along with the type of disease is secondary to impaired phagocytosis, suppressed T cell function, and oxidative cascade.
Vascular invasion can also occur if fungal cell surface components bind to the vessel wall components ultimately resulting in necrosis, infarction, or hemorrhage.
Chronic necrotizing pulmonary aspergillosis is characterized by granuloma formation and alveolar consolidation.
Symptoms
The signs and symptoms of aspergillosis vary with the type of illness you develop:
Allergic reaction
Some people with asthma or cystic fibrosis have an allergic reaction to aspergillus mold. Signs and symptoms of this condition, known as allergic bronchopulmonary aspergillosis, include:
- Fever
- A cough that may bring up blood or plugs of mucus
- Worsening asthma
Aspergilloma
Certain chronic lung (pulmonary) conditions, such as emphysema, tuberculosis, or advanced sarcoidosis, can cause air spaces (cavities) to form in the lungs. When people with lung cavities are also infected with aspergillus, fungus fibers may find their way into the cavities and grow into tangled masses (fungus balls) known as aspergillomas.
Aspergillomas may produce no symptoms or cause only a mild cough at first. Over time and without treatment, however, aspergillomas can worsen the underlying chronic lung condition and possibly cause:
- A cough that often brings up blood (hemoptysis)
- Wheezing
- Shortness of breath
- Unintentional weight loss
- Fatigue
Invasive aspergillosis
This is the most severe form of aspergillosis. It occurs when the infection spreads rapidly from the lungs to the brain, heart, kidneys, or skin. Invasive aspergillosis occurs only in people whose immune systems are weakened as a result of cancer chemotherapy, bone marrow transplantation, or a disease of the immune system. Untreated, this form of aspergillosis may be fatal.
Signs and symptoms depend on which organs are affected, but in general, invasive aspergillosis can cause:
- Fever and chills
- A cough that brings up blood (hemoptysis)
- Shortness of breath
- Chest or joint pain
- Headaches or eye symptoms
- Skin lesions
Other types of aspergillosis
Aspergillus can invade areas of your body other than your lungs, such as your sinuses. In your sinuses, the fungus can cause a stuffy nose sometimes accompanied by drainage that may contain blood. Fever, facial pain, and headache may also occur.
Diagnosis
Aspergillosis is defined as infection with histopathological confirmation and a positive result of the specimen from a normally sterile site.
Biopsies carry the risk of bleeding, the reason for which noninvasive testing is usually done as the initial step. These include serum biomarkers and sputum analysis.
If a biopsy is warranted, it is usually guided by imaging such as bronchoscopy, video-assisted thoracoscopy surgery, or CT.
History and Physical
Clinical presentation of Aspergillus-related infections manifests on a large spectrum. There are two important variables: underlying immune status and underlying pulmonary disease.
This spectrum can range from acute bronchopulmonary aspergillosis, chronic pulmonary aspergillosis, bronchitis, acute community-acquired, chronic cavitary nodules/aspergilloma to invasive disease in those severely immunocompromised.
Allergic bronchopulmonary aspergillosis, most commonly found in patients with underlying asthma/cystic fibrosis, presents as asthma (shortness of breath with associated wheezing) with recurrent exacerbations which could in some cases be complicated by systemic symptoms such as fever, malaise, bronchial obstruction, or brown mucous plugs. This can be associated with allergic fungal rhinosinusitis characterized by common symptoms of sinusitis but associated with dark-colored nasal discharge.
Chronic pulmonary aspergillosis presents as a progressive course over months of fatigue, malaise, fever, night sweats, shortness of breath, weight loss, cough, hemoptysis, and sputum production. Its presentation also ranges from a spectrum of aspergilloma, aspergillus nodule, chronic cavitary aspergillosis, chronic fibrosing aspergillosis, and subacute invasive pulmonary aspergillosis formerly known as chronic necrotizing aspergillosis.
Of note, subacute invasive aspergillosis is present in patients with evidence of immunosuppression, however, whereas invasive presentations have a short progression of 4 weeks, subacute presentation progresses over 1 to 3 months.
Invasive aspergillosis is commonly seen in states of severe immunosuppression such as organ transplanted patients, AIDS, prolonged neutropenia, advanced cancer, and prolonged use of steroids. It most frequently presents as a pulmonary infection after airway inoculation of conidia, however gastrointestinal and skin forms are also seen. Suspicion for pulmonary aspergillosis in the setting of the comorbidities mentioned above should arise if any of the following present: fever, shortness of breath, hemoptysis, cough, pleuritic chest pain. Tracheobronchitis is commonly seen in organ transplant patients. Rhinocerebral aspergillosis is seen in the setting of hematological malignancies in neutropenic patients. Disseminated infection correlates with poor prognosis, and it can be seen affecting organs such as the brain, (brain abscesses and infarction), eye (endophthalmitis), and skin (cutaneous aspergillosis), liver, heart (endocarditis), and kidneys.
Evaluation of suspected aspergillosis infection varies depending on the patient’s presentation and immune state.[rx][rx]
Initial management should include laboratory studies such as:
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Complete blood count with differential to determine eosinophil count (which is usually elevated by more than 500 cells/microliters), and serum IgE (elevated by more than 1000 IU/mL).
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Aspergillus skin test positivity or detectable IgE against Aspergillus
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Sputum analysis Gram stain plus culture: with findings of eosinophils, Charcot-Leyden crystals, and Aspergillus in culture.
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Imaging: Aspergillus bronchopulmonary infection can be evidenced on chest x-ray with findings of mucous plugs or central bronchiectasis. Upper lobe parenchymal opacities with atelectasis secondary to bronchial obstruction are also commonly seen. Imaging can be further assessed with a high-resolution CT scan which can also detect mucous plugging, tree-in-bud opacities, ground-glass attenuation, and atelectasis. In cases of early invasive aspergillosis, a CT scan can provide an early diagnosis when detecting focal lesions in the presence of fever: nodules with ground-glass infiltrates are seen in neutropenic patients (halo sign). CT head is warranted in cases of suspected CNS aspergillosis with evidence of ring-enhancing lesions (abscesses) and cortical or subcortical infarction.
Aspergillomas are radiologically characterized by a rounded mass (fungal ball) in a pulmonary cavity associated with a positive culture or positive IgG. Nodules can also be a form of radiological presentation after lung cancer is excluded with biopsy. Chronic cavitary/fibrosing forms present as 1 large or more than 2 cavities without a fungal ball associated with the previously mentioned chronic symptoms and positive cultures/IgG.
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In cases of severe invasive aspergillosis an emerging tool has been used especially in intensive care unit patients, beta-(1,3)-d-glucan which is a cell wall component of Aspergillus and useful in cases where the onset of treatment is essential to improve prognosis. This component is also present in other organisms such as Candida, Fusarium, and Pneumocystis.
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Serum galactomannan is another Aspergillus cell wall component released into the bloodstream during intravascular hyphal growth. However, it is captured by a neutrophil concentration that may be falsely low which makes its sensitivity lower in non-neutropenic patients.
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The key test for chronic pulmonary aspergillosis is a positive Aspergillus immunoglobin (IgG) serum test. Only a minority of patients have positive cultures (less than 10%). Elevated galactomannan assay from bronchoalveolar lavage fluid yields higher sensitivity in these cases. Other nonspecific markers are elevated CRP and ESR.
Treatment
Treatment of acute bronchopulmonary aspergillosis consists of a glucocorticoid regimen plus itraconazole. Voriconazole is another alternative in cases where itraconazole is not well tolerated. Systemic glucocorticoids are the mainstay of treatment followed by a slow oral taper over 3 months. The initial dose of prednisone is usually 0.5 mg/kg.[rx][rx][rx]
Monitoring consists of measuring serum total IgE every 1 to 2 months.
In poorly controlled patients, asthma studies have shown that omalizumab a humanized monoclonal antibody against IgE has suggested benefits in patients without cystic fibrosis.
Chronic pulmonary aspergillosis treatment varies with the manifestations of the disease in the wide range previously described and the patient’s pulmonary status:
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Aspergilloma: surgical resection with or without embolization can be considered in patients with limited disease and good respiratory function to prevent hemoptysis, along with pre and postoperative antifungal therapy such as Voriconazole to avoid pleural aspergillosis. However, for patients with stable radiographic findings, asymptomatic, immunocompetent a conservative management guided by close monitoring is also a feasible option.
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Aspergillus nodules that have been resected to rule out lung cancer should not be treated with antifungal therapy unless the patient is symptomatic. Monitoring with imaging and serum antibody titers is recommended.
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Chronic cavitary/fibrosing pulmonary aspergillosis: require antifungal treatment. Studies have been done with Itraconazole, Voriconazole, Posaconazole, Isavuconazole, Amphotericin B, and Micafungin, leaving the latter 2 for severely ill patients who have failed azole therapy. Embolization is reserved for patients who develop hemoptysis. The treatment duration recommended is 6 months, however, if the disease progresses lifelong therapy may be warranted.
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Invasive aspergillosis treatment can either be monotherapy with voriconazole or in combination with an echinocandin. However, it is important to take into account the species of Aspergillus when choosing the right antifungal therapy. If there is no good response to the initial therapy or progression/deterioration of the patient’s status is noted then salvage therapy with other drug regimens such as isavuconazole, amphotericin B plus echinocandins should be considered. The length of treatment depends on the location of the infection with a minimum duration of 6 to 12 weeks that could be prolonged for months or years. Debridement of necrotic tissue might be required as adjunctive therapy in severe cases.
References
Aspergillosis
