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Aspergillosis

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by Sanjay G. Revankar, MD, Jack D. Sobel, MD

Aspergillosis is an opportunistic infection caused by inhaling spores of the mold Aspergillus, commonly present in the environment; the spores invade blood vessels, causing hemorrhagic necrosis and infarction. Symptoms may be those of asthma, pneumonia, sinusitis, or rapidly progressing systemic illness. Diagnosis is primarily clinical but may be aided by imaging, histopathology, and specimen staining and culture. Treatment is with voriconazole, amphotericin B (or its lipid formulations), caspofungin, or itraconazole. Fungus balls may require surgical resection.

(See also the Infectious Diseases Society of America’s Practice Guidelines for Diseases Caused by Aspergillus .)

Pathophysiology

Invasive infections are usually acquired by inhalation of spores or, occasionally, by direct invasion through damaged skin.

Major risk factors include

  • Neutropenia when prolonged (typically > 7 days)

  • Long-term high-dose corticosteroid therapy

  • Organ transplantation (especially bone marrow transplantation with graft-vs-host disease [GVHD])

  • Hereditary disorders of neutrophil function (eg, chronic granulomatous disease)

Aspergillus sp tends to infect open spaces, such as pulmonary cavities caused by previous lung disorders (eg, bronchiectasis, tumor, TB), the sinuses, or ear canals (otomycosis). Such infections tend to be locally invasive and destructive, although systemic spread sometimes occurs, particularly in immunocompromised patients. However, aspergillosis is unusual in those with HIV infection.

A. fumigatus is the most common cause of invasive pulmonary disease; A. flavus most often causes invasive extrapulmonary disease, probably because these patients are more severely immunosuppressed than patients infected with A. fumigatus.

Focal infections, typically in the lung, sometimes form a fungus ball (aspergilloma), a characteristic growth of tangled masses of hyphae, with fibrin exudate and few inflammatory cells, typically encapsulated by fibrous tissue. Occasionally, there is some local invasion of tissue at the periphery of the cavity, but usually the fungus just resides within the cavity with no appreciable local invasion.

A chronic form of invasive aspergillosis occasionally occurs, particularly in patients taking corticosteroids long-term and those with chronic granulomatous disease, which is characterized by a hereditary phagocytic cell defect.

Aspergillus sp can also cause endophthalmitis after trauma or surgery to the eye or by hematogenous seeding and can infect intravascular and intracardiac prostheses.

Primary superficial aspergillosis is uncommon but may occur in burns; beneath occlusive dressings; after corneal trauma (keratitis); or in the sinuses, mouth, nose, or ear canal.

Allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to A. fumigatus that results in lung inflammation unrelated to fungal invasion of tissues (see Allergic Bronchopulmonary Aspergillosis (ABPA)).

Symptoms and Signs

Acute invasive pulmonary aspergillosis usually causes cough, often with hemoptysis, pleuritic chest pain, and shortness of breath. If untreated, invasive pulmonary aspergillosis may lead to rapidly progressive, ultimately fatal respiratory failure.

Chronic pulmonary aspergillosis may manifest with mild, indolent symptoms despite significant disease.

In severely immunocompromised patients, extrapulmonary invasive aspergillosis begins with skin lesions, sinusitis, or pneumonia and may involve the liver, kidneys, brain, and other tissues; it is often rapidly fatal.

Aspergillosis in the sinuses can form an aspergilloma or cause allergic fungal sinusitis or a chronic, slowly invasive granulomatous inflammation with fever, rhinitis, and headache. Patients may have necrosing cutaneous lesions overlying the nose or sinuses, palatal or gingival ulcerations, signs of cavernous sinus thrombosis, or pulmonary or disseminated lesions.

Diagnosis

  • Usually fungal culture and histopathology of tissue samples

  • Galactomannan antigen test on serum and bronchoalveolar lavage fluid

Because Aspergillus sp are common in the environment, positive sputum cultures may be due to environmental contamination or noninvasive colonization in patients with chronic lung disease; positive cultures are significant mainly when sputum is obtained from patients with increased susceptibility due to immunosuppression or when there is high suspicion due to typical imaging findings. Conversely, sputum cultures from patients with aspergillomas or invasive pulmonary aspergillosis are often negative because cavities are often walled off from airways and because invasive disease progresses mainly by vascular invasion and tissue infarction.

Chest x-rays are taken; however, chest CT is far more sensitive and should be done if patients are at high risk (ie, neutropenic). CT of sinuses is done if sinus infection is suspected. A movable fungus ball within a cavitary lesion is characteristic on both, although most lesions are focal and solid. Sometimes imaging detects a halo sign (a hazy shadow surrounding a nodule) or cavitation within a necrotic lesion. Diffuse, generalized pulmonary infiltrates are seen in some patients.

Culture and histopathology of a tissue sample are usually necessary for confirmation; histopathology helps distinguish invasive infection from colonization. The sample is typically taken from the lungs via bronchoscopy or percutaneous needle biopsy and from the sinuses via anterior rhinoscopy. Because cultures take time and histopathology results may be false-negative, most decisions to treat are based on strong presumptive clinical evidence. In aspergillus endocarditis, large vegetations often release sizable emboli that may occlude blood vessels and provide specimens for diagnosis.

Detection of antigens such as galactomannan can be specific but, in serum, is often not sufficiently sensitive to identify most cases in their early stages. In invasive pulmonary aspergillosis, the galactomannan test on bronchoalveolar lavage fluid is much more sensitive than that on serum and is often the only option for patients with thrombocytopenia, for whom biopsy is contraindicated. Blood cultures are almost always negative, even in rare cases of endocarditis.

Treatment

  • Voriconazole

  • Amphotericin B (including lipid formulations)

  • Echinocandins as salvage therapy

  • Sometimes surgery for aspergillomas

Invasive infections usually require aggressive treatment with voriconazole (considered the first-choice drug). Amphotericin B (particularly lipid formulations) is also effective, although more toxic. Oral posaconazole or itraconazole (but not fluconazole) can be effective in some cases. Caspofungin or other echinocandins may be used as salvage therapy. Combination therapy with voriconazole and echinocandins may be effective in certain patients.

Usually, complete cure requires reversal of immunosuppression (eg, resolution of neutropenia, discontinuation of corticosteroids). Recrudescence is common if neutropenia recurs.

Aspergillomas neither require nor respond to systemic antifungal therapy but may require resection because of local effects, especially hemoptysis.

Prophylaxis with posaconazole or itraconazole can be considered for high-risk patients (those with GVHD or neutropenia due to acute myelocytic leukemia).

Key Points

  • Inhaling spores of the mold Aspergillus can cause localized or invasive pulmonary disease and, rarely, disseminated infection (eg, to the brain) in severely immunocompromised patients.

  • Aspergillosis is more common among immunocompromised patients, although it is unusual in those with HIV infection.

  • Focal infections, typically in the lung or sinuses, sometimes form a fungus ball (aspergilloma).

  • Culture and histopathology of a tissue sample are usually necessary, but the galactomannan test on bronchoalveolar lavage fluid can help diagnose pulmonary infection.

  • Voriconazole is the drug of choice; amphotericin B is an alternative.

  • Aspergillomas neither require nor respond to antifungal drugs but may need surgical resection if they cause bleeding or other symptoms.

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Drugs Mentioned In This Article

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  • VFEND
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  • SPORANOX
  • DIFLUCAN
  • NOXAFIL

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