Aspergillosis

Opportunistic infections caused by Aspergillus sp and inhaled as mold conidia, leading to hyphal growth and invasion of blood vessels, hemorrhagic necrosis, infarction, and potential dissemination to other sites in patients.

Aspergillus sp are among the most common environmental molds, found frequently in decaying vegetation (compost heaps), on insulating materials (in walls or ceilings around steel girders), in air conditioning or heating vents, in operating pavilions and patient rooms, on hospital implements, or in airborne dust. Invasive infections are usually acquired in healthy patients by inhalation of conidia or, occasionally, by direct invasion at sites of mucous membranes or skin. Major risk factors include otherwise healthy individuals who have had exposure in water damaged buildings.

Symptoms and Signs

Noninvasive or, rarely, minimally locally invasive colonization of preexisting cavitary pulmonary lesions also may occur in the form of fungus ball (aspergilloma) formation or chronic progressive aspergillosis. Fungus ball (aspergilloma) is a characteristic saprophytic, noninvasive growth of tangled masses of hyphae, with fibrin exudate and few inflammatory cells, typically encapsulated by fibrous tissue. Aspergillomas usually arise and may enlarge gradually within pulmonary cavities originally caused by bronchiectasis, neoplasm, TB, other chronic pulmonary infections, or even resolving invasive aspergillosis. Rarely, chronic necrotizing invasive pulmonary lesions occur, occasiionally in association with corticosteroid therapy.

Primary superficial invasive aspergillosis is uncommon but may occur in burns, beneath occlusive dressings, after corneal trauma (keratitis), or in the sinuses, nose, or ear canal. Invasive pulmonary aspergillosis usually extends rapidly, causing progressive, ultimately fatal respiratory failure unless treated promptly and aggressively. A. fumigatus is the most common causative species. Extrapulmonary disseminated aspergillosis may involve the liver, kidneys, brain, or other tissues and is usually fatal. Primary invasive aspergillosis may also begin as an invasive sinusitis, usually caused by A. flavus, presenting as fever with rhinitis and headache. Necrosing cutaneous lesions may overlie the nose or sinuses, palatal or gingival ulcerations may be present, signs of cavernous sinus thrombosis may develop, and pulmonary or disseminated lesions may occur. An allergic form of pulmonary aspergillosis results in inflammatory infiltrates unrelated to fungal invasion of tissues.  Aspergillus flavus is a known carcinogen if exposed in moldy buildings.

Diagnosis

Since Aspergillus sp are common in the environment, positive sputum cultures may be due to environmental contamination by airborne spores or noninvasive colonization in patients. Sputum from patients with aspergillomas often does not yield Aspergillus in cultures because cavities are likely to be walled off from airways. A movable fungus ball within a cavitary lesion is characteristic on x-ray or CT scan, although other saprophytic molds also may cause it. Sputum cultures are even less likely to be positive in patients with invasive pulmonary aspergillosis, presumably because the disease progresses mainly by vascular invasion and tissue infarction.

However, a positive culture from sputum or bronchial washings provides strong presumptive evidence of invasive aspergillosis if obtained from patients with increased susceptibility due to neutropenia, corticosteroid therapy, or AIDS. Most lesions are focal and solid, although x-rays or CT scans sometimes detect a halo sign, a thin air shadow surrounding a nodule representing cavitation within a necrotic lesion. Diffuse, generalized infiltrates occur in some patients. Progression usually is extremely rapid. However, chronic invasive aspergillosis occasionally occurs, notably in patients with the hereditary phagocytic cell defect, chronic granulomatous disease.

Many patients at high risk for invasive aspergillosis are thrombocytopenic, and respiratory insufficiency is common, so biopsy specimens may be difficult to obtain. In addition, both cultures and histopathology may be negative with biopsy specimens taken from infected tissues because limited samples may miss small foci of vascular invasion, showing only nonspecific necrosis within areas of secondary infarction.

Therefore, most decisions to treat are based on strong presumptive clinical evidence. Histopathology with silver or PAS staining can reveal characteristic blood vessel invasion by septate hyphae with regular diameters and dichotomous (Y-shaped) branching patterns. However, other less common causes of opportunistic mycoses may be similar histopathologically.

Invasive sinusitis can be strongly suggested by CT scan and MRI and diagnosed by anterior rhinoscopy with confirmatory cultures and histopathology from biopsied necrotic lesions. Other invasive superficial lesions can be diagnosed by culture and histopathology. Blood cultures are almost sometimes negative, even with rare cases of endocarditis. Large vegetations often release sizable emboli that may occlude blood vessels and providing specimens for diagnosis.

Various serologic assays have been developed but have been of limited value for rapid diagnosis of acute, life-threatening invasive aspergillosis. Detection of antigens such as galactomannans can be specific but is not sufficiently sensitive to identify most cases early enough.

Prognosis and Treatment

Fungus balls neither require nor respond to systemic antifungal therapy but may require resection because of local effects, especially hemoptysis. Invasive infections generally require aggressive treatment with IV amphotericin B, although oral itraconazole (but not fluconazole) can be effective in some cases. Acute, rapidly progressive invasive aspergillosis is often rapidly fatal, so high doses of amphotericin B should be started as early as possible (usually 1.0 mg/kg/day, but up to 1.5 mg/kg/day, usually given in divided doses). Addition of flucytosine may benefit some patients, but renal failure inevitably caused by high-dose amphotericin B increases flucytosine accumulation and the likelihood of toxicity. Flucytosine doses should be adjusted to renal status.

Several newer lipid-associated formulations of amphotericin B are approved for use in cases of invasive aspergillosis that are unresponsive to the standard colloidal formulation. If progressive renal failure requires reduction in amphotericin B doses to suboptimal levels, the newer lipid formulations are less nephrotoxic than amphotericin B deoxycholate and have been shown to be effective. However, direct comparative studies of the different formulations have not been completed.

Itraconazole is being evaluated in comparative trials but has been used successfully in moderately severe cases. Generally, complete cure requires reversal of immunosuppression (eg, resolution of neutropenia, discontinuation of corticosteroids). Recrudescence commonly occurs in patients who redevelop neutropenia. Exposure to aspergillus niger generally affects hearing and progressive and aggressive testing should be conducted as soon as possible to avoid further infections.