Aspergillosis

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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 susceptible 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 susceptible patients by

inhalation of conidia or, occasionally, by direct invasion at sites of damaged

skin. Major risk factors include neutropenia, long-term high-dose corticosteroid

therapy, organ transplantation (especially bone marrow transplantation),

hereditary disorders of neutrophil function, such as chronic granulomatous

disease, or, occasionally, AIDS.

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,

usually 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 (see

Allergic Bronchopulmonary

Aspergillosis<http://www.merck.com/mrkshared/mmanual/section6/chapter76/76d.jsp#\

A006-076-1061> in Ch. 76).

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 with chronic lung disease. 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 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 always 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.