Aspergillosis is the collective term used to describe all disease entities caused by any one of ~35 pathogenic and allergenic species of Aspergillosis. Only those species that grow at 37°C can cause invasive infection, although some species without this capability can cause allergic syndromes. A. fumigatus is responsible for most cases of invasive aspergillosis, almost all cases of chronic aspergillosis, and most allergic syndromes. A. flavus is more prevalent in some hospitals and causes a higher proportion of cases of sinus and cutaneous infections and keratitis than A. fumigatus. A. niger can cause invasive infection but more commonly colonizes the respiratory tract and causes external otitis. A. terreus causes only invasive disease, usually with a poor prognosis. A. nidulans occasionally causes invasive infection, primarily in patients with chronic granulomatous disease.
Aspergillus has a worldwide distribution, most commonly growing in decomposing plant materials (i.e., compost) and in bedding. This hyaline (nonpigmented), septate, branching mold produces vast numbers of conidia (spores) on stalks above the surface of mycelial growth. Aspergilli are found in indoor and outdoor air, on surfaces, and in water from surface reservoirs. Daily exposures vary from a few to many millions of conidia; the latter high numbers of conidia are encountered in hay barns and other very dusty environments. The required size of the infecting inoculum is uncertain; however, only intense exposures (e.g., during construction work, handling of moldy bark or hay, or composting) are sufficient to cause disease in healthy immunocompetent individuals. Allergic syndromes may be exacerbated by continuous antigenic exposure arising from sinus or airway colonization or from nail infection. High-efficiency particulate air (HEPA) filtration is often protective against infection; thus HEPA filters should be installed and monitored for efficiency in operating rooms and in hospital environments that house high-risk patients.
The incubation period of invasive aspergillosis after exposure is highly variable, extending in documented cases from 2 to 90 days. Thus community-acquired acquisition of an infecting strain frequently manifests as invasive infection during hospitalization, although nosocomial acquisition is also common. Outbreaks usually are directly related to a contaminated air source in the hospital.
Risk Factors and Pathogenesis
The primary risk factors for invasive aspergillosis are profound neutropenia and glucocorticoid use; risk increases with longer duration of these conditions. Higher doses of glucocorticoids increase the risk of both acquisition of invasive aspergillosis and death from the infection. Neutrophil and/or phagocyte dysfunction is also an important risk factor, as evidenced by aspergillosis in chronic granulomatous disease, advanced HIV infection, and relapsed leukemia. An increasing incidence of invasive aspergillosis in medical intensive care units suggests that, in patients who are not immunocompromised, temporary abrogation of protective responses as a result of glucocorticoid use or a general anti-inflammatory state is a significant risk factor. Many patients have some evidence of prior pulmonary disease—typically, a history of pneumonia or chronic obstructive pulmonary disease. Glucocorticoid use does not appear to predispose to invasive Aspergillus sinusitis but probably increases the risk of dissemination after pulmonary infection. Anti–tumor necrosis factor therapy also carries an increased risk of infection.
Patients with chronic pulmonary aspergillosis have a wide spectrum of underlying pulmonary disease, often tuberculosis or sarcoidosis. Patients are immunocompetent except for some cytokine regulation defects, most of which are consistent with an inability to mount an inflammatory immune (TH1-like) response. Glucocorticoids accelerate disease progression.
Allergic bronchopulmonary aspergillosis (ABPA) is associated with polymorphisms of interleukin (IL) 4Ra, IL-10, and SPA2 genes (and others) and with heterozygosity of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These associations suggest a strong genetic basis for the development of a TH2-like and "allergic" response to A. fumigatus.
CD4+CD25+ T (Treg) cells also appear to be pivotal in determining the disease phenotype. Remarkably, high-dose glucocorticoid treatment for exacerbations of ABPA almost never leads to invasive aspergillosis.
Clinical Features and Approach to the Patient
Table 204-1 Major Manifestations of Aspergillosis
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Table 204-1 Major Manifestations of Aspergillosis
|Type of Disease|
|Organ||Invasive (Acute and Subacute)||Chronic||Saprophytic||Allergic|
|Lung||Angioinvasive in neutropenia, non-angioinvasive, granulomatous||Chronic cavitary, chronic fibrosing||Aspergilloma (single), airway colonization||Allergic bronchopulmonary, severe asthma with fungal sensitization, extrinsic allergic alveolitis|
|Sinus||Acute invasive||Chronic invasive, chronic granulomatous||Maxillary fungal ball||Allergic fungal sinusitis, eosinophilic fungal rhinosinusitis|
|Brain||Abscess, hemorrhagic infarction, meningitis||Granulomatous, meningitis||None||None|
|Skin||Acute disseminated, locally invasive (trauma, burns, IV access)||External otitis, onychomycosis||None||None|
|Heart||Endocarditis (native or prosthetic), pericarditis||None||None||None|
|Eye||Keratitis, endophthalmitis||None||None||None described|
Invasive Pulmonary Aspergillosis
Both the frequency of invasive disease and the pace of its progression increase with greater degrees of immunocompromise (Fig. 204-1). Invasive aspergillosis is arbitrarily divided into acute and subacute forms that have courses of ≤1 month and 1–3 months, respectively. More than 80% of cases of invasive aspergillosis involve the lungs. The most common clinical features are no symptoms at all, fever, cough (sometimes productive), nondescript chest discomfort, trivial hemoptysis, and shortness of breath. Although the fever often responds to glucocorticoids, the disease progresses. The keys to early diagnosis in at-risk patients are a high index of suspicion, screening for circulating antigen (in leukemia), and urgent CT of the thorax.
Invasive aspergillosis: conditions placing patients at elevated risk of acquisition and relatively rapid progression. CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; GVHD, graft-versus-host disease; ICU, intensive care unit.
The sinuses are involved in 5–10% of cases of invasive aspergillosis, especially in patients with leukemia and recipients of hematopoietic stem cell transplants. ...