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Epidemiology and clinical manifestations of invasive aspergillosis

Epidemiology and clinical manifestations of invasive aspergillosis
Literature review current through: May 2024.
This topic last updated: Aug 08, 2022.

INTRODUCTION — The term "aspergillosis" refers to illness due to allergy, airway or lung invasion, cutaneous infection, or extrapulmonary dissemination caused by species of Aspergillus, most commonly A. fumigatus, A. flavus, A. niger, and A. terreus. Aspergillus species are ubiquitous in nature, and inhalation of infectious conidia is a frequent event. Tissue invasion is uncommon and occurs most frequently in the setting of immunosuppression associated with therapy for hematologic malignancies, hematopoietic cell transplantation, or solid organ transplantation.

The pathogenesis, epidemiology, clinical manifestations, and differential diagnosis of invasive aspergillosis will be reviewed here. The diagnosis and treatment of invasive aspergillosis are discussed separately. (See "Diagnosis of invasive aspergillosis" and "Treatment and prevention of invasive aspergillosis" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis" and "Chronic pulmonary aspergillosis: Treatment".)

PATHOGENESIS — Inhaled conidia are met by the innate defenses provided by resident phagocytes, specifically airway epithelial cells and alveolar macrophages [1,2]. Little is known about the contribution of epithelial cells in clearing conidia. Relatively more is known about macrophages, which contribute to both conidial clearance and the production of secondary inflammation. These cells secrete inflammatory mediators after recognition of key cell wall components (eg, beta-D-glucan) exposed after conidial germination into hyphal forms. These mediators result in neutrophil recruitment and the activation of cellular immunity, which are important in killing potentially invasive microbial forms (hyphae) and determining the extent and nature of the immune response. Hence, risks for disease and the type of disease that occurs are the combined result of multiple cellular functions that impact proximal events in conidial clearance, production of inflammation, and killing of invasive forms [1].

Microbial factors that impact disease potential include toxins, proteases, and secondary metabolites that exert multiple effects on the host's local pulmonary and systemic defense. These include cellular products that:

Inhibit phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, a key component in host defense against filamentous fungi

Inhibit macrophage phagocytosis and killing

Suppress functional T cell responses

Histopathologically, invasive aspergillosis is characterized by progression of the infection across tissue planes. One hallmark of infection is vascular invasion with subsequent infarction and tissue necrosis. Presumably, fungal cell surface components bind to vessel wall components, including basement membrane, extracellular matrix, and cellular constituents, and can cause ischemia and infarction of structures distal to invaded arteries.

MICROBIAL EPIDEMIOLOGY

Classification — In the past, mycologists utilized phenotypic characteristics to identify Aspergillus organisms to the species level; however, some species are not distinguishable based on phenotypic typing. Use of molecular methods has expanded the number of recognized species and increased our knowledge of the organism's pathogenicity and other characteristics [3].

Given the complexity of the classification scheme and lack of routine molecular typing, it has been suggested that isolates be referred to as being members of a "species complex."

Species prevalence — Most invasive infections are caused by members of the A. fumigatus species complex. In a report of 218 infections in 24 transplant centers in the United States, 67 percent were caused by members of the A. fumigatus complex, followed by A. flavus (13 percent), A. niger (9 percent), and A. terreus (7 percent). These data contrast with epidemiologic data from a decade earlier when the vast majority of cases (90 percent) were secondary to A. fumigatus species [4], likely reflecting changes in microbial epidemiology, center-based differences, and/or changes in typing methods.

RISK FACTORS — Underlying conditions that compromise pulmonary and systemic immune responses to inhaled Aspergillus species serve as risk factors for invasive disease.

Classic risk factors include:

Severe and prolonged neutropenia

Receipt of high doses of glucocorticoids

Other drugs or conditions that lead to chronically impaired cellular immune responses (eg, immunosuppressive regimens administered to treat autoimmune diseases and to prevent organ rejection, AIDS)

Use of certain biologic agents (eg, Bruton’s tyrosine kinase inhibitors [ibrutinib], small molecule kinase inhibitors) also raise the invasive aspergillosis [5,6]. Other agents such as venetoclax, a B-cell leukemia/lymphoma-2 inhibitor used in hematologic malignancies, may increase risk for invasive aspergillosis although venetoclax is often used in combination with other chemotherapeutic agents like rituximab so that individual risk is unclear [7]. A large number of novel agents impacting numerous immunologic pathways are widely used. Many of these agents have theoretic risks for invasive aspergillosis, which should be considered in patients being evaluated for invasive aspergillosis [8].

Specific risk factors in certain immunocompromised patients include:

In hematopoietic cell transplant (HCT) recipients, risks are different early versus late after receipt of stem cells. Underlying disease, persistent neutropenia, and types of stem cells and conditioning impact risks early after transplant. Additional risk factors during the latter period include graft-versus-host disease (and accompanying therapies) and cytomegalovirus (CMV) infection and disease [9]. Immunologic variables that correlate with risk include impaired production of reactive oxygen species and qualitative and quantitative defects in NK and T cells [10-12].

Various gene polymorphisms (in HCT donors, HCT and solid organ transplant recipients, or patients with hematologic malignancies) have been associated with an increased risk of invasive aspergillosis. Examples include polymorphisms in genes involved in the innate immune response, such as the toll-like receptor 4 gene [13], interleukin 1 beta and beta-defensin 1 [14], the soluble pattern recognition receptor, long pentraxin 3 [15,16], dectin-1 [17,18], and others [11].

Airway colonization in lung transplant recipients with cystic fibrosis is a risk factor for disease following transplantation [19,20]. (See "Fungal infections following lung transplantation", section on 'Risk factors'.)

In liver transplant recipients, increasing immunosuppression, hemodialysis, and CMV infection are risks factors [21,22].

In renal transplant recipients, a longer duration of hemodialysis before transplantation and leukopenia are risk factors for early-onset infection (≤3 months following transplantation) [23]. Donor CMV seropositivity is a risk factor for late-onset infection (>3 months following transplantation).

Emerging risk factors described patients with no or milder immunosuppression include:

Chronic obstructive pulmonary disease, with receipt of glucocorticoid therapy [24]

Intensive care unit (ICU) admission [25-27]

Certain viral infections (eg, influenza, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], respiratory syncytial virus) [26,28-30]

Invasive aspergillosis associated with viral infections typically occurs in patient with respiratory failure in ICUs. In these settings, invasive aspergillosis is thought to occur secondary to epithelial airway injury facilitating Aspergillus colonization and invasion. Influenza-associated aspergillosis (IAA) was evaluated over a seven-year period in Belgian and Dutch ICUs; among patients who had influenza pneumonia admitted to ICUs, 19 percent developed invasive aspergillosis. Forty-four percent lacked classic risk factors [31]. Mortality of IAA was 51 percent compared with 28 percent in patients with influenza alone.

SARS-CoV-2 (COVID-19) has also been associated with pulmonary aspergillosis in multiple case series [28,32-38]. The reported incidence varies widely across studies (0 to 33 percent) [34]. This wide range may in part be due to the difficulty of distinguishing airway colonization from invasive infection and varied diagnostic criteria. When relying on strict criteria for diagnosis (including autopsy data), the incidence appears to be approximately 2 to 6 percent [35,39]. Among reported cases, age >65 years, chronic structural lung disease, receipt of immunomodulatory agents, immunocompromising conditions, and invasive ventilatory support appear to be the most significant risk factors for its acquisition [32-35,40-42]. Extensive use of corticosteroids or receipt of tocilizumab or other interleukin-6 inhibitors or Janus kinase/signal transducer and activator of transcription inhibitors, such as baricitinib, may also increase the risk [28,42].

The nature of the immune suppression, including degree, duration, and type of immunocompromise and concomitant therapy influences the pathogenesis of disease. Thus, invasive aspergillosis can be manifested as a spectrum of diseases involving predominantly the airways (eg, tracheobronchitis), the lung, or both and also as disseminated disease, involving the central nervous system and other organs.

Invasive disease is most frequent when there is a high amount of airway exposure, for instance, in the setting of construction [43] or when the host has a condition in which conidia are not effectively cleared. Historically, the highest risks for invasive infections have been seen in severely immunosuppressed patients, particularly allogeneic HCT recipients, solid organ transplant (especially lung, heart-lung, and liver) recipients, and patients who experience prolonged neutropenia. There are some inherited immunodeficiencies, such as chronic granulomatous disease, that lead to high risk for pulmonary aspergillosis [1].

CLINICAL FEATURES — Invasive aspergillosis most frequently occurs in the lungs or sinuses after inhalation of conidia, although, less commonly, disease can spread from the gastrointestinal tract or result from direct inoculation into the skin.

Pulmonary aspergillosis — Invasive aspergillosis most commonly involves the lungs (picture 1). Patients can present with a number of signs and symptoms: fever, chest pain, shortness of breath, cough, and/or hemoptysis. The classic triad that has been described in neutropenic patients with pulmonary aspergillosis is fever, pleuritic chest pain, and hemoptysis. However, absence of this triad should not discourage consideration of this diagnosis in the patient with risk factors for disease since neutropenic patients frequently present with fever in the absence of localizing pulmonary symptoms. In such patients, lung imaging often reveals pulmonary nodules and/or infiltrates.

Imaging — Chest radiograph is insensitive for detecting the earliest stages of pulmonary disease, but computed tomography (CT) scans typically demonstrate focal lesions (image 1). The type of radiographic abnormality is variable, depending upon the host and the type of disease: bronchopneumonia, angioinvasive aspergillosis, tracheobronchitis, or chronic necrotizing aspergillosis.

Pulmonary aspergillosis typically manifests as single or multiple nodules (with or without cavitation), patchy or segmental consolidation, or peribronchial infiltrates with or without tree-in-bud patterns. One relatively large review noted that small nodules (<1 cm) were most common (20 of 46; 43 percent), followed by consolidation (12 of 46; 26 percent), large nodules (masses, 10 of 46; 21 percent), and peribronchial infiltrates (4 of 46; 9 percent) [44]. Another large study that included neutropenic and nonneutropenic patients showed that the more specific signs (nodules and cavitation) were infrequent, and radiographic findings of consolidation, ground-glass infiltrates, and pleural effusions were more commonly seen [45].

Radiographic findings, as with disease manifestations, can be variable and largely depend upon the host. The radiographic progression of disease has been studied best in neutropenic patients in whom the initial findings typically include nodules that have surrounding ground-glass infiltrates (the halo sign), reflecting hemorrhage into the area surrounding the fungus (image 1) [46]. These nodules typically enlarge, even during appropriate therapy, and may eventually cavitate, producing the air-crescent sign [47,48].

However, in one study, it was noted that neutropenic patients more frequently presented with segmental areas of consolidation rather than demonstrating the classic nodule progression to cavitation (image 2) [45]. Similar findings were reported in a cohort of solid organ transplant recipients, with the majority of patients presenting with "pulmonary pneumonia" (focal infiltrates, 39 percent) or "pulmonary nodular" (21 percent) findings on CT scan [49]. In a cohort of 139 children, the most common radiographic presentation was nodules (35 percent); few children developed cavitary disease (2 percent) [50].

There may be a role for CT pulmonary angiography for distinguishing between invasive mold infections and other causes of pulmonary infiltrates, by virtue of detection of angioinvasion [51,52]. However, the studies that evaluated this modality were small and did not evaluate patients with a heterogeneous group of underlying diseases. In addition, the risk of nephrotoxicity associated with the use of intravenous (IV) contrast has not been adequately evaluated. Larger studies will be needed to define the role of CT pulmonary angiography for diagnosing invasive aspergillosis.

COVID-19-associated infection — Clinical features associated with pulmonary aspergillosis in patients with coronavirus disease 2019 (COVID-19) vary considerably. Most reported cases have occurred in patients who are critically ill and/or mechanically ventilated [38,53,54]. In one case series of 20 patients, pulmonary aspergillosis was diagnosed a median of 11 days after symptom onset of COVID-19 and 9 days after intensive care unit admission [55]. Radiographic findings included ground glass opacities, consolidation, bronchiectasis, and in some cases, nodules and cavities. These findings likely reflect both viral pneumonia, and the array of findings due to aspergillosis, ranging from early airway inflammation, to invasive pneumonia with necrotic cavitary disease.

Because clinical features of COVID-19 and pulmonary aspergillosis vary and overlap, diagnosis is challenging [34,37]. In general, suspicion for invasive aspergillosis should be raised in any patient with COVID-19 with radiographic features suggestive of invasive aspergillosis (ie, multiple nodules or cavitary disease). Because patients with severe COVID-19 often have marked bilateral ground glass opacities, typical findings can be obscured; thus, suspicion should also be raised in patients with prolonged or relapsing respiratory failure, particularly in those with structural lung disease, age >65 years, and/or immunocompromising conditions [28].

Our approach to diagnosis and treatment is discussed separately. (See "Treatment and prevention of invasive aspergillosis".)

Tracheobronchitis — Aspergillus tracheobronchitis has been reported most commonly in lung transplant recipients but has also been described in other types of hosts (eg, recipients of other solid organ transplants, patients with hematologic malignancies, patients with HIV infection) [56]. (See "Fungal infections following lung transplantation", section on 'Tracheobronchial aspergillosis'.)

Affected patients typically present with prominent dyspnea, cough, and wheezing; they occasionally expectorate intraluminal mucus plugs. Chest imaging may be normal or reveal areas of airway thickening, patchy infiltrates, consolidation, or centrilobular nodules.

Different patterns of Aspergillus tracheobronchitis have been described:

Obstructive bronchial aspergillosis, a condition in which thick mucus plugs filled with Aspergillus hyphae are found in the airways, with little mucosal inflammation or invasion

Ulcerative tracheobronchitis, in which there is focal invasion of the tracheobronchial mucosa and/or cartilage by fungal hyphae

Pseudomembranous tracheobronchitis, which is characterized by extensive inflammation and invasion of the tracheobronchial tree with a pseudomembrane composed of necrotic debris and Aspergillus hyphae overlying the mucosa

Lung transplant recipients can also develop aspergillosis of the bronchial stump. This complication results from infection of the suture material and its incidence can be reduced with the use of nylon monofilaments rather than silk sutures. Patients complain of cough and may have hemoptysis.

Tracheobronchial disease can also occur in other hosts, including those who have hematologic malignancies, hematopoietic cell transplantation [57], and chronic obstructive pulmonary disease.

Chronic necrotizing and chronic cavitary pulmonary aspergillosis — Patients who have underlying chronic lung disease are at risk for indolent forms of pulmonary aspergillosis, characterized by cavities or infiltrates that may or may not demonstrate hyphal invasion of tissue on histopathology. Presumably, the slowly progressive nature of this infection is a function of the host immune response, which is enough to hold the organism in check but not to eliminate it. Cough, weight loss, fatigue, and chest pain are common, and the chest radiograph shows a slowly progressive lesion, which can be better defined by CT scanning. However, interpretation of radiologic studies may be complicated by the presence of concomitant lung disease, since this is the setting in which chronic aspergillosis usually occurs. (See "Chronic pulmonary aspergillosis: Epidemiology, clinical manifestations and diagnosis".)

Disseminated infection — In the presence of angioinvasive disease, Aspergillus spp can disseminate beyond the respiratory tract to multiple different organs, including the skin, brain, eyes, liver, and kidneys. Disseminated infection is associated with a very poor prognosis. (See "Treatment and prevention of invasive aspergillosis", section on 'Prognostic factors'.)

Rhinosinusitis — In the paranasal sinuses, aspergillosis can present in an identical fashion to mucormycosis. However, rhinocerebral aspergillosis is usually seen in neutropenic patients with hematologic malignancy, whereas mucormycosis occurs most commonly in those with diabetes mellitus or hematologic malignancy. (See "Fungal rhinosinusitis".)

The inflammatory response to the infection may be blunted because of neutropenia, and findings may be subtle. Nevertheless, nasal congestion, fever, and pain in the face and around the eye are common presenting features. If the orbit becomes involved, additional symptoms may include blurred vision, proptosis, and chemosis. The infection can also extend locally into the vasculature and the brain, leading to cavernous sinus thrombosis and a variety of central nervous system (CNS) manifestations.

CT findings may be subtle and can include focal soft tissue lesions, subtle focal bony erosions, and focal hypodense areas; magnetic resonance imaging (MRI) may also show soft tissue lesions as well as focal enhancement of the sinus lining [58].

Biopsy is necessary to establish the diagnosis; multiple biopsies are sometimes necessary [58]. (See "Diagnosis of invasive aspergillosis", section on 'Culture' and "Fungal rhinosinusitis", section on 'Diagnosis'.)

Central nervous system infection — CNS aspergillosis may occur in the setting of disseminated infection as well as from local extension from the paranasal sinuses. Patients with CNS involvement with Aspergillus spp may present with seizures or focal neurologic signs [1]. Mycotic aneurysms develop in some cases and can rupture, resulting in a hemorrhagic cerebrovascular accident, subarachnoid hemorrhage, and/or empyema formation [59].

In a study of the CT and/or MRI findings associated with CNS aspergillosis, three patterns were observed [60]:

Ring-enhancing lesions consistent with brain abscesses (image 3)

Cerebral cortical and subcortical infarction with or without superimposed hematomas (image 4)

Mucosal thickening of a paranasal sinus with secondary intracranial dural enhancement consistent with direct extension from the sinuses (image 5)

CNS infection is associated with a very poor prognosis. (See "Treatment and prevention of invasive aspergillosis", section on 'Prognostic factors'.)

Endophthalmitis — Aspergillus endophthalmitis may be a presenting feature of disseminated aspergillosis, in which involvement of the deep structures of the eye results not only from hematogenous spread. In other patients, corneal infection or direct inoculation following trauma is the genesis of infection [61]. Patients present with eye pain and visual changes [62].

Progressive infection is characterized by destruction of multiple components of the eye. The outcome is usually poor with loss of useful vision in the affected eye and a requirement for enucleation in some cases. (See "Treatment of endophthalmitis due to molds", section on 'Introduction'.)

Endocarditis — Aspergillus spp are second only to Candida spp as a cause of fungal endocarditis [63]. This infection occurs primarily in patients with prosthetic heart valves. In many patients, infection occurs at the time of surgery, with the fungus contaminating the surgical site. Patients may present at any time postoperatively. (See "Mechanical prosthetic valve thrombosis or obstruction: Clinical manifestations and diagnosis".)

Other patients at risk for the development of Aspergillus endocarditis include patients with indwelling central venous catheters and people who inject intravenous drugs.

Patients typically present with fever and embolic phenomena. Blood cultures are rarely positive, even when a fungal isolator system is used. Microscopic examination of an embolus will reveal the typical hyphae suggestive of aspergillosis, but definitive microbiologic diagnosis depends upon culture of the organism. (See "Diagnosis of invasive aspergillosis", section on 'Culture'.)

The prognosis of Aspergillus endocarditis is poor. Even with combined medical and surgical therapy, the mortality rate has approached 100 percent [64]. (See "Treatment and prevention of invasive aspergillosis", section on 'Prognostic factors'.)

Cutaneous aspergillosis — Cutaneous aspergillosis can be either primary, occurring from direct inoculation, usually in the presence of trauma, or secondary, occurring from contiguous extension or bloodborne spread (picture 2 and picture 3) [65].

A review noted that otherwise healthy hosts can develop cutaneous disease in surgical wounds or by traumatic inoculation, especially when this occurs in the presence of high spore counts, such as might occur during a farming accident [65]. While burn victims, neonates, and solid organ transplant recipients tend to develop primary cutaneous disease in the presence of prolonged local skin injury, patients with hematologic malignancies and hematopoietic cell transplant recipients more frequently develop disease due to contiguous or hematogenous spread to the skin.

Diagnosis can only be verified by skin biopsy, which should be taken from the center of the lesion and reach the subcutaneous fat in order to visualize hyphae invading blood vessels of the dermis and subcutis [65]. (See "Diagnosis of invasive aspergillosis", section on 'Culture'.)

Gastrointestinal aspergillosis — Aspergillosis can involve the gastrointestinal (GI) tract, causing focal invasion as a primary site of inoculation and presenting as neutropenic enterocolitis (typhlitis), appendicitis, colonic ulcers, abdominal pain, and/or GI bleeding [66-68]. Direct inoculation from the GI tract is likely, with risk factors including neutropenia, receipt of glucocorticoids, and mucosal breakdown (mucositis).

DIFFERENTIAL DIAGNOSIS — Several fungi can cause invasive infections that are indistinguishable from invasive aspergillosis on clinical or radiographic grounds alone. Furthermore, the risk factors for invasive aspergillosis are similar to those for other invasive fungal infections. It is important to establish a microbiologic diagnosis since the treatment regimen depends upon the species isolated. (See "Diagnosis of invasive aspergillosis".)

Fungi that can cause invasive pulmonary infections with clinical and radiographic features (eg, halo sign) that are similar to those caused by Aspergillus spp include:

Mucorales (see "Mucormycosis (zygomycosis)")

Fusarium spp (see "Mycology, pathogenesis, and epidemiology of Fusarium infection")

Scedosporium apiospermum complex (see "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections")

Lomentospora prolificans (formerly Scedosporium prolificans) (see "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections")

The halo sign can also be seen with other fungal infections and Pseudomonas aeruginosa infections [1]. (See 'Imaging' above.)

Imaging findings of invasive pulmonary aspergillosis can also overlap with those of tuberculosis [69]. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Radiologic findings'.)

Mucormycosis can also cause rhinosinusitis with extension into the central nervous system that is clinically and radiographically similar to invasive aspergillosis. However, rhinocerebral aspergillosis is usually seen in neutropenic patients with hematologic malignancy, whereas mucormycosis also occurs in those with diabetes mellitus. (See "Mucormycosis (zygomycosis)".)

In addition to Aspergillus spp, brain abscesses can be caused by a variety of fungi including the Mucorales, Fusarium spp, Scedosporium spp, and dematiaceous fungi. (See "Central nervous system infections due to dematiaceous fungi (cerebral phaeohyphomycosis)" and "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Aspergillosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Invasive aspergillosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Background − The term "aspergillosis" refers to illness due to allergy, airway or lung invasion, cutaneous infection, or extrapulmonary dissemination caused by species of Aspergillus. Aspergillus species are ubiquitous in nature, and inhalation of infectious conidia is a frequent event. Tissue invasion is uncommon and occurs most frequently in the setting of immunosuppression associated with therapy for hematologic malignancies, hematopoietic cell transplantation, or solid organ transplantation. (See 'Introduction' above.)

Pathogenesis − Inhaled conidia are met by the innate defenses provided by resident phagocytes, specifically airway epithelial cells and alveolar macrophages. Macrophages secrete inflammatory mediators after recognition of key cell wall components (eg, beta-D-glucan) exposed after conidial germination into hyphal forms. These mediators result in neutrophil recruitment and the activation of cellular immunity, which are important in killing potentially invasive microbial forms (hyphae) and determining the extent and nature of the immune response. (See 'Pathogenesis' above.)

Histopathology − Invasive aspergillosis is characterized by progression of the infection across tissue planes. One hallmark of infection is vascular invasion with subsequent infarction and tissue necrosis. (See 'Pathogenesis' above.)

Aspergillus species − Most invasive infections are caused by members of the A. fumigatus species complex. In a report of 218 infections in the United States, 67 percent were caused by members of the A. fumigatus complex, followed by A. flavus (13 percent), A. niger (9 percent), and A. terreus (7 percent). (See 'Species prevalence' above.)

Risk factors − Underlying conditions that compromise pulmonary and systemic immune responses to inhaled Aspergillus species serve as risk factors for invasive pulmonary aspergillosis. Classic risk factors for invasive aspergillosis include:

Severe and prolonged neutropenia

Receipt of high doses of glucocorticoids

Other drugs or conditions that lead to chronically impaired cellular responses (eg, immunosuppressive regimens administered to treat autoimmune diseases and to prevent organ rejection, AIDS, ibrutinib, small molecule tyrosine kinase inhibitors) (see 'Risk factors' above)

Other risk factors described in patients with little or no immunosuppression include, COPD (with receipt of glucocorticoids), intensive care unit admission, and certain viral infections (eg, influenza, severe acute respiratory syndrome coronavirus 2). (See 'Risk factors' above.)

Range of symptoms with pulmonary disease − Invasive aspergillosis most commonly involves the lungs (picture 1). Disease can present with a number of signs and symptoms: fever, chest pain, shortness of breath, cough, and/or hemoptysis. However, absence of symptoms should not discourage consideration of this diagnosis in the patient who has risk factors for disease since neutropenic patients frequently present with fever in the absence of localizing pulmonary symptoms. (See 'Pulmonary aspergillosis' above.)

Radiographic findings − Pulmonary aspergillosis typically manifests as single or multiple nodules with or without cavitation, patchy or segmental consolidation, or peribronchial infiltrates with or without tree-in-bud patterns. The radiographic progression of disease has been studied best in neutropenic patients in whom the initial findings typically include nodules that have surrounding ground-glass infiltrates (the halo sign), reflecting hemorrhage into the area surrounding the fungus (image 1). These nodules typically enlarge, even during appropriate therapy, and may eventually cavitate, producing the air-crescent sign. Other fungal infections and Pseudomonas aeruginosa can show similar radiographic findings as invasive aspergillosis. (See 'Imaging' above and 'Differential diagnosis' above.)

Disseminated disease − In the presence of angioinvasive disease, Aspergillus spp can disseminate beyond the respiratory tract to multiple different organs, including the skin (picture 2 and picture 3), brain, eyes, liver, and kidneys. Disseminated infection is associated with a very poor prognosis. (See 'Disseminated infection' above.)

Other clinical manifestations − Other manifestations of invasive aspergillosis include tracheobronchitis, rhinosinusitis, brain abscess, endophthalmitis, endocarditis, and gastrointestinal disease. (See 'Clinical features' above.)

Differential diagnosis − The differential diagnosis of invasive pulmonary aspergillosis includes other angioinvasive fungal infections, such as mucormycosis, fusariosis, and scedosporiosis. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Kieren A Marr, MD, and Daniel J Sexton, MD, who contributed to an earlier version of this topic review.

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Topic 2454 Version 45.0

References

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