Highlights & Basics
- Aspergillosis is caused by filamentous fungi of the Aspergillus species, which are found ubiquitously in soil. Aerosolized conidia (spores) are inhaled, which may result in infection.
- Invasive aspergillosis (IA) mostly affects immunocompromised patients (e.g., stem cell transplant recipients, prolonged severe neutropenia, immunosuppressive therapy). It is rare in immunocompetent individuals.
- Chronic pulmonary aspergillosis (CPA) generally affects people who are not immunocompromised, but have an underlying lung condition. Aspergilloma (fungal ball) may form in cavities.
- Clinical findings of IA are nonspecific and include fever, cough, and pleuritic pain. High index of suspicion is required for early diagnosis. Lungs, sinuses, brain, and skin are sites of involvement.
- High-resolution computer tomography (CT) scan and serum Aspergillus galactomannan antigen test are useful tests for early diagnosis of IA.
- Isavuconazonium and voriconazole are the antifungal agents of choice for IA. Lipid-based formulations of amphotericin B are an alternative.
- Early diagnosis and therapy significantly improve prognosis of patients with IA.
- Treatment of CPA depends on the type.
Quick Reference
History & Exam
Key Factors
pleuritic chest pain
pleural rub
nasal ulcer
skin rash
Other Factors
cough
headache
fever
congestion or sinus tenderness
hemoptysis
dyspnea
facial pain
seizure
altered mental status
cranial nerve palsy
malaise
weight loss
Diagnostics Tests
1st Tests to Order
CXR
high-resolution chest CT scan
high-resolution sinuses CT scan
high-resolution brain CT scan
MRI sinuses
MRI brain
serum Aspergillus galactomannan (GM) antigen by enzyme immunoassay (EIA)
sputum culture
sputum smear
Other Tests to consider
BAL Aspergillus galactomannan (GM) antigen
bronchoscopy with bronchoalveolar lavage (BAL) fungal stain
bronchoscopy with BAL fungal culture
polymerase chain reaction
serum (1-3)-beta-D-glucan
serum Aspergillus IgG
tissue biopsy
tissue fungal culture
tissue fungal stain
Treatment Options
presumptive
suspected invasive aspergillosis
empiric antifungal therapy
acute
confirmed invasive aspergillosis
antifungal therapy
reversal of the underlying immune deficiency
surgical resection of the infected focus
Definition
Classifications
Types of aspergillosis
- Invasive sino-pulmonary aspergillosis: inhalation of conidia most commonly results in sinus and pulmonary involvement.
- Disseminated aspergillosis: in profoundly immunocompromised patients, focal disease may spread to multiple organ sites.
- Single-organ IA: common sites include skin (via trauma), bone, and brain.
- Chronic cavitary pulmonary aspergillosis (previously termed complex aspergilloma)
- Aspergillus colonizes and grows in pulmonary cavities. Aspergilloma may grow in the cavities.
- Chronic fibrosing pulmonary aspergillosis
- Occurs following untreated chronic cavitary pulmonary aspergillosis.
- Aspergilloma (fungal ball)
- Consists of mycelia, inflammatory cells, fibrin, mucus, and tissue debris. Occurs in pre-existing lung cavities.Image
- A single aspergilloma in a single cavity, with no progression and few or no symptoms is termed simple aspergilloma.
- Subacute invasive aspergillosis (previously termed chronic necrotizing aspergillosis)
- An indolent destructive process due to invasion by Aspergillus.
- Usually seen in patients with lung disease such as COPD, pneumoconiosis, or cystic fibrosis, and in patients with mild immunosuppression.
- Aspergillus nodule
- Nodules do not usually form cavities; an unusual form of aspergillosis.
- Hypersensitivity reaction to Aspergillus antigens, mostly due to A fumigatus.
- Typically seen in patients with long-standing asthma or cystic fibrosis.
Vignette
Common Vignette 1
Common Vignette 2
Other Presentations
Epidemiology
Etiology
Pathophysiology
- IA mostly affects immunocompromised patients (e.g., stem cell transplant recipients, prolonged severe neutropenia, immunosuppressive therapy). It is rare in immunocompetent individuals. When conidia survive, germination leads to hyphae (filamentous form), which invade the pulmonary parenchyma. Polymorphonuclear leukocytes phagocytose the swollen conidia and hyphae.[22] [23]
- During invasion, interaction occurs between Aspergillus ligands and the pattern recognition receptors, including Toll-like receptors (TLR) and Dectin, on macrophages leading to the production of pro-inflammatory cytokines.[24] Fever is the resultant clinical manifestation.
- TLR-4 polymorphisms in humans have been implicated as a risk factor of IA.[25] Angioinvasive hyphae gain entry and locally disseminate via the pulmonary microvasculature and cause thrombus formation and tissue infarction. Infected areas of lung with associated inflammation and pulmonary infarction contribute to clinical symptoms of cough, shortness of breath, and pleuritic chest pain. Lung function may worsen with increased areas of involvement.
- Dissemination from the lung via the hematogenous route may commonly occur into the brain and skin, leading to tissue infarction at those sites. Virtually all body sites, including the heart, kidney, liver/spleen, bone, and gastrointestinal tract, may be affected.[2] Direct invasion from the paranasal sinus cavity into the orbit, sphenoidal sinus, and brain parenchyma may also occur.[2]
- Aspergilloma (fungal ball) consist of Aspergillus mycelia, inflammatory cells, fibrin, mucus, and tissue debris.[4] May form in pulmonary cavities. The growth of Aspergillus on the walls of the cavity is facilitated by inadequate drainage. Bleeding is uncommon; however, severe hemoptysis may sometimes occur secondary to erosion of bronchial blood vessels lining the cavity, and mechanical friction of the fungal ball against the blood vessels.[27]
Images
Aspergilloma in a pre-existing tuberculous lung cavity
Morphology of conidiophores and conidia of Aspergillus fumigatus
"Halo" sign in early pulmonary aspergillosis
"Air-crescent" sign in late pulmonary aspergillosis
Gomori methenamine silver (GMS) of lung tissue showing dichotomously branching, septate hyphae of Aspergillus
Diagnostic algorithm for suspected invasive aspergillosis
Treatment approach for invasive aspergillosis
Diagnostic Approach
- Solid organ transplant recipients (particularly in lung and/or heart recipients)
- Patients with chronic granulomatous disease (CGD)
- Patients receiving high-dose corticosteroids or other immunosuppressive drugs
- Patients with poorly controlled diabetes mellitus
- Patients with primary immunodeficiency disorders.
Clinical manifestations
Imaging
- CXR may reveal nodules, consolidation, or frequently nonspecific infiltrates. Often CXR shows no abnormalities. If index of suspicion is high, chest CT scan should be obtained.
- High-resolution CT scan of chest is the preferred radiologic method as it is useful in detecting early lesions suggestive of pulmonary aspergillosis. The scan may show single or multiple nodules scattered over 1 or both lungs, generally in the periphery of the lung fields. Smaller nodules (<1 cm), ground-glass opacities, and consolidation are nonspecific features and do not necessarily suggest pulmonary IA.[67] The presence of macronodules (1 cm or larger) in a high-risk patient is highly suggestive of IA, and may be seen in other conditions including other invasive fungal infections, tuberculosis, nocardiosis, and bacterial infections.[67] In the leukemic patient with neutropenia, early disease is characterized by a haziness representing hemorrhage/edema surrounding the nodules ("halo sign").[68] With clinical improvement (e.g., reversal of underlying immune deficiency), the halo sign may disappear. The "air-crescent sign" can be observed instead. It is indicative of a necrotic lesion contracting from viable lung tissue, creating a cavity within where the air is trapped. The halo sign is indicative of early disease and thus is useful in early diagnosis, while the air-crescent sign indicates that the disease has been present for >6 to 7 days. Therapy initiated in patients with halo sign is associated with improved outcome.[69] During therapy, the nodular lesions initially enlarge, suggesting that the process may be worsening. After about 7 days of therapy, however, CT scans show improvement. Pulmonary macronodules, the halo sign, and the air-crescent sign have been best studied in patients with IA and hematologic malignancy or stem cell transplantation. Radiologic features are not as well characterized in other settings with IA.
- IA suspected at other sites such as sinuses and brain may also be evaluated with CT scan or MRI. X-rays of the sinuses are not helpful. CT is the preferred imaging modality.[68] [67] With sinus disease, in addition to the opacity/mass within the sinus cavity, bone erosion of the surrounding sinus walls is highly suggestive of an aggressive infection. In brain disease, space-occupying lesions with surrounding edema, abscesses, and hemorrhage can be seen.
- Single upper lobe lesions are the most common finding on CXR. Multiple lesions are rarely seen. An upper lobe, mobile, intracavitary mass with an air-crescent in the periphery (Monod's sign) is strongly suggestive of aspergilloma. Plain x-rays are usually adequate. Occasionally chest CT is required. In radiographs a change in the position of the fungal ball may be seen with a change in the position of the patient.[71] Periodic CXRs are adequate for the follow-up of asymptomatic aspergilloma.
Serology/bronchoalveolar lavage (BAL)
- The diagnosis of IA has remained a challenge due to the nonspecific clinical presentation of IA, the low sensitivity of microscopy and culture of lower respiratory specimens, and the difficulty of obtaining tissue for histopathology in critically ill patients. As a result, biomarkers such as Aspergillus galactomannan (GM) antigen and serum beta-D-glucan have been evaluated, mostly in stem cell recipients and leukemic patients with neutropenia.[72] [73] [74]
- Galactomannan (GM) antigen
- GM antigen is a polysaccharide cell wall component of Aspergillus species that is released into the systemic circulation during fungal growth in tissue.
- Serial monitoring of GM has detected IA between 6 and 14 days earlier than radiographic findings.[79]
- False-positive results are seen with other fungi such as Histoplasma, Blastomyces, Geotrichum, and Penicillium species, and bacteria (e.g., Bifidobacterium).[72] [80] The use of beta-lactam antibiotics such as piperacillin-tazobactam and amoxicillin-clavulanic acid may show false-positive results.[81] In the presence of mold-active drugs used as prophylaxis or therapy, the sensitivity of GM assay is reduced. The sensitivity may be lower in non-neutropenic patients, possibly due to a lower fungal burden.
- The combined use of serum GM antigen assay and chest CT improves the detection of pulmonary IA, permitting earlier initiation of therapy.[78] Data suggest that GM antigen measurements in BAL fluid are more sensitive than serum GM and have a better predictive value, and BAL GM antigen test has now become an accepted method for diagnosis.[82] [83] BAL fluid GM antigen measurement of 1.5 optical density index or higher appears to be a strong predictor of IA in immunocompromised patients (specificity >90%).[84]
- Serum (1-3)-beta-D-glucan
- This test is a variation of the limulus assay used to detect endotoxin. The presence of serum glucan is not specific for Aspergillus and false-positive results can occur due to blood collection tubes, gauze, and contaminated membrane filters.
- One Cochrane review found wide variation in sensitivity and specificity of commercially available tests for serum (1-3)-beta-D-glucan in detecting selected invasive fungal infections, including aspergillosis. Sensitivity ranged from 27% to 100%, and specificity ranged from 0% to 100%; therefore, accuracy of diagnosis could not be determined.[85]
- Polymerase chain reaction (PCR)
- Polymerase chain reaction diagnosis, based on amplification of Aspergillus-specific fungal genes (usually ribosomal DNA) in blood and BAL fluid, has shown considerable promise for early diagnosis. In BAL fluid, two positive PCR test results have a higher positive predictive value to rule in IA.[66] PCR testing in histopathology specimens also increases the diagnostic yield.[66] PCR-based test results may be falsely positive because of ubiquitous presence of Aspergillus conidia. Combining the PCR-based test with other noninvasive nonculture-based diagnostic methods (i.e., serum GM test and serum beta-D-glucan assay) is an important area for early diagnosis of invasive aspergillosis.
- Aspergillus antibodies
- Aspergillus IgG antibody test is the most sensitive test for chronic cavitary pulmonary aspergillosis (CCPA).[2] Serum IgG antibodies to Aspergillus or precipitins are positive in most patients with CPA.
- False-negative cases may be seen in patients receiving corticosteroid therapy or in those with aspergilloma due to species other than A fumigatus.[86]
- GM antigen
- When used in the diagnosis of CPA, BAL fluid should be used (not serum). Specificity and sensitivity is lower than Aspergillus antibody tests.[3]
- PCR
Microbiology
- Cough is generally nonproductive in these patients. Sputum, when available, is usually negative by fungal stain and culture. A positive finding is highly significant in a high-risk patient (immunocompromised).[11] However, in a low-risk patient (immunocompetent), Aspergillus in sputum may simply represent colonization needing no further intervention.[11] [88]
- Aspergillus species grow well on standard media and can be identified to a species level in most laboratories. Culture from a sterile site is diagnostic of IA. Blood cultures are usually negative even in disseminated cases.
- Commonly used invasive diagnostic procedures are:
- Bronchoscopy with BAL and/or biopsy
- Percutaneous transthoracic CT-guided needle aspiration
- Video-assisted thoracoscopic biopsy.
- Specimens obtained may show characteristic angular, dichotomously branching, septate hyphae, and Aspergillus species in culture. Culture confirmation is critical to distinguish Aspergillus from other fungi with similar morphologic features, such as Fusarium and Scedosporium.[17] False-negative results occur with specimens obtained from unaffected areas, with inadequate specimens, and in patients already receiving antifungal therapy. Thus, lack of positive fungal smear or culture does not rule out the diagnosis of IA. Also, invasive procedures may not be possible in critically ill patients or those with thrombocytopenia.
- Appropriate tissue specimens obtained by biopsy must be submitted for fungal stain (Gomori methenamine silver) and culture. Gram stain to detect bacteria is inappropriate for fungal detection. Optical brighteners using white stain are helpful in enhancing fungal elements.
- Direct microscopy or fungal culture of respiratory specimens may identify the presence of Aspergillus. However, culture positivity rates vary widely and results should be interpreted with caution.[3] [89] Testing multiple samples increases the probability of a positive culture or microscopy test, but the majority of patients have negative sputum cultures.[2] Additionally, as Aspergillus are ubiquitous in the environment, their presence in sputum is not necessarily diagnostic.[89]
Histopathology
- Transbronchial CT-guided needle aspiration (for peripheral lesions)
- Video-assisted thoracoscopic surgery (VATS) biopsy
- Open lung biopsy.
- In certain cases, microscopic examination of tissue obtained by biopsy is necessary for diagnosis.
- Examination of aspergilloma shows fungal mycelia, inflammatory cells, tissue debris, fibrin, and mucus.[4]
Risk Factors
History & Exam
Tests
Differential Diagnosis
Mucormycosis and other zygomycoses (e.g., phycomycosis, basidiobolomycosis)
Differentiating Signs/Symptoms
- Paranasal sinuses and pulmonary symptoms are more common.
- Presence of black necrotic lesions of the nasal mucosa and hard palate.
- Rapid spread of involvement without regard to anatomical plane, with hypoesthetic skin patches.
- Zygomycoses are common in patients with (poorly controlled) diabetes with sino-orbital or rhinocerebral involvement.
Differentiating Tests
- Culture and histopathology of tissue and specimens.[92] While Zygomycetes appear as broad, nonseptate hyphae with branches occurring at right angles, Aspergillus appears as narrower, septate hyphae with frequent acute-angle branching. Often, these 2 entities may be difficult to distinguish. Blood cultures are negative in zygomycosis as with aspergillosis.
- No serologic test is available.
- Radiologic appearance is similar to that of aspergillosis.
Differentiating Signs/Symptoms
- Common in patients with severe, prolonged neutropenia; the disease may begin at a site of trauma or with onychomycosis.
- Fever and myalgia are common.
- Skin lesions occur in 60% to 80% of infections.
- Less commonly, other filamentous fungi may produce lesions indistinguishable from aspergillosis.
Differentiating Signs/Symptoms
- May involve lungs, bones, joints, and central nervous system.
- In immunocompromised patients, fever, erythematous raised lesions involving the skin, and brain involvement are common.
- Less commonly, other filamentous fungi may produce lesions indistinguishable from aspergillosis.
Differentiating Tests
- Tissue cultures help distinguish the pathogens; histologically, Scedosporium resemble Aspergillus.
- No serologic test is available.
- Radiologic features and patient characteristics are similar to those of aspergillosis.[93]
Nocardiosis
Differentiating Signs/Symptoms
- No differentiating signs or symptoms.
Differentiating Tests
- As the patient characteristics and clinical/radiologic features are similar, culture/histology of the lesion (skin, lung nodule, brain mass/abscess) is required for diagnosis.[94] Histologically, Nocardia appears as gram-positive, branching, slender, filamentous organisms (acid-fast smear positive). Not infrequently, respiratory secretions or aspirate from abscess may reveal the organism.
- Rarely, standard blood cultures are positive with prolonged incubation.
Mycobacterial infection
Differentiating Signs/Symptoms
- Cough, sputum production, and fever may be prominent.
- Country of origin and contact history for tuberculosis may increase suspicion for Mycobacterium tuberculosis infection.
- Atypical Mycobacteria, such as Mycobacterium avium may present with respiratory symptoms, particularly in patients with chronic lung disease.
Differentiating Tests
- Nodules and cavities on CXR or chest CT scan may be seen.
- Respiratory secretions (sputum, bronchoalveolar lavage [BAL] fluid) are helpful for diagnosis.
- Occasionally, biopsy of involved lungs for mycobacterial stain and culture is needed.
Pneumonia
Differentiating Signs/Symptoms
- Due to bacteria such as Pseudomonas aeruginosa may present with clinical features similar to those of aspergillosis.
- Fever, sputum production, cough, and shortness of breath are prominent.
Differentiating Tests
- Gram stain and bacterial cultures if available, or BAL fluid, are useful for diagnosis.
- Blood cultures may be positive.
- CT-guided needle aspiration of the pulmonary lesion may be required for diagnosis.
Endocarditis
Differentiating Signs/Symptoms
- Systemic bacterial infections may secondarily involve the lung and present with features of pneumonia.
Differentiating Tests
- Gram stain and bacterial cultures if available, or BAL fluid, are useful for diagnosis.
- Blood cultures may be positive.
- CT-guided needle aspiration of the pulmonary lesion may be required.
Sepsis
Differentiating Signs/Symptoms
- Systemic bacterial infections may secondarily involve the lung and present with features of pneumonia.
Differentiating Tests
- Gram stain and bacterial cultures if available, or BAL fluid, are useful for diagnosis.
- Blood cultures may be positive.
- CT-guided needle aspiration of the pulmonary lesion may be required.
Pulmonary embolism
Differentiating Signs/Symptoms
- Underlying predisposing condition such as immobility/prolonged bed rest, hypercoagulability, or venous thrombosis of the lower extremities/pelvis.
- Pleuritic chest pain and shortness of breath may be the dominant symptoms. Fever, cough, and sputum production are less common. Pleural rub may be present.
Differentiating Tests
- CXR or chest CT scan of chest typically shows wedge-shaped, peripheral pulmonary emboli/infarcts, at times mimicking findings of aspergillosis; however, multiple nodules, "halo sign", and cavities are generally not seen.
Differentiating Signs/Symptoms
- Lymphoma involving the lung, and other malignancies, primary or metastatic in lungs, may mimic pulmonary aspergillosis. Clinical features may be indistinguishable.
Differentiating Tests
- Comparison of serially obtained CXR/CT scans of chest is extremely helpful to distinguish pre-existing malignancy from recent pulmonary aspergillosis.
- Biopsy of the lesion is required for definitive diagnosis.
- Anecdotal data suggest that PET-CT scan may be useful to distinguish malignancy from an opportunistic process.
Allergic bronchopulmonary aspergillosis
Differentiating Signs/Symptoms
- History of allergic asthma, history of cystic fibrosis; increased shortness of breath and wheeze
Differentiating Tests
- CXR is usually undertaken early in the workup of chest symptoms. Skin testing, serology testing, and high-resolution CT of the chest are usually performed.
Coronavirus disease 2019 (COVID-19)
Differentiating Signs/Symptoms
- Residence in/travel to a country/area or territory with local transmission, or close contact with a confirmed or probable case of COVID-19, in the 14 days prior to symptom onset.
Differentiating Tests
- Real-time reverse transcription polymerase chain reaction (RT-PCR): positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA.
Criteria
- Criteria for proven invasive fungal disease:
- Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae are seen accompanied by evidence of tissue damage
- Culture of a specimen obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid (BAL), a paranasal or mastoid sinus cavity specimen, and urine
- Blood culture that yields a mold (e.g., Fusarium species) in the context of a compatible infectious disease process
- Amplification of fungal DNA by polymerase chain reaction (PCR) combined with DNA sequencing when molds are seen in formalin-fixed paraffin-embedded tissue
- Probable invasive pulmonary mold disease:
- Requires the presence of one host factor, one clinical feature, and mycologic evidence (see below).
- Possible invasive pulmonary mold disease:
- Presence of one host factor and one clinical feature, but mycologic evidence has not been found.
- Recent history of neutropenia (<500 neutrophils/mm³ [<0.5 × 10⁹ neutrophils/L] for >10 days) temporally related to the onset of fungal disease
- Hematologic malignancy
- Receipt of an allogeneic stem cell transplant
- Receipt of a solid organ transplant
- Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a therapeutic dose of ≥0.3 mg/kg/day for ≥3 weeks in the past 60 days
- Treatment with other recognized T-cell immunosuppressants, such as calcineurin inhibitors, tumor necrosis factor-alpha blockers, lymphocyte-specific monoclonal antibodies, immunosuppressive nucleoside analogs during the past 90 days
- Treatment with recognized B-cell immunosuppressants, such as Bruton tyrosine kinase inhibitors, e.g., ibrutinib
- Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency)
- Acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids.
- Pulmonary aspergillosis (presence of one of the following four patterns on CT):
- Tracheobronchitis:
- Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis
- Sinonasal infection:
- Acute localized pain (including pain radiating to the eye)
- Nasal ulcer with black eschar
- Extension from the paranasal sinus across bony barriers, including into the orbit.
- Central nervous system infection (one of the following two signs):
- Focal lesions on imaging
- Meningeal enhancement on MRI or CT.
- Aspergillus recovered by culture from sputum, BAL fluid, bronchial brush, or aspirate
- Microscopic detection of fungal elements indicating a mold from sputum, BAL fluid, bronchial brush, or aspirate
- Aspergillus galactomannan antigen detected in plasma, serum, BAL fluid, or cerebrospinal fluid
- Two or more consecutive PCR tests positive from plasma, serum, or whole blood, or two or more duplicate PCR tests from BAL fluid positive, or at least one PCR test positive in plasma, serum, or whole blood and one PCR test positive in BAL fluid.
- Single pulmonary cavity containing a fungal ball, with serologic or microbiologic evidence implicating Aspergillus species in a non-immunocompromised patient with minor or no symptoms and no radiologic progression over at least 3 months of observation.
- One or more pulmonary cavities (with either a thin or thick wall) possibly containing one or more aspergillomas or irregular intraluminal material, with serologic or microbiologic evidence implicating Aspergillus species with significant pulmonary and/or systemic symptoms and overt radiological progression (new cavities, increasing pericavitary infiltrates, or increasing fibrosis) over at least 3 months of observation.
- Severe fibrotic destruction of at least two lobes of lung complicating CCPA leading to a major loss of lung function. Severe fibrotic destruction of one lobe with a cavity is simply referred to as CCPA affecting that lobe. Usually the fibrosis is manifest as consolidation, but large cavities with surrounding fibrosis may be seen.
- One or more nodules which may or may not cavitate are an unusual form of CPA. They may mimic tuberculoma, carcinoma of the lung, coccidioidomycosis, and other diagnoses and can only be definitively diagnosed on histology. Tissue invasion is not demonstrated, although necrosis is frequent.
- Invasive aspergillosis, usually in mildly immunocompromised patients, occurring over 1-3 months, with variable radiologic features including cavitation, nodules, progressive consolidation with "abscess formation". Biopsy shows hyphae in invading lung tissue and microbiologic investigations reflect those in invasive aspergillosis, notably positive Aspergillus galactomannan antigen in blood (or respiratory fluids).
Screening
Risk groups for screening
Screening test
Treatment Approach
- Reversal of the underlying immune deficiency
- Early introduction of antifungal therapy.
- Definitive treatment is provided in a setting of confirmed/probable diagnosis.
- Empiric treatment is given in a suspected diagnosis in a high-risk patient with clinical features suggestive of the infection without further confirmation (e.g., radiology, serology).
- Preemptive therapy is provided in cases of strongly suspected IA in a high-risk patient with suggestive clinical features plus the presence of additional evidence (e.g., suggestive computed tomography [CT] scan and/or positive biomarkers).
Suspected invasive aspergillosis (possible diagnosis)
Invasive aspergillosis (confirmed/probable diagnosis)
- Polyenes (e.g., amphotericin B)
- Azoles (e.g., voriconazole, posaconazole, isavuconazonium)
- Echinocandins (e.g., caspofungin, micafungin).
Chronic pulmonary aspergillosis
Treatment Options
suspected invasive aspergillosis
empiric antifungal therapy
Primary Options
amphotericin B liposomal
3-5 mg/kg intravenously once daily
amphotericin B lipid complex
5 mg/kg intravenously once daily
- caspofungin
70 mg intravenously on day 1, followed by 50 mg once daily
- caspofungin
- voriconazole
6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours
- voriconazole
Comments
- In high-risk patients, empiric therapy may be used when the diagnosis of invasive aspergillosis is suspected: for example, neutropenic patients with fever unresponsive to broad-spectrum antibacterial agents without an obvious focus of infection. Fever may be due to nonfungal etiology. However, since the diagnosis is difficult to confirm, antifungal drugs are frequently employed. Lipid formulations of amphotericin B or an echinocandin are used in these cases.[97]
- The Infectious Diseases Society of America (IDSA) guidelines also recommend voriconazole.[2]
confirmed invasive aspergillosis
antifungal therapy
Primary Options
- voriconazole
6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours, can switch to oral therapy when clinical improvement; 200 mg orally twice daily
- voriconazole
- isavuconazonium sulfate
372 mg intravenously/orally every 8 hours for 6 doses as a loading dose, followed by 372 mg intravenously/orally once daily (starting 12-24 hours after the last loading dose)
- isavuconazonium sulfate
- posaconazole
300 mg intravenously every 12 hours on day 1, followed by 300 mg every 24 hours, can switch to oral therapy when clinical improvement; 300 mg orally (delayed-release) twice daily on day 1, followed by 300 mg once daily
- posaconazole
amphotericin B liposomal
3-5 mg/kg intravenously once daily
Secondary Options
- caspofungin
70 mg intravenously on day 1, followed by 50 mg once daily
- caspofungin
- micafungin
100-150 mg intravenously once daily
- micafungin
Tertiary Options
- caspofungin
70 mg intravenously on day 1, followed by 50 mg once daily
or
- micafungin
100-150 mg intravenously once daily
AND
- voriconazole
6 mg/kg intravenously every 12 hours on day 1, followed by 4 mg/kg intravenously every 12 hours, can switch to oral therapy when clinical improvement; 200 mg orally twice daily
or
amphotericin B liposomal
3-5 mg/kg intravenously once daily
or
amphotericin B lipid complex
5 mg/kg intravenously once daily
- caspofungin
Comments
- Voriconazole or isavuconazonium are the drugs of choice in the treatment of confirmed/probable invasive aspergillosis (IA). Although efficacies of isavuconazonium and voriconazole are similar, the former appears to have a better safety profile.[16]
- Isavuconazonium is a prodrug of isavuconazole, a broad-spectrum antifungal agent with activity against both Aspergillus and Mucor. It is indicated for the treatment of adults with IA.[120] Isavuconazole is only available as isavuconazonium in the US.
- High-risk patients with a suggestive computed tomography (CT) scan and/or positive biomarkers (e.g., serum galactomannan) are also candidates for preemptive therapy. Invasive procedures may not yield positive results or may be difficult to perform, so these treatments may be employed on the basis of a presumptive diagnosis.[114]
- Within a few days, administration may be changed from the intravenous to the oral route.
- Clinical improvement may be noted within 5 to 7 days of therapy; radiologically the condition may worsen before improvement.
- The alternatives to these agents are posaconazole or a lipid formulation of amphotericin B, either amphotericin B lipid complex or liposomal amphotericin B.[106] [107] [108] Posaconazole demonstrated noninferiority to voriconazole in the treatment of invasive aspergillosis in one randomized controlled trial; posaconazole was also associated with fewer treatment-related adverse events.[109] In areas of known and increasing azole-resistance, a lipid formulation of amphotericin B should be considered a first-line agent until the results of resistance testing are available.[16]
- Treatment with echinocandins (e.g., caspofungin and micafungin) may be used as monotherapy or in combination with a lipid formulation of amphotericin B or voriconazole.[121] In critically ill patients, combination therapy may be attempted.
- Duration of therapy is decided in light of clinical/radiologic improvement and restoration of immune status. Optimal duration is unclear; in general, therapy may be given for 6 to 12 weeks.[2]
reversal of the underlying immune deficiency
Comments
- The use of colony-stimulating factors may reduce the duration of neutropenia. Discontinuing or reducing the dose of corticosteroids may help restore immune function. However, in many situations the underlying immunological deficiency may not be correctable (e.g., in severe graft-versus-host disease). In such cases, the prognosis is generally poor. Early diagnosis followed by early initiation of therapy with antifungal agents improves outcome.[99]
surgical resection of the infected focus
Comments
- Surgical intervention may be indicated in cases of invasive aspergillosis lesions that are contiguous with the great vessels or the pericardium, severe hemoptysis from a single cavity or invasion of the chest wall. A single pulmonary lesion prior to intensive chemotherapy or stem cell transplantation is another relative indication for surgical resection.[2] [115]
aspergilloma with life-threatening hemoptysis
stabilization with intravenous fluids and blood transfusion + surgical resection
Comments
- Patients with severe hemoptysis need to be stabilized with intravenous fluids and blood.
- There is insufficient evidence that aspergilloma responds to antifungal agents.
- In symptomatic patients with severe hemoptysis, bronchial artery embolization may be helpful as a temporizing measure. However, the presence of massive collateral blood vessels makes the procedure suboptimal.[117]
- Peri- and postoperative antifungal therapy is not routinely required, but guidelines suggest that if there is a moderate risk of surgical spillage of the aspergilloma, antifungal therapy with an azole or an echinocandin may be used to prevent Aspergillus empyema.[2]
chronic pulmonary aspergillosis
aspergilloma without life-threatening hemoptysis
chronic cavitary pulmonary aspergillosis or chronic fibrosing pulmonary aspergillosis
antifungal therapy and monitoring
Primary Options
- voriconazole
200-300 mg orally twice daily
- voriconazole
- itraconazole
200 mg orally twice daily
- itraconazole
Secondary Options
- posaconazole
300 mg orally (delayed-release) twice daily for 2 doses, followed by 300 mg once daily
- posaconazole
Tertiary Options
amphotericin B deoxycholate
1 to 1.5 mg/kg intravenously once daily
amphotericin B liposomal
3-5 mg/kg intravenously once daily
- caspofungin
70 mg intravenously on day 1, followed by 50 mg once daily
- caspofungin
- micafungin
100-150 mg intravenously once daily
- micafungin
Comments
- Patients with chronic cavitary pulmonary aspergillosis (CCPA) are treated with antifungal therapy to halt progression, improve symptoms, and minimize hemoptysis.[116]
- Intravenous antifungal therapy may be considered in patients with progressive disease, or who are intolerant to azoles or develop resistance. An initial course of intravenous antifungal therapy may also be considered for some acutely ill patients.[2] [3] Options include amphotericin B deoxycholate, liposomal amphotericin B, or an echinocandin (e.g., micafungin, caspofungin).
subacute invasive aspergillosis
antifungal therapy
Comments
- Subacute invasive aspergillosis should be treated in the same way as acute invasive aspergillosis (see confirmed invasive aspergillosis).[3]
aspergillus nodule
monitoring and consider antifungal therapy
Comments
- Aspergillus nodules are diagnosed after excision biopsy, usually following suspicion for malignancy. Single nodules that are completely excised may not need antifungal therapy, unless the patient is immunocompromised.[3] [4] Single nodules that are not completely resected should be closely monitored. Antifungal therapy may be considered in patients with multiple nodules.[3] Consult an infectious disease specialist for guidance on the choice of an appropriate antifungal regimen for these patients.
Emerging Tx
Hematopoietic growth factors in invasive aspergillosis (IA)
Granulocyte transfusions in invasive aspergillosis
Interferon gamma in invasive aspergillosis
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
- Early diagnosis and consequent early initiation of antifungal therapy
- Restoration of underlying immunological deficiency.
Risk of death
- After hematopoietic stem cell transplantation: graft-versus-host disease; neutropenia; cytomegalovirus seropositivity; prolonged use of corticosteroids; prolonged immunosuppression; disseminated IA; presence of pleural effusion and monocyte count <120 cells/mm³
- After heart, lung, liver, and kidney transplantation: hyperimmunosuppression; renal failure; stormy postoperative course; recurrent bacterial infection; old age.[1]
- Nontuberculous mycobacterial infection, COPD, pleural involvement, cavitary disease, presence of an aspergilloma, shortness of breath, low physical activity, and low body mass.
Recurrence
Monitoring
Complications
Citations
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
Recommendations for the use of diagnostic testing in invasive aspergillosis.Published by
American Thoracic Society
Published
2019
Summary
Consensus definitions for "proven", "probable", and "possible" invasive fungal diseases (including invasive aspergillosis).Published by
European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium
Published
2020
Summary
Guidelines on the diagnosis of invasive and chronic aspergillosis.Published by
European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology, and the European Respiratory Society
Published
2018
Summary
Guidelines on the diagnosis of chronic aspergillosis.Published by
European Society for Clinical Microbiology and Infectious Diseases and the European Respiratory Society
Published
2016
Treatment
Summary
These guidelines summarize the current evidence for treatment of different forms of aspergillosis including invasive aspergillosis and aspergilloma.Published by
Infectious Diseases Society of America
Published
2016
Summary
Consensus guidelines reviewing current therapeutic approaches for fungal infections of interest in pulmonary and critical care practice. There are 3 primary areas of focus: the endemic mycoses; fungal infections of special concern for immune-compromised and critically ill patients; and rare and emerging fungal infections.Published by
American Thoracic Society
Published
2011
Summary
Guidelines on the management of invasive and chronic aspergillosis.Published by
European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society
Published
2018
Summary
Recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis in patients with hematologic malignancies or hematopoietic stem cell transplantation recipients.Published by
European Conference on Infections in Leukemia
Published
2017