Aspergillosis

5 Interesting Facts of Aspergillosis

1. Aspergillus species are ubiquitous in soil, water, and air
2. Aspergillus spores are regularly inhaled and normally are cleared by ciliary and other mechanisms without harmful consequences; however, in some patients, colonization or saprophytic growth occurs without tissue invasion
3. Saprophytic growth may occur in sinuses and in preexisting lung cavities. If asymptomatic, no treatment is required, but in some patients, periodic monitoring reveals increasing symptoms and radiographic evidence of progressive (locally invasive) disease that warrants treatment
   • Medical treatment with antifungals may suffice in some cases, but surgical intervention is sometimes required, especially if hemoptysis occurs
4. Aspergillus can also trigger an allergic response; this is seen most commonly in patients with asthma and cystic fibrosis
   • Symptomatic patients with allergic bronchopulmonary aspergillosis or sinusitis should be treated with steroids and antifungal azoles
5. In immunocompromised patients, particularly those with hematologic malignancies and hematopoietic stem-cell and organ transplants, risk of local or disseminated invasive infection is high, and clinical vigilance as well as screening must be carried out. Some patients benefit from antifungal prophylaxis, as well as exposure precautions
   • Prompt empiric treatment is warranted in patients at high risk who have persistent fever despite broad-spectrum antibacterial antibiotics

Pitfalls

• Patients most susceptible to invasive Aspergillus infection—those with severe immunosuppression—will often show the mildest and most nonspecific symptoms and may not mount immune responses that can be measured in some laboratory testing
• Despite multiple medications including azoles and amphotericin that are available to treat aspergillosis, invasive or disseminated Aspergillus infection carries a high mortality

• Aspergillosis is a disease caused by various species of Aspergillus, a ubiquitous mold 
  • Aspergillus spores are ubiquitous, regularly inhaled, and normally cleared by ciliary and other mechanisms without harmful consequences; however, in some patients, colonization or saprophytic growth occurs without tissue invasion
  • Aspergillus can also trigger an allergic response; this is seen most commonly in patients with asthma and cystic fibrosis
  • Infection caused by Aspergillus occurs almost exclusively in patients with cavitary lung disease (in which case it may invade surrounding lung parenchyma) or immune defects (in which case it may be locally invasive or disseminated)

Classification

• Classified by anatomic location, presence (and degree) or absence of tissue invasion, and presence or absence of an allergic response
• Saprophytic, noninvasive
  • Allergic bronchopulmonary aspergillosis 
    • Usually occurs in patients with underlying chronic pulmonary condition (eg, asthma, cystic fibrosis)
    • Characterized by superimposition or exacerbation of pulmonary (and sometimes constitutional) symptoms; expectoration of golden-brown mucus plugs is common
    • Will have characteristic radiographic abnormalities, skin reactivity, and laboratory evidence of hypersensitivity
  • Allergic Aspergillus sinusitis
    • Characterized by upper respiratory symptoms of nasal obstruction (often due to nasal polyps) and discharge, headache, and facial pain
    • Will have skin reactivity and laboratory evidence of hypersensitivity
  • Otomycosis
    • Superficial colonization of the ear canal
    • Characterized by itching, pain, and discharge from the ear
  • Tracheobronchitis
    • Increasingly recognized but poorly studied
    • Characterized by cough, dyspnea, chest discomfort, and mucus plugging
  • Aspergilloma (‘fungus ball’)
    • Pulmonary
      • Hyphal elements and mucinous material form a mass in a preformed cavity resulting from tuberculosis, COPD, sarcoidosis, or other chronic cavitary lung disease
    • Sinus
      • Hyphal elements and mucinous material form a mass in a paranasal sinus
  • Chronic pulmonary aspergillosis
    • Characterized by pulmonary nodules and/or slowly evolving or enlarging single or multiple cavities, with or without aspergillomas
      • By definition, symptoms (chronic cough with or without hemoptysis; dyspnea; and constitutional symptoms) and radiographic findings have been present for at least 3 months
      • Chronic cavitary pulmonary aspergillosis may progress to chronic fibrosing pulmonary aspergillosis, an end-stage complication of chronic cavitary pulmonary aspergillosis
      • There is believed to be a continuum of chronic pulmonary aspergillosis with subacute invasive pulmonary aspergillosis 
• Invasive
  • Pulmonary
    • Subacute invasive pulmonary aspergillosis (chronic necrotizing aspergillosis) 
      • May evolve from chronic cavitary pulmonary aspergillosis, with direct invasion of Aspergillus into the surrounding lung parenchyma, causing enlargement of the cavity and progressive lung damage, or may occur de novo
      • Respiratory and constitutional symptoms are usually present and Aspergillus-specific IgG or serum-precipitating antibodies may be detected
    • Invasive pulmonary aspergillosis 
      • Severe, life-threatening disease that occurs in patients with significant immune dysfunction (eg, neutropenia, immunosuppressive therapy for hematologic stem-cell or solid organ transplant, AIDS, chronic corticosteroid use); increasingly recognized in critically ill ICU patients
      • May invade blood vessels (angioinvasion), resulting in pulmonary infarction and/or dissemination to brain, heart, eye, bone, joints, visceral organs, and skin 
  • Invasive aspergillosis of other organs may occur as an isolated (primary, non-hematogenous) infection including skin, eye, bone, and upper airways (including sinuses) 
    • Invasive tracheobronchial aspergillosis is a common complication in lung transplant recipients and is also seen occasionally in patients with hematologic malignancies or hematologic stem-cell transplantation

Clinical Presentation

History

• Will vary widely depending on:
  • Form of aspergillosis (saprophytic, allergic, or invasive)
  • Site or sites of infection
  • Severity of disease
• Medical history may identify underlying conditions that foster colonization, invasive disease, or allergic response
• Unifying factor in almost all aspergillosis is presence of chronic structural pulmonary disease, an immune defect, or both
  • Allergic bronchopulmonary aspergillosis and allergic Aspergillus sinusitis occur almost exclusively in patients with asthma or cystic fibrosis 
  • Pulmonary aspergilloma requires the presence of immunologically protected cystic lung spaces typically from earlier infection, COPD, malignancy, or inflammatory lung disease 
  • Aspergillus otomycosis is seen in patients with impaired mucosal immunity such as hypogammaglobulinemia, diabetes mellitus, chronic eczema, HIV infection, and chronic steroid use 
  • Chronic cavitary pulmonary aspergillosis and subacute invasive cavitary pulmonary aspergillosis (chronic necrotizing aspergillosis) are associated with subtle immunocompromised states such as chronic steroid use, diabetes, and alcoholism
  • Invasive aspergillosis is seen in those with more severe immunocompromise (eg, caused by neutropenia, immunosuppressive therapy for hematologic stem-cell or solid organ transplant, AIDS, genetic disorders of immune regulation, chronic corticosteroid use) 
• There may be a history of likely exposure or inoculation (eg, gardening/composting, construction, trauma, burns)
• Symptoms
  • Noninvasive disease
    • Allergic forms of aspergillosis
      • Allergic bronchopulmonary aspergillosis
        • Symptoms are that of new-onset asthma or patient’s baseline asthma with exacerbation
          • Cough, wheeze, shortness of breath
          • Expectoration of golden-brown mucus plugs is characteristic
      • Allergic Aspergillus sinusitis
        • Symptoms similar to other types of subacute or chronic allergic sinusitis, including nasal obstruction and discharge, headache, and facial pain
    • Aspergilloma
      • Pulmonary disease is often asymptomatic but hemoptysis may occur if there is invasion of a blood vessel, and may be very severe
      • Sinus disease may be asymptomatic or associated with nasal obstruction and discharge, headache, and facial pain
    • Otomycosis
      • Presents as otitis externa with pain or pruritus of ear canal, with or without otorrhea
      • Patient may report discolored (eg, black) cerumen
    • Chronic cavitary pulmonary aspergillosis
      • Persistent (3 months or more) respiratory symptoms (productive or nonproductive cough, wheezing, dyspnea), which may be progressive
  • Invasive disease
    • May be characterized by constitutional symptoms (fever, diaphoresis, weight loss, fatigue) in addition to localizing symptoms
    • Persistent or recurrent fever despite antibacterial antibiotic treatment is characteristic of fungal infection in patients with neutropenia due to hematologic malignancy and/or chemotherapy
    • Specific localizing symptoms depend on the area or areas of involvement
    • Tempo of the illness depends on the degree of underlying immune dysfunction, developing more rapidly in more profoundly immunocompromised patients
    • Pulmonary or tracheobronchial symptoms include cough, dyspnea and—with angioinvasive disease—pleuritic pain, hemoptysis, or both
    • Rhinosinusitis may result in purulent, discolored nasal discharge, epistaxis, sinus pain, and altered vision
    • Ocular involvement may be associated with eye pain, discharge, or impaired vision
    • Visceral disease may be occult or may be associated with diffuse or localizing abdominal pain
    • Bone and joint infection may cause localized pain, swelling, erythema, or loss of function
    • Central nervous system disease usually presents as symptoms of mass lesion (headache, focal weakness, seizures, altered level of consciousness/cognition) rather than meningitis

Physical examination

• Noninvasive disease
  • Allergic
    • There may be edema and erythema of the nasal turbinates, thick and discolored nasal drainage, and percussion tenderness over the sinuses
    • Wheezing and decreased air movement may be noted on pulmonary examination
  • Aspergilloma
    • Lung examination findings may be normal or may reflect the predisposing pulmonary condition
    • Results of nasal and sinus examination may be normal or may show sinus tenderness and drainage
  • Otomycosis
    • Erythema of tympanic canal
    • Discharge or purulence in canal, discolored cerumen
  • Chronic cavitary pulmonary aspergillosis and chronic fibrosing pulmonary aspergillosis
    • Wheezing, rhonchi, and decreased air movement may be observed on pulmonary examination
• Invasive disease
  • Patients may appear chronically or acutely ill; neutropenic patients with aspergillosis may appear profoundly ill
  • Fever, diaphoresis, and weight loss may be present
  • Other physical findings depend on the site or sites of infection (lung, paranasal sinus, eye, hematogenous infection with endocarditis, gastrointestinal viscera, bone/joint, skin, central nervous system)
    • With invasive pulmonary disease there may be signs of consolidation and a pleural friction rub
    • Sinus infection characteristically produces discolored nasal discharge
    • Invasive infection at other sites may cause conjunctival injection and cloudy cornea, new or changing cardiac murmur, and necrotic lesions on skin or mucosa; mental status changes with focal neurologic deficit

Causes

• Most common cause is inhalation of Aspergillus mold
  • Aspergillus species are ubiquitous in air, water, food, and soil, and are regularly inhaled without ill effect
    • Marijuana has been shown to contain Aspergillus spores
  • Patients who develop pulmonary disease (the most common form) often have a predisposing abnormality of lung architecture and/or an immune defect; allergic mechanisms play a role in some cases
  • Primary infection elsewhere is usually due to contamination of wounds or burns
  • Primary infection may extend to adjacent sites or may disseminate hematogenously
• There are more than 250 species of Aspergillus
  • The most common species isolated in invasive disease are:
    • Aspergillosis fumigatus 57% 
    • Aspergillosis flavus 12% 
    • Aspergillosis niger 10% 
    • Aspergillosis terreus 12% 

Risk factors and/or associations

Age

• Age is not a significant risk factor except in chronic pulmonary aspergillosis, which usually occurs in middle age 

Sex

• No data suggest a sex differential in incidence of aspergillosis except for chronic cavitary pulmonary aspergillosis, which shows a male predominance 

Genetics

• Polymorphisms in CLEC1A and CLEC7A in hematopoietic stem-cell transplantation donors (OMIM #614079) appear to increase the risk of invasive aspergillosis in the recipient
• Genetic diseases of immunodeficiency indirectly increase the risk for invasive aspergillosis (eg, chronic granulomatous disease, leukocyte adhesions deficiency disorders, syndromes resulting in leukopenias, Job syndrome) 

Ethnicity/race

• Ethnicity and race are not factors in risk of Aspergillus infection itself
• The risk of some forms of immune dysfunction may be related to race or ethnicity

Other risk factors/associations

• Allergic Aspergillus disease
  • Allergic bronchopulmonary aspergillosis
    • Asthma
      • Incidence of allergic bronchopulmonary aspergillosis in persistent asthma is approximately 2.5% 
    • Cystic fibrosis
      • Incidence of allergic bronchopulmonary aspergillosis in cystic fibrosis is approximately 7% 
  • Allergic Aspergillus sinusitis
    • Chronic allergic rhinosinusitis often associated with hyperplastic nasal polyps 
• Aspergilloma
  • Pulmonary
    • Occurs in preexisting lung cavity (eg, bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, lung abscess, congenital cyst, bleb)
  • Sinus
    • Occurs in areas of structural or functional abnormality in the sinuses
• Chronic cavitary and subacute invasive aspergillosis 
  • Immune defects, some of which are relatively subtle (eg, diabetes mellitus, alcoholism, malnutrition)
  • Underlying lung disease (eg, COPD, current or previous tuberculosis or other mycobacterial disease, sarcoidosis)
• Invasive aspergillosis
  • Primarily occurs in immunocompromised patients with T-cell or neutrophil insufficiency or dysfunction; depth and duration of immune dysfunction also correlate with degree of risk
    • Highest risk includes acute myelogenous leukemia (especially during induction/reinduction chemotherapy); allogeneic hematopoietic stem-cell transplantation (especially with cord blood); and lung, liver, or heart transplantation 
    • Intermediate risk includes acute and chronic lymphocytic leukemias, lymphoma, myelodysplastic syndrome, COPD, and AIDS 
    • Lower (but not absent) risk includes autologous hematopoietic stem-cell transplantation, many other hematologic malignancies, solid malignancies, renal transplant, chronic immunologic disorders, and systemic lupus erythematosus 
  • Also may occur in critically ill patients without specific immune deficiencies 

Diagnostic Procedures

Primary diagnostic tools

• Diagnosis of aspergillosis is complicated because of myriad clinical presentations and the ubiquitous presence of the organism in the environment, making it difficult in some circumstances to distinguish pathogenicity from colonization or contamination 
• One of the most important tools in diagnosing Aspergillus is maintaining a high suspicion in susceptible patients 
  • Chronic or poorly controlled lung symptoms in a patient with asthma or cystic fibrosis, or sinus symptoms in a patient with nasal polyposis, should trigger suspicion of allergic Aspergillus disease
  • Presence of chronic pulmonary symptoms and a history of cavitary lung disease should raise consideration of chronic pulmonary aspergillosis spectrum
  • Invasive aspergillosis should be suspected in patients with T-cell or neutrophil dysfunction or insufficiency who have fever refractory to antibacterial antibiotics or who develop suggestive symptoms (pleuritic chest pain, dyspnea, hemoptysis), signs (pleural friction rub, necrotic lesions on skin or mucosa, mental status changes with focal neurologic deficit), or radiographic evidence (nodular or cavitary lung lesions)
• Conversely, the diagnosis is often suggested by radiographic findings or results of culture and histopathology studies obtained during workup of pulmonary or other localized symptoms
• Various sets of criteria are used for diagnosing allergic bronchopulmonary aspergillosis
  • These criteria require positive Aspergillus skin test result, elevated Aspergillus IgE levels, or both
  • Additionally, the International Society for Human and Animal Mycology criteria require elevated total IgE level plus combinations of other laboratory and/or imaging findings:
    • Serum precipitins or IgG against Aspergillus fumigatus
    • Elevated total eosinophil count
    • Consistent chest radiographic or CT imaging results
• Allergic Aspergillus sinusitis is diagnosed by visualization of nasal polyps, demonstration of Aspergillus hyphae in eosinophilic mucinous discharge, and either a positive Aspergillus skin test result or detection of Aspergillus-specific serum IgE 
• In an asymptomatic patient, an aspergilloma may be an incidental finding on chest radiography 
• Diagnostic criteria for chronic cavitary pulmonary aspergillosis include progressive symptoms for 3 or more months, presence and progression of pulmonary cavities on imaging, and serologic or microbiologic evidence of Aspergillus
• For invasive aspergillosis (including subacute invasive aspergillosis), definitive diagnosis requires either histologic demonstration of tissue invasion with hyphal elements and a positive culture for Aspergillus sp., or growth of Aspergillus sp. from normally sterile fluid
  • Assays for surrogate markers such as galactomannan and (1-3)-β-D-glucan may provide supporting evidence of infection
• Patients with allergic bronchopulmonary aspergillosis or chronic pulmonary aspergillosis should undergo pulmonary function testing to guide management of airway disease and as a baseline for yearly monitoring 

Laboratory

• Culture
  • Aspergillus generally grows well on standard media, although use of fungal media may increase likelihood of growth
    • Sometimes an unanticipated finding from specimens submitted for routine culture; because of ubiquitous presence in the environment, positive cultures from nonsterile sites (eg, nasal discharge, sputum, wound drainage) must be interpreted cautiously and in light of clinical context and supporting laboratory and radiographic evidence
    • Recovery from normally sterile fluid such as blood, pleural or peritoneal fluid, cerebrospinal fluid, or bronchoalveolar lavage is considered to be evidence of infection
    • Antifungal therapy, either prophylactic or therapeutic, may decrease yield of cultures
• Non-culture–based diagnostics provide supporting evidence of infection or allergic response
  • Aspergillus IgG antibody by ELISA and anti-IgG precipitins
    • May be positive in allergic bronchopulmonary aspergillosis, but these are not sensitive markers for the disease 
    • Positive in more than 90% of patients with chronic pulmonary aspergillosis 
    • Of limited use in immunocompromised patients because of poor sensitivity (as low as 29%, perhaps caused in part by impaired antibody production in such patients), and because antibody formation is a delayed indicator of infection 
  • Aspergillus fumigatus-specific IgE
    • May be more sensitive than skin test for allergic bronchopulmonary aspergillosis
    • Most sensitive single test in allergic bronchopulmonary aspergillosis
    • Combination of serum Aspergillus-specific IgE and skin test is more sensitive than either alone for diagnosis of allergic bronchopulmonary aspergillosis
  • Total IgE and eosinophil count are nonspecific indicators of allergic hypersensitivity; response may wax and wane with disease activity, and may be blunted by corticosteroid treatment
    • Elevated total IgE level (above 1000 IU/mL) and total eosinophil count above 500 cells/L (in patients who have not been treated with corticosteroids) are the cut points used for these tests within the International Society for Human and Animal Mycology criteria for allergic bronchopulmonary aspergillosis 
  • Galactomannan antigen test
    • Galactomannan is a major cell wall component of Aspergillus 
    • Most useful in patients with hematologic malignancy or hematopoietic stem-cell transplantation 
    • Sensitivity varies depending on underlying immunologic disease and whether mold-active prophylaxis is being used 
  • β-D-glucan assay 
    • Recommended for diagnosis of invasive fungal infection in high-risk patients (hematologic malignancy, allogeneic hematopoietic stem-cell transplantation); not specific for invasive aspergillosis 
    • Nonspecific because β-D-glucan is a constituent of the cell wall of many species of fungi
    • Sensitivity varies; combination with galactomannan or polymerase chain reaction tests improves detection
  • Polymerase chain reaction test
    • Not widely adopted owing to lack of standardization
    • A Cochrane review suggests high negative predictive value (ie, confidence that a negative result excludes invasive infection) 
    • Results should be considered in conjunction with other diagnostic tests and the clinical context 
• Skin testing (allergic bronchopulmonary aspergillosis)
  • Intradermal testing is more sensitive than skin prick 

Imaging

• Allergic aspergillosis
  • Allergic bronchopulmonary aspergillosis 
    • Chest radiograph may be normal early in disease, and findings may wax and wane with clinical disease activity
      • Characteristic findings, when present, include pulmonary infiltrates, bronchial wall thickening (“tram tracks,” “finger-in-glove” signs), and mucus plugs (“toothpaste shadow”)
    • High-resolution CT is more sensitive than radiographic imaging
  • Allergic Aspergillus sinusitis
    • Sinus CT shows high attenuation mucus within the sinuses
• Sinus aspergilloma
  • Sinus CT shows heterogeneous opacities with punctate calcification in the sinus cavity 
• Chronic pulmonary aspergillosis
  • Aspergillus nodule
    • Chest radiograph or CT shows 1 or several nodules; may cavitate or remain solid 
  • Pulmonary aspergilloma
    • Chest radiograph or chest CT shows a thick-walled cavity, typically in upper lobe, containing a mass that may move with position change
      • An “air crescent” is often seen between the aspergilloma and the cavity wall
      • Chest CT is more sensitive than radiographic imaging
  • Chronic cavitary pulmonary aspergillosis
    • Chest radiograph or CT shows single or multiple thin- or thick-walled cavities that may or may not contain an aspergilloma; cavities expand over time
  • Chronic fibrosing pulmonary aspergillosis
    • Chest radiograph or CT scan shows fibrosis appearing as consolidation of the parenchyma (in at least 2 lobes); large cavities with surrounding fibrosis may be seen 
• Invasive aspergillosis
  • Subacute invasive pulmonary aspergillosis (chronic necrotizing pulmonary aspergillosis)
    • Constellation of progressive changes over a 1- to 3-month period, including nodules, consolidation, and cavitation; usually involves upper lobes 
  • Invasive pulmonary aspergillosis
    • Radiographic images are relatively nonspecific and may be normal in up to 30% of patients, even in advanced disease 
    • Non-contrast chest CT (preferably high resolution) is recommended whenever there is clinical suspicion of invasive pulmonary aspergillosis, regardless of chest radiography results 
      • CT imaging may show features suggestive of invasive disease, especially in neutropenic patients
      • These features include nodules, consolidation, and a “halo zone” surrounding a nodule
  • Invasive Aspergillus rhinosinusitis
    • CT imaging shows opacification of sinuses; pus may extend beyond the sinuses 
      • May be normal in 12% of cases; positive findings are not specific for aspergillosis
  • Cerebral aspergillosis
    • Brain MRI or CT imaging may show extension from a primary focus such as ear or sinus 
      • Hematogenous infection may result in single or multiple small abscesses at the gray/white junction; there may be ring enhancement and surrounding edema
  • Abdominal aspergillosis
    • CT findings vary depending on affected organ or organs
  • Aspergillus osteomyelitis
    • Radiographs, CT, or MRI imaging show nonspecific bone destruction; vertebral disease may involve the disk 

Differential Diagnosis

Most common

• Allergic bronchopulmonary aspergillosis
  • Exacerbation or progression of chronic lung disease (especially asthma or cystic fibrosis)
    • Clinically difficult to distinguish from exacerbation, often presenting with wheeze, cough, dyspnea, and worsening pulmonary function
    • Should suspect allergic bronchopulmonary aspergillosis in patients with worsening disease despite conventional therapy, or (in patients with asthma) if they are requiring chronic steroids
    • The distinction is based on presence or absence of diagnostic criteria for allergic bronchopulmonary aspergillosis, particularly total and Aspergillus-specific IgE levels
    • Can be particularly challenging in cystic fibrosis as many patients with cystic fibrosis are colonized with Aspergillus, or have sensitivity to it but do not fulfill criteria for allergic bronchopulmonary aspergillosis
  • Viral or bacterial pneumonia
    • In addition to similar pulmonary symptoms, allergic bronchopulmonary aspergillosis may present with pulmonary infiltrates, which resemble pneumonia
    • Unlike in pneumonia, fever is lacking; unlike in bacterial pneumonia, there is no clinical response to antibiotics
    • Diagnosis of bacterial or viral pneumonia can be made in some cases by identifying the causative organism by culture, antigen testing, or molecular technology; other laboratory indicators may also provide support (eg, elevated WBC count)
    • Clinical resolution without recurrence also suggests an interim infectious disease
• Allergic Aspergillus rhinosinusitis
  • Bacterial sinusitis
    • May present with similar symptoms of congestion, nasal discharge, obstruction, and facial pain
    • Occasionally, unlike in allergic Aspergillus rhinosinusitis, fever is present
    • Unlike allergic Aspergillus rhinosinusitis, may spontaneously resolve or may respond to antibiotics
    • Distinction is based on clinical behavior, although may be difficult in patients with chronic infection; however, laboratory criteria for allergic Aspergillus sinusitis are absent
  • Allergic sinusitis caused by other allergens
    • May also present with nasal and sinus congestion nasal discharge
    • May be associated with patterns of exposure (eg, seasonal, pets)
    • May respond to antihistamines and avoidance of suspected allergens
    • Laboratory evidence may overlap (elevated total IgE level and eosinophil count), but Aspergillus is not implicated by stain or culture of secretions, or by serologic testing; true allergens may be identified by skin testing
• Aspergilloma
  • Pulmonary
    • Often asymptomatic unless bleeding or hemoptysis occurs, and differential diagnosis is largely radiographic
    • Conditions with a similar appearance on chest imaging (and which also may be associated with hemoptysis) include:
      • Cavitating hematoma
      • Malignant neoplasm
      • Wegener granulomatosis
      • Hydatid (echinococcal) cyst
    • Distinction is most often made by bronchoscopic examination (with or without biopsy) or needle aspiration
    • Other distinguishing features include:
      • Pulmonary hematoma may be associated with known coagulopathy, embolic event, trauma, or procedure
      • Cavitary neoplasm may be clinically indistinguishable from pulmonary aspergilloma, although constitutional symptoms may be more common and a smoking history is typical
      • Wegener granulomatosis is an autoimmune disease of the lungs (sometimes with kidney involvement) in which autoantibodies such as antineutrophil cytoplasmic autoantibodies or antinuclear antibodies are often detected
        • Biopsy shows granulomatous inflammation and necrotizing small-vessel angiitis
      • Echinococcosis
  • Sinus
    • Chronic sinusitis
      • Chronic bacterial or allergic sinusitis with congestion, pain, and nasal discharge
      • Sinus CT may not be able to distinguish mass from opacification
      • Sinus endoscopy to obtain sinus aspirate and/or biopsy for microscopy and culture is the most effective way to differentiate
    • Sinus neoplasm
      • Obstruction of sinus drainage may result in symptoms of congestion and pain similar to sinus aspergilloma
      • Neoplastic mass in sinus may appear similar to sinus aspergilloma on imaging
      • Sinus endoscopy for biopsy for pathology and culture is the most effective way to differentiate
• Other forms of chronic pulmonary aspergillosis (chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis) and subacute invasive pulmonary aspergillosis/chronic necrotizing pulmonary aspergillosis
  • Progressive pulmonary diseases that, like chronic pulmonary aspergillosis, may appear on imaging as infiltrates, multiple small cavities or nodules, or areas of fibrosis and may clinically present as cough, dyspnea, weight loss, and/or general fatigue/malaise:
    • Malignant neoplasm
      • Diagnosis is made by bronchoscopic, image-guided needle or open-lung biopsy, with histopathologic identification of malignant cells and characteristic architectural changes in tissue
    • Sarcoidosis
      • A chronic multisystem disease of unknown cause; pulmonary involvement is usual. May be associated with hypercalcemia and elevated serum levels of ACE. Biopsy reveals noncaseating granulomas
    • Wegener granulomatosis
      • Distinguished by biopsy findings of granulomatous inflammation and necrotizing small vessel angiitis. Noninvasive evidence may include autoantibodies such as antineutrophil cytoplasmic autoantibodies or antinuclear antibodies, although they are not invariably detected
    • Tuberculosis
      • Distinguished from pulmonary aspergillosis by culture or polymerase chain reaction demonstration of Mycobacterium tuberculosis in sputum or tissue
      • Microscopic examination of sputum shows acid-fast organisms, which can also be seen (along with caseating granulomas) in histopathology of biopsied tissue
    • Histoplasmosis
      • Occurs in certain geographic areas (eg, Ohio and Mississippi valleys), so history may be helpful in excluding likelihood
      • Histoplasma antigen may be detected in urine, although this test is not sensitive in chronic disease
      • Definitive diagnosis is through identification of the organism in sputum or tissue
    • Bacterial lung abscess
      • Unlike chronic pulmonary aspergillosis, characterized by halitosis and production of copious amounts of foul-smelling, purulent secretions
      • Culture of sputum or (ideally) bronchoscopic aspirate usually shows polymicrobial mixture of anaerobes
      • Response to antibacterial antibiotics is a further distinguishing factor
• Invasive aspergillosis (other than subacute invasive pulmonary aspergillosis/chronic necrotizing pulmonary aspergillosis) in immunocompromised or critically ill host
  • Differential diagnosis will depend on site of invasion, if localized
    • Lung
      • Bacterial pneumonia
        • Like invasive pulmonary aspergillosis, characterized by fever and cough; pleuritic chest pain may be present
        • Unlike aspergillosis, bacteria may be cultured from sputum or blood, and antibacterial antibiotics result in clinical improvement
      • Pulmonary embolism
        • Like invasive pulmonary aspergillosis, characterized by cough, dyspnea, and pleuritic chest pain; fever may be present
        • Like invasive pulmonary aspergillosis, chest imaging may show wedge-shaped peripheral infiltrates
        • Distinction may be difficult, as Aspergillus angioinvasion may cause infarction; in embolic disease, venous source may be located in distal extremities or inferior vena cava
    • Brain
      • Brain abscess
        • Like cerebral aspergillosis, may present as fever, headache, and focal neurologic findings
        • History may suggest bacterial brain infection (eg, recent bacteremia) over aspergillosis, but definitive distinction is made by aspiration of the lesion
      • Stroke
        • Like cerebral aspergillosis, may present as headache with focal neurologic findings
        • Unlike cerebral aspergillosis, fever is usually absent
        • History and imaging findings may help to distinguish (eg, carotid atherosclerosis, cardiac clot)
  • In immunocompromised patients, especially neutropenic patients with hematologic malignancy or recipients of stem-cell transplantation, invasive aspergillosis presents as a fever without localizing signs
    • Multiple other sources need to be considered:
      • Bacterial infection, including bacteremia, line sepsis, urinary tract infection, pneumonia, and typhlitis
        • Unusual pathogens such as Nocardia sp., nontuberculous mycobacteria are also possible in immunocompromised patients
      • Viral infection such as influenza, respiratory syncytial virus, and cytomegalovirus
      • Other fungal infections (eg, yeasts [Candida, Torulopsis], molds [Mucor])
      • Drug fever
    • Differentiating these requires clinical vigilance (eg, at least daily interim history and thorough physical examination, including careful inspection of skin, oral and perineal mucosa, and line insertion sites) with empiric and targeted laboratory testing and imaging
    • Guidelines and protocols exist for the workup and management of these patients 

Treatment Goals

• Goals for allergic disease, chronic disease, and invasive or disseminated disease differ
  • In allergic disease: to control the symptoms and inflammation caused by the organism
  • In chronic pulmonary disease: to prevent progressive tissue damage and to alleviate symptoms
  • In invasive or disseminated disease: to kill the organism, prevent or reverse physiologic manifestations of sepsis, and prevent further damage to tissue

Admission criteria

In many cases, invasive aspergillosis develops during the course of inpatient treatment of a hematologic malignancy or pre- and posttransplant care

Most immunocompromised outpatients with persistent fever are admitted to the hospital

Criteria for ICU admission

• Disseminated disease with septic physiology, multi-organ system failure
• Hemoptysis
• Significant hypoxia requiring ventilatory support
• Central nervous system involvement with obtundation or seizures

Recommendations for specialist referral

• Suspected or proven allergic Aspergillus disease may be referred to pulmonologist or allergist
• Suspected chronic pulmonary aspergillosis should be referred to a pulmonologist
• Immunocompromised patients with known or possible invasive aspergillosis are usually managed by a multidisciplinary team including infectious disease specialist, hematologist/oncologist and/or transplant specialist, and others, depending on involved organs

Treatment Options

• Treatment depends on the form of Aspergillus disease and the site of infection
  • Allergic Aspergillus disease
    • Pulmonary
      • Oral or inhaled corticosteroids are the first line agents
      • Steroid-sparing agent such as omalizumab may be added, although a Cochrane review found scant efficacy data 
      • Antifungal therapy may be added in patients who do not respond adequately; itraconazole is recommended as the first line agent
    • Rhinosinusitis
      • Polypectomy and irrigation of the sinuses is recommended initially
      • Topical nasal steroids may improve symptom control and prevent relapse
      • Oral antifungal agents such as itraconazole or voriconazole are recommended for patients who do not respond adequately or who relapse early or frequently
  • Saprophytic conditions in non-immunocompromised patients
    • Otomycosis
      • Mechanical cleansing is recommended, followed by use of a topical antifungal preparation or boric acid
    • Tracheobronchitis
      • Bronchoscopic removal of thick mucus
    • Aspergilloma
      • Lung
        • If asymptomatic and no progression of cavity size over 6 to 24 months of single aspergilloma, continue to observe
        • If symptomatic or increasing cavity size, surgical resection is recommended if feasible, with pre- and perioperative administration of antifungal therapy with voriconazole or an echinocandin if spillage occurs or is anticipated
        • If surgery is not possible, antifungal therapy alone may mitigate progression and further hemoptysis
      • Sinus
        • Surgical removal alone suffices in the absence of tissue invasion
        • If tissue invasion is present, systemic treatment with voriconazole or a lipid formulation of amphotericin is recommended
    • Chronic cavitary pulmonary aspergillosis 
      • Stable patients without severe or systemic symptoms may not require therapy; otherwise, can treat with itraconazole or voriconazole for at least 6 months
      • Hemoptysis may require administration of tranexamic acid or localized arterial embolization
  • Invasive disease (including tracheobronchitis in lung transplant and other immunocompromised patients) 
    • Early empiric therapy is recommended in severely immunocompromised patients in whom invasive aspergillosis is a likely possibility
    • Requires systemic antifungal medication; voriconazole is the first choice in most cases
      • Alternatives include liposomal amphotericin B, isavuconazole, and echinocandins
      • A 6- to12-week course of therapy is usually appropriate and may be followed with secondary prophylaxis if immunocompromise is ongoing
    • In addition to systemic therapy, local instillation or topical therapy is appropriate in some sites (eg, endophthalmitis, keratitis, renal pelvis)
    • Depending on site and extent of disease, surgical debridement may be necessary
    • If feasible, reduction or reversal of immunosuppression is recommended; colony-stimulating factors or granulocyte transfusion may be considered in neutropenic patients 

Drug therapy

• Antifungal agents
  • Voriconazole
    • For allergic bronchopulmonary aspergillosis
      • Voriconazole Oral tablet; Children 2 to 11 years: 9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours recommended by guidelines and this dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pediatric patients will require higher doses to achieve therapeutic concentrations. Therapeutic drug monitoring is essential to guide dosage adjustments. Recommended as alternative to itraconazole.
      • Voriconazole Oral tablet; Children and Adolescents 12 to 14 years weighing less than 50 kg: 9 mg/kg/dose (Max: 350 mg/dose) PO every 12 hours recommended by guidelines and this dose has been shown to provide comparable exposure to adults receiving 200 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Some pediatric patients will require higher doses to achieve therapeutic concentrations. Therapeutic drug monitoring is essential to guide dosage adjustments. Recommended as alternative to itraconazole.
      • Voriconazole Oral tablet; Children and Adolescents 12 to 14 years weighing 50 kg or more: 200 mg PO every 12 hours as an alternative to itraconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Voriconazole Oral tablet; Adults: 200 mg PO every 12 hours as an alternative to itraconazole. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • For other indications (invasive disease or symptomatic saprophytic conditions)
      • Voriconazole Solution for injection; Children 2 to 11 years: 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy after 7 days if clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks.
      • Voriconazole Solution for injection; Children and Adolescents 12 to 14 years weighing less than 50 kg: 9 mg/kg/dose IV every 12 hours on day 1, followed by 8 mg/kg/dose IV every 12 hours. May increase dose in 1 mg/kg increments for inadequate response if initial dose is tolerated; if initial dose not tolerated, reduce dose by 1 mg/kg increments. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy after 7 days if clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks.
      • Voriconazole Solution for injection; Children and Adolescents 12 to 14 years weighing 50 kg or more: 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours; if maintenance dose not tolerated, decrease to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy after 7 days if clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks.
      • Voriconazole Solution for injection; Adults: 6 mg/kg/dose IV every 12 hours on day 1, followed by 4 mg/kg/dose IV every 12 hours; if maintenance dose not tolerated, decrease to 3 mg/kg/dose IV every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Stepdown to oral therapy after 7 days if clinical improvement. Guidelines suggest voriconazole as primary therapy. Treat for at least 6 to 12 weeks.
    • For noninvasive conditions (eg, chronic cavitary pulmonary disease, aspergilloma of lungs, sinuses)
      • Voriconazole Solution for injection or Oral tablet; Adults: 6 mg/kg/dose IV/PO every 12 hours on day 1, followed by 4 mg/kg/dose IV/PO every 12 hours. Adjust with therapeutic drug monitoring. Lower doses advised in those 70 years of age or older, low weight, significant liver disease and those of North East Asian descent who may be slow metabolizers. 
    • Treatment of some conditions (eg, chronic cavitary, fibrosing, or subacute invasive pulmonary aspergillosis) may require indefinite antifungal medication 
  • Isavuconazole
    • Isavuconazonium sulfate Solution for injection; Adults: Initiate treatment with a loading dose of 372 mg IV every 8 hours for 6 doses. Then, 12 to 24 hours after the last loading dose, administer a maintenance dose of 372 mg IV once daily. The IV infusion set must contain a 0.2 to 1.2 micron in-line filter. Infuse over a minimum of 1 hour. There is an established bioequivalence with the oral formulation; an additional loading dose is NOT required when switching the patient to PO dosing. Recommended as an alternative therapy for invasive aspergillosis by the IDSA.
  • Itraconazole
    • For allergic pulmonary aspergillosis
      • Itraconazole Oral solution; Infants, Children, and Adolescents: 5 mg/kg/dose (Max: 200 mg/dose) PO every 12 hours as primary treatment.
      • Itraconazole Oral solution; Adults: 200 mg PO every 12 hours as primary treatment.
    • For other indications (invasive disease or symptomatic saprophytic conditions)
      • Itraconazole Oral solution; Infants, Children, and Adolescents: 5 mg/kg/dose (Max: 200 mg/dose) PO every 12 hours as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.
      • Itraconazole Oral solution; Adults: 200 mg PO every 12 hours as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on extent and length of immunosuppression, infection site, and disease improvement.
    • For chronic cavitary pulmonary disease
      • Itraconazole Oral capsule; Adults: 200 mg PO every 12 hours. 
  • Liposomal amphotericin
    • Amphotericin B Liposomal Suspension for injection; Infants, Children, and Adolescents: 3 to 5 mg/kg/dose IV every 24 hours. Clinical guidelines suggest lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. Treat for at least 6 to 12 weeks with duration dependent on immunosuppression, infection site, and disease improvement.
    • Amphotericin B Liposomal Suspension for injection; Adults: 3 to 5 mg/kg/dose IV every 24 hours. Clinical guidelines suggest lipid formulation amphotericin B for initial and salvage therapy when triazoles are contraindicated or not tolerated. Treat for at least 6 to 12 weeks with duration dependent on immunosuppression, infection site, and disease improvement.
  • Caspofungin
    • Caspofungin Solution for injection; Infants 3 months and older, Children, and Adolescents: 70 mg/m2 IV (Max: 70 mg/dose) on day 1, then 50 mg/m2/dose IV (Max: 70 mg/dose) once daily. If inadequate response, may increase to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on immunosuppression, infection site, and disease improvement.
    • Caspofungin Solution for injection; Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Clinical guidelines suggest caspofungin as salvage therapy. Treat for at least 6 to 12 weeks with duration dependent on immunosuppression, infection site, and disease improvement.
  • Micafungin
    • Micafungin Sodium Solution for injection; Infants and Children: Limited data available; optimal dosage undetermined. 1.5 mg/kg/dose IV once daily for patients weighing 40 kg or less and 75 mg IV for those weighing more than 40 kg; if inadequate response after 5 to 7 days, may increase in 1.5 mg/kg/day increments (75 mg/day increments for more than 40 kg) up to Max: 4.5 mg/kg/day (Max: 225 mg/day for those more than 40 kg). Max FDA-approved adult dose: 150 mg/day. Clinical guidelines recommend micafungin as salvage therapy or in settings in which azole and polyene antifungals are contraindicated. Treat for at least 6 to 12 weeks.
    • Micafungin Sodium Solution for injection; Adolescents: Limited data available; optimal dosage undetermined. 100 to 150 mg IV once daily recommended in HIV-infected patients. Alternately, 1.5 mg/kg/dose IV once daily for patients weighing 40 kg or less and 75 mg IV once daily for those weighing more than 40 kg; if inadequate response after 5 to 7 days, may increase in 1.5 mg/kg/day increments (75 mg/day increments for those more than 40 kg) up to Max: 4.5 mg/kg/day (Max: 225 mg/day for those more than 40 kg). Max FDA-approved adult dose: 150 mg/day. Clinical guidelines recommend micafungin as salvage therapy or in settings in which azole and polyene antifungals are contraindicated. Treat for at least 6 to 12 weeks.
    • Micafungin Sodium Solution for injection; Adults: 100 to 150 mg IV once daily. Clinical guidelines recommend micafungin as salvage therapy or in settings in which azole and polyene antifungals are contraindicated. Treat for at least 6 to 12 weeks.
• Corticosteroids for allergic aspergillosis (bronchopulmonary, rhinosinus)
  • Prednisone
    • Optimal dosing unknown
    • Prednisone Oral tablet; Infants, Children, Adolescents, and Adults: 0.5 mg/kg/day PO in divided doses for 1 to 2 weeks, then 0.5 mg/kg PO every other day for 6 to 8 weeks, followed by a taper of 5 to 10 mg every 2 weeks, until discontinuation. 
  • Pulse therapy
    • Methylprednisolone Sodium Succinate Solution for injection; Children, Adolescents, and Adults: 10 to 15 mg/kg/day IV for 3 consecutive days every 3 to 4 weeks. 
• Monoclonal antibody
  • Omalizumab
    • Omalizumab (Hamster) Solution for injection; Children and Adolescents: 300 to 600 mg subcutaneously every 15 days has been reported. 

Special populations

• Pediatric patients are generally treated in the same way as adults, with appropriate dose adjustments 

Monitoring

• Therapeutic drug monitoring
  • There is some evidence that therapeutic drug monitoring in patients with aspergillosis leads to improved patient outcomes and reduced toxicity
  • Therapeutic drug monitoring is recommended, when available, for voriconazole, itraconazole, and the suspension form of posaconazole in chronic and invasive Aspergillus disease 
    • Serum concentrations are measured at steady state (4 to 7 days after starting treatment); guidelines differ somewhat in defining optimal trough levels
  • The value of therapeutic drug monitoring with other antifungals is unclear 
  • Liver function tests should be monitored with azoles
• Serial monitoring of biomarkers
  • Galactomannan
    • Useful in patients with invasive aspergillosis with hematologic malignancy or hematopoietic stem-cell transplantation who have an elevated galactomannan level at baseline to monitor disease progression and therapeutic response
    • May be predictive of outcome 
  • β-D-glucan
    • Not extensively studied for monitoring, but may add information when added to galactomannan
  • Serum IgE level
    • In allergic aspergillosis, serial serum IgE measurement is helpful in guiding treatment and should be followed every 2 months until patient is clinically stable. Response to therapy is indicated by a 25% drop in IgE level 
• Follow-up radiologic studies
  • Allergic bronchopulmonary aspergillosis
    • Until patient stabilizes, monitor chest radiographs every 2 months 
  • Pulmonary aspergilloma
    • If asymptomatic, follow with CT or chest radiography periodically for 6 to 24 months to determine rate of progression 
    • After surgery, monitor with radiographs every 4 to 6 months for up to 3 years if spillage has occurred; no evidence for radiologic monitoring if no spillage 
  • Chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, subacute invasive pulmonary aspergillosis
    • Low-dose CT or chest radiograph every 3 to 12 months 
  • Invasive pulmonary aspergillosis
    • Repeated chest CT scans are recommended to assess response to therapy; appropriate schedule or frequency has not been defined, but radiographic evidence of improvement is slow, and may actually worsen for the first week to 10 days into therapy 
  • There are no specific guidelines for radiographic monitoring other sites of aspergillosis
• Serial pulmonary function tests
  • In allergic bronchopulmonary aspergillosis and chronic cavitary pulmonary aspergillosis/chronic fibrosing pulmonary aspergillosis/subacute invasive pulmonary aspergillosis, change in pulmonary function can add information regarding success of treatment/stability of disease 

Complications

• Allergic Aspergillus disease
  • Mucus plugging may lead to severe and extensive atelectasis (eg, lobar or total lung)
  • Progressive bronchiectasis
  • Asthma or cystic fibrosis exacerbations associated with allergic bronchopulmonary aspergillosis may lead to acute respiratory failure
  • Allergic sinus inflammation may cause tissue destruction in sinuses
• Aspergilloma
  • Hemoptysis, which may be severe or life-threatening
  • Tissue destruction can be extensive
• Other noninvasive Aspergillus disease
  • Tissue destruction and fibrosis can be extensive
  • Advancement to more invasive disease
  • Respiratory failure
• Invasive Aspergillus
  • Tissue necrosis
  • Dissemination
  • Sepsis syndrome, organ failure
  • Death

Prognosis

• Varies depending on the type of Aspergillus disease and the site
  • Allergic Aspergillus disease
    • Allergic bronchopulmonary aspergillosis
      • Good prognosis when treated early, but bronchiectasis develops when left untreated for long periods 
    • Allergic Aspergillus sinus disease
      • Generally has good prognosis
      • If left untreated and invasion into adjacent tissue occurs, prognosis worsens
  • Aspergilloma
    • In asymptomatic cases has good outcome, generally depending more on underlying lung disease
  • Chronic cavitary pulmonary aspergillosis/chronic fibrosing pulmonary aspergillosis/subacute invasive pulmonary aspergillosis
    • Antifungal treatment can initially result in stabilization or improvement in 71% of patients, but relapse is common and appropriate length of treatment is unclear 
  • Invasive aspergillosis
    • Despite improvements in antifungal therapy, mortality from invasive aspergillosis remains high and is worst in patients with central nervous system or disseminated disease 
    • A 2012 study showed a 12-week mortality of 38.9% and a complete response rate of 29.6% in treatment of invasive pulmonary aspergillosis, the most common form of invasive aspergillosis, in patients with underlying hematologic malignancy 

Screening

At-risk populations

• Immunocompromised patients
  • “Screening” for invasive aspergillosis is undertaken only in the highest risk patients (prolonged neutropenia; allogeneic hematopoietic stem-cell transplantation)
    • In this case, “screening” is actually monitoring for laboratory evidence of invasive Aspergillus infection before clinical picture may suggest it
    • Recommended only in patients who are not on antifungal prophylaxis with mold-active agents
• Infectious Diseases Society of America guidelines recommend screening for allergic bronchopulmonary aspergillosis with Aspergillus fumigatus-specific IgE in asthma and cystic fibrosis patients annually, especially if they have frequent exacerbations 

Screening tests

• Asthma
  • Aspergillosis fumigatus-specific and total serum IgE levels 
• Cystic fibrosis
  • Skin prick test
    • If negative result, follow by intradermal test
      • If intradermal test result is negative, allergic bronchopulmonary aspergillosis is ruled out
    • If skin prick or air filtration; results are positive, order serum total IgE and precipitins to Aspergillus
      • Total IgE less than 1000 ng/mL or negative result on precipitins test excludes allergic bronchopulmonary aspergillosis
• Hematopoietic stem-cell transplantation and prolonged neutropenia
  • Serum galactomannan measurement is most commonly used 
• Lung transplant
  • Fungal culture from intraoperative bronchoalveolar lavage is most sensitive for Aspergillus colonization 
  • Many centers screen pre- and posttransplant (or explanted lung and transplanted lung) by culture or galactomannan on tracheobronchial secretions to detect colonization in both the native lung and the transplanted lung 

Prevention

• Reduction of exposure to airborne conidia in immunosuppressed or neutropenic patients 
  • In hospital, private room with high efficiency particulate air filtration; good home room aeration
  • Avoidance of airborne dust and contaminated materials
    • Construction sites, soil (including in potted plants), compost, mulch, cut flowers, and marijuana (commonly contaminated with Aspergillus)
    • Provide clean water distribution systems
• Targeted mold chemoprophylaxis (different centers may employ different strategies for prophylaxis)
  • Hematologic disorders and hematopoietic stem-cell transplantation 
  • Solid organ transplant
    • Lung
      • Individuals colonized with Aspergillus, as shown by bronchoalveolar lavage culture, at the time of transplant should have prophylaxis and also be monitored with high suspicion for invasive aspergillosis and low threshold to treat
    • Other solid organ transplant
      • Poor evidence for invasive aspergillosis prophylaxis; there are no current guidelines. Azoles may be used in some centers 
  • Chronic granulomatous disease
    • Recombinant interferon-γ is recommended as prophylaxis in chronic granulomatous disease 

References

Patterson TF: Aspergillus species. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, Updated edition 2895-908