Aspergillus: Difference between revisions

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βˆ’
== Microbiology ==
 +
==Background==
  +
===Microbiology===
   
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* ''Aspergillus'' is a mold with hyaline (lightly-pigmented) hyphae, septated, and usually branched at acute angle (45ΒΊ)
 +
*''Aspergillus'' is a mold with hyaline (lightly-pigmented) hyphae, septated, and usually branched at acute angle (45ΒΊ)
βˆ’
* Named for the appearance of the sporulating head, which looks like an aspergillum used to sprinkle holy water (in 1729)
 +
*Named for the appearance of the sporulating head, which looks like an aspergillum used to sprinkle holy water (in 1729)
βˆ’
* Most species reproduce asexually, although ''A. fumigatus'' and a few others have teleomorphs (sexual form with fruiting body)
 +
*Most species reproduce asexually, although ''A. fumigatus'' and a few others have teleomorphs (sexual form with fruiting body)
βˆ’
* Culture is important, but molecular methods are often required to identify the particular species
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*Culture is important, but molecular methods are often required to identify the particular species
βˆ’
** Pathogenic species grow quickly on common media
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**Pathogenic species grow quickly on common media
βˆ’
** Can grow at 37ΒΊ C, and ''A. fumigatus'' can grow up to 50ΒΊ C
 +
**Can grow at 37ΒΊ C, and ''A. fumigatus'' can grow up to 50ΒΊ C
βˆ’
* Organized into complexes, which cannot be differentiated phenotypically, but rather need molecular methods
 +
*Organized into complexes, which cannot be differentiated phenotypically, but rather need molecular methods
βˆ’
** Fumigatus: fumigatus, lentulus, udagawae
 +
**Fumigatus: ''A. fumigatus'', ''A. lentulus'', ''A. udagawae''
βˆ’
** Ustus: ''A. calidoustus'' (inherent resistance to ampho B)
 +
**Ustus: ''A. calidoustus'' (often resistant to ampho B)
βˆ’
** Niger: ''A. tubingensis'' and ''A. niger''
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**Niger: ''A. tubingensis'' and ''A. niger''
βˆ’
** Versicolor: ''A. versicolor'' and ''A. sydowii''
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**Versicolor: ''A. versicolor'' and ''A. sydowii''
   
 
{| class="wikitable"
  
{| class="wikitable"
βˆ’
! '''Species'''
 +
!'''Species'''
βˆ’
! '''Colonies'''
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!'''Colonies'''
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! '''Head'''
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!'''Conidiophore'''
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! '''Conidiophore'''
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!'''Phialides'''
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! '''Phialides'''
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!'''Other'''
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! '''Other'''
  
 
|-
  
|-
βˆ’
| ''A. flavus''
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|''A. flavus''
βˆ’
| Yellow green, yellow, brownish
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|Yellow green, yellow, brownish
  +
|Rough colourless
βˆ’
| [[File:media/image11.png]]
  
  +
|Uniseriate and biseriate
βˆ’
| Rough colourless
  
  +
|Sclerotia sometimes present
βˆ’
| Uniseriate and biseriate
  
βˆ’
| Sclerotia sometimes present
  
 
|-
  
|-
βˆ’
| ''A. fumigatus'' complex
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|''A. fumigatus'' complex
βˆ’
| Grey-green, blue green, yellowish
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|Grey-green, blue green, yellowish
  +
|Smooth, colourless or greenish
βˆ’
| [[File:media/image5.png]]
  
  +
|Uniseriate
βˆ’
| Smooth, colourless or greenish
  
  +
|Good growth at 48ΒΊC
βˆ’
| Uniseriate
  
βˆ’
| Good growth at 48ΒΊC
  
 
|-
  
|-
βˆ’
| ''A. glaucus''
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|''A. glaucus''
βˆ’
| Green and yellow, yellowish, brown
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|Green and yellow, yellowish, brown
  +
|Smooth, colourless
βˆ’
| [[File:media/image2.png]]
  
  +
|Uniseriate
βˆ’
| Smooth, colourless
  
  +
|Yellow to orange cleistothecia present
βˆ’
| Uniseriate
  
βˆ’
| Yellow to orange cleistothecia present
  
 
|-
  
|-
βˆ’
| ''A. nidulans''
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|''A. nidulans''
βˆ’
| Green buff, purplish red, olive
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|Green buff, purplish red, olive
  +
|Smooth, brown
βˆ’
| [[File:media/image8.png]]
  
  +
|Biseriate
βˆ’
| Smooth, brown
  
  +
|Round hΓΌlle cells and cleistothecia with purple ascospores usually present
βˆ’
| Biseriate
  
βˆ’
| Round hΓΌlle cells and cleistothecia with purple ascospores usually present
  
 
|-
  
|-
βˆ’
| ''A. niger''
 +
|''A. niger''
βˆ’
| Black, white, yellowish
 +
|Black, white, yellowish
  +
|Smooth, colourless or brown
βˆ’
| [[File:media/image1.png]]
  
  +
|Biseriate
βˆ’
| Smooth, colourless or brown
  
βˆ’
| Biseriate
  
 
|
  
|
 
|-
  
|-
βˆ’
| ''A. terreus''
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|''A. terreus''
βˆ’
| Brown cinnamon, yellowish brown
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|Brown cinnamon, yellowish brown
  +
|Smooth, colourless
βˆ’
| [[File:media/image4.png]]
  
  +
|Biseriate
βˆ’
| Smooth, colourless
  
  +
|Round, solitary aleurioconidia produced directly on hyphae
βˆ’
| Biseriate
  
βˆ’
| Round, solitary aleurioconidia produced directly on hyphae
  
 
|-
  
|-
βˆ’
| ''A. ustus''
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|''A. ustus''
βˆ’
| Light brown, grayish brown, yellowish brown
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|Light brown, grayish brown, yellowish brown
  +
|Smooth, brown
βˆ’
|
  
  +
|Biseriate
βˆ’
| Smooth, brown
  
  +
|Long, brown-walled conidiophores, small vesicles, rough-walled conidia
βˆ’
| Biseriate
  
βˆ’
| Long, brown-walled conidiophores, small vesicles, rough-walled conidia
  
 
|-
  
|-
βˆ’
| ''A. versicolor''
 +
|''A. versicolor''
βˆ’
| White, buff, yellow, pink, pale green, white, yellow, purplish red
 +
|White, buff, yellow, pink, pale green, white, yellow, purplish red
  +
|Smooth, colourless
βˆ’
|
  
  +
|Biseriate
βˆ’
| Smooth, colourless
  
  +
|Round hΓΌlle cells sometimes present
βˆ’
| Biseriate
  
βˆ’
| Round hΓΌlle cells sometimes present
  
 
|}
  
|}
   
βˆ’
* Of note, ''A. ustus'' complex (''A. caladustus'') are resistant to [[azoles]] and [[echinocandins]], and variable resistance to [[amphotericin]] (but susceptible to [[terbinafine]])
 +
*Of note, ''A. ustus'' complex (''A. caladustus'') are resistant to [[azoles]] and [[echinocandins]], and variable resistance to [[amphotericin]] (but susceptible to [[terbinafine]])
   
βˆ’
== Epidemiology ==
 +
===Epidemiology===
   
βˆ’
* Ubiquitous worldwide, found in soil, water, food, air, and decaying vegetation
 +
*Ubiquitous worldwide, found in soil, water, food, air, and decaying vegetation
βˆ’
* There is increasing antifungal resistance worldwide
 +
*There is increasing antifungal resistance worldwide
βˆ’
* Outbreaks can occur with construction
 +
*Outbreaks can occur with construction
βˆ’
* May also be possible to have activation of latent infecton or colonization, making infection control more difficult
 +
*May also be possible to have activation of latent infecton or colonization, making infection control more difficult
   
βˆ’
=== High-Risk Populations ===
 +
====High-Risk Populations====
   
βˆ’
* The major risk factor is defective function or decreased number of neutrophils
 +
*The major risk factor is defective function or decreased number of neutrophils
βˆ’
* In order of risk: CGD, alloSCT with GVHD, AML with induction or (worse) reinduction, everyone else, etc.
 +
*Highest risk, in order, are: [[CGD]], allogeneic [[hematopoietic stem cell transplantation]] with [[GVHD]], [[AML]] with induction or (worse) reinduction, everyone else
  +
*[[Hematopoietic stem cell transplantation|Hematopoitic stem cell transplantion]] is high risk (7% allo, 1% auto)
βˆ’
* CGD is the highest risk disease; other at-risk groups include lung disease, AIDS, etc.
  
  +
**Peaks <40 days and >100 days
βˆ’
* Hematopoitic stem cell transplants are highest risk (7% allo, 1% auto)
  
  +
**With or without neutropenia, most likely related to steroid use
βˆ’
** Peaks <40 days and >100 days
  
  +
*[[Hematologic malignancy|Hematologic malignancies]]
βˆ’
** With or without neutropenia, most likely related to steroid use
  
  +
**Usually following induction chemotherapy, or refractory or recurrenct disease (50% mortality)
βˆ’
* Hematologic malignancies
  
  +
**3+7 AML induction usually 14-21 days of [[neutropenia]]
βˆ’
** Usually following induction chemotherapy, or refractory or recurrenct disease (50% mortality)
  
  +
*[[Solid organ transplantation]]
βˆ’
** 3+7 AML induction usually 14-21 days of neutropenia
  
  +
**Highest among [[lung transplantation]] recipients (6%) due to ongoing environmental exposure, decreased ciliary clearance, and common concomitant ''Aspergillus'' colonization
βˆ’
* Solid-organ transplants
  
  +
**Followed by small bowel, [[Liver transplantation|liver]] (4%), [[Heart transplantation|heart]] (2%), and [[Renal transplantation|kidney]] (0.5%)
βˆ’
** Highest among lung transplant recipients (6%) due to ongoing environmental exposure, decreased ciliary clearance, and common concomitant ''Aspergillus'' colonization
  
  +
**Usually diagnosed at 6 to 12 months (half within the first 3 months)
βˆ’
** Followed by liver (4%), heart (2%), and kidney (0.5%)
  
  +
*Therapeutic immunosuppression, including [[prednisone]] and [[TNF-Ξ± inhibitors]]
βˆ’
** Usually diagnosed at 6 to 12 months
  
  +
*[[GVHD]] increases the risk, due to the additional immune suppression
βˆ’
* Therapeutic immunosuppression, including prednisone and anti-TNF-alpha
  
  +
**Highest risk within GVHD is with gut involvement
βˆ’
* GVHD increases the risk, due to the additional immune suppression
  
  +
*Solid maligancies are relatively low risk due to the short courses of [[neutropenia]], but increasing risk with newer chemotherapies
βˆ’
** Highest risk within GVHD is with gut involvement
  
βˆ’
* Solid maligancies are relatively low risk due to the short courses of neutropenia, but increasing risk with newer chemotherapies
  
   
  +
==== Other Risk Factors ====
βˆ’
== Pathophysiology ==
  
   
  +
* HIV (2.2 per 10,000/year), associated with low CD4 counts, neutropenia, cirrhosis, liver transplantation, and glucocorticoid therapy
βˆ’
* Initially acquired by inhalation of conidia into lungs or sinuses, or rarely from local tissue invasion
  
  +
* Liver cirrhosis (0.3%)
βˆ’
* The conidia grow and germinate, transforming into hyphae and invading the vasculature
  
  +
* Immunocompetent patients in critical condition from [[ARDS]], [[COPD]], influenza, pneumonia, burns, severe bacterial sepsis, surgery, or malnutrition
βˆ’
** Hydrocortisone appears to be a growth factor for ''Aspergillus''
  
  +
** Glucocorticoid therapy is most common risk factor in these patients
βˆ’
** Vascular invasion is typical of invasive aspergillosis
  
βˆ’
** May cause pulmonary infarction
  
βˆ’
* This can be followed by hematogenous dissemination
  
βˆ’
* The host immune response begins with ciliary clearance to prevent the conidia from reaching the alveoli
  
βˆ’
* Once in the alveoli, the response depends on pulmonary macrophages to phagocytose the conidia
  
βˆ’
* Following germination and growth of hyphae, PMNs act to kill hyphae and swollen conidia
  
βˆ’
** This is helped by opsonization of conidia by complement
  
βˆ’
** Antibodies are common, given the mold's ubiquity, but not protective
  
βˆ’
* ''A. fumigatus'' has small conidia, allowing it to reach the alveoli more easily, and also produces a complement inhibitor
  
   
  +
===Pathophysiology===
βˆ’
== Clinical Presentation ==
  
   
  +
*Initially acquired by inhalation of conidia into lungs or sinuses, or rarely from local tissue invasion
βˆ’
=== Colonization and superficial infections ===
  
  +
*The conidia grow and germinate, transforming into hyphae and invading the vasculature
  +
**[[Hydrocortisone]] appears to be a growth factor for ''Aspergillus''
  +
**Vascular invasion is typical of invasive aspergillosis
  +
**May cause pulmonary infarction
  +
*This can be followed by hematogenous dissemination
  +
*The host immune response begins with ciliary clearance to prevent the conidia from reaching the alveoli
  +
*Once in the alveoli, the response depends on pulmonary macrophages to phagocytose the conidia
  +
*Following germination and growth of hyphae, PMNs act to kill hyphae and swollen conidia
  +
**This is helped by opsonization of conidia by complement
  +
**Antibodies are common, given the mold's ubiquity, but not protective
  +
*''A. fumigatus'' has small conidia, allowing it to reach the alveoli more easily, and also produces a complement inhibitor
   
  +
==Clinical Manifestations==
βˆ’
==== Aspergilloma (fungal ball) ====
  
   
  +
===Colonization and Superficial Infections===
βˆ’
* Ball of hyphae growing in a preexisting cavity, often in bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, congenital cysts, bacterial lung abscesses, or ''Pneumocystis'' bleb
  
βˆ’
* Often asymptomatic, but the most common symptom is hemoptysis, which can be fatal
  
βˆ’
* Can also occur in the sinuses
  
   
  +
====Aspergilloma (Fungal Ball)====
βˆ’
==== Other supreficial infections ====
  
   
  +
*Ball of hyphae growing in a preexisting cavity, often in bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, congenital cysts, bacterial lung abscesses, or ''Pneumocystis'' bleb
βˆ’
* Otomycosis: chronic otitis externa caused by ''A. niger'' or ''A. fumigatus''
  
  +
*Often asymptomatic, but the most common symptom is [[Causes::hemoptysis]], which can be fatal
βˆ’
* Onychomycosis
  
  +
*Can also occur in the sinuses
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* Keratitis
  
   
  +
====Other Superficial Infections====
βˆ’
=== Allergic syndromes ===
  
   
  +
*[[Otomycosis]]: chronic otitis externa caused by ''A. niger'' or ''A. fumigatus''
βˆ’
==== Allergic bronchopulmonary aspergillosis (ABPA) ====
  
  +
*[[Onychomycosis]]
  +
*[[Keratitis]]
   
  +
===Allergic Syndromes===
βˆ’
* Caused by a Th2 response to ''Aspergillus'', usually in patients with asthma or cystic fibrosis
  
βˆ’
* Criteria include: asthma, central bronchiectasis on CT, positive skin test for ''Aspergillus'', total IgE >417 IU/mL, IgE or IgG antibodies to ''A. fumigatus'', transient CXR infiltrates, ''Aspergillus'' precipitans, and eosinophilia
  
βˆ’
* Supported by ''Aspergillus'' on sputum culture, brown mucous plugs with dead eosinophils, and CXR showing bronchiectasis
  
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* The course is characterized by exacerbations and remissions, leading to eventual pulmonary fibrosis and chronic pulmonary aspergillosis
  
   
βˆ’
==== Allergic fungal sinusitis ====
 +
====Allergic Bronchopulmonary Aspergillosis (ABPA)====
   
  +
*Allergic reaction to airway colonization, usually in patients with [[asthma]] or [[cystic fibrosis]]
βˆ’
* Can be ''Aspergillus'' or other molds
  
  +
*Characterized by poorly-controlled asthma or pneumonia, mucoid impaction, persistent eosinophilia
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* Mangement is mostly surgical
  
  +
*See also [[Allergic bronchopulmonary aspergillosis]]
   
  +
====Allergic Fungal Sinusitis====
βˆ’
=== Chronic cavitary pulmonary aspergillosis (CCPA) ===
  
   
  +
*Can be ''Aspergillus'' or other molds
βˆ’
* One or more cavities that can contain solid or liquid material or a fungal ball, usually following creation of multiple cavities from another process
  
  +
*Management is mostly surgical
βˆ’
* May present with pulmonary or constitutional symptoms, including hemoptysis, dyspnea, and productive cough
  
βˆ’
** Weight loss and fatigue are common and profound, while fevers are less common
  
βˆ’
** May mimic TB
  
βˆ’
* Diagnosis requires:
  
βˆ’
** 3 months of symptoms or chronic illness or progressive radiological abnormalities with cavitation, pleural thickening, perivacitary infiltrates +/- fungal ball
  
βˆ’
** ''Aspergillus'' IgG antibodies
  
βˆ’
** No or minimal immunocompromise
  
βˆ’
* Must rule out other causes of symptoms, including other causes of weight loss
  
   
  +
=== Chronic Pulmonary Aspergillosis (CPA) ===
βˆ’
=== Invasive aspergillosis ===
  
   
  +
* Inclues chronic cavitary pulmonary aspergillosis (CCPA), chronic necrotising pulmonary aspergillosis (CNPA), and chronic fibrosing aspergillosis
βˆ’
* aka. angioinvasive, invading the vasculature
  
   
βˆ’
==== Chronic necrotizing pulmonary aspergillosis ====
 +
==== Chronic Cavitary Pulmonary Aspergillosis (CCPA) ====
  +
*One or more cavities that can contain solid or liquid material or a fungal ball, usually following creation of multiple cavities from another process
  +
*May present with pulmonary or constitutional symptoms, including hemoptysis, dyspnea, and productive cough
  +
**Weight loss and fatigue are common and profound, while fevers are less common
  +
**May mimic TB
  +
*Diagnosis requires:
  +
**3 months of symptoms or chronic illness or progressive radiological abnormalities with cavitation, pleural thickening, perivacitary infiltrates +/- fungal ball
  +
**''Aspergillus'' IgG antibodies
  +
**No or minimal immunocompromise
  +
*Must rule out other causes of symptoms, including other causes of weight loss
   
  +
==== Chronic Necrotising Pulmonary Aspergillosis (CNPA) ====
βˆ’
* With mild or moderate immunosuppression, patients may develop chronic necrotizing pulmonary aspergillosis (CNPA), essentially a subacute form of invasive aspergillosis
  
   
βˆ’
==== Invasive pulmonary aspergillosis ====
 +
==== Chronic Fibrosing Aspergillosis (CFA) ====
   
  +
===Invasive Aspergillosis===
βˆ’
* Usually after 10 to 12 days of severe neutropenia
  
βˆ’
* Non-productive cough, dyspnea, pleuritic chest pain, and fever with pulmonary infiltrates despite broad-spectrum antibiotics
  
βˆ’
** Symptoms may be less prominent in patients with defective immunity
  
βˆ’
** Fever dampened by high dose steroids
  
βˆ’
* Also hemoptysis, pleural effusion, and pneumothorax
  
βˆ’
** Can mimic a pulmonary embolism
  
βˆ’
* Imaging may show multiple dense nodular pulmonary infiltrates without air bronchograms, suggesting extensive infection
  
βˆ’
** Classic, though, is pleural-based wedge-shaped densities or cavitary lesions
  
βˆ’
** Pleural effusions are common
  
βˆ’
** A nodular lesion wth a halo is suggestive of early aspergillosis, followed by cavitation in later disease
  
   
  +
*aka. angioinvasive, invading the vasculature
βˆ’
==== Other sites of invasive respiratory aspergillosis ====
  
   
  +
====Subacute Invasive Aspergillosis====
βˆ’
* Ulcerative tracheobronchitis, a high concern in lung transplant
  
βˆ’
** May mimic graft rejection
  
βˆ’
* Invasive rhinosinusitis, with mortality of 10-20%
  
βˆ’
* Hematogenous dissemination to any organ, associated with 90% mortality
  
   
βˆ’
==== Other sites of invasive aspergillosis ====
 +
*Previously called chronic necrotizing pulmonary aspergillosis
  +
*Occurs in mildly immunocompromised or very debilitated patients
  +
**Risk factors include diabetes mellitus, malnutrition, alcoholism, advanced age, prolonged corticosteroids or other immunosuppressive agents, chronic obstructive lung disease, connective tissue disorders, radiation therapy, non-tuberculous mycobacterial infection, or HIV infection
  +
*Similar clinical and radiological findings as chronic cavitary pulmonary aspergillosis, but progresses more rapidly into frank invasive pulmonary aspergillosis
   
  +
====Invasive Pulmonary Aspergillosis====
βˆ’
* Cerebral aspergillosis, which may explain half of all CNS lesions in HSCT
  
βˆ’
** Presents >100 days after transplant, usually with concomitant pulmonary disease
  
βˆ’
** Presents with focal neuro signs, altered mental status, and headaches
  
βˆ’
* Osteomyelitis
  
βˆ’
** Vertebral osteomyelitis may result from extension of empyema, but is also the most common site of hematogenous dissemination
  
βˆ’
* Skin and soft tissue infection
  
βˆ’
** Either from hematogenous spread or local invasion
  
βˆ’
** Often around IVs or adhesive dressings
  
βˆ’
** Neutropenic patients as well as burns and surgical sites
  
   
  +
*Usually after 10 to 12 days of severe [[neutropenia]]
βˆ’
=== Specific risk groups ===
  
  +
*Non-productive [[Causes::cough]], [[Causes::dyspnea]], [[Causes::pleuritic chest pain]], and [[Causes::fever]] with pulmonary infiltrates despite broad-spectrum antibiotics
  +
**Symptoms may be less prominent in patients with defective immunity
  +
**Fever dampened by high dose steroids
  +
*Also [[Causes::hemoptysis]], [[Causes::pleural effusion]], and [[Causes::pneumothorax]]
  +
**Can mimic a pulmonary embolism
  +
*Imaging may show multiple dense nodular pulmonary infiltrates without air bronchograms, suggesting extensive infection
  +
**Classic, though, is pleural-based wedge-shaped densities or cavitary lesions
  +
**[[Pleural effusion|Pleural effusions]] are common
  +
**A nodular lesion wth a halo is suggestive of early aspergillosis, followed by cavitation in later disease
   
  +
====Other Sites of Invasive Respiratory Aspergillosis====
βˆ’
* For CGD and AML induction and SOT, it tends to be isolated pulmonary aspergillosis
  
βˆ’
* In SCT with GVHD, you tend to see more CNS aspergillosis and disseminated aspergillosis
  
   
  +
*Ulcerative tracheobronchitis, a high concern in lung transplant
βˆ’
== Diagnosis ==
  
  +
**May mimic graft rejection
  +
*Invasive [[rhinosinusitis]], with mortality of 10-20%
  +
*Hematogenous dissemination to any organ, associated with 90% mortality
   
  +
====Other Sites of Invasive Aspergillosis====
βˆ’
* '''Culture''' positive for ''Aspergillus'' and histology with invasive hyphae
  
βˆ’
** Only 10-30% of patients with IA have a positive BAL culture, improved with use of fungal media
  
βˆ’
* '''Serology'''
  
βˆ’
** Antibodies is unhelpful, given that the mold is ubiquitous
  
βˆ’
** '''Galactomannan''' by EIA
  
βˆ’
*** Best-studied and most sensitive in HSCT patients
  
βˆ’
*** It is a meleased from the fungal cell wall on growth
  
βˆ’
*** Cutoff of 0.5 is good, 80% Sn and Sp (up to 90% in HSCT patients' serum)
  
βˆ’
*** BAL is more sensitive, but prophylaxis decreases sensitivity
  
βˆ’
*** Can be done from CSF
  
βˆ’
*** False-positives may occur with pip/tazo and other beta-lactams (though mostly of historical interest now)
  
βˆ’
** '''1,3-beta-D-glucan''' (BDG): can detect ''Candida'' and ''Pneumocystis'' as well, so less specific. May be useful in combination with GM.
  
βˆ’
*** Utility in invasive fungal infections: from [https://doi.org/10.1371/journal.pone.0131602 a systematic review in 2015], it is about 80% sensitive and 85% specific for IFI. Identified ''Candida'' and ''Aspergillus''. In [https://doi.org/10.1016/j.jinf.2014.04.008 a retrospective review from 2014], it had similar specific and inferior sensitivity compared to GM.
  
βˆ’
** Combination serologies: GM (BAL) Sn 43-56% and Sp 97%; BDG (blood) Sn 56-65% and Sp 97%; combination of ''either'' test positive Sn 78-92%% and Sp 93%, while PCR did not have any additional benefit ([https://doi.org/10.1016/j.cmi.2016.06.021 source]).
  
βˆ’
* '''Molecular testing'''
  
βˆ’
** '''Fungal PCR''' possible, but not routinely done; may not be helpful since the fungus is ubiquitous and wouldn’t differentiate invasive disease vs. colonization.
  
βˆ’
** '''Microarray DNA''': Microbiologic diagnostics are often combined with imaging to diagnose probable invasive fungal infection.
  
βˆ’
* '''Imaging''' can be helpful
  
βˆ’
** Halo sign on CT is present for about the first 7 days of disease in neutropenic patients
  
βˆ’
** Can also have nodules, pleural-based infarctions, or vacitation, as well as non-specific consolidation
  
   
  +
*[[Cerebral aspergillosis]], which may explain half of all CNS lesions in HSCT
βˆ’
== Management ==
  
  +
**Presents >100 days after transplant, usually with concomitant pulmonary disease
  +
**Presents with focal neurological signs, altered mental status, and headache
  +
*[[Osteomyelitis]]
  +
**Vertebral osteomyelitis may result from extension of empyema, but is also the most common site of hematogenous dissemination
  +
*[[Skin and soft tissue infection]]
  +
**Either from hematogenous spread or local invasion
  +
**Often around IVs or adhesive dressings
  +
**Neutropenic patients as well as burns and surgical sites
   
βˆ’
=== Aspergilloma ===
 +
===Specific Risk Groups===
   
  +
*For [[CGD]], [[AML]] induction, and [[SOT]], it tends to be isolated pulmonary aspergillosis
βˆ’
* If asymptomatic and single aspergilloma, monitor
  
  +
*In [[HSCT]] with [[GVHD]], you tend to see more CNS aspergillosis and disseminated aspergillosis
βˆ’
* If symptoms, especially hemoptysis, surgical resection (if possible)
  
βˆ’
* No role for antifungals
  
   
  +
==Diagnosis==
βˆ’
=== Allergic bronchopulmonary aspergillosis (ABPA) ===
  
   
  +
*'''Culture''' positive for ''Aspergillus'' and histology with invasive hyphae
βˆ’
* Indications for treatment
  
  +
**Only 10-30% of patients with IA have a positive BAL culture, improved with use of fungal media
βˆ’
** Diagnose with ''Aspergillus''-IgE
  
  +
*'''Serology'''
βˆ’
** If ongoing symptoms despite appropriate management of asthma (including oral steroids), treat with itraconazole
  
  +
**Antibodies is unhelpful, given that the mold is ubiquitous
βˆ’
** If CF patient has frequent exacerbations or falling FEV1, treat with itraconazole
  
  +
**'''Galactomannan''' by EIA
βˆ’
* Itraconazole 200 mg/day for 16 weeks, which decreases steroid use and increases patient function
  
  +
***Best-studied and most sensitive in HSCT patients
  +
***It is a released from the fungal cell wall on growth
  +
***Cutoff of 0.5 is good, 80% Sn and Sp (up to 90% in HSCT patients' serum)
  +
***BAL is more sensitive, but prophylaxis decreases sensitivity
  +
***Can be done from CSF
  +
***False-positives may occur with pip/tazo and other beta-lactams (though mostly of historical interest now)
  +
**'''1,3-beta-D-glucan''' (BDG): can detect ''Candida'' and ''Pneumocystis'' as well, so less specific. May be useful in combination with GM.
  +
***Utility in invasive fungal infections: from [https://doi.org/10.1371/journal.pone.0131602 a systematic review in 2015], it is about 80% sensitive and 85% specific for IFI. Identified ''Candida'' and ''Aspergillus''. In [https://doi.org/10.1016/j.jinf.2014.04.008 a retrospective review from 2014], it had similar specific and inferior sensitivity compared to GM.
  +
**Combination serologies: GM (BAL) Sn 43-56% and Sp 97%; BDG (blood) Sn 56-65% and Sp 97%; combination of ''either'' test positive Sn 78-92%% and Sp 93%, while PCR did not have any additional benefit ([https://doi.org/10.1016/j.cmi.2016.06.021 source]).
  +
*'''Molecular testing'''
  +
**'''Fungal PCR''' possible, but not routinely done; may not be helpful since the fungus is ubiquitous and wouldn’t differentiate invasive disease vs. colonization.
  +
**'''Microarray DNA''': Microbiologic diagnostics are often combined with imaging to diagnose probable invasive fungal infection.
  +
*'''Imaging''' can be helpful
  +
**Halo sign on CT is present for about the first 7 days of disease in neutropenic patients
  +
**Can also have nodules, pleural-based infarctions, or vacitation, as well as non-specific consolidation
  +
**See review [[CiteRef::franquet2001sp]]
   
  +
==Management==
βˆ’
=== Allergic fungal rhinosinusitis ===
  
   
  +
===Antifungal Resistance===
βˆ’
* Polypectomy and sinus washout
  
βˆ’
* Topical nasal steroids
  
βˆ’
* Oral antifungal therapy can be tried if above does not work, but rarely effective
  
   
  +
*'''Broth microdilution''' is the main method for determining ''Aspergillus'' susceptibility recommended by CLSI and EUCAST. Microdilution results are affected by a number of factors (shape of the microdilution well, inoculum concentration, temperature and length of incubation time), so testing must be rigorously standardized.
βˆ’
=== Chronic cavitary pulmonary aspergillosis (CCPA) ===
  
  +
*'''Antifungal mechanisms'''
  +
**'''Polyenes''' ([[amphotericin]]): binds ergosterol to create pores within the cell membrane.
  +
**'''Triazoles''' (except [[fluconazole]]): inhibit sterol synthesis of ergosterol by disrupting 14-alpha demethylase. The mechanisms of resistance are myriad: modification of target enzymes, an increased expression of drug efflux mechanisms, an overexpression of target enzymes, an incorporation of exogenous cholesterol, an overexpression of HSP90 and of a sterole-regulatory element binding protein.
  +
**'''Echinocandins''' (the fungins): disrupt synthesis of beta-glucan in the cell wall by inhibiting 1,3-beta glucan synthase.
  +
*'''Resistance patterns'''
  +
**All species are resistant to [[fluconazole]]. Historically, [[amphotericin]] has been the most reliable anti-''Aspergillus'' antifungal; now, [[voriconazole]] is the standard.
  +
**Resistance to [[amphotericin]] is seen in ''A. terreus'', ''A. flavus'', and other less common species.
  +
**''A. niger'' has variable susceptibility to azoles. There is increasing ''A. fumigatus'' resistance to azoles, with reports being most common from Europe. ''A. calidoustus'' (within ''A. ustus'' complex) is a growing cause, with late presentation, intrinsic antifungal resistance, and high mortality.
   
  +
{| class="wikitable"
βˆ’
* If asymptomatic, monitor every 3-6 months, with investigations every 3-12 months including
  
  +
!Organism
βˆ’
** Low-dose CT chest or CXR
  
  +
!AmB
βˆ’
** ESR/CRP
  
  +
!Fluc
βˆ’
** ''Aspergillus'' IgG titres
  
  +
!Itra
βˆ’
** Annual PFTs
  
  +
!Vori
βˆ’
* If pulmonary symptoms, constitutional symptoms, or worsening lung function, treat with 6+ months of antifungal therapy
  
  +
!Posa
βˆ’
** Itraconazole or voriconazole
  
  +
!Anidula
βˆ’
** If this fails, try IV micafungin, caspofungin, or amphotericin B
  
  +
!Caspo
βˆ’
* If hemoptysis, treat with tranexamic acid, pulmonary artery embolization, or antifungal therapy
  
  +
!Mica
βˆ’
* May need surgical resection if localized disease refractory to medical management
  
  +
!Flucyt
  +
|-
  +
|''Aspergillus'' spp.
  +
| +
  +
|–
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
|–
  +
|-
  +
|'' A. flavus''
  +
|Β±
  +
|–
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
|–
  +
|-
  +
|'' A. fumigatus''
  +
| +
  +
|–
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
|–
  +
|-
  +
|'' A. terreus''
  +
|–
  +
|–
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
|–
  +
|-
  +
|'' A. niger''
  +
| +
  +
|–
  +
|Β±
  +
| +
  +
| +
  +
| +
  +
| +
  +
| +
  +
|–
  +
|}
   
  +
===Aspergilloma===
βˆ’
=== Invasive aspergillosis ===
  
   
  +
*If asymptomatic and single aspergilloma, monitor
βˆ’
* Voriconazole 6 mg/kg IV q12h x2 then 4 mg/kg IV q12h, or 200 mg po q12h
  
  +
*If symptoms, especially hemoptysis, surgical resection (if possible)
βˆ’
** Alternative: liposomal amphotericin B 3 mg/kg/day
  
  +
*No role for antifungals
βˆ’
** Salvage: echinocandins (caspo, or other)
  
  +
βˆ’
** If hepatotoxicity with voriconazole, switch to posaconazole
  
  +
===Allergic Bronchopulmonary Aspergillosis (ABPA)===
βˆ’
** Vori superior to amphofor mortality
  
  +
βˆ’
** Combo vori+anidula no better than vori except in post-hoc analysis of possible early treatment
  
  +
*Not always treated with antifungals
βˆ’
** In the future, watch out for isuvaconazoleβ€”may be superior to vori
  
  +
*See [[Allergic bronchopulmonary aspergillosis#Management|Allergic bronchopulmonary aspergillosis]]
βˆ’
* Duration 6-12 weeks depending on immunosuppression
  
  +
βˆ’
* Follow-up CT after a minimum of 2 weeks, or earlier if deterioration
  
  +
===Allergic Fungal Rhinosinusitis===
  +
  +
*Polypectomy and sinus washout
  +
*Topical nasal steroids
  +
*Oral antifungal therapy can be tried if above does not work, but rarely effective
  +
  +
===Chronic Cavitary Pulmonary Aspergillosis (CCPA)===
  +
  +
*If asymptomatic, monitor every 3-6 months, with investigations every 3-12 months including
  +
**Low-dose CT chest or CXR
  +
**ESR/CRP
  +
**''Aspergillus'' IgG titres
  +
**Annual PFTs
  +
*If pulmonary symptoms, constitutional symptoms, or worsening lung function, treat with 6+ months of antifungal therapy
  +
**[[Itraconazole]] or [[voriconazole]]
  +
**If this fails, try IV [[micafungin]], [[caspofungin]], or [[amphotericin B]]
  +
**An RCT of [[itraconazole]] found that the relapse rate was significantly lower with 12 months of therapy compared to 6 months[[CiteRef::sehgal2022ef]]
  +
*If [[hemoptysis]], treat with [[tranexamic acid]], pulmonary artery embolization, or antifungal therapy
  +
*May need surgical resection if localized disease refractory to medical management
  +
  +
===Invasive Aspergillosis===
  +
  +
*[[Voriconazole]] 6 mg/kg IV q12h x2 then 4 mg/kg IV q12h, or 200 mg po q12h
  +
**Alternative: [[liposomal amphotericin B]] 3 mg/kg/day
  +
**Salvage: echinocandins ([[caspofungin]], or other)
  +
**If hepatotoxicity with [[voriconazole]], switch to [[posaconazole]]
  +
**[[Voriconazole]] is superior to [[amphotericin]] for mortality
  +
**Combination [[voriconazole]] plus [[anidulafungin]] is no better than [[voriconazole]] except in post-hoc analysis of possible early treatment
  +
**[[Isuvaconazole]] may be superior to [[voriconazole]]
  +
*Duration 6-12 weeks depending on immunosuppression
  +
*Follow-up CT after a minimum of 2 weeks, or earlier if deterioration
  +
*Non-pharmacologic management for neutropenic patients includes:
  +
**Reducing or eliminating immunosuppression
  +
**Granulocyte colony-stimulating factor
  +
**Granulocyte transfusions
  +
  +
===Breakthrough Infection===
  +
  +
*Base empiric treatment on local epidemiology
  +
*Probably fewer breakthroughs in HSCT patients with posaconazole prophylaxis
  +
  +
=== Therapeutic Drug Monitoring ===
  +
{| class="wikitable"
  +
!Antifungal
  +
!When to Measure Trough Level
  +
!Target for Treatment
  +
!Target for Prophylaxis
  +
!Target for Safety
  +
|-
  +
|[[Itraconazole]]
  +
|day 5 of therapy
  +
|1-4 mg/L by HPLC
  +
3-17 mg/L by bioassay
  +
|0.5-4 mg/L by HPLC
  +
3-17 mg/L by bioassay
  +
|≀~4 mg/L by HPLC
  +
≀17.1 mg/L by bioassay
  +
|-
  +
|[[Voriconazole]]
  +
|after 2 to 5 days of therapy, and 4 days after any change
  +
|1-5.5 mg/L
  +
|1-5.5 mg/L
  +
|
  +
|-
  +
|[[Posaconazole]]
  +
|day 5 of therapy
  +
|>1 mg/L
  +
|>0.7 mg/L
  +
|≀3.75 mg/L
  +
|-
  +
|[[Isavuconazole]]
  +
|day 5 of therapy, but not clearly needed
  +
|
  +
|
  +
|
  +
|}
   
  +
===Failure===
βˆ’
=== Breakthrough infection ===
  
   
  +
*Technically should be assessed at 6 weeks (2 weeks at a minimum, based on pharmacokinetics)
βˆ’
* Base empiric treatment on local epidemiology
  
βˆ’
* Probably fewer breakthroughs in HSCT patients with posaconazole prophylaxis
  
   
βˆ’
=== Failure ===
 +
==Prevention==
   
  +
*For high-risk patients in hospital (e.g. HSCT), use air filters, frequent air exchanges, and positive-pressure ventilation
βˆ’
* Technically should be assessed at 6 weeks (2 weeks at a minimum, based on pharmacokinetics)
  
   
  +
===Antifungal Prophylaxis===
βˆ’
== Prevention ==
  
   
  +
*Posaconazole prophylaxis is first to demonstrate survival benefit for AML/induction patients
βˆ’
* For high-risk patients in hospital (e.g. HSCT), use air filters, frequent air exchanges, and positive-pressure ventilation
  
  +
*'''AML induction''': [[posaconazole]], [[voriconazole]], or [[micafungin]]
  +
**[[Caspofungin]] probably also effective
  +
**[[Itraconazole]] also effective but poorly tolerated
  +
*'''HSCT with moderate to severe GVHD:''' [[posaconazole]] ([[voriconazole]] is alternative)
  +
**Reduces invasive fungal infections, but no mortality benefit
  +
*'''Immunosuppression for GVHD:''' prophylaxis for duration of immunosuppression ([[steroids]] >1mg/kg/d for >2 weeks, or lymphocyte-depleting agents, or [[TNF-Ξ± inhibitors]])
  +
*'''Lung transplant:''' [[voriconazole]], [[itraconazole]], or inhaled [[amphotericin B]] for 3 to 4 months after transplant, and when receiving [[thymoglobulin]], [[alemtuzumab]], or high-dose [[steroids]]
  +
*'''Other solid organ transplant:''' decision based on per-patient risk factors
  +
*'''Prior IA requiring new immunosuppression:''' may also benefit from prophylaxis
  +
*'''[[Chronic granulomatous disease]]''': [[itraconazole]] and [[interferon-Ξ³]]
   
  +
==Further Reading==
βˆ’
=== Antifungal prophylaxis ===
  
   
  +
*Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. ''Clin Infect Dis''. 2016;63(4):e1-e60. doi: [https://doi.org/10.1093/cid/ciw326 10.1093/cid/ciw326]
βˆ’
* Posaconazole prophylaxis is first to demonstrate survival benefit for AML/induction patients
  
  +
*Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. ''Clin Microbiol Infect''. 2018. doi: [https://doi.org/10.1016/j.cmi.2018.01.002 10.1016/j.cmi.2018.01.002]
βˆ’
* '''AML induction''': posaconazole, voriconazole, or micafungin
  
βˆ’
** Caspofungin probably also effective
  
βˆ’
** Itraconazole also effective but poorly tolerated
  
βˆ’
* '''HSCT with moderate to severe GVHD:''' posaconazole (voriconazole is alternative)
  
βˆ’
** Reduces invasive fungal infections, but no mortality benefit
  
βˆ’
* '''Immunosuppression for GVHD:''' prophylaxis for duration of immunosuppression (steroids >1mg/kg/d for >2 weeks, or lymphocyte-depleting agents, or TNF-alpha inhibition)
  
βˆ’
* '''Lung transplant:''' vori/itra/inhaled amphoB for 3 to 4 months after transplant, and when receiving thymoglobulin, alemtuzumab, or high-dose steroids
  
βˆ’
* '''Other solid-organ transplant:''' decision based on per-patient risk factors
  
βˆ’
* '''Prior IA requiring new immunosuppression:''' may also benefit from prophylaxis
  
   
βˆ’
{{DISPLAYTITLE:''Aspergillus'' species}}
 +
{{DISPLAYTITLE:''Aspergillus''}}
 
[[Category:Hyaline molds]]
  
[[Category:Hyaline molds]]

Latest revision as of 07:18, 20 March 2024

Background

Microbiology

  • Aspergillus is a mold with hyaline (lightly-pigmented) hyphae, septated, and usually branched at acute angle (45ΒΊ)
  • Named for the appearance of the sporulating head, which looks like an aspergillum used to sprinkle holy water (in 1729)
  • Most species reproduce asexually, although A. fumigatus and a few others have teleomorphs (sexual form with fruiting body)
  • Culture is important, but molecular methods are often required to identify the particular species
    • Pathogenic species grow quickly on common media
    • Can grow at 37ΒΊ C, and A. fumigatus can grow up to 50ΒΊ C
  • Organized into complexes, which cannot be differentiated phenotypically, but rather need molecular methods
    • Fumigatus: A. fumigatus, A. lentulus, A. udagawae
    • Ustus: A. calidoustus (often resistant to ampho B)
    • Niger: A. tubingensis and A. niger
    • Versicolor: A. versicolor and A. sydowii
Species Colonies Conidiophore Phialides Other
A. flavus Yellow green, yellow, brownish Rough colourless Uniseriate and biseriate Sclerotia sometimes present
A. fumigatus complex Grey-green, blue green, yellowish Smooth, colourless or greenish Uniseriate Good growth at 48ΒΊC
A. glaucus Green and yellow, yellowish, brown Smooth, colourless Uniseriate Yellow to orange cleistothecia present
A. nidulans Green buff, purplish red, olive Smooth, brown Biseriate Round hΓΌlle cells and cleistothecia with purple ascospores usually present
A. niger Black, white, yellowish Smooth, colourless or brown Biseriate
A. terreus Brown cinnamon, yellowish brown Smooth, colourless Biseriate Round, solitary aleurioconidia produced directly on hyphae
A. ustus Light brown, grayish brown, yellowish brown Smooth, brown Biseriate Long, brown-walled conidiophores, small vesicles, rough-walled conidia
A. versicolor White, buff, yellow, pink, pale green, white, yellow, purplish red Smooth, colourless Biseriate Round hΓΌlle cells sometimes present

Epidemiology

  • Ubiquitous worldwide, found in soil, water, food, air, and decaying vegetation
  • There is increasing antifungal resistance worldwide
  • Outbreaks can occur with construction
  • May also be possible to have activation of latent infecton or colonization, making infection control more difficult

High-Risk Populations

  • The major risk factor is defective function or decreased number of neutrophils
  • Highest risk, in order, are: CGD, allogeneic hematopoietic stem cell transplantation with GVHD, AML with induction or (worse) reinduction, everyone else
  • Hematopoitic stem cell transplantion is high risk (7% allo, 1% auto)
    • Peaks <40 days and >100 days
    • With or without neutropenia, most likely related to steroid use
  • Hematologic malignancies
    • Usually following induction chemotherapy, or refractory or recurrenct disease (50% mortality)
    • 3+7 AML induction usually 14-21 days of neutropenia
  • Solid organ transplantation
    • Highest among lung transplantation recipients (6%) due to ongoing environmental exposure, decreased ciliary clearance, and common concomitant Aspergillus colonization
    • Followed by small bowel, liver (4%), heart (2%), and kidney (0.5%)
    • Usually diagnosed at 6 to 12 months (half within the first 3 months)
  • Therapeutic immunosuppression, including prednisone and TNF-Ξ± inhibitors
  • GVHD increases the risk, due to the additional immune suppression
    • Highest risk within GVHD is with gut involvement
  • Solid maligancies are relatively low risk due to the short courses of neutropenia, but increasing risk with newer chemotherapies

Other Risk Factors

  • HIV (2.2 per 10,000/year), associated with low CD4 counts, neutropenia, cirrhosis, liver transplantation, and glucocorticoid therapy
  • Liver cirrhosis (0.3%)
  • Immunocompetent patients in critical condition from ARDS, COPD, influenza, pneumonia, burns, severe bacterial sepsis, surgery, or malnutrition
    • Glucocorticoid therapy is most common risk factor in these patients

Pathophysiology

  • Initially acquired by inhalation of conidia into lungs or sinuses, or rarely from local tissue invasion
  • The conidia grow and germinate, transforming into hyphae and invading the vasculature
    • Hydrocortisone appears to be a growth factor for Aspergillus
    • Vascular invasion is typical of invasive aspergillosis
    • May cause pulmonary infarction
  • This can be followed by hematogenous dissemination
  • The host immune response begins with ciliary clearance to prevent the conidia from reaching the alveoli
  • Once in the alveoli, the response depends on pulmonary macrophages to phagocytose the conidia
  • Following germination and growth of hyphae, PMNs act to kill hyphae and swollen conidia
    • This is helped by opsonization of conidia by complement
    • Antibodies are common, given the mold's ubiquity, but not protective
  • A. fumigatus has small conidia, allowing it to reach the alveoli more easily, and also produces a complement inhibitor

Clinical Manifestations

Colonization and Superficial Infections

Aspergilloma (Fungal Ball)

  • Ball of hyphae growing in a preexisting cavity, often in bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, congenital cysts, bacterial lung abscesses, or Pneumocystis bleb
  • Often asymptomatic, but the most common symptom is hemoptysis, which can be fatal
  • Can also occur in the sinuses

Other Superficial Infections

Allergic Syndromes

Allergic Bronchopulmonary Aspergillosis (ABPA)

Allergic Fungal Sinusitis

  • Can be Aspergillus or other molds
  • Management is mostly surgical

Chronic Pulmonary Aspergillosis (CPA)

  • Inclues chronic cavitary pulmonary aspergillosis (CCPA), chronic necrotising pulmonary aspergillosis (CNPA), and chronic fibrosing aspergillosis

Chronic Cavitary Pulmonary Aspergillosis (CCPA)

  • One or more cavities that can contain solid or liquid material or a fungal ball, usually following creation of multiple cavities from another process
  • May present with pulmonary or constitutional symptoms, including hemoptysis, dyspnea, and productive cough
    • Weight loss and fatigue are common and profound, while fevers are less common
    • May mimic TB
  • Diagnosis requires:
    • 3 months of symptoms or chronic illness or progressive radiological abnormalities with cavitation, pleural thickening, perivacitary infiltrates +/- fungal ball
    • Aspergillus IgG antibodies
    • No or minimal immunocompromise
  • Must rule out other causes of symptoms, including other causes of weight loss

Chronic Necrotising Pulmonary Aspergillosis (CNPA)

Chronic Fibrosing Aspergillosis (CFA)

Invasive Aspergillosis

  • aka. angioinvasive, invading the vasculature

Subacute Invasive Aspergillosis

  • Previously called chronic necrotizing pulmonary aspergillosis
  • Occurs in mildly immunocompromised or very debilitated patients
    • Risk factors include diabetes mellitus, malnutrition, alcoholism, advanced age, prolonged corticosteroids or other immunosuppressive agents, chronic obstructive lung disease, connective tissue disorders, radiation therapy, non-tuberculous mycobacterial infection, or HIV infection
  • Similar clinical and radiological findings as chronic cavitary pulmonary aspergillosis, but progresses more rapidly into frank invasive pulmonary aspergillosis

Invasive Pulmonary Aspergillosis

  • Usually after 10 to 12 days of severe neutropenia
  • Non-productive cough, dyspnea, pleuritic chest pain, and fever with pulmonary infiltrates despite broad-spectrum antibiotics
    • Symptoms may be less prominent in patients with defective immunity
    • Fever dampened by high dose steroids
  • Also hemoptysis, pleural effusion, and pneumothorax
    • Can mimic a pulmonary embolism
  • Imaging may show multiple dense nodular pulmonary infiltrates without air bronchograms, suggesting extensive infection
    • Classic, though, is pleural-based wedge-shaped densities or cavitary lesions
    • Pleural effusions are common
    • A nodular lesion wth a halo is suggestive of early aspergillosis, followed by cavitation in later disease

Other Sites of Invasive Respiratory Aspergillosis

  • Ulcerative tracheobronchitis, a high concern in lung transplant
    • May mimic graft rejection
  • Invasive rhinosinusitis, with mortality of 10-20%
  • Hematogenous dissemination to any organ, associated with 90% mortality

Other Sites of Invasive Aspergillosis

  • Cerebral aspergillosis, which may explain half of all CNS lesions in HSCT
    • Presents >100 days after transplant, usually with concomitant pulmonary disease
    • Presents with focal neurological signs, altered mental status, and headache
  • Osteomyelitis
    • Vertebral osteomyelitis may result from extension of empyema, but is also the most common site of hematogenous dissemination
  • Skin and soft tissue infection
    • Either from hematogenous spread or local invasion
    • Often around IVs or adhesive dressings
    • Neutropenic patients as well as burns and surgical sites

Specific Risk Groups

  • For CGD, AML induction, and SOT, it tends to be isolated pulmonary aspergillosis
  • In HSCT with GVHD, you tend to see more CNS aspergillosis and disseminated aspergillosis

Diagnosis

  • Culture positive for Aspergillus and histology with invasive hyphae
    • Only 10-30% of patients with IA have a positive BAL culture, improved with use of fungal media
  • Serology
    • Antibodies is unhelpful, given that the mold is ubiquitous
    • Galactomannan by EIA
      • Best-studied and most sensitive in HSCT patients
      • It is a released from the fungal cell wall on growth
      • Cutoff of 0.5 is good, 80% Sn and Sp (up to 90% in HSCT patients' serum)
      • BAL is more sensitive, but prophylaxis decreases sensitivity
      • Can be done from CSF
      • False-positives may occur with pip/tazo and other beta-lactams (though mostly of historical interest now)
    • 1,3-beta-D-glucan (BDG): can detect Candida and Pneumocystis as well, so less specific. May be useful in combination with GM.
    • Combination serologies: GM (BAL) Sn 43-56% and Sp 97%; BDG (blood) Sn 56-65% and Sp 97%; combination of either test positive Sn 78-92%% and Sp 93%, while PCR did not have any additional benefit (source).
  • Molecular testing
    • Fungal PCR possible, but not routinely done; may not be helpful since the fungus is ubiquitous and wouldn’t differentiate invasive disease vs. colonization.
    • Microarray DNA: Microbiologic diagnostics are often combined with imaging to diagnose probable invasive fungal infection.
  • Imaging can be helpful
    • Halo sign on CT is present for about the first 7 days of disease in neutropenic patients
    • Can also have nodules, pleural-based infarctions, or vacitation, as well as non-specific consolidation
    • See review 1

Management

Antifungal Resistance

  • Broth microdilution is the main method for determining Aspergillus susceptibility recommended by CLSI and EUCAST. Microdilution results are affected by a number of factors (shape of the microdilution well, inoculum concentration, temperature and length of incubation time), so testing must be rigorously standardized.
  • Antifungal mechanisms
    • Polyenes (amphotericin): binds ergosterol to create pores within the cell membrane.
    • Triazoles (except fluconazole): inhibit sterol synthesis of ergosterol by disrupting 14-alpha demethylase. The mechanisms of resistance are myriad: modification of target enzymes, an increased expression of drug efflux mechanisms, an overexpression of target enzymes, an incorporation of exogenous cholesterol, an overexpression of HSP90 and of a sterole-regulatory element binding protein.
    • Echinocandins (the fungins): disrupt synthesis of beta-glucan in the cell wall by inhibiting 1,3-beta glucan synthase.
  • Resistance patterns
    • All species are resistant to fluconazole. Historically, amphotericin has been the most reliable anti-Aspergillus antifungal; now, voriconazole is the standard.
    • Resistance to amphotericin is seen in A. terreus, A. flavus, and other less common species.
    • A. niger has variable susceptibility to azoles. There is increasing A. fumigatus resistance to azoles, with reports being most common from Europe. A. calidoustus (within A. ustus complex) is a growing cause, with late presentation, intrinsic antifungal resistance, and high mortality.
Organism AmB Fluc Itra Vori Posa Anidula Caspo Mica Flucyt
Aspergillus spp. + – + + + + + + –
 A. flavus Β± – + + + + + + –
 A. fumigatus + – + + + + + + –
 A. terreus – – + + + + + + –
 A. niger + – Β± + + + + + –

Aspergilloma

  • If asymptomatic and single aspergilloma, monitor
  • If symptoms, especially hemoptysis, surgical resection (if possible)
  • No role for antifungals

Allergic Bronchopulmonary Aspergillosis (ABPA)

Allergic Fungal Rhinosinusitis

  • Polypectomy and sinus washout
  • Topical nasal steroids
  • Oral antifungal therapy can be tried if above does not work, but rarely effective

Chronic Cavitary Pulmonary Aspergillosis (CCPA)

  • If asymptomatic, monitor every 3-6 months, with investigations every 3-12 months including
    • Low-dose CT chest or CXR
    • ESR/CRP
    • Aspergillus IgG titres
    • Annual PFTs
  • If pulmonary symptoms, constitutional symptoms, or worsening lung function, treat with 6+ months of antifungal therapy
  • If hemoptysis, treat with tranexamic acid, pulmonary artery embolization, or antifungal therapy
  • May need surgical resection if localized disease refractory to medical management

Invasive Aspergillosis

Breakthrough Infection

  • Base empiric treatment on local epidemiology
  • Probably fewer breakthroughs in HSCT patients with posaconazole prophylaxis

Therapeutic Drug Monitoring

Antifungal When to Measure Trough Level Target for Treatment Target for Prophylaxis Target for Safety
Itraconazole day 5 of therapy 1-4 mg/L by HPLC

3-17 mg/L by bioassay

0.5-4 mg/L by HPLC

3-17 mg/L by bioassay

≀~4 mg/L by HPLC

≀17.1 mg/L by bioassay

Voriconazole after 2 to 5 days of therapy, and 4 days after any change 1-5.5 mg/L 1-5.5 mg/L
Posaconazole day 5 of therapy >1 mg/L >0.7 mg/L ≀3.75 mg/L
Isavuconazole day 5 of therapy, but not clearly needed

Failure

  • Technically should be assessed at 6 weeks (2 weeks at a minimum, based on pharmacokinetics)

Prevention

  • For high-risk patients in hospital (e.g. HSCT), use air filters, frequent air exchanges, and positive-pressure ventilation

Antifungal Prophylaxis

Further Reading

  • Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. Clin Infect Dis. 2016;63(4):e1-e60. doi: 10.1093/cid/ciw326
  • Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018. doi: 10.1016/j.cmi.2018.01.002

References

  1. ^  Inderpaul S Sehgal, Sahajal Dhooria, Valliappan Muthu, Kuruswamy T Prasad, Ashutosh N Aggarwal, Arunaloke Chakrabarti, Hansraj Choudhary, Mandeep Garg, Ritesh Agarwal. Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India. The Lancet Infectious Diseases. 2022. doi:10.1016/s1473-3099(22)00057-3.

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