Aspergillus: Difference between revisions
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Aspergillus
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+ | ==Background== |
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− | = ''Aspergillus'' spp. = |
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+ | ===Microbiology=== |
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+ | *''Aspergillus'' is a mold with hyaline (lightly-pigmented) hyphae, septated, and usually branched at acute angle (45º) |
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− | == Microbiology == |
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+ | *Named for the appearance of the sporulating head, which looks like an aspergillum used to sprinkle holy water (in 1729) |
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+ | *Most species reproduce asexually, although ''A. fumigatus'' and a few others have teleomorphs (sexual form with fruiting body) |
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+ | *Culture is important, but molecular methods are often required to identify the particular species |
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+ | **Pathogenic species grow quickly on common media |
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+ | **Can grow at 37º C, and ''A. fumigatus'' can grow up to 50º C |
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+ | *Organized into complexes, which cannot be differentiated phenotypically, but rather need molecular methods |
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+ | **Fumigatus: ''A. fumigatus'', ''A. lentulus'', ''A. udagawae'' |
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+ | **Ustus: ''A. calidoustus'' (often resistant to ampho B) |
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+ | **Niger: ''A. tubingensis'' and ''A. niger'' |
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+ | **Versicolor: ''A. versicolor'' and ''A. sydowii'' |
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+ | {| class="wikitable" |
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− | * ''Aspergillus'' is a mold with hyaline (lightly-pigmented) hyphae, septated, and usually branched at acute angle (45º) |
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+ | !'''Species''' |
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− | * Named for the appearance of the sporulating head, which looks like an aspergillum used to sprinkle holy water (in 1729) |
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+ | !'''Colonies''' |
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− | * Most species reproduce asexually, although ''A. fumigatus'' and a few others have teleomorphs (sexual form with fruiting body) |
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+ | !'''Conidiophore''' |
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− | * Culture is important, but molecular methods are often required to identify the particular species |
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+ | !'''Phialides''' |
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− | ** Pathogenic species grow quickly on common media |
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+ | !'''Other''' |
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− | ** Can grow at 37º C, and ''A. fumigatus'' can grow up to 50º C |
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− | |||
− | {| |
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− | ! Species |
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− | ! Colony Characteristics |
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− | ! Microscopy |
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− | ! Clinical Significant |
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− | | |
+ | |''A. flavus'' |
+ | |Yellow green, yellow, brownish |
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− | | Smoky gray-green; may have pale yellow or lavender reverse; '''grows at 50 ºC''' |
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+ | |Rough colourless |
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− | | Columnar; '''uniseriate'''; smooth to finely roughened conidia |
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+ | |Uniseriate and biseriate |
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− | | Most common invasive species (90+%) and most pathogenic |
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+ | |Sclerotia sometimes present |
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|- |
|- |
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− | | |
+ | |''A. fumigatus'' complex |
+ | |Grey-green, blue green, yellowish |
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− | | Olive to lime green |
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+ | |Smooth, colourless or greenish |
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− | | Radiate to loosely columnar; uniseriate or biseriate; rough conidiophore |
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+ | |Uniseriate |
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− | | Sinusitis; skin infection; produces aflatoxin |
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+ | |Good growth at 48ºC |
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|- |
|- |
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− | | |
+ | |''A. glaucus'' |
+ | |Green and yellow, yellowish, brown |
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− | | Beige to cinnamon buff |
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+ | |Smooth, colourless |
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− | | Columnar; biseriate; globose; small conidia; '''globose accessory conidia''' along hyphae |
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+ | |Uniseriate |
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− | | Increasingly detected; intrinsically resistant to '''ampho B''', though more susceptible to new azoles |
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+ | |Yellow to orange cleistothecia present |
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|- |
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− | | |
+ | |''A. nidulans'' |
+ | |Green buff, purplish red, olive |
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− | | Initially white, rapidly turning '''black with yellow reverse''' |
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+ | |Smooth, brown |
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− | | Radiate; biseriate; globose, black, very rough conidia |
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+ | |Biseriate |
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− | | Uncommon in invasive infections; superficial cause of otic disease; colonizer |
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+ | |Round hülle cells and cleistothecia with purple ascospores usually present |
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− | | |
+ | |''A. niger'' |
+ | |Black, white, yellowish |
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− | | |
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+ | |Smooth, colourless or brown |
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− | | |
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+ | |Biseriate |
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| |
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+ | |- |
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+ | |''A. terreus'' |
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+ | |Brown cinnamon, yellowish brown |
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+ | |Smooth, colourless |
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+ | |Biseriate |
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+ | |Round, solitary aleurioconidia produced directly on hyphae |
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+ | |- |
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+ | |''A. ustus'' |
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+ | |Light brown, grayish brown, yellowish brown |
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+ | |Smooth, brown |
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+ | |Biseriate |
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+ | |Long, brown-walled conidiophores, small vesicles, rough-walled conidia |
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+ | |- |
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+ | |''A. versicolor'' |
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+ | |White, buff, yellow, pink, pale green, white, yellow, purplish red |
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+ | |Smooth, colourless |
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+ | |Biseriate |
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+ | |Round hülle cells sometimes present |
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|} |
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− | ''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]]) |
− | == |
+ | ===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 |
+ | *[[Hematopoietic stem cell transplantation|Hematopoitic stem cell transplantion]] is high risk (7% allo, 1% auto) |
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− | * CGD is the highest risk disease; other at-risk groups include lung disease, AIDS, etc. |
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+ | **Peaks <40 days and >100 days |
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− | * Hematopoitic stem cell transplants are highest risk (7% allo, 1% auto) |
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+ | **With or without neutropenia, most likely related to steroid use |
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− | ** Peaks <40 days and >100 days |
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+ | *[[Hematologic malignancy|Hematologic malignancies]] |
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− | ** With or without neutropenia, most likely related to steroid use |
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+ | **Usually following induction chemotherapy, or refractory or recurrenct disease (50% mortality) |
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− | * Hematologic malignancies |
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+ | **3+7 AML induction usually 14-21 days of [[neutropenia]] |
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− | ** Usually following induction chemotherapy, or refractory or recurrenct disease (50% mortality) |
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+ | *[[Solid organ transplantation]] |
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− | ** 3+7 AML induction usually 14-21 days of neutropenia |
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+ | **Highest among [[lung transplantation]] recipients (6%) due to ongoing environmental exposure, decreased ciliary clearance, and common concomitant ''Aspergillus'' colonization |
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− | * Solid-organ transplants |
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+ | **Followed by small bowel, [[Liver transplantation|liver]] (4%), [[Heart transplantation|heart]] (2%), and [[Renal transplantation|kidney]] (0.5%) |
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− | ** Highest among lung transplant recipients (6%) due to ongoing environmental exposure, decreased ciliary clearance, and common concomitant ''Aspergillus'' colonization |
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+ | **Usually diagnosed at 6 to 12 months (half within the first 3 months) |
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− | ** Followed by liver (4%), heart (2%), and kidney (0.5%) |
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+ | *Therapeutic immunosuppression, including [[prednisone]] and [[TNF-α inhibitors]] |
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− | ** Usually diagnosed at 6 to 12 months |
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+ | *[[GVHD]] increases the risk, due to the additional immune suppression |
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− | * Therapeutic immunosuppression, including prednisone and anti-TNF-alpha |
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+ | **Highest risk within GVHD is with gut involvement |
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− | * GVHD increases the risk, due to the additional immune suppression |
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+ | *Solid maligancies are relatively low risk due to the short courses of [[neutropenia]], but increasing risk with newer chemotherapies |
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− | ** Highest risk within GVHD is with gut involvement |
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− | * Solid maligancies are relatively low risk due to the short courses of neutropenia, but increasing risk with newer chemotherapies |
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+ | ==== Other Risk Factors ==== |
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− | == Pathophysiology == |
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+ | * HIV (2.2 per 10,000/year), associated with low CD4 counts, neutropenia, cirrhosis, liver transplantation, and glucocorticoid therapy |
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− | * Initially acquired by inhalation of conidia into lungs or sinuses, or rarely from local tissue invasion |
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+ | * Liver cirrhosis (0.3%) |
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− | * The conidia grow and germinate, transforming into hyphae and invading the vasculature |
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+ | * Immunocompetent patients in critical condition from [[ARDS]], [[COPD]], influenza, pneumonia, burns, severe bacterial sepsis, surgery, or malnutrition |
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− | ** Hydrocortisone appears to be a growth factor for ''Aspergillus'' |
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+ | ** Glucocorticoid therapy is most common risk factor in these patients |
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− | ** Vascular invasion is typical of invasive aspergillosis |
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− | ** May cause pulmonary infarction |
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− | * This can be followed by hematogenous dissemination |
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− | * The host immune response begins with ciliary clearance to prevent the conidia from reaching the alveoli |
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− | * Once in the alveoli, the response depends on pulmonary macrophages to phagocytose the conidia |
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− | * Following germination and growth of hyphae, PMNs act to kill hyphae and swollen conidia |
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− | ** This is helped by opsonization of conidia by complement |
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− | ** Antibodies are common, given the mold's ubiquity, but not protective |
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− | * ''A. fumigatus'' has small conidia, allowing it to reach the alveoli more easily, and also produces a complement inhibitor |
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+ | ===Pathophysiology=== |
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− | == Clinical Presentation == |
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+ | *Initially acquired by inhalation of conidia into lungs or sinuses, or rarely from local tissue invasion |
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− | === Colonization and superficial infections === |
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+ | *The conidia grow and germinate, transforming into hyphae and invading the vasculature |
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+ | **[[Hydrocortisone]] appears to be a growth factor for ''Aspergillus'' |
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+ | **Vascular invasion is typical of invasive aspergillosis |
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+ | **May cause pulmonary infarction |
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+ | *This can be followed by hematogenous dissemination |
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+ | *The host immune response begins with ciliary clearance to prevent the conidia from reaching the alveoli |
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+ | *Once in the alveoli, the response depends on pulmonary macrophages to phagocytose the conidia |
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+ | *Following germination and growth of hyphae, PMNs act to kill hyphae and swollen conidia |
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+ | **This is helped by opsonization of conidia by complement |
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+ | **Antibodies are common, given the mold's ubiquity, but not protective |
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+ | *''A. fumigatus'' has small conidia, allowing it to reach the alveoli more easily, and also produces a complement inhibitor |
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+ | ==Clinical Manifestations== |
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− | ==== Aspergilloma (fungal ball) ==== |
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+ | ===Colonization and Superficial Infections=== |
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− | * Ball of hyphae growing in a preexisting cavity, often in bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, congenital cysts, bacterial lung abscesses, or ''Pneumocystis'' bleb |
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− | * Often asymptomatic, but the most common symptom is hemoptysis, which can be fatal |
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− | * Can also occur in the sinuses |
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+ | ====Aspergilloma (Fungal Ball)==== |
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− | ==== Other supreficial infections ==== |
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+ | *Ball of hyphae growing in a preexisting cavity, often in bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, congenital cysts, bacterial lung abscesses, or ''Pneumocystis'' bleb |
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− | * Otomycosis: chronic otitis externa caused by ''A. niger'' or ''A. fumigatus'' |
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+ | *Often asymptomatic, but the most common symptom is [[Causes::hemoptysis]], which can be fatal |
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− | * Onychomycosis |
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+ | *Can also occur in the sinuses |
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− | * Keratitis |
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+ | ====Other Superficial Infections==== |
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− | === Allergic syndromes === |
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+ | *[[Otomycosis]]: chronic otitis externa caused by ''A. niger'' or ''A. fumigatus'' |
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− | ==== Allergic bronchopulmonary aspergillosis (ABPA) ==== |
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+ | *[[Onychomycosis]] |
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+ | *[[Keratitis]] |
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+ | ===Allergic Syndromes=== |
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− | * Caused by a Th2 response to ''Aspergillus'', usually in patients with asthma or cystic fibrosis |
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− | * 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 |
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− | * 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 |
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− | ==== |
+ | ====Allergic Bronchopulmonary Aspergillosis (ABPA)==== |
+ | *Allergic reaction to airway colonization, usually in patients with [[asthma]] or [[cystic fibrosis]] |
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− | * Can be ''Aspergillus'' or other molds |
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+ | *Characterized by poorly-controlled asthma or pneumonia, mucoid impaction, persistent eosinophilia |
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− | * Mangement is mostly surgical |
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+ | *See also [[Allergic bronchopulmonary aspergillosis]] |
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+ | ====Allergic Fungal Sinusitis==== |
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− | === Chronic cavitary pulmonary aspergillosis (CCPA) === |
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+ | *Can be ''Aspergillus'' or other molds |
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− | * One or more cavities that can contain solid or liquid material or a fungal ball, usually following creation of multiple cavities from another process |
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+ | *Management is mostly surgical |
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− | * May present with pulmonary or constitutional symptoms, including hemoptysis, dyspnea, and productive cough |
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− | ** Weight loss and fatigue are common and profound, while fevers are less common |
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− | ** May mimic TB |
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− | * Diagnosis requires: |
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− | ** 3 months of symptoms or chronic illness or progressive radiological abnormalities with cavitation, pleural thickening, perivacitary infiltrates +/- fungal ball |
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− | ** ''Aspergillus'' IgG antibodies |
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− | ** No or minimal immunocompromise |
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− | * Must rule out other causes of symptoms, including other causes of weight loss |
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+ | === Chronic Pulmonary Aspergillosis (CPA) === |
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− | === Invasive aspergillosis === |
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+ | * Inclues chronic cavitary pulmonary aspergillosis (CCPA), chronic necrotising pulmonary aspergillosis (CNPA), and chronic fibrosing aspergillosis |
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− | * aka. angioinvasive, invading the vasculature |
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− | ==== Chronic |
+ | ==== 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 |
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+ | *May present with pulmonary or constitutional symptoms, including hemoptysis, dyspnea, and productive cough |
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+ | **Weight loss and fatigue are common and profound, while fevers are less common |
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+ | **May mimic TB |
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+ | *Diagnosis requires: |
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+ | **3 months of symptoms or chronic illness or progressive radiological abnormalities with cavitation, pleural thickening, perivacitary infiltrates +/- fungal ball |
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+ | **''Aspergillus'' IgG antibodies |
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+ | **No or minimal immunocompromise |
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+ | *Must rule out other causes of symptoms, including other causes of weight loss |
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+ | ==== Chronic Necrotising Pulmonary Aspergillosis (CNPA) ==== |
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− | * With mild or moderate immunosuppression, patients may develop chronic necrotizing pulmonary aspergillosis (CNPA), essentially a subacute form of invasive aspergillosis |
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− | ==== |
+ | ==== Chronic Fibrosing Aspergillosis (CFA) ==== |
+ | ===Invasive Aspergillosis=== |
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− | * Usually after 10 to 12 days of severe neutropenia |
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− | * Non-productive cough, dyspnea, pleuritic chest pain, and fever with pulmonary infiltrates despite broad-spectrum antibiotics |
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− | ** Symptoms may be less prominent in patients with defective immunity |
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− | ** Fever dampened by high dose steroids |
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− | * Also hemoptysis, pleural effusion, and pneumothorax |
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− | ** Can mimic a pulmonary embolism |
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− | * Imaging may show multiple dense nodular pulmonary infiltrates without air bronchograms, suggesting extensive infection |
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− | ** Classic, though, is pleural-based wedge-shaped densities or cavitary lesions |
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− | ** Pleural effusions are common |
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− | ** A nodular lesion wth a halo is suggestive of early aspergillosis, followed by cavitation in later disease |
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+ | *aka. angioinvasive, invading the vasculature |
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− | ==== Other sites of invasive respiratory aspergillosis ==== |
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+ | ====Subacute Invasive Aspergillosis==== |
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− | * Ulcerative tracheobronchitis, a high concern in lung transplant |
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− | ** May mimic graft rejection |
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− | * Invasive rhinosinusitis, with mortality of 10-20% |
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− | * Hematogenous dissemination to any organ, associated with 90% mortality |
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− | + | *Previously called chronic necrotizing pulmonary aspergillosis |
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+ | *Occurs in mildly immunocompromised or very debilitated patients |
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+ | **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 |
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+ | *Similar clinical and radiological findings as chronic cavitary pulmonary aspergillosis, but progresses more rapidly into frank invasive pulmonary aspergillosis |
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+ | ====Invasive Pulmonary Aspergillosis==== |
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− | * Cerebral aspergillosis, which may explain half of all CNS lesions in HSCT |
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− | ** Presents >100 days after transplant, usually with concomitant pulmonary disease |
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− | ** Presents with focal neuro signs, altered mental status, and headaches |
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− | * Osteomyelitis |
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− | ** Vertebral osteomyelitis may result from extension of empyema, but is also the most common site of hematogenous dissemination |
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− | * Skin and soft tissue infection |
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− | ** Either from hematogenous spread or local invasion |
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− | ** Often around IVs or adhesive dressings |
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− | ** Neutropenic patients as well as burns and surgical sites |
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+ | *Usually after 10 to 12 days of severe [[neutropenia]] |
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− | ==== Specific risk groups ==== |
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+ | *Non-productive [[Causes::cough]], [[Causes::dyspnea]], [[Causes::pleuritic chest pain]], and [[Causes::fever]] with pulmonary infiltrates despite broad-spectrum antibiotics |
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+ | **Symptoms may be less prominent in patients with defective immunity |
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+ | **Fever dampened by high dose steroids |
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+ | *Also [[Causes::hemoptysis]], [[Causes::pleural effusion]], and [[Causes::pneumothorax]] |
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+ | **Can mimic a pulmonary embolism |
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+ | *Imaging may show multiple dense nodular pulmonary infiltrates without air bronchograms, suggesting extensive infection |
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+ | **Classic, though, is pleural-based wedge-shaped densities or cavitary lesions |
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+ | **[[Pleural effusion|Pleural effusions]] are common |
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+ | **A nodular lesion wth a halo is suggestive of early aspergillosis, followed by cavitation in later disease |
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+ | ====Other Sites of Invasive Respiratory Aspergillosis==== |
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− | * For CGD and AML induction and SOT, it tends to be isolated pulmonary aspergillosis |
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− | * In SCT with GVHD, you tend to see more CNS aspergillosis and disseminated aspergillosis |
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+ | *Ulcerative tracheobronchitis, a high concern in lung transplant |
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− | == Diagnosis == |
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+ | **May mimic graft rejection |
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+ | *Invasive [[rhinosinusitis]], with mortality of 10-20% |
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+ | *Hematogenous dissemination to any organ, associated with 90% mortality |
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+ | ====Other Sites of Invasive Aspergillosis==== |
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− | * Culture positive for ''Aspergillus'' and histology with invasive hyphae |
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− | ** Only 10-30% of patients with IA have a positive BAL culture, improved with use of fungal media |
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− | * Serology for antibodies is unhelpful, given that the mold is ubiquitous |
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− | * Galactomannan by EIA |
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− | ** Best-studied and most sensitive in HSCT patients |
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− | ** Released from the fungal cell wall on growth |
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− | ** Cutoff of 0.5 is good, 80% Sn and Sp |
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− | ** BAL is more sensitive, but prophylaxis decreases sensitivity |
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− | * Imaging can be helpful |
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− | ** Halo sign on CT is present for about the first 7 days of disease in neutropenic patients |
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− | ** Can also have nodules, pleural-based infarctions, or vacitation, as well as non-specific consolidation |
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+ | *[[Cerebral aspergillosis]], which may explain half of all CNS lesions in HSCT |
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− | == Management == |
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+ | **Presents >100 days after transplant, usually with concomitant pulmonary disease |
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+ | **Presents with focal neurological signs, altered mental status, and headache |
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+ | *[[Osteomyelitis]] |
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+ | **Vertebral osteomyelitis may result from extension of empyema, but is also the most common site of hematogenous dissemination |
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+ | *[[Skin and soft tissue infection]] |
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+ | **Either from hematogenous spread or local invasion |
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+ | **Often around IVs or adhesive dressings |
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+ | **Neutropenic patients as well as burns and surgical sites |
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− | === |
+ | ===Specific Risk Groups=== |
+ | *For [[CGD]], [[AML]] induction, and [[SOT]], it tends to be isolated pulmonary aspergillosis |
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− | * If asymptomatic and single aspergilloma, monitor |
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+ | *In [[HSCT]] with [[GVHD]], you tend to see more CNS aspergillosis and disseminated aspergillosis |
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− | * If symptoms, especially hemoptysis, surgical resection (if possible) |
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− | * No role for antifungals |
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+ | ==Diagnosis== |
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− | === Allergic bronchopulmonary aspergillosis (ABPA) === |
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+ | *'''Culture''' positive for ''Aspergillus'' and histology with invasive hyphae |
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− | * Indications for treatment |
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+ | **Only 10-30% of patients with IA have a positive BAL culture, improved with use of fungal media |
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− | ** Diagnose with ''Aspergillus''-IgE |
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+ | *'''Serology''' |
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− | ** If ongoing symptoms despite appropriate management of asthma (including oral steroids), treat with itraconazole |
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+ | **Antibodies is unhelpful, given that the mold is ubiquitous |
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− | ** If CF patient has frequent exacerbations or falling FEV1, treat with itraconazole |
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+ | **'''Galactomannan''' by EIA |
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− | * Itraconazole 200 mg/day for 16 weeks, which decreases steroid use and increases patient function |
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+ | ***Best-studied and most sensitive in HSCT patients |
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+ | ***It is a released from the fungal cell wall on growth |
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+ | ***Cutoff of 0.5 is good, 80% Sn and Sp (up to 90% in HSCT patients' serum) |
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+ | ***BAL is more sensitive, but prophylaxis decreases sensitivity |
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+ | ***Can be done from CSF |
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+ | ***False-positives may occur with pip/tazo and other beta-lactams (though mostly of historical interest now) |
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+ | **'''1,3-beta-D-glucan''' (BDG): can detect ''Candida'' and ''Pneumocystis'' as well, so less specific. May be useful in combination with GM. |
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+ | ***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. |
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+ | **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]). |
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+ | *'''Molecular testing''' |
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+ | **'''Fungal PCR''' possible, but not routinely done; may not be helpful since the fungus is ubiquitous and wouldn’t differentiate invasive disease vs. colonization. |
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+ | **'''Microarray DNA''': Microbiologic diagnostics are often combined with imaging to diagnose probable invasive fungal infection. |
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+ | *'''Imaging''' can be helpful |
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+ | **Halo sign on CT is present for about the first 7 days of disease in neutropenic patients |
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+ | **Can also have nodules, pleural-based infarctions, or vacitation, as well as non-specific consolidation |
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+ | **See review [[CiteRef::franquet2001sp]] |
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+ | ==Management== |
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− | === Allergic fungal rhinosinusitis === |
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+ | ===Antifungal Resistance=== |
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− | * Polypectomy and sinus washout |
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− | * Topical nasal steroids |
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− | * Oral antifungal therapy can be tried if above does not work, but rarely effective |
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+ | *'''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. |
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− | === Chronic cavitary pulmonary aspergillosis (CCPA) === |
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+ | *'''Antifungal mechanisms''' |
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+ | **'''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" |
||
− | * If asymptomatic, monitor every 3-6 months, with investigations every 3-12 months including |
||
+ | !Organism |
||
− | ** Low-dose CT chest or CXR |
||
+ | !AmB |
||
− | ** ESR/CRP |
||
+ | !Fluc |
||
− | ** ''Aspergillus'' IgG titres |
||
+ | !Itra |
||
− | ** Annual PFTs |
||
+ | !Vori |
||
− | * If pulmonary symptoms, constitutional symptoms, or worsening lung function, treat with 6+ months of antifungal therapy |
||
+ | !Posa |
||
− | ** Itraconazole or voriconazole |
||
+ | !Anidula |
||
− | ** If this fails, try IV micafungin, caspofungin, or amphotericin B |
||
+ | !Caspo |
||
− | * If hemoptysis, treat with tranexamic acid, pulmonary artery embolization, or antifungal therapy |
||
+ | !Mica |
||
− | * May need surgical resection if localized disease refractory to medical management |
||
+ | !Flucyt |
||
+ | |- |
||
+ | |''Aspergillus'' spp. |
||
+ | | + |
||
+ | |– |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | |– |
||
+ | |- |
||
+ | |'' A. flavus'' |
||
+ | |± |
||
+ | |– |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | |– |
||
+ | |- |
||
+ | |'' A. fumigatus'' |
||
+ | | + |
||
+ | |– |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | |– |
||
+ | |- |
||
+ | |'' A. terreus'' |
||
+ | |– |
||
+ | |– |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | |– |
||
+ | |- |
||
+ | |'' A. niger'' |
||
+ | | + |
||
+ | |– |
||
+ | |± |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | | + |
||
+ | |– |
||
+ | |} |
||
+ | ===Aspergilloma=== |
||
− | === Invasive aspergillosis === |
||
+ | |||
+ | *If asymptomatic and single aspergilloma, monitor |
||
+ | *If symptoms, especially hemoptysis, surgical resection (if possible) |
||
+ | *No role for antifungals |
||
+ | |||
+ | ===Allergic Bronchopulmonary Aspergillosis (ABPA)=== |
||
+ | |||
+ | *Not always treated with antifungals |
||
+ | *See [[Allergic bronchopulmonary aspergillosis#Management|Allergic bronchopulmonary aspergillosis]] |
||
+ | |||
+ | ===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=== |
||
− | * 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 (caspo, or other) |
||
− | ** If hepatotoxicity with voriconazole, switch to posaconazole |
||
− | ** Vori superior to amphofor mortality |
||
− | ** Combo vori+anidula no better than vori except in post-hoc analysis of possible early treatment |
||
− | ** In the future, watch out for isuvaconazole—may be superior to vori |
||
− | * Duration 6-12 weeks depending on immunosuppression |
||
− | * Follow-up CT after a minimum of 2 weeks, or earlier if deterioration |
||
+ | *Technically should be assessed at 6 weeks (2 weeks at a minimum, based on pharmacokinetics) |
||
− | === Breakthrough infection === |
||
+ | ==Prevention== |
||
− | * Base empiric treatment on local epidemiology |
||
− | * Probably fewer breakthroughs in HSCT patients with posaconazole prophylaxis |
||
+ | *For high-risk patients in hospital (e.g. HSCT), use air filters, frequent air exchanges, and positive-pressure ventilation |
||
− | === Failure === |
||
+ | ===Antifungal Prophylaxis=== |
||
− | * Technically should be assessed at 6 weeks (2 weeks at a minimum, based on pharmacokinetics) |
||
+ | *Posaconazole prophylaxis is first to demonstrate survival benefit for AML/induction patients |
||
− | == Prevention == |
||
+ | *'''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-α 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-γ]] |
||
+ | ==Further Reading== |
||
− | * For high-risk patients in hospital (e.g. HSCT), use air filters, frequent air exchanges, and positive-pressure ventilation |
||
+ | *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] |
||
− | === Antifungal prophylaxis === |
||
+ | *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] |
||
+ | {{DISPLAYTITLE:''Aspergillus''}} |
||
− | * Posaconazole prophylaxis is first to demonstrate survival benefit for AML/induction patients |
||
+ | [[Category:Hyaline molds]] |
||
− | * '''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-alpha inhibition) |
||
− | * '''Lung transplant:''' vori/itra/inhaled amphoB 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 |
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 (45º)
- 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 37º C, and A. fumigatus can grow up to 50º 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 48ºC |
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 hülle 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 hülle cells sometimes present |
- Of note, A. ustus complex (A. caladustus) are resistant to azoles and echinocandins, and variable resistance to amphotericin (but susceptible to terbinafine)
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-α 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
- Otomycosis: chronic otitis externa caused by A. niger or A. fumigatus
- Onychomycosis
- Keratitis
Allergic Syndromes
Allergic Bronchopulmonary Aspergillosis (ABPA)
- Allergic reaction to airway colonization, usually in patients with asthma or cystic fibrosis
- Characterized by poorly-controlled asthma or pneumonia, mucoid impaction, persistent eosinophilia
- See also Allergic bronchopulmonary aspergillosis
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.
- Utility in invasive fungal infections: from a systematic review in 2015, it is about 80% sensitive and 85% specific for IFI. Identified Candida and Aspergillus. In 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 (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 | ± | – | + | + | + | + | + | + | – |
A. fumigatus | + | – | + | + | + | + | + | + | – |
A. terreus | – | – | + | + | + | + | + | + | – |
A. niger | + | – | ± | + | + | + | + | + | – |
Aspergilloma
- If asymptomatic and single aspergilloma, monitor
- If symptoms, especially hemoptysis, surgical resection (if possible)
- No role for antifungals
Allergic Bronchopulmonary Aspergillosis (ABPA)
- Not always treated with antifungals
- See Allergic bronchopulmonary aspergillosis
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 months2
- 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
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
- Posaconazole prophylaxis is first to demonstrate survival benefit for AML/induction patients
- 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-α 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-γ
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
- ^ 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.