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Subtypes

6

Invasive aspergillosis (including invasive pulmonary aspergillosis) MONDO:0000240

Acute, tissue-invasive infection of the severely immunocompromised host — prolonged neutropenia after chemotherapy or allogeneic transplantation, high-dose corticosteroids, chronic granulomatous disease — and, increasingly, of the non-classically-immunocompromised ICU patient with severe influenza or COVID-19. Hyphae invade lung parenchyma and blood vessels, producing thrombosis, infarction and haematogenous spread. Mortality is high.

Show evidence (1 reference)

PMID:33563417 SUPPORT Other

"Invasive Aspergillosis usually occurs in severely immunocompromised patients, typically in neutropenic but also in non-neutropenic patients."

Defines the host context of the invasive subtype and notes that it is not restricted to neutropenic hosts. Evidence source is OTHER because this is a review.

Chronic pulmonary aspergillosis (CCPA and chronic fibrosing forms)

Slowly progressive cavitary and fibrosing lung infection in a patient with prior or current structural lung disease (treated tuberculosis, COPD, sarcoidosis, prior thoracic surgery) but without significant systemic immunocompromise. Chronic cavitary pulmonary aspergillosis is the commonest form and may progress to chronic fibrosing pulmonary aspergillosis. No subtype_term is bound: MONDO carries a term for pulmonary aspergilloma (bound on the Aspergilloma subtype) and for invasive aspergillosis, but none for chronic cavitary or chronic fibrosing pulmonary aspergillosis, which are covered only by the parent term MONDO:0005657 already on this entry.

Show evidence (2 references)

PMID:26699723 SUPPORT Other

"The most common form of CPA is chronic cavitary pulmonary aspergillosis (CCPA), which untreated may progress to chronic fibrosing pulmonary aspergillosis."

The ESCMID/ERS guideline names CCPA as the commonest chronic form and its fibrosing endpoint, which is what this subtype covers. Evidence source is OTHER because this is a guideline review.

PMID:33563417 SUPPORT Other

"Chronic pulmonary Aspergillosis affects patients with chronic structural lung disease such as COPD or previous mycobacterial lung disease, but without other significant immunocompromise."

States the defining host context that separates this subtype from the invasive one — structural lung disease without systemic immunocompromise. Evidence source is OTHER because this is a review.

Aspergilloma (pulmonary fungal ball) MONDO:0000266

Saprophytic colonisation of a pre-existing pulmonary cavity by a conglomerate of hyphae, mucus and cellular debris, without tissue invasion. Usually minimally symptomatic, but haemoptysis from the bronchial circulation surrounding the cavity can be life-threatening. Formally a subset of chronic pulmonary aspergillosis; kept as its own subtype because it has its own MONDO identity, its own natural history and a distinct management pathway (surgical excision rather than long-term azole therapy).

Show evidence (1 reference)

PMID:31536274 SUPPORT Other

"Aspergilloma and chronic cavitary pulmonary aspergillosis (CCPA) refer to the inert saprophytic colonization of preexisting cavitary spaces in the pulmonary parenchyma"

Establishes the aspergilloma as saprophytic colonisation of a pre-existing cavity, the feature that distinguishes it from invasive disease. Evidence source is OTHER because this is a review.

Allergic bronchopulmonary aspergillosis MONDO:0015243

Th2-driven hypersensitivity to Aspergillus antigens in a host with asthma or cystic fibrosis, with no tissue invasion. Presents as poorly controlled asthma with recurrent pulmonary infiltrates, mucus plugging, marked total and Aspergillus-specific IgE elevation, eosinophilia and, over time, central bronchiectasis. The dismech entries for Cystic_Fibrosis and Hypersensitivity_Pneumonitis are the adjacent host-context and allergic-lung-disease entries.

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis."

The ISHAM working-group review defines ABPA as a hypersensitivity disorder with this manifestation triad. Evidence source is OTHER because this is a review.

Aspergillus bronchitis

Aspergillus infection confined to the bronchial tree in a patient with pre-existing bronchial disease, typically bronchiectasis, without parenchymal invasion and without the IgE-mediated hypersensitivity that defines ABPA. No subtype_term is bound: MONDO carries no term for Aspergillus bronchitis and it is covered only by the parent term MONDO:0005657 already on this entry.

Show evidence (1 reference)

PMID:33563417 SUPPORT Other

"Aspergillus bronchitis affects patients with bronchial disease such as bronchiectasis."

Names Aspergillus bronchitis as a distinct member of the pulmonary aspergillosis spectrum and gives its host context. Evidence source is OTHER because this is a review.

Disseminated and extrapulmonary aspergillosis

Haematogenous spread from an angioinvasive pulmonary focus to brain, skin, eye, heart, bone or viscera, or primary cutaneous inoculation at a catheter or burn site. CNS involvement (neuroaspergillosis, MONDO:0005873) is the commonest and most lethal extrapulmonary site. No subtype_term is bound at this level: MONDO codes individual organ forms such as neuroaspergillosis but has no general disseminated-aspergillosis term, and binding the CNS term here would misdescribe the non-CNS forms this subtype also covers.

Show evidence (1 reference)

PMID:17050430 SUPPORT In Vitro

"Some of these hyphal fragments can break off and circulate in the bloodstream. In severely immunocompromised hosts, these blood-borne hyphal fragments adhere to the luminal surface of the endothelial cells and they penetrate the endothelial cell lining of the vasculature by passing from the..."

The authors' characterisation of the vascular route by which an invasive pulmonary focus seeds distant organs, which is what defines this subtype. Graded PARTIAL because this sentence frames their model rather than reporting a measurement.

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Discussions and Knowledge Gaps

1

Does gliotoxin production contribute materially to Aspergillus virulence in human disease, or is its measured virulence contribution specific to invertebrate infection models?

HUMAN MODEL MISMATCH OPEN gliotoxin_virulence_model_fidelity

Attached to

pathophysiology#Gliotoxin-Mediated Suppression of Host Phagocyte Function

The direct evidence tying virulence to gliotoxin production rather than to growth rate or enzyme activity comes from Galleria mellonella, and the authors qualify the finding to that model. Galleria has no adaptive immunity and no neutrophils, so it cannot test the phagocyte suppression that the mechanism is proposed to act through in humans. Human aspergillosis is dominated by host-side phagocyte defects, which this entry models upstream. The gap matters because gliotoxin is periodically proposed as a therapeutic or diagnostic target on the strength of model-system data.

Show evidence (1 reference)

PMID:15487324 SUPPORT Model Organism

"implicating a critical role for gliotoxin production rather than growth rate or enzymatic activity in the virulence of A. fumigatus in this model"

The authors themselves restrict the virulence conclusion to the Galleria model, which is the mismatch this discussion records.

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Pathophysiology

21

Inhalation and Alveolar Deposition of Airborne Aspergillus Conidia

Aspergillus conidia are small enough to bypass mucociliary clearance and reach the distal airway and alveolus. Everybody inhales them daily; this node is therefore the shared entry point of every clinical form and is by itself insufficient for disease. What happens next is decided by the host.

alveolus of lung UBERON:0002299

Downstream

Alveolar Macrophage Dectin-1 Recognition of Aspergillus Deposited conidia are met by resident alveolar macrophages, whose beta-glucan recognition starts the response.

Oxidase-Independent Neutrophil Killing of Conidia Recruited neutrophils engage ungerminated conidia by an intracellular, oxidase-independent route.

NADPH Oxidase-Dependent Neutrophil Killing of Hyphae Conidia that escape early killing and germinate are attacked extracellularly by a separate, oxidase-dependent route.

Th2 Sensitisation and IgE-Mediated Hypersensitivity to Aspergillus Antigens In an atopic or cystic-fibrosis airway, the same inhaled conidia germinate and release antigen that drives an allergic rather than an invasive response.

Saprophytic Cavity Colonisation and Fungal Ball Formation Where a pre-existing pulmonary cavity is present, inhaled conidia may colonise it saprophytically without ever invading tissue.

Show evidence (1 reference)

PMID:33563417 SUPPORT Other

"Aspergillus species are ubiquitous in the environment. Aspergillosis is acquired by inhalation of Aspergillus spores. In normal hosts, spore inhalation rarely causes lung disease."

Establishes inhalation as the initiating step and that it is not sufficient for disease in an immunocompetent host, which is what makes this node a trigger rather than a cause. Evidence source is OTHER because this is a review.

Alveolar Macrophage Dectin-1 Recognition of Aspergillus

Resident alveolar macrophages recognise beta-1,3-glucan exposed on the surface of swollen conidia and early germlings through dectin-1. Recognition tracks the fungal morphotype rather than the organism as such, and it drives the proinflammatory cytokine and chemokine output that recruits neutrophils.

alveolar macrophage CL:0000583

defense response to fungus GO:0050832

Show evidence (2 references)

PMID:16344862 SUPPORT In Vitro

"The inflammatory response was triggered at the highest level by A. fumigatus swollen conidia and early germlings and correlated to the levels of surface-exposed beta glucans, indicating that dectin-1 preferentially recognizes specific morphological forms of A. fumigatus."

Establishes dectin-1 recognition of surface beta-glucan as the trigger for the alveolar macrophage inflammatory response, and that recognition tracks the fungal morphotype.

PMID:16344862 SUPPORT Model Organism

"Intratracheal administration of A. fumigatus conidia to mice in the presence of a soluble dectin-Fc fusion protein reduced both lung proinflammatory cytokine/chemokine levels and cellular recruitment while modestly increasing the A. fumigatus fungal burden"

In vivo blockade of dectin-1 reduces recruitment and increases fungal burden, showing the recognition step is load-bearing and not merely correlative. Graded separately from the in vitro item because this sentence reports the murine arm of the same paper.

Oxidase-Independent Neutrophil Killing of Conidia

Neutrophils recognise ungerminated conidia through integrin CD11b/CD18 — not dectin-1 — and kill them intracellularly by a PI3K-dependent route that does not require the oxidative burst. This is the arm that survives in chronic granulomatous disease and is lost in neutropenia, which is why the two defects behave differently.

neutrophil CL:0000775

neutrophil-mediated killing of Aspergillus conidia GO:0070947

Show evidence (1 reference)

PMID:26718340 SUPPORT In Vitro

"Recognition of conidia involves integrin CD11b/CD18 (and not dectin-1), which triggers a PI3K-dependent nonoxidative intracellular mechanism of killing."

Establishes the receptor, the signalling route, and the oxidase independence of the anti-conidial mechanism this node models.

NADPH Oxidase-Dependent Neutrophil Killing of Hyphae

Hyphae are too large to phagocytose, so neutrophils kill them extracellularly: antibody opsonisation, Fc-gamma receptor recognition, and Syk/PI3K/PKC signalling to the NADPH oxidase and myeloperoxidase. This is the arm lost in chronic granulomatous disease, and it is why CGD patients control conidia but not established hyphal growth. NET formation is induced by A. fumigatus but did not contribute to killing in this work.

neutrophil CL:0000775

neutrophil-mediated killing of Aspergillus hyphae GO:0070947 respiratory burst GO:0045730

Show evidence (2 references)

PMID:26718340 SUPPORT In Vitro

"the extracellular destruction of the Aspergillus hyphae needs opsonization by Abs and involves predominantly recognition via Fcγ receptors, signaling via Syk, PI3K, and protein kinase C to trigger the production of toxic reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase"

Establishes the opsonisation requirement, the signalling route, and the NADPH oxidase/myeloperoxidase dependence of the anti-hyphal mechanism.

PMID:26718340 SUPPORT In Vitro

"A. fumigatus induces NET formation; however, NETs did not contribute to A. fumigatus killing."

A negative result, recorded because it excludes NETs from the anti-hyphal mechanism this node describes.

Failure of Phagocyte Clearance of Aspergillus

The branch point of the whole entry. Prolonged chemotherapy-induced neutropenia removes the effector cell; corticosteroids and calcineurin inhibitors impair macrophage and neutrophil function while the cells are still present; chronic granulomatous disease removes the NADPH oxidase-dependent anti-hyphal mechanism specifically; and severe influenza or COVID-19 produces a comparable functional defect in hosts with no classical EORTC/MSG host factor at all. Whatever the cause, ungated conidia germinate.

neutrophil CL:0000775

defense response to fungus GO:0050832 ↓ DECREASED

Downstream

Conidial Germination and Hyphal Tissue Invasion Unkilled conidia swell, germinate and extend hyphae into lung tissue.

Show evidence (2 references)

PMID:26718340 SUPPORT In Vitro

"This is illustrated by the prevalence of Aspergillus infections in patients with neutropenia or phagocyte functional defects, such as chronic granulomatous disease."

States the clinical corollary the paper's mechanism explains: both the number defect and the function defect produce Aspergillus disease.

PMID:10844935 SUPPORT Human Clinical

"Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause)"

In a 368-patient CGD registry, Aspergillus is the leading cause of the commonest infection, which is the human evidence that losing the NADPH oxidase route specifically permits Aspergillus disease.

Gliotoxin-Mediated Suppression of Host Phagocyte Function

A. fumigatus secretes gliotoxin, an epipolythiodioxopiperazine mycotoxin with immunosuppressive activity that has long been implicated in assisting tissue penetration. This node is deliberately modelled as a contributory fungal-side input to phagocyte failure rather than as a sufficient cause: the direct virulence evidence is from an invertebrate infection model, and human disease is dominated by the host-side defects modelled upstream.

Downstream

Failure of Phagocyte Clearance of Aspergillus Secreted gliotoxin is proposed to add a fungal-side contribution to the phagocyte defect, on top of the host-side causes.

Show evidence (2 references)

PMID:15487324 SUPPORT Model Organism

"Gliotoxin is an immunosuppressive agent previously implicated in assisting tissue penetration."

States the proposed immunosuppressive and tissue-penetration role. Graded PARTIAL because the claim is background in this paper rather than its own result.

PMID:15487324 SUPPORT Model Organism

"implicating a critical role for gliotoxin production rather than growth rate or enzymatic activity in the virulence of A. fumigatus in this model"

Ties virulence to gliotoxin production rather than growth rate. Graded PARTIAL and MODEL_ORGANISM because the finding is from Galleria mellonella and the authors themselves qualify it to that model.

Conidial Germination and Hyphal Tissue Invasion

Surviving conidia swell, germinate and extend filamentous hyphae that penetrate alveolar epithelium and lung parenchyma. This is the step that separates the tissue-invasive forms from the allergic and saprophytic ones, which never reach it.

spore germination GO:0009847 filamentous hyphal growth GO:0030447

lung UBERON:0002048

Downstream

Angioinvasion and Thrombotic Tissue Infarction Hyphae reach and cross the vessel wall from the abluminal side.

Chronic Cavitary Lung Destruction and Fibrosis Where the host retains innate immunity but the lung is structurally abnormal, the same hyphal growth produces slow cavitary destruction rather than acute angioinvasion.

Show evidence (1 reference)

PMID:17050430 SUPPORT In Vitro

"During pulmonary aspergillosis, hyphae are initially outside of the pulmonary vasculature and they invade the endothelial cell lining of the blood vessels by passing from the abluminal to the luminal surface."

The authors' characterisation of the invasion route their in-vitro models reproduce: hyphae grow through lung tissue from outside the vasculature inwards. Graded PARTIAL because this sentence frames the model rather than reporting a measurement.

Angioinvasion and Thrombotic Tissue Infarction

Hyphae penetrate the endothelial lining, damage endothelial cells and induce tissue factor expression. The sourced steps here are the endothelial damage and the procoagulant induction; the thrombosis and ischaemic infarction usually described as following from them are the accepted clinical reading of the nodular, halo-sign and air-crescent radiology, not something the cited in-vitro work measured.

endothelial cell of vascular tree CL:0002139

blood coagulation GO:0007596 ↑ INCREASED

Downstream

Haematogenous Dissemination to Extrapulmonary Sites Hyphal fragments shed into the bloodstream from an invaded vessel seed distant organs.

Show evidence (1 reference)

PMID:17050430 SUPPORT In Vitro

"Luminal invasion by hyphae results in both endothelial cell damage and stimulation of tissue factor expression."

Links hyphal contact with endothelium directly to endothelial damage and to tissue factor induction, the procoagulant step behind thrombotic infarction.

Haematogenous Dissemination to Extrapulmonary Sites

Blood-borne hyphal fragments adhere to and cross the luminal endothelial surface at distant sites, establishing cerebral, cutaneous, ocular, cardiac and visceral foci. This route is specific to the severely immunocompromised host.

Show evidence (1 reference)

PMID:17050430 SUPPORT In Vitro

"In severely immunocompromised hosts, these blood-borne hyphal fragments adhere to the luminal surface of the endothelial cells and they penetrate the endothelial cell lining of the vasculature by passing from the luminal to the abluminal surface."

The authors' characterisation of the luminal-to-abluminal re-invasion step by which circulating fragments establish metastatic foci, tied to host immune status. Graded PARTIAL because this sentence frames the model rather than reporting a measurement.

Saprophytic Cavity Colonisation and Fungal Ball Formation

In a pre-existing pulmonary cavity — most often post-tuberculous — hyphae, mucus and cellular debris accumulate into a mobile fungal ball without invading the cavity wall. Symptoms are minor or absent until bleeding from the hypertrophied bronchial vessels around the cavity produces haemoptysis.

lung UBERON:0002048

Downstream

Chronic Cavitary Lung Destruction and Fibrosis Saprophytic colonisation and chronic cavitary disease overlap clinically and a simple aspergilloma may be found within, or progress to, the broader chronic cavitary form.

Show evidence (1 reference)

PMID:31536274 SUPPORT Other

"Simple Aspergilloma A single pulmonary cavity containing a fungal ball, with serological or microbiological evidence of Aspergillus spp. in a non-immunocompromised patient."

Gives the consensus definition of the fungal ball in a pre-existing cavity in a non-immunocompromised host, which is what this node models. Evidence source is OTHER because this is a review of consensus definitions.

Chronic Cavitary Lung Destruction and Fibrosis

Over months to years, one or more pulmonary cavities expand and coalesce with surrounding pleural thickening and a vigorous Aspergillus antibody response; untreated, this progresses to the fibrosing form with irreversible loss of lung volume. The host here is immunocompetent enough to contain the organism but not to clear it.

lung UBERON:0002048

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"The most common form of CPA is chronic cavitary pulmonary aspergillosis (CCPA), which untreated may progress to chronic fibrosing pulmonary aspergillosis. Less common manifestations include: Aspergillus nodule and single aspergilloma. All these entities are found in non-immunocompromised..."

Establishes both the cavitary-to-fibrosing trajectory and the non-immunocompromised, structurally-abnormal-lung host context that distinguishes this branch. Evidence source is OTHER because this is a guideline review.

Th2 Sensitisation and IgE-Mediated Hypersensitivity to Aspergillus Antigens

In a genetically predisposed atopic or cystic-fibrosis airway, germinating conidia release antigen that drives a Th2 CD4-positive T-cell response, IgE class switching and a large rise in total and Aspergillus-specific IgE. The organism is never cleared and never invades; the disease is the response to it. This is the mechanism that makes ABPA a member of the aspergillosis spectrum despite sharing none of the invasive branch's tissue pathology.

CD4-positive helper T cell CL:0000492

T-helper 2 cell differentiation GO:0045064 ↑ INCREASED isotype switching to IgE isotypes GO:0048289 ↑ INCREASED

Downstream

Eosinophilic Airway Inflammation and Mucus Plugging The Th2/IgE response recruits eosinophils and drives the mucus hypersecretion that produces the recurrent infiltrates of ABPA.

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"In a genetically predisposed individual, inhaled conidia of A. fumigatus germinate into hyphae with release of antigens that activate the innate and adaptive immune responses (Th2 CD4(+) T cell responses) of the lung."

States the germination-antigen-Th2 sequence and the requirement for host genetic predisposition, which is exactly what this node asserts. Evidence source is OTHER because this is a review.

Eosinophilic Airway Inflammation and Mucus Plugging

Eosinophil-rich inflammation with tenacious, hyphae-containing mucus plugs that occlude segmental bronchi, giving the fleeting pulmonary infiltrates and poorly controlled asthma of ABPA.

eosinophil CL:0000771

bronchus UBERON:0002185

Downstream

Bronchiectasis and Fixed Airway Damage Repeated plugging and inflammation destroy the bronchial wall, producing the central bronchiectasis that is the permanent structural sequela of ABPA.

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis"

Names the recurrent infiltrates and poorly controlled asthma that this inflammatory node produces, and the bronchiectasis modelled downstream. Evidence source is OTHER because this is a review.

Bronchiectasis and Fixed Airway Damage

Irreversible central bronchial dilatation, the endpoint that makes early recognition of ABPA worthwhile: it is the manifestation that antifungal and corticosteroid therapy aim to prevent rather than to reverse.

bronchus UBERON:0002185

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA."

Identifies bronchiectasis as permanent lung damage and the target of early recognition, which is the claim this consequence node makes. Evidence source is OTHER because this is a review.

Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase

Aspergillus membrane ergosterol is made by a pathway whose rate-limiting demethylation step is catalysed by the cytochrome P450 lanosterol 14-alpha-demethylase encoded by cyp51A and cyp51B. Triazoles bind heme iron at this enzyme, so ergosterol is depleted and toxic 14-alpha-methylsterols accumulate. This node is intentionally target-only: it describes the normal fungal biosynthetic activity that azole therapy inhibits, not a step that causes disease.

ergosterol biosynthetic process GO:0006696

sterol 14-alpha-demethylase activity GO:0008398

Downstream

Ergosterol-Enriched Aspergillus Plasma Membrane Completing the demethylase step and the reactions downstream of it yields the ergosterol that is incorporated into the fungal plasma membrane.

Show evidence (2 references)

PMID:32178468 SUPPORT Other

"The mechanism of action of triazoles (Figure 2D-H) is based on the inhibition of the microsomal cytochrome P450 (CYP450) monooxygenase dependent 14-α-demethylase (Figure 3)."

Identifies the enzyme this node models as the triazole target. Evidence source is OTHER because this is a review.

PMID:32178468 SUPPORT Other

"The combination of the accumulation of toxic 14-α-methylsterols and depletion of ergosterol results in the fungistatic effect"

States the consequence of inhibiting this step, which is why the node is a therapeutic vulnerability. Evidence source is OTHER because this is a review.

Ergosterol-Enriched Aspergillus Plasma Membrane

Ergosterol is the fungal-specific end-product sterol of the pathway and the principal sterol of the Aspergillus plasma membrane, where it maintains fluidity, integrity and the function of membrane-embedded proteins. It is the target of the polyenes, which bind and extract it rather than inhibiting its synthesis — which is why a cyp51A target-site substitution does not by itself confer polyene cross-resistance. This node is the bridge between the two drug-target branches and the growth the disease depends on.

ergosterol metabolic process GO:0008204

Downstream

Conidial Germination and Hyphal Tissue Invasion A functional ergosterol-containing membrane is required for the fungal growth that invades tissue. This entry does not claim membrane integrity alone is sufficient for invasion; the edge records that both antifungal target branches ultimately act on this growth.

Show evidence (1 reference)

PMID:32178468 SUPPORT Other

"the polyene class includes the heptaene amphotericin B (AMB), which interacts with ergosterol, the major part of the fungal cell membrane"

Establishes ergosterol as the major sterol of the fungal cell membrane and as the polyene target, which is the state this node models. Evidence source is OTHER because this is a review.

Environmental cyp51A-Mediated Azole Resistance

Agricultural azole fungicides share the Cyp51 target with clinical triazoles, so field application selects pan-azole-resistant A. fumigatus in the environment rather than in the treated patient. The dominant genotype is TR34/L98H — a 34-bp tandem repeat in the cyp51A promoter driving overexpression, plus a leucine-to-histidine substitution at codon 98 — with TR46/Y121F/T289A the second common allele. Because selection happens outside the host, azole-naive patients can present with resistant disease, and the resistant genotypes have spread across Europe from a common ancestor.

sterol 14-alpha-demethylase activity GO:0008398

Downstream

Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase Promoter-driven overexpression plus an active-site substitution keep ergosterol synthesis running at achievable azole concentrations, which is what makes triazole therapy fail.

Resistance-Gated Narrowing of Antifungal Options A resistant isolate removes the triazole class from the viable options for that patient, which has to be established by susceptibility testing rather than predicted from the organism's identity.

Show evidence (3 references)

PMID:33203147 SUPPORT Other

"Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as Aspergillus fumigatus having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A (CYP51A) gene..."

Gives both the agricultural selection mechanism and the exact molecular composition of the TR34/L98H allele this node names. Evidence source is OTHER because this is a review.

PMID:22675126 SUPPORT Other

"The dominant resistance mechanism appears to be of environmental origin and involves the TR(34)/L98H mutations in cyp51A. This resistance mechanism is now also increasingly being found in other countries."

Establishes the environmental rather than patient origin of the dominant resistance mechanism and its international spread. Evidence source is OTHER because this is a molecular-epidemiology study of fungal isolates rather than of human, animal, or cell-culture subjects.

PMID:31236587 SUPPORT Human Clinical

"All but one resistant case harboured environment-associated resistance mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A (12 cases)."

Confirms in a clinical haematology cohort that essentially all voriconazole-resistant invasive aspergillosis carried the environment-associated cyp51A alleles this node models.

Aspergillus beta-1,3-Glucan Synthesis by Fks Glucan Synthase

The Aspergillus plasma-membrane glucan-synthase complex polymerises beta-1,3-glucan, an essential structural polymer of the fungal cell wall and the target of the echinocandins. In Aspergillus the echinocandins are fungistatic rather than fungicidal — they cause hyphal tip lysis but not death of the organism — which is why they are a salvage and combination option here and a first-line option in candidiasis. As in the module, this node is target-only and does not assert that normal wall synthesis causes the intervention-conditional wall failure that follows inhibition.

beta-1,3-Glucan Biosynthesis GO:0006075

1,3-beta-D-Glucan Synthase Activity GO:0003843

Downstream

Aspergillus Cell-Wall Integrity and Viability Beta-1,3-glucan is an essential structural component of the Aspergillus cell wall and supports hyphal integrity.

Show evidence (2 references)

PMID:31138565 SUPPORT Other

"Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections."

Names the echinocandin agents and identifies beta-1,3-glucan synthesis as their shared target, which is the activity this node models. Evidence source is OTHER because this is a review.

PMID:31138565 SUPPORT Other

"Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA)."

Qualifies the vulnerability: the target exists in Aspergillus but the class is second-line here, which is the caveat this node states. Graded PARTIAL because it supports the target's relevance while limiting the strength of the therapeutic claim.

Aspergillus Cell-Wall Integrity and Viability

The beta-1,3-glucan-rich wall cross-links chitin and mannoproteins into the load-bearing hyphal wall that lets Aspergillus extend through tissue. It is also the surface the host reads: the same beta-glucan is the ligand dectin-1 recognises on swollen conidia and germlings, so the wall is simultaneously the drug target and the immune epitope.

fungal-type cell wall organization GO:0031505

Downstream

Conidial Germination and Hyphal Tissue Invasion An intact wall is required for the hyphal extension that invades tissue, although this entry does not claim wall integrity alone is sufficient for invasion.

Show evidence (1 reference)

PMID:32178468 SUPPORT Other

"Echinocandins block the synthesis of β-d-glucans located in the fungal cell wall. Echinocandins are fungicidal and fungistatic against Candida and Aspergillus spp., respectively."

Locates beta-glucan in the fungal cell wall and records that the consequence of blocking its synthesis is fungistatic rather than fungicidal in Aspergillus. Evidence source is OTHER because this is a review.

Aspergillus Intrinsic Fluconazole Resistance

Aspergillus species are intrinsically resistant to fluconazole, so identifying the organism as Aspergillus excludes that agent before any susceptibility result and mandates a mould-active triazole (voriconazole, isavuconazole, posaconazole, itraconazole) or amphotericin B. This lineage-determined exclusion is deliberately kept separate from the acquired environmental cyp51A resistance modelled above: one is fixed by taxonomy and gates empiric therapy, the other is isolate-dependent and requires susceptibility testing to detect.

Downstream

Resistance-Gated Narrowing of Antifungal Options Identifying the organism as Aspergillus removes fluconazole from the viable options before any susceptibility result, which is the empiric gating this node exists to record.

Show evidence (1 reference)

PMID:32178468 SUPPORT Other

"Whereas some intrinsic resistance has been found naturally, e.g., fluconazole-resistant ... and Aspergillus species"

Identifies naturally occurring fluconazole resistance in Aspergillus species, the species-level exclusion this gating node represents. Evidence source is OTHER because this is a review.

Resistance-Gated Narrowing of Antifungal Options

The shared consequence of the two resistance arms is a smaller set of viable agents. The fixed lineage-level exclusion constrains empiric therapy from the moment the organism is identified; the acquired environmental cyp51A alleles remove agents only once susceptibility testing detects them. Convergence here does not assert that either arm causes the other. The clinical cost is measurable: in a haematology cohort, 12-week mortality among non-ICU patients was 54.4% with voriconazole-resistant invasive aspergillosis against 30.7% with susceptible disease.

Downstream

Conidial Germination and Hyphal Tissue Invasion With fewer active agents, hyphal growth is less likely to be pharmacologically controlled. The edge is typed as indirect with unknown intermediates because it runs through prescribing decisions and drug exposure rather than through a molecular step.

Show evidence (2 references)

PMID:31236587 SUPPORT Human Clinical

"Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P = 0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4% versus 30.7%; P = 0.035), compared with susceptible ones."

Quantifies the cost of losing the triazole option, which is what makes this narrowing node a consequence rather than a bookkeeping label.

PMID:32178468 SUPPORT Other

"Currently, four antifungal drug classes are used by clinicians and veterinarians for systemic treatment"

Establishes how few systemic antifungal classes exist, which is why removing one materially narrows the options. Evidence source is OTHER because this is a review.

✶

Histopathology

1

Septate hyphae with acute-angle branching and angioinvasion

On GMS or PAS-stained tissue, Aspergillus appears as thin, narrow, septate hyphae branching at an acute angle, with vascular invasion and tissue necrosis. The morphology is the point of the finding: it is what separates Aspergillus from the Mucorales, whose hyphae are broad, aseptate and branch at right angles, and the two moulds need different drugs.

Show evidence (1 reference)

PMID:36407132 SUPPORT Human Clinical

"Six of the 45 cases also reveal thin, narrow septate, acute angle branching hyphae, indicating co-existing Aspergillosis (6/45)."

Gives the histomorphology by which Aspergillus is identified in tissue, which is the finding this entry records.

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Pathograph

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Phenotypes

11

Blood 1

Eosinophilia Increased total eosinophil count HP:0001880

Show evidence (2 references)

PMID:22118718 SUPPORT Human Clinical

"The median (IQR) eosinophil count at diagnosis was 850 (510-1541)cells/μl, and 60% of the patients had an eosinophil count of <1000 cells/μl."

Quantifies the eosinophil count actually observed at ABPA diagnosis and shows most patients fall below the traditional criterion.

PMID:22118718 SUPPORT Human Clinical

"The median eosinophil count was higher in patients with an high resolution computed tomography (HRCT) chest finding of bronchiectasis (986 vs. 620, p<0.001) vs. those without and in patients with high-attenuation mucus (1200 vs. 800, p<0.001) compared to those without high-attenuation mucus."

Links the eosinophil count to the bronchiectasis and mucus-plugging phenotypes that this entry models downstream of eosinophilic airway inflammation.

Immune 1

Pneumonia HP:0002090

Temporal: ACUTE

Show evidence (3 references)

PMID:16088462 SUPPORT Other

"Invasive pulmonary aspergillosis (IPA) is the most common fungal pulmonary infection in severely immunocompromised patients. Aspergillus species are commonly isolated from the soil, plant debris, and the indoor environment, including the hospital."

Establishes invasive pulmonary aspergillosis as the pneumonic manifestation in severely immunocompromised patients. Evidence source is OTHER because this is a review.

PMID:16088462 SUPPORT Other

"The diagnosis of IPA is based on clinical, radiological, and mycological data. Clinical signs have a low specificity."

Supports the statement in the description that the clinical presentation is non-specific, which is why diagnosis depends on imaging and mycology. Graded PARTIAL because it addresses diagnostic specificity rather than the pneumonia itself. Evidence source is OTHER because this is a review.

PMID:10844935 SUPPORT Human Clinical

"Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause)"

In a 368-patient chronic granulomatous disease registry pneumonia was the commonest infection and Aspergillus its commonest cause, which is direct human evidence that pneumonia is the dominant tissue presentation of invasive aspergillosis in a susceptible host.

Metabolism 1

Fever HP:0001945

Show evidence (4 references)

PMID:34947041 SUPPORT Human Clinical

"The clinical signs of CAPA are nonspecific, but typically include: fever (98%), cough (89%) and hemoptysis (36%)."

Counts fever in 98% of 45 patients with COVID-19-associated pulmonary aspergillosis, the highest-frequency clinical sign in that cohort, and states that the signs are non-specific.

PMID:34947041 SUPPORT Human Clinical

"Patients with CAPA had increases body temperature above 38.5 °C that were resistant to antibiotic drugs (98% vs. 85%, p = 0.007)"

Adds the feature that makes the fever diagnostically useful: measured against COVID-19 controls without aspergillosis, it is refractory to antibacterial therapy.

PMID:29049239 SUPPORT Human Clinical

"The most common symptoms in the CPA patients were cough (92.8%), hemoptysis (63.8%), sputum production (23.2%), fever (17.4%), breathlessness (7.2%), chest pain (5.8%), and constitutional symptoms (5.8%)."

Counts fever in 17.4% of 69 patients with chronic pulmonary aspergillosis, the much lower frequency the description contrasts with the invasive forms.

+ 1 more reference

Respiratory 5

Hemoptysis HP:0002105

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"Haemoptysis may be controlled with tranexamic acid and bronchial artery embolisation, rarely surgical resection, and may be a sign of therapeutic failure and/or antifungal resistance."

Records haemoptysis as a management problem in chronic pulmonary aspergillosis and as a marker of treatment failure. Evidence source is OTHER because this is a guideline review.

Pulmonary Infiltrates HP:0002113

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis"

Names recurrent pulmonary infiltrates as a defining ABPA manifestation. Evidence source is OTHER because this is a review.

Bronchiectasis HP:0002110

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA."

Identifies bronchiectasis as the permanent lung damage of ABPA. Evidence source is OTHER because this is a review.

Dyspnea HP:0002094

Show evidence (2 references)

PMID:24299422 SUPPORT Other

"Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases usually presenting with prolonged and relapsing cough, dyspnoea and weight loss."

Names dyspnoea among the three defining presenting symptoms of chronic pulmonary aspergillosis. Evidence source is OTHER because this is a review.

PMID:29049239 SUPPORT Human Clinical

"The most common symptoms in the CPA patients were cough (92.8%), hemoptysis (63.8%), sputum production (23.2%), fever (17.4%), breathlessness (7.2%), chest pain (5.8%), and constitutional symptoms (5.8%)."

Counts breathlessness in 7.2% of 69 patients with chronic pulmonary aspergillosis, which is the measured frequency behind the qualitative symptom triad and the reason the description states both.

Chronic Cough HP:0012735

Temporal: CHRONIC

Show evidence (1 reference)

PMID:24299422 SUPPORT Other

"Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases usually presenting with prolonged and relapsing cough, dyspnoea and weight loss."

Names prolonged relapsing cough as the leading presenting symptom of chronic pulmonary aspergillosis. Evidence source is OTHER because this is a review.

Growth 1

Weight Loss HP:0001824

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:24299422 SUPPORT Other

"Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases usually presenting with prolonged and relapsing cough, dyspnoea and weight loss."

Names weight loss as one of the three defining presenting symptoms of chronic pulmonary aspergillosis. Evidence source is OTHER because this is a review.

Other 2

Pulmonary Cavity HP:0033655

Temporal: CHRONIC

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"The diagnosis of CPA requires a combination of characteristics: one or more cavities with or without a fungal ball present or nodules on thoracic imaging"

The cavity is the first required diagnostic characteristic in the guideline criteria. Evidence source is OTHER because this is a guideline review.

Poorly Controlled Asthma HP:0002099

Show evidence (1 reference)

PMID:23889240 SUPPORT Other

"Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma"

Names poorly controlled asthma as the presenting manifestation of ABPA. Evidence source is OTHER because this is a review.

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Genetic Associations

3

CYBB

Gene: CYBB hgnc:2578 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:10844935 SUPPORT Human Clinical

"The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients)."

In the 368-patient CGD registry Aspergillus is the leading cause of death, which is the clinical measure of how much the NADPH oxidase route matters for this organism.

PMID:26718340 SUPPORT In Vitro

"the extracellular destruction of the Aspergillus hyphae needs opsonization by Abs and involves predominantly recognition via Fcγ receptors, signaling via Syk, PI3K, and protein kinase C to trigger the production of toxic reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase"

The anti-hyphal killing mechanism requires the NADPH oxidase, the enzyme complex whose catalytic subunit CYBB encodes. This is the mechanistic link between a CYBB loss-of-function genotype and susceptibility to Aspergillus.

TLR4

Gene: TLR4 hgnc:11850 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:18946062 SUPPORT Human Clinical

"In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002)."

Quantifies the donor-genotype effect on invasive aspergillosis risk after allogeneic transplantation.

PMID:18946062 SUPPORT Human Clinical

"the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07)"

The replication limits the association to unrelated-donor transplants. Graded PARTIAL because it qualifies rather than uniformly supports the susceptibility claim.

CARD9

Gene: CARD9 hgnc:16391 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:30136218 SUPPORT Human Clinical

"Strikingly, all the causal fungi belonged to the phylum Ascomycota: commensal Candida and saprophytic Trychophyton, Aspergillus, Phialophora, Exophiala, Corynesprora, Aureobasidium, and Ochroconis."

Names Aspergillus among the fungi causing invasive disease in CARD9 deficiency, which is the susceptibility this entry records.

PMID:30136218 SUPPORT Human Clinical

"Patients with CARD9 deficiency present impaired cytokine and chemokine production by macrophages, dendritic cells, and peripheral blood mononuclear cells and defective killing of some fungi by neutrophils in vitro. Neutrophil recruitment to sites of infection is impaired in vivo."

Gives the mechanism: the same macrophage recognition-to-recruitment and neutrophil killing steps this entry models are the ones CARD9 deficiency degrades.

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Medical Actions

11

Voriconazole

Action: Antifungal Therapy NCIT:C15704

Agent: voriconazole CHEBI:10023

Mould-active triazole and the agent that established triazole primacy for invasive aspergillosis: in the pivotal randomised trial it beat amphotericin B deoxycholate on both response (52.8% vs 31.6%) and 12-week survival (70.8% vs 57.9%) with fewer severe drug-related adverse events. Transient visual disturbance is common and its narrow therapeutic index makes serum-level monitoring routine.

Mechanism Target:

INHIBITS Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase — Voriconazole binds heme iron at fungal lanosterol 14-alpha-demethylase, depleting ergosterol and accumulating toxic methylsterols.

Show evidence (2 references)

PMID:12167683 SUPPORT Human Clinical

"At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group"

The randomised comparison establishing voriconazole's superiority over amphotericin B for primary therapy of invasive aspergillosis.

PMID:12167683 SUPPORT Human Clinical

"Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients)."

Records the tolerability advantage and the characteristic visual adverse effect that shape how the drug is used.

Isavuconazole

Action: Antifungal Therapy NCIT:C15704

Agent: isavuconazole CHEBI:85979

Mould-active triazole, non-inferior to voriconazole for all-cause 42-day mortality in invasive mould disease in the SECURE trial (19% vs 20%), with fewer hepatobiliary, eye and skin adverse events. Preferred where voriconazole toxicity, drug interactions or level variability are limiting.

Mechanism Target:

INHIBITS Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase — Isavuconazole inhibits the same fungal lanosterol 14-alpha-demethylase step as the other triazoles.

Show evidence (2 references)

PMID:26684607 SUPPORT Human Clinical

"All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7)."

The primary efficacy result establishing non-inferiority to voriconazole.

PMID:26684607 SUPPORT Human Clinical

"However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002)"

Quantifies the tolerability advantage over voriconazole that drives agent choice when both are active.

Itraconazole for chronic and allergic disease

Action: Antifungal Therapy NCIT:C15704

Agent: itraconazole CHEBI:6076

Oral triazole and the workhorse of the non-invasive forms. In ABPA that has become corticosteroid-dependent it doubles the response rate over placebo (46% vs 19%) as a steroid-sparing agent; in chronic cavitary pulmonary aspergillosis it beats supportive care alone (76.5% vs 35.7% overall response at six months). Therapy in chronic disease is prolonged, and azole levels, drug interactions and toxicity need monitoring throughout.

Mechanism Target:

INHIBITS Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase — Itraconazole inhibits fungal lanosterol 14-alpha-demethylase, reducing the antigenic fungal burden in ABPA and the organism load in chronic cavitary disease.

Show evidence (2 references)

PMID:10717010 SUPPORT Human Clinical

"There were responses in 13 of 28 patients in the itraconazole group (46 percent), as compared with 5 of 27 patients in the placebo group (19 percent, P=0.04)."

The randomised placebo-controlled result establishing itraconazole as a steroid-sparing agent in ABPA.

PMID:23496375 SUPPORT Human Clinical

"The number of patients showing overall response was significantly higher in the itraconazole group (76.5%) vs. the control (35.7%) group (P = 0.02)."

The randomised result supporting itraconazole over supportive care alone in chronic cavitary pulmonary aspergillosis.

Oral corticosteroid therapy for ABPA

Action: Pharmacotherapy NCIT:C15986

Agent: prednisolone CHEBI:8378

Systemic corticosteroids remain primary therapy for ABPA exacerbations, suppressing the Th2/IgE-driven eosinophilic inflammation rather than the fungus. The tension with the rest of this entry is real and worth naming: the same drug class that treats the allergic form is an independent risk factor for the invasive form, so the host phenotype has to be established before the agent is chosen.

Mechanism Target:

INHIBITS Eosinophilic Airway Inflammation and Mucus Plugging — Corticosteroids suppress the eosinophilic airway inflammation and mucus impaction that produce the recurrent infiltrates of ABPA.

Show evidence (2 references)

PMID:23889240 SUPPORT Other

"Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and optimized asthma therapy."

The ISHAM working group names oral corticosteroids as primary therapy for ABPA exacerbations. Evidence source is OTHER because this is a review.

PMID:30076119 SUPPORT Human Clinical

"along with a higher APACHE II score, male sex, and use of corticosteroids"

Supports the caution stated in the description: corticosteroid use is an independent risk factor for the invasive form of the same disease this treatment is used for in its allergic form.

Anti-type-2 biologic therapy for ABPA

Action: Pharmacotherapy NCIT:C15986

Agent: omalizumab NCIT:C29299

For ABPA that stays dependent on oral corticosteroids, biologics directed at the type-2 pathway are used as steroid-sparing add-ons. A systematic review and meta-analysis of 86 studies covering 346 patients found that the anti-IgE antibody omalizumab reduced exacerbation rates, oral corticosteroid dose and total IgE while improving FEV1; dupilumab and mepolizumab showed the same direction on an individual-patient-data meta-analysis. This is adjunctive and the evidence is pooled case series rather than randomised trials, which is why it sits behind corticosteroids and itraconazole here.

Mechanism Target:

INHIBITS Th2 Sensitisation and IgE-Mediated Hypersensitivity to Aspergillus Antigens — Omalizumab binds free IgE, and the anti-IL-4-receptor and anti-IL-5 agents interrupt the type-2 cytokine signalling that drives IgE class switching and eosinophil recruitment.

Show evidence (2 references)

PMID:38898129 SUPPORT Human Clinical

"Omalizumab therapy significantly reduced exacerbation rates (- 2.29 [95%CI - 3.32, - 1.26]), OCS dosage (- 10.91 mg [95%CI - 18.98, - 2.85]), and total IgE levels (- 273.07 IU/mL [95%CI - 379.30, - 166.84]), meanwhile improving FEV1% predicted (10.09% [95%CI 6.62, 13.55])."

Quantifies the omalizumab effect on exacerbations, steroid dose, IgE and lung function in pooled ABPA data.

PMID:38898129 SUPPORT Human Clinical

"Further randomized, controlled studies with a larger sample size and longer follow-up are needed to confirm these findings."

The authors' own limitation, quoted because it is the reason this entry places biologics behind corticosteroids and itraconazole. Graded PARTIAL because it qualifies rather than supports the efficacy claim.

Echinocandin salvage therapy

Action: Antifungal Therapy NCIT:C15704

Agent: caspofungin CHEBI:474180

Caspofungin and the other echinocandins inhibit beta-1,3-glucan synthesis. Against Aspergillus they are fungistatic rather than fungicidal and their single-agent activity is limited, so they are an alternative or combination option rather than first-line — a genuinely different position from the one the same class holds in candidiasis. They are exceptionally well tolerated and have almost no drug-drug interactions, which is why they remain useful when triazoles cannot be given.

Mechanism Target:

INHIBITS Aspergillus beta-1,3-Glucan Synthesis by Fks Glucan Synthase — Echinocandins are non-competitive inhibitors of the beta-1,3-glucan synthase complex, depleting the wall polymer.

Show evidence (2 references)

PMID:31138565 SUPPORT Other

"Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA)."

States both the limited activity and the alternative-option role that this treatment entry claims. Evidence source is OTHER because this is a review.

PMID:31138565 SUPPORT Other

"This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals."

Supports the tolerability and combination rationale that keeps the class in use despite limited monotherapy activity. Evidence source is OTHER because this is a review.

Amphotericin B

Action: Antifungal Therapy NCIT:C15704

Agent: amphotericin B CHEBI:2682

Polyene that binds and sequesters membrane ergosterol, forming pores that release intracellular ions, and that additionally drives reactive oxygen species accumulation. Because it acts on ergosterol itself rather than on the biosynthetic enzyme the azoles inhibit, a cyp51A target-site substitution does not by itself confer polyene cross-resistance — which is the basis for its role in azole-resistant disease, alongside use where triazoles are contraindicated. This is not a claim of universal polyene activity against Aspergillus: A. terreus is characteristically amphotericin B resistant by an unrelated oxidative-stress-response mechanism. Nephrotoxicity limits the deoxycholate formulation; lipid formulations are used in practice.

Mechanism Target:

INHIBITS Ergosterol-Enriched Aspergillus Plasma Membrane — Amphotericin B binds membrane ergosterol directly, forming pores and permeabilising the fungal plasma membrane.

Show evidence (4 references)

PMID:32178468 SUPPORT Other

"First, several molecules of AMB incorporate into the fungal lipid bilayer and bind to ergosterol. By ergosterol sequestration, pores are formed, and both the ions (K+, Mg2+, Ca2+, and Cl−) and electrolyte glucose are released."

Gives the ergosterol-binding, pore-forming mechanism of action, which is the target the description says is distinct from the azoles' enzyme target. Evidence source is OTHER because this is a review.

PMID:32178468 SUPPORT Other

"Second, AMB induces the accumulation of reactive oxygen species (ROS), resulting in DNA, protein, mitochondrial, and membrane damage"

Sources the second mechanism named in the description. Evidence source is OTHER because this is a review.

PMID:32178468 SUPPORT Other

"the higher activity of catalase and superoxide dismutase and the more intense stress response through heat shock proteins 70 and 90 (Hsp70, Hsp90) contribute to the intrinsic resistance of A. terreus"

Sources the A. terreus caveat, and identifies its mechanism as an oxidative-stress response unrelated to azole target-site resistance. Evidence source is OTHER because this is a review.

+ 1 more reference

Posaconazole antifungal prophylaxis in prolonged neutropenia

Action: Antifungal Therapy NCIT:C15704

Agent: posaconazole CHEBI:64355

Primary prevention rather than treatment: in patients neutropenic from chemotherapy for acute myelogenous leukaemia or myelodysplastic syndrome, posaconazole prophylaxis cut invasive aspergillosis from 7% to 1% versus fluconazole or itraconazole and improved overall survival. Fluconazole is inactive against Aspergillus, so part of this effect is simply the switch to a mould-active agent — the intrinsic-resistance gate modelled in the pathophysiology, applied prospectively.

Mechanism Target:

INHIBITS Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase — Posaconazole inhibits fungal lanosterol 14-alpha-demethylase, suppressing fungal growth during the period of maximal host susceptibility.

Show evidence (2 references)

PMID:17251531 SUPPORT Human Clinical

"Significantly fewer patients in the posaconazole group had invasive aspergillosis (2 [1%] vs. 20 [7%], P<0.001)."

The randomised result establishing prophylactic efficacy specifically against invasive aspergillosis.

PMID:17251531 SUPPORT Human Clinical

"Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (P=0.04)."

Establishes that the prophylactic benefit extends to overall survival, not only to infection incidence.

Surgical excision of simple aspergilloma

Action: Surgical Procedure NCIT:C15329

For a single fungal ball in a resectable cavity, excision is the definitive treatment and is preferred over prolonged antifungal therapy, ideally by video-assisted thoracic surgery. This is the clearest point at which the subtype distinction changes management: the same organism in the same lung is treated by resection here and by months of oral azole in chronic cavitary disease.

Mechanism Target:

INHIBITS Saprophytic Cavity Colonisation and Fungal Ball Formation — Resection removes the colonised cavity and the fungal ball within it, eliminating the lesion rather than suppressing the organism.

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"Surgical excision of simple aspergilloma is recommended, if technically possible, and preferably via video-assisted thoracic surgery technique."

The guideline recommendation for surgical management of simple aspergilloma, including the preferred approach. Evidence source is OTHER because this is a guideline review.

Tranexamic acid for haemoptysis

Action: Pharmacotherapy NCIT:C15986

Agent: tranexamic acid CHEBI:48669

Antifibrinolytic used to control bleeding from the bronchial circulation around a colonised or destroyed cavity. Symptomatic rather than antifungal.

Target Phenotypes: Hemoptysis HP:0002105

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"Haemoptysis may be controlled with tranexamic acid and bronchial artery embolisation, rarely surgical resection"

Names tranexamic acid as a haemoptysis-control option in chronic pulmonary aspergillosis. Evidence source is OTHER because this is a guideline review.

Bronchial artery embolisation for haemoptysis

Action: Embolization Therapy NCIT:C15230

Interventional-radiology occlusion of the hypertrophied bronchial arteries supplying a colonised or destroyed cavity. Together with tranexamic acid it is the intervention that most often decides whether a patient with chronic pulmonary aspergillosis survives an acute haemoptysis, and surgical resection is a last resort.

Target Phenotypes: Hemoptysis HP:0002105

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"Haemoptysis may be controlled with tranexamic acid and bronchial artery embolisation, rarely surgical resection"

Names bronchial artery embolisation as a haemoptysis-control option and places surgical resection behind it. Evidence source is OTHER because this is a guideline review.

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Environmental Factors

3

Inhalation of airborne Aspergillus conidia

Continuous, essentially unavoidable inhalational exposure to conidia dispersed from soil, decaying vegetation, compost, and construction or ventilation dust. The exposure is universal, which is why it explains the disease only in combination with a host factor. The bound term is the general ECTO organism-exposure class: ECTO has no term for exposure to Aspergillus, to fungi, or to airborne spores, so the most specific accurate binding available is used rather than a narrower approximate one.

Show evidence (1 reference)

PMID:33563417 SUPPORT Other

"Aspergillus species are ubiquitous in the environment. Aspergillosis is acquired by inhalation of Aspergillus spores. In normal hosts, spore inhalation rarely causes lung disease."

Establishes both the ubiquity of the exposure and that it is insufficient by itself, which is exactly the claim this entry makes. Evidence source is OTHER because this is a review.

Mechanism Target:

TRIGGERS Inhalation and Alveolar Deposition of Airborne Aspergillus Conidia — Airborne conidia reaching the alveolus are the initiating event of every form of the disease.

Show evidence (1 reference)

PMID:33563417 SUPPORT Other

"Aspergillus species are ubiquitous in the environment. Aspergillosis is acquired by inhalation of Aspergillus spores."

States that the disease is acquired by inhaling environmental spores, the exposure-to-mechanism link this edge asserts. Evidence source is OTHER because this is a review.

Systemic corticosteroid therapy

Corticosteroids impair macrophage and neutrophil antifungal function while leaving cell counts intact, so they produce invasive disease by a different route from chemotherapy-induced neutropenia. Corticosteroid use was an independent risk factor for invasive pulmonary aspergillosis in the ICU influenza cohort alongside influenza itself.

Show evidence (1 reference)

PMID:30076119 SUPPORT Human Clinical

"along with a higher APACHE II score, male sex, and use of corticosteroids"

Names corticosteroid use among the independent risk factors identified by the study's logistic regression.

Mechanism Target:

PREDISPOSES Failure of Phagocyte Clearance of Aspergillus — Corticosteroid exposure degrades phagocyte antifungal function, the permissive state this node models.

Show evidence (1 reference)

PMID:30076119 SUPPORT Human Clinical

"In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI 2·63-10·26; p<0·0001), along with a higher APACHE II score, male sex, and use of corticosteroids."

Corticosteroid use is one of the factors independently associated with invasive pulmonary aspergillosis in this multivariable analysis.

Severe influenza or COVID-19 critical illness

Severe respiratory viral infection is a distinct and comparatively recent route into invasive aspergillosis: it produces the phenotype in ICU patients who carry no EORTC/MSG host factor at all. In seven influenza seasons across seven Belgian and Dutch ICUs, 14% of non-immunocompromised influenza patients developed invasive pulmonary aspergillosis against 5% of influenza-negative severe community-acquired pneumonia controls. Ninety-day mortality was 51% among influenza patients who developed it versus 28% among those who did not. The same pattern was then reported for COVID-19-associated pulmonary aspergillosis. No exposure_term is bound: this is an acute infectious comorbidity rather than an environmental exposure, and ECTO has no term that describes it without overstating it as an environmental agent.

Show evidence (2 references)

PMID:30076119 SUPPORT Human Clinical

"The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001)."

Quantifies the mortality cost of the association, establishing it as a clinically consequential predisposition rather than an incidental finding.

PMID:32339350 SUPPORT Human Clinical

"COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS."

Extends the same viral-critical-illness association from influenza to COVID-19.

Mechanism Target:

PREDISPOSES Failure of Phagocyte Clearance of Aspergillus — Severe viral pneumonitis produces a functional antifungal defect sufficient to permit conidial germination in hosts with no classical immunocompromise. The intermediates are not established, so the edge is typed as indirect with unknown intermediates.

Show evidence (1 reference)

PMID:30076119 SUPPORT Human Clinical

"whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis."

The comparison in non-immunocompromised patients isolates influenza itself, rather than pre-existing immunocompromise, as the factor permitting invasive disease.

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Biochemical Markers

3

Serum galactomannan (increased)

Show evidence (2 references)

PMID:26716951 SUPPORT Human Clinical

"When using an optical density index (ODI) of 0.5 as a cut-off value, the sensitivity of the test was 82% (73% to 90%) and the specificity was 81% (72% to 90%)."

Cochrane meta-analysis of 54 studies giving the diagnostic accuracy at the commonly used 0.5 cut-off.

PMID:26716951 SUPPORT Human Clinical

"At a cut-off value of 1.5 ODI, the sensitivity was 61% (47% to 75%) and the specificity was 93% (89% to 97%)."

Gives the higher-threshold operating point, establishing the sensitivity-specificity trade-off this entry describes.

Aspergillus IgG precipitins (increased)

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"Aspergillus antibody (precipitins) is elevated in over 90% of patients."

Gives the sensitivity of Aspergillus antibody in chronic pulmonary aspergillosis. Evidence source is OTHER because this is a guideline review.

Total and Aspergillus-specific serum IgE (increased)

Show evidence (1 reference)

PMID:10717010 SUPPORT Human Clinical

"A response was defined as a reduction of at least 50 percent in the corticosteroid dose, a decrease of at least 25 percent in the serum IgE concentration"

Serum IgE concentration is used as a quantitative response endpoint in the pivotal ABPA trial, which establishes it as the tracked biomarker of this subtype.

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Diagnosis

5

Serum or bronchoalveolar lavage galactomannan enzyme immunoassay

The standard non-invasive test for invasive aspergillosis, detecting the Aspergillus cell-wall polysaccharide released during hyphal growth. The cut-off is a clinical decision rather than a fixed property of the assay: at an optical density index of 0.5 the Cochrane meta-analysis of 54 studies and 5660 patients reports 82% sensitivity and 81% specificity, at 1.0 it is 72% and 88%, and at 1.5 it is 61% and 93%. Which point to use depends on the pre-test probability in the population being screened, and the evidence base is confined to patients with neutropenia or functionally compromised neutrophils.

serum or bronchoalveolar galactomannan enzyme immunoassay NCIT:C154817

Markers: Serum galactomannan

Show evidence (2 references)

PMID:26716951 SUPPORT Human Clinical

"When using an optical density index (ODI) of 0.5 as a cut-off value, the sensitivity of the test was 82% (73% to 90%) and the specificity was 81% (72% to 90%). At a cut-off value of 1.0 ODI, the sensitivity was 72% (65% to 80%) and the specificity was 88% (84% to 92%). At a cut-off value of 1.5..."

Gives the diagnostic accuracy at all three cut-offs named in the description, which is the substance of this diagnostic entry.

PMID:26716951 SUPPORT Human Clinical

"We included cross-sectional studies, case-control designs and consecutive series of patients assessing the diagnostic accuracy of galactomannan detection for the diagnosis of invasive aspergillosis in patients with neutropenia or patients whose neutrophils are functionally compromised."

Delimits the population in which this accuracy was established, which is the caveat stated in the description.

Aspergillus IgG antibody (precipitins)

The immunological limb of the chronic pulmonary aspergillosis criteria, and the most useful single test in that setting because the host is immunocompetent enough to mount a strong antibody response. Elevated in over 90% of patients. It is not useful for invasive disease, where the host cannot mount the response.

Aspergillus IgG precipitin measurement NCIT:C166028

Markers: Aspergillus IgG precipitins

Show evidence (2 references)

PMID:26699723 SUPPORT Other

"Aspergillus antibody (precipitins) is elevated in over 90% of patients."

Gives the sensitivity of the test in chronic pulmonary aspergillosis. Evidence source is OTHER because this is a guideline review.

PMID:24299422 SUPPORT Other

"Diagnostics largely rely on serologic Aspergillus precipitins and findings on thoracic computed tomography."

Names serology plus CT as the pair on which the chronic-form diagnosis rests. Evidence source is OTHER because this is a review.

Composite criteria for chronic pulmonary aspergillosis

Chronic pulmonary aspergillosis has no single confirmatory test. The diagnosis requires a cavity or nodules on thoracic imaging, direct or immunological evidence of Aspergillus, exclusion of alternatives, and all of it persisting for at least three months. The persistence requirement is what separates this from subacute invasive aspergillosis, which progresses in under three months and is managed as invasive disease.

composite clinical, radiological and immunological assessment NCIT:C124351

Show evidence (2 references)

PMID:26699723 SUPPORT Other

"The diagnosis of CPA requires a combination of characteristics: one or more cavities with or without a fungal ball present or nodules on thoracic imaging, direct evidence of Aspergillus infection (microscopy or culture from biopsy) or an immunological response to Aspergillus spp. and exclusion..."

States the composite criteria in full, including the three-month persistence requirement. Evidence source is OTHER because this is a guideline review.

PMID:26699723 SUPPORT Other

"Subacute invasive pulmonary aspergillosis (formerly called chronic necrotising pulmonary aspergillosis) is a more rapidly progressive infection (<3 months) usually found in moderately immunocompromised patients, which should be managed as invasive aspergillosis."

Supports the distinction the description draws between the chronic forms and the subacute invasive form, and its management consequence. Evidence source is OTHER because this is a guideline review.

Total and Aspergillus-specific IgE for ABPA

ABPA is diagnosed on a composite of asthma or cystic fibrosis, A. fumigatus-specific IgE, a markedly raised total IgE, and supporting radiological and haematological features. Serum IgE also serves as the quantitative response measure: a fall of at least 25% is one component of the accepted treatment-response definition.

total and Aspergillus-specific serum IgE measurement NCIT:C81970

Markers: Total and Aspergillus-specific serum IgE

Show evidence (2 references)

PMID:23889240 SUPPORT Other

"New diagnosis and staging criteria for ABPA are proposed."

Identifies this ISHAM working-group paper as the source of the current ABPA diagnostic and staging criteria. Graded PARTIAL because the abstract announces the criteria without enumerating them. Evidence source is OTHER because this is a review.

PMID:10717010 SUPPORT Human Clinical

"A response was defined as a reduction of at least 50 percent in the corticosteroid dose, a decrease of at least 25 percent in the serum IgE concentration"

Establishes serum IgE as a quantitative response measure in ABPA, the second use this diagnostic entry records.

Thoracic computed tomography

Imaging carries the diagnosis in both directions of the spectrum, because the clinical signs do not: nodules with a halo or air-crescent sign in invasive disease, cavities with or without a fungal ball in the chronic forms. The structured findings are curated under imaging_findings.

thoracic computed tomography NCIT:C191501

Show evidence (1 reference)

PMID:16088462 SUPPORT Other

"The diagnosis of IPA is based on clinical, radiological, and mycological data. Clinical signs have a low specificity. The most typical computed tomographic (CT) findings are nodules with or without the halo sign or the air crescent sign."

States that clinical signs are non-specific and names the CT findings that carry the diagnosis instead. Evidence source is OTHER because this is a review.

🩻

Imaging Findings

2

Nodules with halo sign or air crescent sign on chest CT

The characteristic CT appearance of invasive pulmonary aspergillosis: pulmonary nodules, early on surrounded by a rim of ground-glass attenuation (the halo sign) and later cavitating with a crescent of air between the necrotic centre and the cavity wall (the air crescent sign). These are the macroscopic reading of the angioinvasive, infarcting lesion modelled in the pathophysiology, and they are what carries the diagnosis when clinical signs do not.

Ct Diagnostic Invasive

lung UBERON:0002048

Show evidence (1 reference)

PMID:16088462 SUPPORT Other

"The most typical computed tomographic (CT) findings are nodules with or without the halo sign or the air crescent sign."

Names the two signs and identifies them as the typical CT appearance of invasive pulmonary aspergillosis. Evidence source is OTHER because this is a review.

Pulmonary cavity with intracavitary fungal ball on chest CT

One or more pulmonary cavities, with or without a mobile intracavitary fungal ball, often with adjacent pleural thickening. Together with an Aspergillus antibody response and three months of persistence this is the diagnosis of chronic pulmonary aspergillosis.

Ct Diagnostic Chronic Pulmonary

lung UBERON:0002048 Pulmonary cavity HP:0033655

Show evidence (1 reference)

PMID:24299422 SUPPORT Other

"Diagnostics largely rely on serologic Aspergillus precipitins and findings on thoracic computed tomography. The latter are manifold comprising cavity formation, pleural involvement and sometimes aspergilloma."

Names the CT features this finding records and their diagnostic weight in chronic pulmonary aspergillosis. Evidence source is OTHER because this is a review.

📈

Progression

2

Acute angioinvasive infection

Invasive Duration: Days to weeks

In the profoundly immunocompromised host the interval from conidial germination to established angioinvasive disease is short. In the ICU influenza cohort, invasive pulmonary aspergillosis was diagnosed a median of three days after ICU admission.

Show evidence (1 reference)

PMID:30076119 SUPPORT Human Clinical

"Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU."

Quantifies how rapidly invasive disease becomes clinically apparent in a susceptible ICU population.

Chronic cavitary and fibrosing progression

Chronic Pulmonary Duration: Months to years

Chronic pulmonary aspergillosis is defined in part by persistence: the diagnostic criteria require the radiological, microbiological and immunological features to have been present for at least three months. Untreated chronic cavitary disease may progress over years to chronic fibrosing pulmonary aspergillosis.

Show evidence (1 reference)

PMID:26699723 SUPPORT Other

"exclusion of alternative diagnoses, all present for at least 3 months"

The three-month persistence requirement in the diagnostic criteria is what makes this a chronic rather than a subacute phase. Evidence source is OTHER because this is a guideline review.

📊

Prevalence

3

Worldwide

Annual Incidence 26.4 per 100,000 1–9 per 10,000 Invasive

Derived from the 2024 global fungal-disease burden estimate of over 2 113 000 incident invasive aspergillosis cases per year, normalised against a world population of approximately 8 billion. The source counts cases arising in adults with COPD, critical illness, lung cancer or haematological malignancy; the rate here is expressed against the whole population, not against that at-risk denominator. This is a modelled estimate over at-risk denominators, not a measured population rate, and it deliberately excludes influenza- and COVID-19-associated outbreaks.

Show evidence (1 reference)

PMID:38224705 SUPPORT Other

"Annually, over 2 113 000 people develop invasive aspergillosis in the context of chronic obstructive pulmonary disease, intensive care, lung cancer, or haematological malignancy, with a crude annual mortality of 1 801 000 (85·2%)."

Source of the incidence figure and of the accompanying crude mortality. Evidence source is OTHER because this is a modelling and literature-synthesis study rather than a primary clinical cohort.

Worldwide

Annual Incidence 23.0 per 100,000 1–9 per 10,000 Chronic Pulmonary

Derived from the modelled global annual incidence of 1 837 272 chronic pulmonary aspergillosis cases, normalised against a world population of approximately 8 billion. Case-fatality is far lower than for the invasive subtype.

Show evidence (1 reference)

PMID:38224705 SUPPORT Other

"The annual incidence of chronic pulmonary aspergillosis is 1 837 272, with 340 000 (18·5%) deaths."

Source of the chronic pulmonary aspergillosis incidence and mortality figures. Evidence source is OTHER because this is a modelling study.

Adults with active asthma

Point Prevalence 2500.0 per 100,000 (720.0–3500.0) >1 in 1,000 ABPA

2.5% of adults with active asthma (range 0.72-3.5%), from a scoping review of five referral cohorts. The denominator is asthmatic adults, not the general population, and referral-cohort estimates are likely to overstate the rate in unselected asthma.

Show evidence (1 reference)

PMID:23210682 SUPPORT Other

"From five referral cohorts (China, Ireland, New Zealand, Saudi Arabia and South Africa), we estimated the prevalence of ABPA in adults with asthma at 2.5% (range 0.72-3.5%) (scoping review)."

Source of the ABPA-in-asthma prevalence and of its stated range. Evidence source is OTHER because this is a burden-modelling study.

🦠

Infectious Agent

1

Aspergillus species

Aspergillus fumigatus causes the large majority of human aspergillosis; A. flavus, A. terreus, A. niger and A. nidulans account for most of the remainder and matter clinically because susceptibility differs by species (A. terreus is characteristically amphotericin B resistant). A. fumigatus is a soil saprotroph whose small hydrophobic conidia are dispersed in air and reach the alveolus on inhalation; its capacity to grow at 37 C and to tolerate host oxidative and nutritional stress is an adaptation to that saprotrophic niche rather than to parasitism, which is why disease is opportunistic.

Aspergillus NCBITaxon:5052

Show evidence (1 reference)

PMID:31722890 SUPPORT Other

"Aspergillus fumigatus is a saprotrophic fungus; its primary habitat is the soil. In its ecological niche, the fungus has learned how to adapt and proliferate in hostile environments. This capacity has helped the fungus to resist and survive against human host defenses"

Establishes A. fumigatus as an environmental saprotroph whose host-defence resistance derives from its environmental niche, which is the basis for treating aspergillosis as an opportunistic rather than an obligate infection. Evidence source is OTHER because this is a review.

↔️

Transmission

1

Inhalation of airborne conidia

Acquired by inhaling airborne Aspergillus conidia from the ambient environment. There is no established person-to-person transmission; the reservoir is soil, decaying vegetation and construction or ventilation dust.

Show evidence (1 reference)

PMID:33563417 SUPPORT Other

"Aspergillus species are ubiquitous in the environment. Aspergillosis is acquired by inhalation of Aspergillus spores. In normal hosts, spore inhalation rarely causes lung disease."

States the route of acquisition and that inhalation alone is not sufficient for disease in a normal host. Evidence source is OTHER because this is a review.

⚖️

Clinical Burden

High

Invasive aspergillosis carries a crude annual mortality of 85.2% against its global incidence, and 90-day mortality among ICU influenza patients who develop it is 51%. Chronic pulmonary aspergillosis is less lethal but consuming and lifelong, with 18.5% annual mortality against an incidence comparable to the invasive form. ABPA is rarely fatal but causes irreversible bronchiectasis in a young asthmatic population.

Show evidence (2 references)

PMID:38224705 SUPPORT Other

"Annually, over 2 113 000 people develop invasive aspergillosis in the context of chronic obstructive pulmonary disease, intensive care, lung cancer, or haematological malignancy, with a crude annual mortality of 1 801 000 (85·2%)."

Source of the invasive-aspergillosis mortality figure behind this burden assessment. Evidence source is OTHER because this is a modelling study.

PMID:30076119 SUPPORT Human Clinical

"The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001)."

Gives the measured mortality among a defined ICU cohort, complementing the modelled global figure.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Aspergillosis:

Mucormycosis

Overlapping Features The clinically decisive differential, because the treatment diverges: the Mucorales are intrinsically resistant to voriconazole and to the echinocandins, so an Aspergillus-directed regimen is inactive against them. The two are separated on tissue morphology.

Distinguishing Features

Broad, aseptate, ribbon-like hyphae branching at right angles, versus the thin, narrow, septate, acute-angle-branching hyphae of Aspergillus
Serum and BAL galactomannan is negative in mucormycosis
Intrinsic resistance to voriconazole and the echinocandins, leaving amphotericin B or isavuconazole

Show evidence (1 reference)

PMID:36407132 SUPPORT Human Clinical

"All the surgical debridement specimens from post-COVID cases had histomorphology of mucormycosis displaying broad, aseptate, ribbon-like fungal hyphae with right-angle branching (45/45)."

Gives the contrasting mucormycosis histomorphology against which Aspergillus is distinguished, in a series where six of the same 45 cases carried both.

🔬

Clinical Trials

3

NCT00412893 PHASE_III COMPLETED

SECURE: phase 3 double-blind randomised non-inferiority trial of isavuconazole versus voriconazole for primary treatment of invasive mould disease, 527 patients randomised across seven years, with 42-day all-cause mortality as the primary endpoint.

Show evidence (2 references)

PMID:26684607 SUPPORT Human Clinical

"This study is registered with ClinicalTrials.gov, number NCT00412893."

The trial publication records the registration identifier used here.

clinicaltrials:NCT00412893 SUPPORT Human Clinical

"The purpose of this study is to compare the efficacy and safety of isavuconazole versus voriconazole in the treatment of patients with invasive aspergillosis."

The ClinicalTrials.gov registry record, from which the phase and status recorded in this entry were taken.

NCT01259336 PHASE_IV COMPLETED

Prospective randomised controlled trial of itraconazole 400 mg daily for six months plus supportive therapy versus supportive therapy alone in chronic cavitary pulmonary aspergillosis.

Show evidence (2 references)

PMID:23496375 SUPPORT Human Clinical

"Itraconazole was found to be superior to standard supportive treatment alone in stabilising cases of CCPA. (clinicaltrials.gov; NCT01259336)"

The trial publication records both the result and the registration identifier used here.

clinicaltrials:NCT01259336 SUPPORT Human Clinical

"The purpose of this study is to determine whether there itraconazole is effective in the treatment of chronic cavitary pulmonary aspergillosis"

The ClinicalTrials.gov registry record, from which the phase and status recorded in this entry were taken.

NCT00044486 PHASE_III COMPLETED

Randomised multicentre trial of posaconazole versus fluconazole or itraconazole prophylaxis in 602 patients with prolonged neutropenia from chemotherapy for acute myelogenous leukaemia or myelodysplastic syndrome.

Show evidence (2 references)

PMID:17251531 SUPPORT Human Clinical

"A total of 304 patients were randomly assigned to receive posaconazole, and 298 patients were randomly assigned to receive fluconazole (240) or itraconazole (58)."

Describes the randomised allocation of the registered trial, establishing its design and enrolment.

clinicaltrials:NCT00044486 SUPPORT Human Clinical

"This trial is in high risk patients to determine the safety and efficacy of posaconazole vs. fluconazole in the prophylaxis against development of invasive fungal infections."

The ClinicalTrials.gov registry record, from which the phase and status recorded in this entry were taken.

{ }

Source YAML

click to show

name: Aspergillosis
creation_date: "2026-08-28T00:00:00Z"
category: Infectious Disease
description: >-
  Disease caused by inhaled Aspergillus species, predominantly Aspergillus
  fumigatus. Conidia are ubiquitous in air and are inhaled continuously by
  everyone, so the organism is not by itself the determinant of disease: the
  clinical form is set far more by the host than by the fungus. Where phagocyte
  number or function is lost — chemotherapy-induced neutropenia, corticosteroid
  therapy, transplantation, chronic granulomatous disease, severe influenza or
  COVID-19 — conidia germinate, hyphae invade tissue and blood vessels, and the
  disease is acute, angioinvasive and frequently fatal. Where innate immunity is
  intact but the lung is structurally damaged, the same organism produces
  indolent cavitary and fibrosing disease over months to years. Where immunity is
  intact but dysregulated toward a Th2/IgE response, it produces allergic disease
  in asthma and cystic fibrosis without tissue invasion at all. This entry curates
  the shared root mechanism — inhalation, phagocyte gating, and the branch point
  set by host status — and carries the clinical forms as subtypes.
parents:
- Fungal infection
synonyms:
- Aspergillus infection
- Pulmonary aspergillosis
disease_term:
  preferred_term: aspergillosis
  term:
    id: MONDO:0005657
    label: aspergillosis
infectious_agent:
- name: Aspergillus species
  infectious_agent_term:
    preferred_term: Aspergillus
    term:
      id: NCBITaxon:5052
      label: Aspergillus
  description: >-
    Aspergillus fumigatus causes the large majority of human aspergillosis;
    A. flavus, A. terreus, A. niger and A. nidulans account for most of the
    remainder and matter clinically because susceptibility differs by species
    (A. terreus is characteristically amphotericin B resistant). A. fumigatus is
    a soil saprotroph whose small hydrophobic conidia are dispersed in air and
    reach the alveolus on inhalation; its capacity to grow at 37 C and to
    tolerate host oxidative and nutritional stress is an adaptation to that
    saprotrophic niche rather than to parasitism, which is why disease is
    opportunistic.
  evidence:
  - reference: PMID:31722890
    reference_title: Aspergillus fumigatus and Aspergillosis in 2019.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus fumigatus is a saprotrophic fungus; its primary habitat is the
      soil. In its ecological niche, the fungus has learned how to adapt and
      proliferate in hostile environments. This capacity has helped the fungus to
      resist and survive against human host defenses
    explanation: >-
      Establishes A. fumigatus as an environmental saprotroph whose host-defence
      resistance derives from its environmental niche, which is the basis for
      treating aspergillosis as an opportunistic rather than an obligate
      infection. Evidence source is OTHER because this is a review.
transmission:
- name: Inhalation of airborne conidia
  description: >-
    Acquired by inhaling airborne Aspergillus conidia from the ambient
    environment. There is no established person-to-person transmission; the
    reservoir is soil, decaying vegetation and construction or ventilation dust.
  evidence:
  - reference: PMID:33563417
    reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus species are ubiquitous in the environment. Aspergillosis is
      acquired by inhalation of Aspergillus spores. In normal hosts, spore
      inhalation rarely causes lung disease.
    explanation: >-
      States the route of acquisition and that inhalation alone is not
      sufficient for disease in a normal host. Evidence source is OTHER because
      this is a review.
has_subtypes:
- name: Invasive
  display_name: Invasive aspergillosis (including invasive pulmonary aspergillosis)
  subtype_term:
    preferred_term: invasive aspergillosis
    term:
      id: MONDO:0000240
      label: invasive aspergillosis
  description: >-
    Acute, tissue-invasive infection of the severely immunocompromised host —
    prolonged neutropenia after chemotherapy or allogeneic transplantation,
    high-dose corticosteroids, chronic granulomatous disease — and, increasingly,
    of the non-classically-immunocompromised ICU patient with severe influenza or
    COVID-19. Hyphae invade lung parenchyma and blood vessels, producing
    thrombosis, infarction and haematogenous spread. Mortality is high.
  evidence:
  - reference: PMID:33563417
    reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Invasive Aspergillosis usually occurs in severely immunocompromised
      patients, typically in neutropenic but also in non-neutropenic patients.
    explanation: >-
      Defines the host context of the invasive subtype and notes that it is not
      restricted to neutropenic hosts. Evidence source is OTHER because this is
      a review.
- name: Chronic Pulmonary
  display_name: Chronic pulmonary aspergillosis (CCPA and chronic fibrosing forms)
  description: >-
    Slowly progressive cavitary and fibrosing lung infection in a patient with
    prior or current structural lung disease (treated tuberculosis, COPD,
    sarcoidosis, prior thoracic surgery) but without significant systemic
    immunocompromise. Chronic cavitary pulmonary aspergillosis is the commonest
    form and may progress to chronic fibrosing pulmonary aspergillosis. No
    subtype_term is bound: MONDO carries a term for pulmonary aspergilloma
    (bound on the Aspergilloma subtype) and for invasive aspergillosis, but none
    for chronic cavitary or chronic fibrosing pulmonary aspergillosis, which are
    covered only by the parent term MONDO:0005657 already on this entry.
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common form of CPA is chronic cavitary pulmonary aspergillosis
      (CCPA), which untreated may progress to chronic fibrosing pulmonary
      aspergillosis.
    explanation: >-
      The ESCMID/ERS guideline names CCPA as the commonest chronic form and its
      fibrosing endpoint, which is what this subtype covers. Evidence source is
      OTHER because this is a guideline review.
  - reference: PMID:33563417
    reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic pulmonary Aspergillosis affects patients with chronic structural
      lung disease such as COPD or previous mycobacterial lung disease, but
      without other significant immunocompromise.
    explanation: >-
      States the defining host context that separates this subtype from the
      invasive one — structural lung disease without systemic immunocompromise.
      Evidence source is OTHER because this is a review.
- name: Aspergilloma
  display_name: Aspergilloma (pulmonary fungal ball)
  subtype_term:
    preferred_term: pulmonary aspergilloma
    term:
      id: MONDO:0000266
      label: pulmonary aspergilloma
  description: >-
    Saprophytic colonisation of a pre-existing pulmonary cavity by a conglomerate
    of hyphae, mucus and cellular debris, without tissue invasion. Usually
    minimally symptomatic, but haemoptysis from the bronchial circulation
    surrounding the cavity can be life-threatening. Formally a subset of chronic
    pulmonary aspergillosis; kept as its own subtype because it has its own MONDO
    identity, its own natural history and a distinct management pathway
    (surgical excision rather than long-term azole therapy).
  evidence:
  - reference: PMID:31536274
    reference_title: Aspergilloma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergilloma and chronic cavitary pulmonary aspergillosis (CCPA) refer to
      the inert saprophytic colonization of preexisting cavitary spaces in the
      pulmonary parenchyma
    explanation: >-
      Establishes the aspergilloma as saprophytic colonisation of a pre-existing
      cavity, the feature that distinguishes it from invasive disease. Evidence
      source is OTHER because this is a review.
- name: ABPA
  display_name: Allergic bronchopulmonary aspergillosis
  subtype_term:
    preferred_term: allergic bronchopulmonary aspergillosis
    term:
      id: MONDO:0015243
      label: allergic bronchopulmonary aspergillosis
  description: >-
    Th2-driven hypersensitivity to Aspergillus antigens in a host with asthma or
    cystic fibrosis, with no tissue invasion. Presents as poorly controlled
    asthma with recurrent pulmonary infiltrates, mucus plugging, marked total and
    Aspergillus-specific IgE elevation, eosinophilia and, over time, central
    bronchiectasis. The dismech entries for Cystic_Fibrosis and
    Hypersensitivity_Pneumonitis are the adjacent host-context and
    allergic-lung-disease entries.
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Allergic bronchopulmonary aspergillosis (ABPA) is an immunological
      pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus,
      manifesting with poorly controlled asthma, recurrent pulmonary infiltrates
      and bronchiectasis.
    explanation: >-
      The ISHAM working-group review defines ABPA as a hypersensitivity disorder
      with this manifestation triad. Evidence source is OTHER because this is a
      review.
- name: Aspergillus Bronchitis
  display_name: Aspergillus bronchitis
  description: >-
    Aspergillus infection confined to the bronchial tree in a patient with
    pre-existing bronchial disease, typically bronchiectasis, without parenchymal
    invasion and without the IgE-mediated hypersensitivity that defines ABPA.
    No subtype_term is bound: MONDO carries no term for Aspergillus bronchitis
    and it is covered only by the parent term MONDO:0005657 already on this
    entry.
  evidence:
  - reference: PMID:33563417
    reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus bronchitis affects patients with bronchial disease such as
      bronchiectasis.
    explanation: >-
      Names Aspergillus bronchitis as a distinct member of the pulmonary
      aspergillosis spectrum and gives its host context. Evidence source is
      OTHER because this is a review.
- name: Disseminated
  display_name: Disseminated and extrapulmonary aspergillosis
  description: >-
    Haematogenous spread from an angioinvasive pulmonary focus to brain, skin,
    eye, heart, bone or viscera, or primary cutaneous inoculation at a catheter
    or burn site. CNS involvement (neuroaspergillosis, MONDO:0005873) is the
    commonest and most lethal extrapulmonary site. No subtype_term is bound at
    this level: MONDO codes individual organ forms such as neuroaspergillosis but
    has no general disseminated-aspergillosis term, and binding the CNS term here
    would misdescribe the non-CNS forms this subtype also covers.
  evidence:
  - reference: PMID:17050430
    reference_title: Interactions of Aspergillus fumigatus with vascular endothelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Some of these hyphal fragments can break off and circulate in the
      bloodstream. In severely immunocompromised hosts, these blood-borne hyphal
      fragments adhere to the luminal surface of the endothelial cells and they
      penetrate the endothelial cell lining of the vasculature by passing from
      the luminal to the abluminal surface.
    explanation: >-
      The authors' characterisation of the vascular route by which an invasive
      pulmonary focus seeds distant organs, which is what defines this subtype.
      Graded PARTIAL because this sentence frames their model rather than
      reporting a measurement.
prevalence:
- subtype: Invasive
  population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 26.4
  notes: >-
    Derived from the 2024 global fungal-disease burden estimate of over 2 113 000
    incident invasive aspergillosis cases per year, normalised against a world
    population of approximately 8 billion. The source counts cases arising in
    adults with COPD, critical illness, lung cancer or haematological malignancy;
    the rate here is expressed against the whole population, not against that
    at-risk denominator. This is a modelled estimate over
    at-risk denominators, not a measured population rate, and it deliberately
    excludes influenza- and COVID-19-associated outbreaks.
  evidence:
  - reference: PMID:38224705
    reference_title: Global incidence and mortality of severe fungal disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Annually, over 2 113 000 people develop invasive aspergillosis in the
      context of chronic obstructive pulmonary disease, intensive care, lung
      cancer, or haematological malignancy, with a crude annual mortality of
      1 801 000 (85·2%).
    explanation: >-
      Source of the incidence figure and of the accompanying crude mortality.
      Evidence source is OTHER because this is a modelling and literature-synthesis
      study rather than a primary clinical cohort.
- subtype: Chronic Pulmonary
  population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 23.0
  notes: >-
    Derived from the modelled global annual incidence of 1 837 272 chronic
    pulmonary aspergillosis cases, normalised against a world population of
    approximately 8 billion. Case-fatality is far lower than for the invasive
    subtype.
  evidence:
  - reference: PMID:38224705
    reference_title: Global incidence and mortality of severe fungal disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The annual incidence of chronic pulmonary aspergillosis is 1 837 272, with
      340 000 (18·5%) deaths.
    explanation: >-
      Source of the chronic pulmonary aspergillosis incidence and mortality
      figures. Evidence source is OTHER because this is a modelling study.
- subtype: ABPA
  population: Adults with active asthma
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 2500.0
  rate_low: 720.0
  rate_high: 3500.0
  notes: >-
    2.5% of adults with active asthma (range 0.72-3.5%), from a scoping review of
    five referral cohorts. The denominator is asthmatic adults, not the general
    population, and referral-cohort estimates are likely to overstate the rate in
    unselected asthma.
  evidence:
  - reference: PMID:23210682
    reference_title: Global burden of allergic bronchopulmonary aspergillosis with asthma and its complication chronic pulmonary aspergillosis in adults.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      From five referral cohorts (China, Ireland, New Zealand, Saudi Arabia and
      South Africa), we estimated the prevalence of ABPA in adults with asthma at
      2.5% (range 0.72-3.5%) (scoping review).
    explanation: >-
      Source of the ABPA-in-asthma prevalence and of its stated range. Evidence
      source is OTHER because this is a burden-modelling study.
progression:
- phase: Acute angioinvasive infection
  subtype: Invasive
  duration: Days to weeks
  notes: >-
    In the profoundly immunocompromised host the interval from conidial
    germination to established angioinvasive disease is short. In the ICU
    influenza cohort, invasive pulmonary aspergillosis was diagnosed a median of
    three days after ICU admission.
  evidence:
  - reference: PMID:30076119
    reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients
      admitted with influenza (influenza cohort), a median of 3 days after
      admission to the ICU.
    explanation: >-
      Quantifies how rapidly invasive disease becomes clinically apparent in a
      susceptible ICU population.
- phase: Chronic cavitary and fibrosing progression
  subtype: Chronic Pulmonary
  duration: Months to years
  notes: >-
    Chronic pulmonary aspergillosis is defined in part by persistence: the
    diagnostic criteria require the radiological, microbiological and
    immunological features to have been present for at least three months.
    Untreated chronic cavitary disease may progress over years to chronic
    fibrosing pulmonary aspergillosis.
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      exclusion of alternative diagnoses, all present for at least 3 months
    explanation: >-
      The three-month persistence requirement in the diagnostic criteria is what
      makes this a chronic rather than a subacute phase. Evidence source is OTHER
      because this is a guideline review.
pathophysiology:
- name: Inhalation and Alveolar Deposition of Airborne Aspergillus Conidia
  biological_scale: ORGANISM
  role: trigger
  description: >-
    Aspergillus conidia are small enough to bypass mucociliary clearance and
    reach the distal airway and alveolus. Everybody inhales them daily; this node
    is therefore the shared entry point of every clinical form and is by itself
    insufficient for disease. What happens next is decided by the host.
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  evidence:
  - reference: PMID:33563417
    reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus species are ubiquitous in the environment. Aspergillosis is
      acquired by inhalation of Aspergillus spores. In normal hosts, spore
      inhalation rarely causes lung disease.
    explanation: >-
      Establishes inhalation as the initiating step and that it is not sufficient
      for disease in an immunocompetent host, which is what makes this node a
      trigger rather than a cause. Evidence source is OTHER because this is a
      review.
  downstream:
  - target: Alveolar Macrophage Dectin-1 Recognition of Aspergillus
    causal_link_type: DIRECT
    description: >-
      Deposited conidia are met by resident alveolar macrophages, whose
      beta-glucan recognition starts the response.
  - target: Oxidase-Independent Neutrophil Killing of Conidia
    causal_link_type: DIRECT
    description: >-
      Recruited neutrophils engage ungerminated conidia by an intracellular,
      oxidase-independent route.
  - target: NADPH Oxidase-Dependent Neutrophil Killing of Hyphae
    causal_link_type: DIRECT
    description: >-
      Conidia that escape early killing and germinate are attacked
      extracellularly by a separate, oxidase-dependent route.
  - target: Th2 Sensitisation and IgE-Mediated Hypersensitivity to Aspergillus Antigens
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      In an atopic or cystic-fibrosis airway, the same inhaled conidia germinate
      and release antigen that drives an allergic rather than an invasive
      response.
  - target: Saprophytic Cavity Colonisation and Fungal Ball Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Where a pre-existing pulmonary cavity is present, inhaled conidia may
      colonise it saprophytically without ever invading tissue.
- name: Alveolar Macrophage Dectin-1 Recognition of Aspergillus
  biological_scale: CELLULAR
  role: effector
  description: >-
    Resident alveolar macrophages recognise beta-1,3-glucan exposed on the
    surface of swollen conidia and early germlings through dectin-1. Recognition
    tracks the fungal morphotype rather than the organism as such, and it drives
    the proinflammatory cytokine and chemokine output that recruits neutrophils.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  biological_processes:
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
  evidence:
  - reference: PMID:16344862
    reference_title: The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The inflammatory response was triggered at the highest level by A.
      fumigatus swollen conidia and early germlings and correlated to the levels
      of surface-exposed beta glucans, indicating that dectin-1 preferentially
      recognizes specific morphological forms of A. fumigatus.
    explanation: >-
      Establishes dectin-1 recognition of surface beta-glucan as the trigger for
      the alveolar macrophage inflammatory response, and that recognition tracks
      the fungal morphotype.
  - reference: PMID:16344862
    reference_title: The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Intratracheal administration of A. fumigatus conidia to mice in the
      presence of a soluble dectin-Fc fusion protein reduced both lung
      proinflammatory cytokine/chemokine levels and cellular recruitment while
      modestly increasing the A. fumigatus fungal burden
    explanation: >-
      In vivo blockade of dectin-1 reduces recruitment and increases fungal
      burden, showing the recognition step is load-bearing and not merely
      correlative. Graded separately from the in vitro item because this
      sentence reports the murine arm of the same paper.
- name: Oxidase-Independent Neutrophil Killing of Conidia
  biological_scale: CELLULAR
  role: effector
  description: >-
    Neutrophils recognise ungerminated conidia through integrin CD11b/CD18 —
    not dectin-1 — and kill them intracellularly by a PI3K-dependent route that
    does not require the oxidative burst. This is the arm that survives in
    chronic granulomatous disease and is lost in neutropenia, which is why the
    two defects behave differently.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil-mediated killing of Aspergillus conidia
    term:
      id: GO:0070947
      label: neutrophil-mediated killing of fungus
  evidence:
  - reference: PMID:26718340
    reference_title: "Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Recognition of conidia involves integrin CD11b/CD18 (and not dectin-1),
      which triggers a PI3K-dependent nonoxidative intracellular mechanism of
      killing.
    explanation: >-
      Establishes the receptor, the signalling route, and the oxidase
      independence of the anti-conidial mechanism this node models.
- name: NADPH Oxidase-Dependent Neutrophil Killing of Hyphae
  biological_scale: CELLULAR
  role: effector
  description: >-
    Hyphae are too large to phagocytose, so neutrophils kill them
    extracellularly: antibody opsonisation, Fc-gamma receptor recognition, and
    Syk/PI3K/PKC signalling to the NADPH oxidase and myeloperoxidase. This is
    the arm lost in chronic granulomatous disease, and it is why CGD patients
    control conidia but not established hyphal growth. NET formation is induced
    by A. fumigatus but did not contribute to killing in this work.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil-mediated killing of Aspergillus hyphae
    term:
      id: GO:0070947
      label: neutrophil-mediated killing of fungus
  - preferred_term: respiratory burst
    term:
      id: GO:0045730
      label: respiratory burst
  evidence:
  - reference: PMID:26718340
    reference_title: "Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the extracellular destruction of the Aspergillus hyphae needs opsonization
      by Abs and involves predominantly recognition via Fcγ receptors, signaling
      via Syk, PI3K, and protein kinase C to trigger the production of toxic
      reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase
    explanation: >-
      Establishes the opsonisation requirement, the signalling route, and the
      NADPH oxidase/myeloperoxidase dependence of the anti-hyphal mechanism.
  - reference: PMID:26718340
    reference_title: "Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A. fumigatus induces NET formation; however, NETs did not contribute to A.
      fumigatus killing.
    explanation: >-
      A negative result, recorded because it excludes NETs from the anti-hyphal
      mechanism this node describes.
- name: Failure of Phagocyte Clearance of Aspergillus
  biological_scale: CELLULAR
  role: consequence
  description: >-
    The branch point of the whole entry. Prolonged chemotherapy-induced
    neutropenia removes the effector cell; corticosteroids and calcineurin
    inhibitors impair macrophage and neutrophil function while the cells are
    still present; chronic granulomatous disease removes the NADPH
    oxidase-dependent anti-hyphal mechanism specifically; and severe influenza or
    COVID-19 produces a comparable functional defect in hosts with no classical
    EORTC/MSG host factor at all. Whatever the cause, ungated conidia germinate.
  biological_processes:
  - preferred_term: defense response to fungus
    modifier: DECREASED
    term:
      id: GO:0050832
      label: defense response to fungus
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  evidence:
  - reference: PMID:26718340
    reference_title: "Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This is illustrated by the prevalence of Aspergillus infections in patients
      with neutropenia or phagocyte functional defects, such as chronic
      granulomatous disease.
    explanation: >-
      States the clinical corollary the paper's mechanism explains: both the
      number defect and the function defect produce Aspergillus disease.
  - reference: PMID:10844935
    reference_title: Chronic granulomatous disease. Report on a national registry of 368 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pneumonia was the most prevalent infection (79% of patients; Aspergillus
      most prevalent cause)
    explanation: >-
      In a 368-patient CGD registry, Aspergillus is the leading cause of the
      commonest infection, which is the human evidence that losing the NADPH
      oxidase route specifically permits Aspergillus disease.
  downstream:
  - target: Conidial Germination and Hyphal Tissue Invasion
    causal_link_type: DIRECT
    description: >-
      Unkilled conidia swell, germinate and extend hyphae into lung tissue.
- name: Gliotoxin-Mediated Suppression of Host Phagocyte Function
  biological_scale: MOLECULAR
  role: virulence_factor
  description: >-
    A. fumigatus secretes gliotoxin, an epipolythiodioxopiperazine mycotoxin with
    immunosuppressive activity that has long been implicated in assisting tissue
    penetration. This node is deliberately modelled as a contributory
    fungal-side input to phagocyte failure rather than as a sufficient cause: the
    direct virulence evidence is from an invertebrate infection model, and human
    disease is dominated by the host-side defects modelled upstream.
  chemical_entities:
  - preferred_term: gliotoxin
    term:
      id: CHEBI:5385
      label: gliotoxin
  evidence:
  - reference: PMID:15487324
    reference_title: Correlation between gliotoxin production and virulence of Aspergillus fumigatus in Galleria mellonella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gliotoxin is an immunosuppressive agent previously implicated in assisting
      tissue penetration.
    explanation: >-
      States the proposed immunosuppressive and tissue-penetration role. Graded
      PARTIAL because the claim is background in this paper rather than its own
      result.
  - reference: PMID:15487324
    reference_title: Correlation between gliotoxin production and virulence of Aspergillus fumigatus in Galleria mellonella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      implicating a critical role for gliotoxin production rather than growth
      rate or enzymatic activity in the virulence of A. fumigatus in this model
    explanation: >-
      Ties virulence to gliotoxin production rather than growth rate. Graded
      PARTIAL and MODEL_ORGANISM because the finding is from Galleria mellonella
      and the authors themselves qualify it to that model.
  downstream:
  - target: Failure of Phagocyte Clearance of Aspergillus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Secreted gliotoxin is proposed to add a fungal-side contribution to the
      phagocyte defect, on top of the host-side causes.
- name: Conidial Germination and Hyphal Tissue Invasion
  biological_scale: CELLULAR
  description: >-
    Surviving conidia swell, germinate and extend filamentous hyphae that
    penetrate alveolar epithelium and lung parenchyma. This is the step that
    separates the tissue-invasive forms from the allergic and saprophytic ones,
    which never reach it.
  biological_processes:
  - preferred_term: spore germination
    term:
      id: GO:0009847
      label: spore germination
  - preferred_term: filamentous hyphal growth
    term:
      id: GO:0030447
      label: filamentous growth
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:17050430
    reference_title: Interactions of Aspergillus fumigatus with vascular endothelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      During pulmonary aspergillosis, hyphae are initially outside of the
      pulmonary vasculature and they invade the endothelial cell lining of the
      blood vessels by passing from the abluminal to the luminal surface.
    explanation: >-
      The authors' characterisation of the invasion route their in-vitro models
      reproduce: hyphae grow through lung tissue from outside the vasculature
      inwards. Graded PARTIAL because this sentence frames the model rather than
      reporting a measurement.
  downstream:
  - target: Angioinvasion and Thrombotic Tissue Infarction
    causal_link_type: DIRECT
    description: >-
      Hyphae reach and cross the vessel wall from the abluminal side.
  - target: Chronic Cavitary Lung Destruction and Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Where the host retains innate immunity but the lung is structurally
      abnormal, the same hyphal growth produces slow cavitary destruction rather
      than acute angioinvasion.
- name: Angioinvasion and Thrombotic Tissue Infarction
  biological_scale: TISSUE
  description: >-
    Hyphae penetrate the endothelial lining, damage endothelial cells and induce
    tissue factor expression. The sourced steps here are the endothelial damage
    and the procoagulant induction; the thrombosis and ischaemic infarction
    usually described as following from them are the accepted clinical reading
    of the nodular, halo-sign and air-crescent radiology, not something the
    cited in-vitro work measured.
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:17050430
    reference_title: Interactions of Aspergillus fumigatus with vascular endothelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Luminal invasion by hyphae results in both endothelial cell damage and
      stimulation of tissue factor expression.
    explanation: >-
      Links hyphal contact with endothelium directly to endothelial damage and
      to tissue factor induction, the procoagulant step behind thrombotic
      infarction.
  downstream:
  - target: Haematogenous Dissemination to Extrapulmonary Sites
    causal_link_type: DIRECT
    description: >-
      Hyphal fragments shed into the bloodstream from an invaded vessel seed
      distant organs.
- name: Haematogenous Dissemination to Extrapulmonary Sites
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Blood-borne hyphal fragments adhere to and cross the luminal endothelial
    surface at distant sites, establishing cerebral, cutaneous, ocular, cardiac
    and visceral foci. This route is specific to the severely immunocompromised
    host.
  evidence:
  - reference: PMID:17050430
    reference_title: Interactions of Aspergillus fumigatus with vascular endothelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In severely immunocompromised hosts, these blood-borne hyphal fragments
      adhere to the luminal surface of the endothelial cells and they penetrate
      the endothelial cell lining of the vasculature by passing from the luminal
      to the abluminal surface.
    explanation: >-
      The authors' characterisation of the luminal-to-abluminal re-invasion step
      by which circulating fragments establish metastatic foci, tied to host
      immune status. Graded PARTIAL because this sentence frames the model
      rather than reporting a measurement.
- name: Saprophytic Cavity Colonisation and Fungal Ball Formation
  biological_scale: TISSUE
  description: >-
    In a pre-existing pulmonary cavity — most often post-tuberculous — hyphae,
    mucus and cellular debris accumulate into a mobile fungal ball without
    invading the cavity wall. Symptoms are minor or absent until bleeding from
    the hypertrophied bronchial vessels around the cavity produces haemoptysis.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:31536274
    reference_title: Aspergilloma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Simple Aspergilloma A single pulmonary cavity containing a fungal ball,
      with serological or microbiological evidence of Aspergillus spp. in a
      non-immunocompromised patient.
    explanation: >-
      Gives the consensus definition of the fungal ball in a pre-existing cavity
      in a non-immunocompromised host, which is what this node models. Evidence
      source is OTHER because this is a review of consensus definitions.
  downstream:
  - target: Chronic Cavitary Lung Destruction and Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Saprophytic colonisation and chronic cavitary disease overlap clinically
      and a simple aspergilloma may be found within, or progress to, the broader
      chronic cavitary form.
- name: Chronic Cavitary Lung Destruction and Fibrosis
  biological_scale: TISSUE
  role: consequence
  description: >-
    Over months to years, one or more pulmonary cavities expand and coalesce with
    surrounding pleural thickening and a vigorous Aspergillus antibody response;
    untreated, this progresses to the fibrosing form with irreversible loss of
    lung volume. The host here is immunocompetent enough to contain the organism
    but not to clear it.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most common form of CPA is chronic cavitary pulmonary aspergillosis
      (CCPA), which untreated may progress to chronic fibrosing pulmonary
      aspergillosis. Less common manifestations include: Aspergillus nodule and
      single aspergilloma. All these entities are found in non-immunocompromised
      patients with prior or current lung disease.
    explanation: >-
      Establishes both the cavitary-to-fibrosing trajectory and the
      non-immunocompromised, structurally-abnormal-lung host context that
      distinguishes this branch. Evidence source is OTHER because this is a
      guideline review.
- name: Th2 Sensitisation and IgE-Mediated Hypersensitivity to Aspergillus Antigens
  biological_scale: ORGANISM
  description: >-
    In a genetically predisposed atopic or cystic-fibrosis airway, germinating
    conidia release antigen that drives a Th2 CD4-positive T-cell response, IgE
    class switching and a large rise in total and Aspergillus-specific IgE. The
    organism is never cleared and never invades; the disease is the response to
    it. This is the mechanism that makes ABPA a member of the aspergillosis
    spectrum despite sharing none of the invasive branch's tissue pathology.
  cell_types:
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000492
      label: CD4-positive helper T cell
  biological_processes:
  - preferred_term: T-helper 2 cell differentiation
    modifier: INCREASED
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
  - preferred_term: isotype switching to IgE isotypes
    modifier: INCREASED
    term:
      id: GO:0048289
      label: isotype switching to IgE isotypes
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In a genetically predisposed individual, inhaled conidia of A. fumigatus
      germinate into hyphae with release of antigens that activate the innate and
      adaptive immune responses (Th2 CD4(+) T cell responses) of the lung.
    explanation: >-
      States the germination-antigen-Th2 sequence and the requirement for host
      genetic predisposition, which is exactly what this node asserts. Evidence
      source is OTHER because this is a review.
  downstream:
  - target: Eosinophilic Airway Inflammation and Mucus Plugging
    causal_link_type: DIRECT
    description: >-
      The Th2/IgE response recruits eosinophils and drives the mucus
      hypersecretion that produces the recurrent infiltrates of ABPA.
- name: Eosinophilic Airway Inflammation and Mucus Plugging
  biological_scale: TISSUE
  description: >-
    Eosinophil-rich inflammation with tenacious, hyphae-containing mucus plugs
    that occlude segmental bronchi, giving the fleeting pulmonary infiltrates and
    poorly controlled asthma of ABPA.
  cell_types:
  - preferred_term: eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      manifesting with poorly controlled asthma, recurrent pulmonary infiltrates
      and bronchiectasis
    explanation: >-
      Names the recurrent infiltrates and poorly controlled asthma that this
      inflammatory node produces, and the bronchiectasis modelled downstream.
      Evidence source is OTHER because this is a review.
  downstream:
  - target: Bronchiectasis and Fixed Airway Damage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Repeated plugging and inflammation destroy the bronchial wall, producing
      the central bronchiectasis that is the permanent structural sequela of
      ABPA.
- name: Bronchiectasis and Fixed Airway Damage
  biological_scale: TISSUE
  role: consequence
  description: >-
    Irreversible central bronchial dilatation, the endpoint that makes early
    recognition of ABPA worthwhile: it is the manifestation that antifungal and
    corticosteroid therapy aim to prevent rather than to reverse.
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The importance of recognizing ABPA relates to the improvement of patient
      symptoms, and delay in development or prevention of bronchiectasis, one
      manifestation of permanent lung damage in ABPA.
    explanation: >-
      Identifies bronchiectasis as permanent lung damage and the target of early
      recognition, which is the claim this consequence node makes. Evidence
      source is OTHER because this is a review.
- name: Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: >-
    fungal_ergosterol_synthesis_inhibition#Lanosterol 14-alpha-Demethylation by
    CYP51 (ERG11)
  description: >-
    Aspergillus membrane ergosterol is made by a pathway whose rate-limiting
    demethylation step is catalysed by the cytochrome P450 lanosterol
    14-alpha-demethylase encoded by cyp51A and cyp51B. Triazoles bind heme iron
    at this enzyme, so ergosterol is depleted and toxic 14-alpha-methylsterols
    accumulate. This node is intentionally target-only: it describes the normal
    fungal biosynthetic activity that azole therapy inhibits, not a step that
    causes disease.
  biological_processes:
  - preferred_term: ergosterol biosynthetic process
    term:
      id: GO:0006696
      label: ergosterol biosynthetic process
  molecular_functions:
  - preferred_term: sterol 14-alpha-demethylase activity
    term:
      id: GO:0008398
      label: sterol 14-demethylase activity
  evidence:
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism of action of triazoles (Figure 2D-H) is based on the
      inhibition of the microsomal cytochrome P450 (CYP450) monooxygenase
      dependent 14-α-demethylase (Figure 3).
    explanation: >-
      Identifies the enzyme this node models as the triazole target. Evidence
      source is OTHER because this is a review.
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The combination of the accumulation of toxic 14-α-methylsterols and
      depletion of ergosterol results in the fungistatic effect
    explanation: >-
      States the consequence of inhibiting this step, which is why the node is
      a therapeutic vulnerability. Evidence source is OTHER because this is a
      review.
  downstream:
  - target: Ergosterol-Enriched Aspergillus Plasma Membrane
    causal_link_type: DIRECT
    description: >-
      Completing the demethylase step and the reactions downstream of it yields
      the ergosterol that is incorporated into the fungal plasma membrane.
- name: Ergosterol-Enriched Aspergillus Plasma Membrane
  biological_scale: CELLULAR
  role: effector
  conforms_to: >-
    fungal_membrane_ergosterol_binding#Ergosterol-Enriched Fungal Plasma
    Membrane
  description: >-
    Ergosterol is the fungal-specific end-product sterol of the pathway and the
    principal sterol of the Aspergillus plasma membrane, where it maintains
    fluidity, integrity and the function of membrane-embedded proteins. It is
    the target of the polyenes, which bind and extract it rather than inhibiting
    its synthesis — which is why a cyp51A target-site substitution does not by
    itself confer polyene cross-resistance. This node is the bridge between the
    two drug-target branches and the growth the disease depends on.
  biological_processes:
  - preferred_term: ergosterol metabolic process
    term:
      id: GO:0008204
      label: ergosterol metabolic process
  evidence:
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the polyene class includes the heptaene amphotericin B (AMB), which
      interacts with ergosterol, the major part of the fungal cell membrane
    explanation: >-
      Establishes ergosterol as the major sterol of the fungal cell membrane and
      as the polyene target, which is the state this node models. Evidence
      source is OTHER because this is a review.
  downstream:
  - target: Conidial Germination and Hyphal Tissue Invasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A functional ergosterol-containing membrane is required for the fungal
      growth that invades tissue. This entry does not claim membrane integrity
      alone is sufficient for invasion; the edge records that both antifungal
      target branches ultimately act on this growth.
- name: Environmental cyp51A-Mediated Azole Resistance
  biological_scale: MOLECULAR
  role: adaptive_escape
  conforms_to: fungal_ergosterol_synthesis_inhibition#Azole-Target Resistance
  description: >-
    Agricultural azole fungicides share the Cyp51 target with clinical
    triazoles, so field application selects pan-azole-resistant A. fumigatus in
    the environment rather than in the treated patient. The dominant genotype is
    TR34/L98H — a 34-bp tandem repeat in the cyp51A promoter driving
    overexpression, plus a leucine-to-histidine substitution at codon 98 — with
    TR46/Y121F/T289A the second common allele. Because selection happens outside
    the host, azole-naive patients can present with resistant disease, and the
    resistant genotypes have spread across Europe from a common ancestor.
  molecular_functions:
  - preferred_term: sterol 14-alpha-demethylase activity
    term:
      id: GO:0008398
      label: sterol 14-demethylase activity
  evidence:
  - reference: PMID:33203147
    reference_title: "Antifungal Drug Repurposing."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Such long-term application of azole fungicides to crop fields provides
      environmental selection pressure for the emergence of pan-azole-resistant
      fungal strains such as Aspergillus fumigatus having TR34/L98H mutations,
      specifically, a 34 bp insertion into the cytochrome P450 51A (CYP51A) gene
      promoter region and a leucine-to-histidine substitution at codon 98 of
      CYP51A.
    explanation: >-
      Gives both the agricultural selection mechanism and the exact molecular
      composition of the TR34/L98H allele this node names. Evidence source is
      OTHER because this is a review.
  - reference: PMID:22675126
    reference_title: Molecular epidemiology of Aspergillus fumigatus isolates harboring the TR34/L98H azole resistance mechanism.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The dominant resistance mechanism appears to be of environmental origin
      and involves the TR(34)/L98H mutations in cyp51A. This resistance
      mechanism is now also increasingly being found in other countries.
    explanation: >-
      Establishes the environmental rather than patient origin of the dominant
      resistance mechanism and its international spread. Evidence source is
      OTHER because this is a molecular-epidemiology study of fungal isolates
      rather than of human, animal, or cell-culture subjects.
  - reference: PMID:31236587
    reference_title: Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All but one resistant case harboured environment-associated resistance
      mutations in the cyp51A gene: TR34/L98H (13 cases) and TR46/Y121F/T289A
      (12 cases).
    explanation: >-
      Confirms in a clinical haematology cohort that essentially all
      voriconazole-resistant invasive aspergillosis carried the
      environment-associated cyp51A alleles this node models.
  downstream:
  - target: Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
    causal_link_type: DIRECT
    description: >-
      Promoter-driven overexpression plus an active-site substitution keep
      ergosterol synthesis running at achievable azole concentrations, which is
      what makes triazole therapy fail.
  - target: Resistance-Gated Narrowing of Antifungal Options
    causal_link_type: DIRECT
    description: >-
      A resistant isolate removes the triazole class from the viable options for
      that patient, which has to be established by susceptibility testing rather
      than predicted from the organism's identity.
- name: Aspergillus beta-1,3-Glucan Synthesis by Fks Glucan Synthase
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  conforms_to: >-
    fungal_cell_wall_glucan_synthesis_inhibition#beta-1,3-Glucan Synthesis at
    the Plasma Membrane by Fks Glucan Synthase
  description: >-
    The Aspergillus plasma-membrane glucan-synthase complex polymerises
    beta-1,3-glucan, an essential structural polymer of the fungal cell wall and
    the target of the echinocandins. In Aspergillus the echinocandins are
    fungistatic rather than fungicidal — they cause hyphal tip lysis but not
    death of the organism — which is why they are a salvage and combination
    option here and a first-line option in candidiasis. As in the module, this
    node is target-only and does not assert that normal wall synthesis causes
    the intervention-conditional wall failure that follows inhibition.
  biological_processes:
  - preferred_term: beta-1,3-Glucan Biosynthesis
    term:
      id: GO:0006075
      label: (1->3)-beta-D-glucan biosynthetic process
  molecular_functions:
  - preferred_term: 1,3-beta-D-Glucan Synthase Activity
    term:
      id: GO:0003843
      label: 1,3-beta-D-glucan synthase activity
  evidence:
  - reference: PMID:31138565
    reference_title: "Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echinocandins (caspofungin, micafungin, anidulafungin), targeting
      β-1,3-glucan synthesis of the cell wall, represent one of the three
      currently available antifungal drug classes for the treatment of invasive
      fungal infections.
    explanation: >-
      Names the echinocandin agents and identifies beta-1,3-glucan synthesis as
      their shared target, which is the activity this node models. Evidence
      source is OTHER because this is a review.
  - reference: PMID:31138565
    reference_title: "Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Despite their limited antifungal activity against Aspergillus spp.,
      echinocandins are considered an alternative option for the treatment of
      invasive aspergillosis (IA).
    explanation: >-
      Qualifies the vulnerability: the target exists in Aspergillus but the
      class is second-line here, which is the caveat this node states. Graded
      PARTIAL because it supports the target's relevance while limiting the
      strength of the therapeutic claim.
  downstream:
  - target: Aspergillus Cell-Wall Integrity and Viability
    causal_link_type: DIRECT
    description: >-
      Beta-1,3-glucan is an essential structural component of the Aspergillus
      cell wall and supports hyphal integrity.
- name: Aspergillus Cell-Wall Integrity and Viability
  biological_scale: CELLULAR
  role: effector
  conforms_to: fungal_cell_wall_glucan_synthesis_inhibition#Cell-Wall Assembly and Integrity
  description: >-
    The beta-1,3-glucan-rich wall cross-links chitin and mannoproteins into the
    load-bearing hyphal wall that lets Aspergillus extend through tissue. It is
    also the surface the host reads: the same beta-glucan is the ligand dectin-1
    recognises on swollen conidia and germlings, so the wall is simultaneously
    the drug target and the immune epitope.
  biological_processes:
  - preferred_term: fungal-type cell wall organization
    term:
      id: GO:0031505
      label: fungal-type cell wall organization
  evidence:
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echinocandins block the synthesis of β-d-glucans located in the fungal
      cell wall. Echinocandins are fungicidal and fungistatic against Candida
      and Aspergillus spp., respectively.
    explanation: >-
      Locates beta-glucan in the fungal cell wall and records that the
      consequence of blocking its synthesis is fungistatic rather than
      fungicidal in Aspergillus. Evidence source is OTHER because this is a
      review.
  downstream:
  - target: Conidial Germination and Hyphal Tissue Invasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      An intact wall is required for the hyphal extension that invades tissue,
      although this entry does not claim wall integrity alone is sufficient for
      invasion.
- name: Aspergillus Intrinsic Fluconazole Resistance
  biological_scale: MOLECULAR
  role: intrinsic_resistance
  conforms_to: "antifungal_intrinsic_resistance_gating#Species-Level Intrinsic Antifungal Resistance"
  description: >-
    Aspergillus species are intrinsically resistant to fluconazole, so
    identifying the organism as Aspergillus excludes that agent before any
    susceptibility result and mandates a mould-active triazole (voriconazole,
    isavuconazole, posaconazole, itraconazole) or amphotericin B. This
    lineage-determined exclusion is deliberately kept separate from the acquired
    environmental cyp51A resistance modelled above: one is fixed by taxonomy and
    gates empiric therapy, the other is isolate-dependent and requires
    susceptibility testing to detect.
  evidence:
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Whereas some intrinsic resistance has been found naturally, e.g.,
      fluconazole-resistant ... and Aspergillus species
    explanation: >-
      Identifies naturally occurring fluconazole resistance in Aspergillus
      species, the species-level exclusion this gating node represents. Evidence
      source is OTHER because this is a review.
  downstream:
  - target: Resistance-Gated Narrowing of Antifungal Options
    causal_link_type: DIRECT
    description: >-
      Identifying the organism as Aspergillus removes fluconazole from the
      viable options before any susceptibility result, which is the empiric
      gating this node exists to record.
- name: Resistance-Gated Narrowing of Antifungal Options
  biological_scale: ORGANISM
  role: consequence
  conforms_to: >-
    antifungal_intrinsic_resistance_gating#Resistance-Gated Narrowing of
    Antifungal Options
  description: >-
    The shared consequence of the two resistance arms is a smaller set of viable
    agents. The fixed lineage-level exclusion constrains empiric therapy from the
    moment the organism is identified; the acquired environmental cyp51A alleles
    remove agents only once susceptibility testing detects them. Convergence here
    does not assert that either arm causes the other. The clinical cost is
    measurable: in a haematology cohort, 12-week mortality among non-ICU patients
    was 54.4% with voriconazole-resistant invasive aspergillosis against 30.7%
    with susceptible disease.
  evidence:
  - reference: PMID:31236587
    reference_title: Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality at 6 and 12 weeks was higher in voriconazole-resistant cases in
      all patients (42.3% versus 28.2%, P = 0.20; and 57.7% versus 36.9%, P =
      0.064) and in non-ICU patients (36.4% versus 21.6%, P = 0.16; and 54.4%
      versus 30.7%; P = 0.035), compared with susceptible ones.
    explanation: >-
      Quantifies the cost of losing the triazole option, which is what makes
      this narrowing node a consequence rather than a bookkeeping label.
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently, four antifungal drug classes are used by clinicians and
      veterinarians for systemic treatment
    explanation: >-
      Establishes how few systemic antifungal classes exist, which is why
      removing one materially narrows the options. Evidence source is OTHER
      because this is a review.
  downstream:
  - target: Conidial Germination and Hyphal Tissue Invasion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      With fewer active agents, hyphal growth is less likely to be
      pharmacologically controlled. The edge is typed as indirect with unknown
      intermediates because it runs through prescribing decisions and drug
      exposure rather than through a molecular step.
phenotypes:
- category: Respiratory
  name: Pneumonia
  subtype: Invasive
  description: >-
    Acute pneumonia with dense nodular or wedge-shaped consolidation reflecting
    hyphal invasion and ischaemic infarction of lung parenchyma. In the
    profoundly neutropenic host the inflammatory signs may be muted, which is
    part of why diagnosis is late.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
    temporality: ACUTE
  evidence:
  - reference: PMID:16088462
    reference_title: Invasive pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Invasive pulmonary aspergillosis (IPA) is the most common fungal pulmonary
      infection in severely immunocompromised patients. Aspergillus species are
      commonly isolated from the soil, plant debris, and the indoor environment,
      including the hospital.
    explanation: >-
      Establishes invasive pulmonary aspergillosis as the pneumonic
      manifestation in severely immunocompromised patients. Evidence source is
      OTHER because this is a review.
  - reference: PMID:16088462
    reference_title: Invasive pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of IPA is based on clinical, radiological, and mycological
      data. Clinical signs have a low specificity.
    explanation: >-
      Supports the statement in the description that the clinical presentation is
      non-specific, which is why diagnosis depends on imaging and mycology.
      Graded PARTIAL because it addresses diagnostic specificity rather than the
      pneumonia itself. Evidence source is OTHER because this is a review.
  - reference: PMID:10844935
    reference_title: Chronic granulomatous disease. Report on a national registry of 368 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pneumonia was the most prevalent infection (79% of patients; Aspergillus
      most prevalent cause)
    explanation: >-
      In a 368-patient chronic granulomatous disease registry pneumonia was the
      commonest infection and Aspergillus its commonest cause, which is direct
      human evidence that pneumonia is the dominant tissue presentation of
      invasive aspergillosis in a susceptible host.
- category: Respiratory
  name: Hemoptysis
  subtypes:
  - Aspergilloma
  - Chronic Pulmonary
  - Invasive
  description: >-
    Bleeding from the hypertrophied bronchial vasculature around a colonised or
    destroyed cavity, or from an infarcted angioinvasive lesion. It is the
    manifestation most likely to be immediately life-threatening in chronic
    disease and can also signal antifungal failure or resistance.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Haemoptysis may be controlled with tranexamic acid and bronchial artery
      embolisation, rarely surgical resection, and may be a sign of therapeutic
      failure and/or antifungal resistance.
    explanation: >-
      Records haemoptysis as a management problem in chronic pulmonary
      aspergillosis and as a marker of treatment failure. Evidence source is
      OTHER because this is a guideline review.
- category: Respiratory
  name: Pulmonary Cavity
  subtypes:
  - Chronic Pulmonary
  - Aspergilloma
  description: >-
    One or more thick- or thin-walled pulmonary cavities, with or without an
    intracavitary fungal ball, persisting for at least three months. The cavity
    is both the diagnostic hallmark of chronic pulmonary aspergillosis and the
    ecological niche that permits it.
  phenotype_term:
    preferred_term: Pulmonary cavity
    term:
      id: HP:0033655
      label: Pulmonary cavity
    temporality: CHRONIC
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of CPA requires a combination of characteristics: one or
      more cavities with or without a fungal ball present or nodules on thoracic
      imaging
    explanation: >-
      The cavity is the first required diagnostic characteristic in the
      guideline criteria. Evidence source is OTHER because this is a guideline
      review.
- category: Respiratory
  name: Pulmonary Infiltrates
  subtypes:
  - ABPA
  - Invasive
  description: >-
    Radiographic pulmonary infiltrates: fleeting and migratory in ABPA, where
    they reflect eosinophilic inflammation and mucus impaction rather than
    invasion, and fixed in invasive disease, where they reflect tissue necrosis.
  phenotype_term:
    preferred_term: Pulmonary infiltrates
    term:
      id: HP:0002113
      label: Pulmonary infiltrates
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      manifesting with poorly controlled asthma, recurrent pulmonary infiltrates
      and bronchiectasis
    explanation: >-
      Names recurrent pulmonary infiltrates as a defining ABPA manifestation.
      Evidence source is OTHER because this is a review.
- category: Respiratory
  name: Bronchiectasis
  subtype: ABPA
  description: >-
    Central (proximal) bronchiectasis from repeated mucus impaction and
    eosinophilic bronchial-wall inflammation. Irreversible, and the reason ABPA
    is worth diagnosing before it develops.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The importance of recognizing ABPA relates to the improvement of patient
      symptoms, and delay in development or prevention of bronchiectasis, one
      manifestation of permanent lung damage in ABPA.
    explanation: >-
      Identifies bronchiectasis as the permanent lung damage of ABPA. Evidence
      source is OTHER because this is a review.
- category: Respiratory
  name: Poorly Controlled Asthma
  subtype: ABPA
  description: >-
    Asthma that deteriorates or becomes refractory to standard therapy is the
    usual presentation of ABPA, and the reason ABPA is characteristically
    diagnosed late — the symptoms are attributed to the underlying asthma.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Allergic bronchopulmonary aspergillosis (ABPA) is an immunological
      pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus,
      manifesting with poorly controlled asthma
    explanation: >-
      Names poorly controlled asthma as the presenting manifestation of ABPA.
      Evidence source is OTHER because this is a review.
- category: Respiratory
  name: Dyspnea
  subtypes:
  - Chronic Pulmonary
  - Invasive
  - ABPA
  description: >-
    Breathlessness belongs to the classic symptom triad of chronic pulmonary
    aspergillosis alongside prolonged cough and weight loss, although a
    69-patient series counted it in only 7.2% of cases, so the triad describes
    the syndrome better than it predicts any individual patient. It is also
    part of the acute respiratory failure that defines the invasive
    presentation in critical illness, and it fluctuates with asthma control in
    ABPA.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:24299422
    reference_title: Chronic pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases
      usually presenting with prolonged and relapsing cough, dyspnoea and weight
      loss.
    explanation: >-
      Names dyspnoea among the three defining presenting symptoms of chronic
      pulmonary aspergillosis. Evidence source is OTHER because this is a review.
  - reference: PMID:29049239
    reference_title: Clinical features and diagnosis of chronic pulmonary aspergillosis in Chinese patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common symptoms in the CPA patients were cough (92.8%),
      hemoptysis (63.8%), sputum production (23.2%), fever (17.4%),
      breathlessness (7.2%), chest pain (5.8%), and constitutional symptoms
      (5.8%).
    explanation: >-
      Counts breathlessness in 7.2% of 69 patients with chronic pulmonary
      aspergillosis, which is the measured frequency behind the qualitative
      symptom triad and the reason the description states both.
- category: Constitutional
  name: Fever
  subtypes:
  - Invasive
  - Chronic Pulmonary
  description: >-
    Fever is the commonest clinical sign of acute invasive disease, recorded in
    98% of one COVID-19-associated pulmonary aspergillosis cohort, and what
    makes it useful is not its presence but its refractoriness: the temperature
    stays above 38.5 degrees Celsius through broad-spectrum antibacterial
    therapy, which is what prompts the search for a fungal cause. It is far
    less common in the chronic forms, counted in 17.4% of a 69-patient series
    and concentrated there in the more inflammatory cavitary and subacute
    invasive presentations.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:34947041
    reference_title: COVID-19-Associated Pulmonary Aspergillosis in Russia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical signs of CAPA are nonspecific, but typically include: fever
      (98%), cough (89%) and hemoptysis (36%).
    explanation: >-
      Counts fever in 98% of 45 patients with COVID-19-associated pulmonary
      aspergillosis, the highest-frequency clinical sign in that cohort, and
      states that the signs are non-specific.
  - reference: PMID:34947041
    reference_title: COVID-19-Associated Pulmonary Aspergillosis in Russia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with CAPA had increases body temperature above 38.5 °C that were
      resistant to antibiotic drugs (98% vs. 85%, p = 0.007)
    explanation: >-
      Adds the feature that makes the fever diagnostically useful: measured
      against COVID-19 controls without aspergillosis, it is refractory to
      antibacterial therapy.
  - reference: PMID:29049239
    reference_title: Clinical features and diagnosis of chronic pulmonary aspergillosis in Chinese patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common symptoms in the CPA patients were cough (92.8%),
      hemoptysis (63.8%), sputum production (23.2%), fever (17.4%),
      breathlessness (7.2%), chest pain (5.8%), and constitutional symptoms
      (5.8%).
    explanation: >-
      Counts fever in 17.4% of 69 patients with chronic pulmonary
      aspergillosis, the much lower frequency the description contrasts with
      the invasive forms.
  - reference: PMID:29049239
    reference_title: Clinical features and diagnosis of chronic pulmonary aspergillosis in Chinese patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, fever and constitutional symptoms were observed to
      be more common in SAIA and CCPA patients.
    explanation: >-
      Locates the fever within the chronic spectrum: it clusters in the
      subacute invasive and chronic cavitary subgroups rather than in simple
      aspergilloma.
- category: Respiratory
  name: Chronic Cough
  subtypes:
  - Chronic Pulmonary
  - Aspergillus Bronchitis
  description: >-
    Persistent cough, often productive, is the commonest symptom of chronic
    pulmonary aspergillosis and of Aspergillus bronchitis, and is part of the
    chronic pulmonary symptom complex the diagnostic criteria require.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
    temporality: CHRONIC
  evidence:
  - reference: PMID:24299422
    reference_title: Chronic pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases
      usually presenting with prolonged and relapsing cough, dyspnoea and weight
      loss.
    explanation: >-
      Names prolonged relapsing cough as the leading presenting symptom of
      chronic pulmonary aspergillosis. Evidence source is OTHER because this is
      a review.
- category: Constitutional
  name: Weight Loss
  subtype: Chronic Pulmonary
  description: >-
    Progressive weight loss is one of the three symptoms that define the usual
    presentation of chronic pulmonary aspergillosis, alongside prolonged
    relapsing cough and dyspnoea. It is why the chronic forms are described as
    consuming diseases.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24299422
    reference_title: Chronic pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic pulmonary aspergillosis (CPA) is a group of consuming diseases
      usually presenting with prolonged and relapsing cough, dyspnoea and weight
      loss.
    explanation: >-
      Names weight loss as one of the three defining presenting symptoms of
      chronic pulmonary aspergillosis. Evidence source is OTHER because this is
      a review.
- category: Laboratory
  name: Eosinophilia
  subtype: ABPA
  description: >-
    Peripheral blood eosinophilia reflects the Th2-driven eosinophilic airway
    inflammation modelled in the pathophysiology, but it is a poor diagnostic
    discriminator: in a 209-patient ABPA series the median count was 850
    cells/microlitre and 60% of patients fell below the traditional 1000
    cells/microlitre criterion. Where it does track disease is with structural
    damage — counts were higher in patients with bronchiectasis and with
    high-attenuation mucus, which is the link between this laboratory finding
    and the airway destruction downstream of it.
  phenotype_term:
    preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:22118718
    reference_title: Clinical relevance of peripheral blood eosinophil count in allergic bronchopulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median (IQR) eosinophil count at diagnosis was 850 (510-1541)cells/μl,
      and 60% of the patients had an eosinophil count of <1000 cells/μl.
    explanation: >-
      Quantifies the eosinophil count actually observed at ABPA diagnosis and
      shows most patients fall below the traditional criterion.
  - reference: PMID:22118718
    reference_title: Clinical relevance of peripheral blood eosinophil count in allergic bronchopulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median eosinophil count was higher in patients with an high resolution
      computed tomography (HRCT) chest finding of bronchiectasis (986 vs. 620,
      p<0.001) vs. those without and in patients with high-attenuation mucus
      (1200 vs. 800, p<0.001) compared to those without high-attenuation mucus.
    explanation: >-
      Links the eosinophil count to the bronchiectasis and mucus-plugging
      phenotypes that this entry models downstream of eosinophilic airway
      inflammation.
diagnosis:
- name: Serum or bronchoalveolar lavage galactomannan enzyme immunoassay
  description: >-
    The standard non-invasive test for invasive aspergillosis, detecting the
    Aspergillus cell-wall polysaccharide released during hyphal growth. The
    cut-off is a clinical decision rather than a fixed property of the assay:
    at an optical density index of 0.5 the Cochrane meta-analysis of 54 studies
    and 5660 patients reports 82% sensitivity and 81% specificity, at 1.0 it is
    72% and 88%, and at 1.5 it is 61% and 93%. Which point to use depends on the
    pre-test probability in the population being screened, and the evidence base
    is confined to patients with neutropenia or functionally compromised
    neutrophils.
  diagnosis_term:
    preferred_term: serum or bronchoalveolar galactomannan enzyme immunoassay
    term:
      id: NCIT:C154817
      label: Galactomannan Antigen Measurement
  markers: Serum galactomannan
  evidence:
  - reference: PMID:26716951
    reference_title: Galactomannan detection for invasive aspergillosis in immunocompromised patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When using an optical density index (ODI) of 0.5 as a cut-off value, the
      sensitivity of the test was 82% (73% to 90%) and the specificity was 81%
      (72% to 90%). At a cut-off value of 1.0 ODI, the sensitivity was 72% (65%
      to 80%) and the specificity was 88% (84% to 92%). At a cut-off value of 1.5
      ODI, the sensitivity was 61% (47% to 75%) and the specificity was 93% (89%
      to 97%).
    explanation: >-
      Gives the diagnostic accuracy at all three cut-offs named in the
      description, which is the substance of this diagnostic entry.
  - reference: PMID:26716951
    reference_title: Galactomannan detection for invasive aspergillosis in immunocompromised patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We included cross-sectional studies, case-control designs and consecutive
      series of patients assessing the diagnostic accuracy of galactomannan
      detection for the diagnosis of invasive aspergillosis in patients with
      neutropenia or patients whose neutrophils are functionally compromised.
    explanation: >-
      Delimits the population in which this accuracy was established, which is
      the caveat stated in the description.
- name: Aspergillus IgG antibody (precipitins)
  description: >-
    The immunological limb of the chronic pulmonary aspergillosis criteria, and
    the most useful single test in that setting because the host is
    immunocompetent enough to mount a strong antibody response. Elevated in over
    90% of patients. It is not useful for invasive disease, where the host
    cannot mount the response.
  diagnosis_term:
    preferred_term: Aspergillus IgG precipitin measurement
    term:
      id: NCIT:C166028
      label: Aspergillus Antibody Measurement
  markers: Aspergillus IgG precipitins
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus antibody (precipitins) is elevated in over 90% of patients.
    explanation: >-
      Gives the sensitivity of the test in chronic pulmonary aspergillosis.
      Evidence source is OTHER because this is a guideline review.
  - reference: PMID:24299422
    reference_title: Chronic pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnostics largely rely on serologic Aspergillus precipitins and findings
      on thoracic computed tomography.
    explanation: >-
      Names serology plus CT as the pair on which the chronic-form diagnosis
      rests. Evidence source is OTHER because this is a review.
- name: Composite criteria for chronic pulmonary aspergillosis
  description: >-
    Chronic pulmonary aspergillosis has no single confirmatory test. The
    diagnosis requires a cavity or nodules on thoracic imaging, direct or
    immunological evidence of Aspergillus, exclusion of alternatives, and all of
    it persisting for at least three months. The persistence requirement is what
    separates this from subacute invasive aspergillosis, which progresses in
    under three months and is managed as invasive disease.
  diagnosis_term:
    preferred_term: composite clinical, radiological and immunological assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of CPA requires a combination of characteristics: one or
      more cavities with or without a fungal ball present or nodules on thoracic
      imaging, direct evidence of Aspergillus infection (microscopy or culture
      from biopsy) or an immunological response to Aspergillus spp. and
      exclusion of alternative diagnoses, all present for at least 3 months.
    explanation: >-
      States the composite criteria in full, including the three-month
      persistence requirement. Evidence source is OTHER because this is a
      guideline review.
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subacute invasive pulmonary aspergillosis (formerly called chronic
      necrotising pulmonary aspergillosis) is a more rapidly progressive
      infection (<3 months) usually found in moderately immunocompromised
      patients, which should be managed as invasive aspergillosis.
    explanation: >-
      Supports the distinction the description draws between the chronic forms
      and the subacute invasive form, and its management consequence. Evidence
      source is OTHER because this is a guideline review.
- name: Total and Aspergillus-specific IgE for ABPA
  description: >-
    ABPA is diagnosed on a composite of asthma or cystic fibrosis, A.
    fumigatus-specific IgE, a markedly raised total IgE, and supporting
    radiological and haematological features. Serum IgE also serves as the
    quantitative response measure: a fall of at least 25% is one component of
    the accepted treatment-response definition.
  diagnosis_term:
    preferred_term: total and Aspergillus-specific serum IgE measurement
    term:
      id: NCIT:C81970
      label: Immunoglobulin E Measurement
  markers: Total and Aspergillus-specific serum IgE
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      New diagnosis and staging criteria for ABPA are proposed.
    explanation: >-
      Identifies this ISHAM working-group paper as the source of the current
      ABPA diagnostic and staging criteria. Graded PARTIAL because the abstract
      announces the criteria without enumerating them. Evidence source is OTHER
      because this is a review.
  - reference: PMID:10717010
    reference_title: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A response was defined as a reduction of at least 50 percent in the
      corticosteroid dose, a decrease of at least 25 percent in the serum IgE
      concentration
    explanation: >-
      Establishes serum IgE as a quantitative response measure in ABPA, the
      second use this diagnostic entry records.
- name: Thoracic computed tomography
  description: >-
    Imaging carries the diagnosis in both directions of the spectrum, because
    the clinical signs do not: nodules with a halo or air-crescent sign in
    invasive disease, cavities with or without a fungal ball in the chronic
    forms. The structured findings are curated under imaging_findings.
  diagnosis_term:
    preferred_term: thoracic computed tomography
    term:
      id: NCIT:C191501
      label: Chest Computed Tomography
  evidence:
  - reference: PMID:16088462
    reference_title: Invasive pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of IPA is based on clinical, radiological, and mycological
      data. Clinical signs have a low specificity. The most typical computed
      tomographic (CT) findings are nodules with or without the halo sign or the
      air crescent sign.
    explanation: >-
      States that clinical signs are non-specific and names the CT findings that
      carry the diagnosis instead. Evidence source is OTHER because this is a
      review.
imaging_findings:
- name: Nodules with halo sign or air crescent sign on chest CT
  modality: CT
  subtype: Invasive
  diagnostic: true
  description: >-
    The characteristic CT appearance of invasive pulmonary aspergillosis:
    pulmonary nodules, early on surrounded by a rim of ground-glass attenuation
    (the halo sign) and later cavitating with a crescent of air between the
    necrotic centre and the cavity wall (the air crescent sign). These are the
    macroscopic reading of the angioinvasive, infarcting lesion modelled in the
    pathophysiology, and they are what carries the diagnosis when clinical signs
    do not.
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:16088462
    reference_title: Invasive pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most typical computed tomographic (CT) findings are nodules with or
      without the halo sign or the air crescent sign.
    explanation: >-
      Names the two signs and identifies them as the typical CT appearance of
      invasive pulmonary aspergillosis. Evidence source is OTHER because this is
      a review.
- name: Pulmonary cavity with intracavitary fungal ball on chest CT
  modality: CT
  subtype: Chronic Pulmonary
  diagnostic: true
  description: >-
    One or more pulmonary cavities, with or without a mobile intracavitary
    fungal ball, often with adjacent pleural thickening. Together with an
    Aspergillus antibody response and three months of persistence this is the
    diagnosis of chronic pulmonary aspergillosis.
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  phenotype_term:
    preferred_term: Pulmonary cavity
    term:
      id: HP:0033655
      label: Pulmonary cavity
  evidence:
  - reference: PMID:24299422
    reference_title: Chronic pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnostics largely rely on serologic Aspergillus precipitins and findings
      on thoracic computed tomography. The latter are manifold comprising cavity
      formation, pleural involvement and sometimes aspergilloma.
    explanation: >-
      Names the CT features this finding records and their diagnostic weight in
      chronic pulmonary aspergillosis. Evidence source is OTHER because this is
      a review.
histopathology:
- name: Septate hyphae with acute-angle branching and angioinvasion
  subtype: Invasive
  diagnostic: true
  description: >-
    On GMS or PAS-stained tissue, Aspergillus appears as thin, narrow, septate
    hyphae branching at an acute angle, with vascular invasion and tissue
    necrosis. The morphology is the point of the finding: it is what separates
    Aspergillus from the Mucorales, whose hyphae are broad, aseptate and branch
    at right angles, and the two moulds need different drugs.
  evidence:
  - reference: PMID:36407132
    reference_title: "Preliminary Experience in Post-COVID-19 Mycoses: A Pathologist's Perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six of the 45 cases also reveal thin, narrow septate, acute angle
      branching hyphae, indicating co-existing Aspergillosis (6/45).
    explanation: >-
      Gives the histomorphology by which Aspergillus is identified in tissue,
      which is the finding this entry records.
differential_diagnoses:
- name: Mucormycosis
  description: >-
    The clinically decisive differential, because the treatment diverges: the
    Mucorales are intrinsically resistant to voriconazole and to the
    echinocandins, so an Aspergillus-directed regimen is inactive against them.
    The two are separated on tissue morphology.
  distinguishing_features:
  - Broad, aseptate, ribbon-like hyphae branching at right angles, versus the thin, narrow, septate, acute-angle-branching hyphae of Aspergillus
  - Serum and BAL galactomannan is negative in mucormycosis
  - Intrinsic resistance to voriconazole and the echinocandins, leaving amphotericin B or isavuconazole
  evidence:
  - reference: PMID:36407132
    reference_title: "Preliminary Experience in Post-COVID-19 Mycoses: A Pathologist's Perspective."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the surgical debridement specimens from post-COVID cases had
      histomorphology of mucormycosis displaying broad, aseptate, ribbon-like
      fungal hyphae with right-angle branching (45/45).
    explanation: >-
      Gives the contrasting mucormycosis histomorphology against which
      Aspergillus is distinguished, in a series where six of the same 45 cases
      carried both.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Invasive aspergillosis carries a crude annual mortality of 85.2% against its
    global incidence, and 90-day mortality among ICU influenza patients who
    develop it is 51%. Chronic pulmonary aspergillosis is less lethal but
    consuming and lifelong, with 18.5% annual mortality against an incidence
    comparable to the invasive form. ABPA is rarely fatal but causes irreversible
    bronchiectasis in a young asthmatic population.
  evidence:
  - reference: PMID:38224705
    reference_title: Global incidence and mortality of severe fungal disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Annually, over 2 113 000 people develop invasive aspergillosis in the
      context of chronic obstructive pulmonary disease, intensive care, lung
      cancer, or haematological malignancy, with a crude annual mortality of
      1 801 000 (85·2%).
    explanation: >-
      Source of the invasive-aspergillosis mortality figure behind this burden
      assessment. Evidence source is OTHER because this is a modelling study.
  - reference: PMID:30076119
    reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 90-day mortality was 51% in patients in the influenza cohort with
      invasive pulmonary aspergillosis and 28% in the influenza cohort without
      invasive pulmonary aspergillosis (p=0·0001).
    explanation: >-
      Gives the measured mortality among a defined ICU cohort, complementing the
      modelled global figure.
biochemical:
- name: Serum galactomannan
  subtype: Invasive
  notes: >-
    Galactomannan is a polysaccharide of the Aspergillus cell wall released
    during hyphal growth; its detection in serum or bronchoalveolar lavage by
    sandwich ELISA is the standard non-invasive marker of invasive disease. The
    trade-off between cut-offs is the point: raising the optical density index
    from 0.5 to 1.5 moves specificity from 81% to 93% but drops sensitivity from
    82% to 61%, so the threshold has to be chosen against the pre-test
    probability of the population being tested.
  presence: increased
  specificity: >-
    Validated in patients with neutropenia or functionally compromised
    neutrophils; performance in other host groups is not established by this
    evidence.
  evidence:
  - reference: PMID:26716951
    reference_title: Galactomannan detection for invasive aspergillosis in immunocompromised patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When using an optical density index (ODI) of 0.5 as a cut-off value, the
      sensitivity of the test was 82% (73% to 90%) and the specificity was 81%
      (72% to 90%).
    explanation: >-
      Cochrane meta-analysis of 54 studies giving the diagnostic accuracy at the
      commonly used 0.5 cut-off.
  - reference: PMID:26716951
    reference_title: Galactomannan detection for invasive aspergillosis in immunocompromised patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At a cut-off value of 1.5 ODI, the sensitivity was 61% (47% to 75%) and
      the specificity was 93% (89% to 97%).
    explanation: >-
      Gives the higher-threshold operating point, establishing the
      sensitivity-specificity trade-off this entry describes.
- name: Aspergillus IgG precipitins
  subtype: Chronic Pulmonary
  notes: >-
    Serum Aspergillus-specific IgG antibody (precipitins) is the immunological
    limb of the chronic pulmonary aspergillosis diagnostic criteria and is
    elevated in over 90% of patients — the single most useful test in a host who,
    being immunocompetent, mounts a strong antibody response.
  presence: increased
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus antibody (precipitins) is elevated in over 90% of patients.
    explanation: >-
      Gives the sensitivity of Aspergillus antibody in chronic pulmonary
      aspergillosis. Evidence source is OTHER because this is a guideline
      review.
- name: Total and Aspergillus-specific serum IgE
  subtype: ABPA
  notes: >-
    Marked elevation of total serum IgE together with A. fumigatus-specific IgE
    is required for the diagnosis of ABPA, and a fall of at least 25% in total
    IgE is one of the components of the accepted treatment-response definition.
  presence: increased
  evidence:
  - reference: PMID:10717010
    reference_title: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A response was defined as a reduction of at least 50 percent in the
      corticosteroid dose, a decrease of at least 25 percent in the serum IgE
      concentration
    explanation: >-
      Serum IgE concentration is used as a quantitative response endpoint in the
      pivotal ABPA trial, which establishes it as the tracked biomarker of this
      subtype.
genetic:
- name: CYBB
  relationship_type: SUSCEPTIBILITY
  notes: >-
    X-linked chronic granulomatous disease is caused by loss-of-function
    variants in CYBB (gp91-phox), the catalytic subunit of the phagocyte NADPH
    oxidase. Losing the oxidative burst removes the antibody-opsonisation- and
    NADPH oxidase-dependent extracellular route that kills Aspergillus hyphae,
    which is why Aspergillus is the leading cause of pneumonia in CGD and its
    commonest cause of death. This is a susceptibility relationship: the variant
    causes CGD, and CGD permits aspergillosis on exposure.
  gene_term:
    preferred_term: CYBB
    term:
      id: hgnc:2578
      label: CYBB
  evidence:
  - reference: PMID:10844935
    reference_title: Chronic granulomatous disease. Report on a national registry of 368 patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common causes of death were pneumonia and/or sepsis due to
      Aspergillus (23 patients) or Burkholderia cepacia (12 patients).
    explanation: >-
      In the 368-patient CGD registry Aspergillus is the leading cause of death,
      which is the clinical measure of how much the NADPH oxidase route matters
      for this organism.
  - reference: PMID:26718340
    reference_title: "Human Neutrophils Use Different Mechanisms To Kill Aspergillus fumigatus Conidia and Hyphae: Evidence from Phagocyte Defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the extracellular destruction of the Aspergillus hyphae needs opsonization
      by Abs and involves predominantly recognition via Fcγ receptors, signaling
      via Syk, PI3K, and protein kinase C to trigger the production of toxic
      reactive oxygen metabolites by the NADPH oxidase and myeloperoxidase
    explanation: >-
      The anti-hyphal killing mechanism requires the NADPH oxidase, the enzyme
      complex whose catalytic subunit CYBB encodes. This is the mechanistic link
      between a CYBB loss-of-function genotype and susceptibility to
      Aspergillus.
- name: TLR4
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Donor TLR4 haplotypes carrying the D299G and T399I substitutions increased
    the risk of invasive aspergillosis in recipients of unrelated-donor
    allogeneic haematopoietic-cell transplants, in a discovery cohort and a
    replication cohort. Note the direction of the effect: it is the donor's
    genotype, not the recipient's, because the relevant innate cells are
    donor-derived after engraftment.
  gene_term:
    preferred_term: TLR4
    term:
      id: hgnc:11850
      label: TLR4
  evidence:
  - reference: PMID:18946062
    reference_title: Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased
      the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20;
      95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio
      for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002).
    explanation: >-
      Quantifies the donor-genotype effect on invasive aspergillosis risk after
      allogeneic transplantation.
  - reference: PMID:18946062
    reference_title: Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the association was present in unrelated recipients of hematopoietic-cell
      transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in
      related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07)
    explanation: >-
      The replication limits the association to unrelated-donor transplants.
      Graded PARTIAL because it qualifies rather than uniformly supports the
      susceptibility claim.
- name: CARD9
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Autosomal recessive CARD9 deficiency causes invasive fungal disease in
    otherwise healthy children and adults. CARD9 sits downstream of the C-type
    lectin receptors — the dectin-1 arm this entry models as the first
    recognition step — and its loss impairs myeloid cytokine and chemokine
    output, neutrophil fungal killing in vitro, and neutrophil recruitment in
    vivo. Every causal fungus reported in these patients belongs to the
    Ascomycota, Aspergillus among them. Like CYBB, this is a susceptibility
    relationship rather than a cause of aspergillosis as such.
  gene_term:
    preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  evidence:
  - reference: PMID:30136218
    reference_title: "Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strikingly, all the causal fungi belonged to the phylum Ascomycota:
      commensal Candida and saprophytic Trychophyton, Aspergillus, Phialophora,
      Exophiala, Corynesprora, Aureobasidium, and Ochroconis.
    explanation: >-
      Names Aspergillus among the fungi causing invasive disease in CARD9
      deficiency, which is the susceptibility this entry records.
  - reference: PMID:30136218
    reference_title: "Inherited CARD9 Deficiency: Invasive Disease Caused by Ascomycete Fungi in Previously Healthy Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with CARD9 deficiency present impaired cytokine and chemokine
      production by macrophages, dendritic cells, and peripheral blood
      mononuclear cells and defective killing of some fungi by neutrophils in
      vitro. Neutrophil recruitment to sites of infection is impaired in vivo.
    explanation: >-
      Gives the mechanism: the same macrophage recognition-to-recruitment and
      neutrophil killing steps this entry models are the ones CARD9 deficiency
      degrades.
environmental:
- name: Inhalation of airborne Aspergillus conidia
  exposure_term:
    preferred_term: exposure to airborne Aspergillus conidia
    term:
      id: ECTO:3000000
      label: exposure to organism
  effect: Necessary exposure for every clinical form of aspergillosis
  description: >-
    Continuous, essentially unavoidable inhalational exposure to conidia
    dispersed from soil, decaying vegetation, compost, and construction or
    ventilation dust. The exposure is universal, which is why it explains the
    disease only in combination with a host factor. The bound term is the
    general ECTO organism-exposure class: ECTO has no term for exposure to
    Aspergillus, to fungi, or to airborne spores, so the most specific accurate
    binding available is used rather than a narrower approximate one.
  influences_mechanisms:
  - target: Inhalation and Alveolar Deposition of Airborne Aspergillus Conidia
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Airborne conidia reaching the alveolus are the initiating event of every
      form of the disease.
    evidence:
    - reference: PMID:33563417
      reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Aspergillus species are ubiquitous in the environment. Aspergillosis is
        acquired by inhalation of Aspergillus spores.
      explanation: >-
        States that the disease is acquired by inhaling environmental spores,
        the exposure-to-mechanism link this edge asserts. Evidence source is
        OTHER because this is a review.
  evidence:
  - reference: PMID:33563417
    reference_title: "Pulmonary Aspergillosis: Spectrum of Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aspergillus species are ubiquitous in the environment. Aspergillosis is
      acquired by inhalation of Aspergillus spores. In normal hosts, spore
      inhalation rarely causes lung disease.
    explanation: >-
      Establishes both the ubiquity of the exposure and that it is insufficient
      by itself, which is exactly the claim this entry makes. Evidence source is
      OTHER because this is a review.
- name: Systemic corticosteroid therapy
  exposure_term:
    preferred_term: exposure to corticosteroid
    term:
      id: ECTO:0000173
      label: exposure to corticosteroid
  effect: Predisposition to invasive aspergillosis
  description: >-
    Corticosteroids impair macrophage and neutrophil antifungal function while
    leaving cell counts intact, so they produce invasive disease by a different
    route from chemotherapy-induced neutropenia. Corticosteroid use was an
    independent risk factor for invasive pulmonary aspergillosis in the ICU
    influenza cohort alongside influenza itself.
  influences_mechanisms:
  - target: Failure of Phagocyte Clearance of Aspergillus
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Corticosteroid exposure degrades phagocyte antifungal function, the
      permissive state this node models.
    evidence:
    - reference: PMID:30076119
      reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In this study, influenza was found to be independently associated with
        invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI
        2·63-10·26; p<0·0001), along with a higher APACHE II score, male sex,
        and use of corticosteroids.
      explanation: >-
        Corticosteroid use is one of the factors independently associated with
        invasive pulmonary aspergillosis in this multivariable analysis.
  evidence:
  - reference: PMID:30076119
    reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with a higher APACHE II score, male sex, and use of corticosteroids
    explanation: >-
      Names corticosteroid use among the independent risk factors identified by
      the study's logistic regression.
- name: Severe influenza or COVID-19 critical illness
  effect: Predisposition to invasive pulmonary aspergillosis in hosts with no classical host factor
  description: >-
    Severe respiratory viral infection is a distinct and comparatively recent
    route into invasive aspergillosis: it produces the phenotype in ICU patients
    who carry no EORTC/MSG host factor at all. In seven influenza seasons across
    seven Belgian and Dutch ICUs, 14% of non-immunocompromised influenza patients
    developed invasive pulmonary aspergillosis against 5% of influenza-negative
    severe community-acquired pneumonia controls. Ninety-day mortality was 51%
    among influenza patients who developed it versus 28% among those who did
    not. The same pattern was then reported for COVID-19-associated pulmonary
    aspergillosis. No exposure_term is bound: this is an acute infectious
    comorbidity rather than an environmental exposure, and ECTO has no term that
    describes it without overstating it as an environmental agent.
  influences_mechanisms:
  - target: Failure of Phagocyte Clearance of Aspergillus
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe viral pneumonitis produces a functional antifungal defect
      sufficient to permit conidial germination in hosts with no classical
      immunocompromise. The intermediates are not established, so the edge is
      typed as indirect with unknown intermediates.
    evidence:
    - reference: PMID:30076119
      reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        whereas in the non-immunocompromised influenza case group, incidence was
        14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in
        the control group developed invasive pulmonary aspergillosis.
      explanation: >-
        The comparison in non-immunocompromised patients isolates influenza
        itself, rather than pre-existing immunocompromise, as the factor
        permitting invasive disease.
  evidence:
  - reference: PMID:30076119
    reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 90-day mortality was 51% in patients in the influenza cohort with
      invasive pulmonary aspergillosis and 28% in the influenza cohort without
      invasive pulmonary aspergillosis (p=0·0001).
    explanation: >-
      Quantifies the mortality cost of the association, establishing it as a
      clinically consequential predisposition rather than an incidental finding.
  - reference: PMID:32339350
    reference_title: COVID-19 associated pulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      COVID-19 associated invasive pulmonary aspergillosis was found in five of
      19 consecutive critically ill patients with moderate to severe ARDS.
    explanation: >-
      Extends the same viral-critical-illness association from influenza to
      COVID-19.
treatments:
- name: Voriconazole
  description: >-
    Mould-active triazole and the agent that established triazole primacy for
    invasive aspergillosis: in the pivotal randomised trial it beat amphotericin
    B deoxycholate on both response (52.8% vs 31.6%) and 12-week survival (70.8%
    vs 57.9%) with fewer severe drug-related adverse events. Transient visual
    disturbance is common and its narrow therapeutic index makes serum-level
    monitoring routine.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: voriconazole
      term:
        id: CHEBI:10023
        label: voriconazole
  target_mechanisms:
  - target: Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
    treatment_effect: INHIBITS
    description: >-
      Voriconazole binds heme iron at fungal lanosterol 14-alpha-demethylase,
      depleting ergosterol and accumulating toxic methylsterols.
  evidence:
  - reference: PMID:12167683
    reference_title: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At week 12, there were successful outcomes in 52.8 percent of the patients
      in the voriconazole group (complete responses in 20.8 percent and partial
      responses in 31.9 percent) and 31.6 percent of those in the amphotericin B
      group
    explanation: >-
      The randomised comparison establishing voriconazole's superiority over
      amphotericin B for primary therapy of invasive aspergillosis.
  - reference: PMID:12167683
    reference_title: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Voriconazole-treated patients had significantly fewer severe drug-related
      adverse events, but transient visual disturbances were common with
      voriconazole (occurring in 44.8 percent of patients).
    explanation: >-
      Records the tolerability advantage and the characteristic visual adverse
      effect that shape how the drug is used.
- name: Isavuconazole
  description: >-
    Mould-active triazole, non-inferior to voriconazole for all-cause 42-day
    mortality in invasive mould disease in the SECURE trial (19% vs 20%), with
    fewer hepatobiliary, eye and skin adverse events. Preferred where
    voriconazole toxicity, drug interactions or level variability are limiting.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: isavuconazole
      term:
        id: CHEBI:85979
        label: isavuconazole
  target_mechanisms:
  - target: Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
    treatment_effect: INHIBITS
    description: >-
      Isavuconazole inhibits the same fungal lanosterol 14-alpha-demethylase
      step as the other triazoles.
  evidence:
  - reference: PMID:26684607
    reference_title: "Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All-cause mortality from first dose of study drug to day 42 for the ITT
      population was 19% with isavuconazole (48 patients) and 20% with
      voriconazole (52 patients), with an adjusted treatment difference of -1·0%
      (95% CI -7·8 to 5·7).
    explanation: >-
      The primary efficacy result establishing non-inferiority to voriconazole.
  - reference: PMID:26684607
    reference_title: "Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, isavuconazole-treated patients had a lower frequency of
      hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39
      [15%] vs 69 [27%]; p=0·002)
    explanation: >-
      Quantifies the tolerability advantage over voriconazole that drives agent
      choice when both are active.
- name: Itraconazole for chronic and allergic disease
  description: >-
    Oral triazole and the workhorse of the non-invasive forms. In ABPA that has
    become corticosteroid-dependent it doubles the response rate over placebo
    (46% vs 19%) as a
    steroid-sparing agent; in chronic cavitary pulmonary aspergillosis it beats
    supportive care alone (76.5% vs 35.7% overall response at six months).
    Therapy in chronic disease is prolonged, and azole levels, drug interactions
    and toxicity need monitoring throughout.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: itraconazole
      term:
        id: CHEBI:6076
        label: itraconazole
  target_mechanisms:
  - target: Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
    treatment_effect: INHIBITS
    description: >-
      Itraconazole inhibits fungal lanosterol 14-alpha-demethylase, reducing the
      antigenic fungal burden in ABPA and the organism load in chronic cavitary
      disease.
  evidence:
  - reference: PMID:10717010
    reference_title: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were responses in 13 of 28 patients in the itraconazole group (46
      percent), as compared with 5 of 27 patients in the placebo group (19
      percent, P=0.04).
    explanation: >-
      The randomised placebo-controlled result establishing itraconazole as a
      steroid-sparing agent in ABPA.
  - reference: PMID:23496375
    reference_title: "Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The number of patients showing overall response was significantly higher
      in the itraconazole group (76.5%) vs. the control (35.7%) group (P = 0.02).
    explanation: >-
      The randomised result supporting itraconazole over supportive care alone
      in chronic cavitary pulmonary aspergillosis.
- name: Oral corticosteroid therapy for ABPA
  description: >-
    Systemic corticosteroids remain primary therapy for ABPA exacerbations,
    suppressing the Th2/IgE-driven eosinophilic inflammation rather than the
    fungus. The tension with the rest of this entry is real and worth naming:
    the same drug class that treats the allergic form is an independent risk
    factor for the invasive form, so the host phenotype has to be established
    before the agent is chosen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  target_mechanisms:
  - target: Eosinophilic Airway Inflammation and Mucus Plugging
    treatment_effect: INHIBITS
    description: >-
      Corticosteroids suppress the eosinophilic airway inflammation and mucus
      impaction that produce the recurrent infiltrates of ABPA.
  evidence:
  - reference: PMID:23889240
    reference_title: "Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary therapy consists of oral corticosteroids to control exacerbations,
      itraconazole as a steroid-sparing agent and optimized asthma therapy.
    explanation: >-
      The ISHAM working group names oral corticosteroids as primary therapy for
      ABPA exacerbations. Evidence source is OTHER because this is a review.
  - reference: PMID:30076119
    reference_title: "Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with a higher APACHE II score, male sex, and use of corticosteroids
    explanation: >-
      Supports the caution stated in the description: corticosteroid use is an
      independent risk factor for the invasive form of the same disease this
      treatment is used for in its allergic form.
- name: Anti-type-2 biologic therapy for ABPA
  description: >-
    For ABPA that stays dependent on oral corticosteroids, biologics directed at
    the type-2 pathway are used as steroid-sparing add-ons. A systematic review
    and meta-analysis of 86 studies covering 346 patients found that the anti-IgE
    antibody omalizumab reduced exacerbation rates, oral corticosteroid dose and
    total IgE while improving FEV1; dupilumab and mepolizumab showed the same direction on an
    individual-patient-data meta-analysis. This is adjunctive and the evidence is
    pooled case series rather than randomised trials, which is why it sits behind
    corticosteroids and itraconazole here.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: omalizumab
      term:
        id: NCIT:C29299
        label: Omalizumab
  target_mechanisms:
  - target: Th2 Sensitisation and IgE-Mediated Hypersensitivity to Aspergillus Antigens
    treatment_effect: INHIBITS
    description: >-
      Omalizumab binds free IgE, and the anti-IL-4-receptor and anti-IL-5
      agents interrupt the type-2 cytokine signalling that drives IgE class
      switching and eosinophil recruitment.
  evidence:
  - reference: PMID:38898129
    reference_title: "Efficacy of Biologics in Patients with Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Omalizumab therapy significantly reduced exacerbation rates (- 2.29 [95%CI
      - 3.32, - 1.26]), OCS dosage (- 10.91 mg [95%CI - 18.98, - 2.85]), and
      total IgE levels (- 273.07 IU/mL [95%CI - 379.30, - 166.84]), meanwhile
      improving FEV1% predicted (10.09% [95%CI 6.62, 13.55]).
    explanation: >-
      Quantifies the omalizumab effect on exacerbations, steroid dose, IgE and
      lung function in pooled ABPA data.
  - reference: PMID:38898129
    reference_title: "Efficacy of Biologics in Patients with Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further randomized, controlled studies with a larger sample size and longer
      follow-up are needed to confirm these findings.
    explanation: >-
      The authors' own limitation, quoted because it is the reason this entry
      places biologics behind corticosteroids and itraconazole. Graded PARTIAL
      because it qualifies rather than supports the efficacy claim.
- name: Echinocandin salvage therapy
  description: >-
    Caspofungin and the other echinocandins inhibit beta-1,3-glucan synthesis.
    Against Aspergillus they are fungistatic rather than fungicidal and their
    single-agent activity is limited, so they are an alternative or combination
    option rather than first-line — a genuinely different position from the one
    the same class holds in candidiasis. They are exceptionally well tolerated
    and have almost no drug-drug interactions, which is why they remain useful
    when triazoles cannot be given.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: caspofungin
      term:
        id: CHEBI:474180
        label: caspofungin
  target_mechanisms:
  - target: Aspergillus beta-1,3-Glucan Synthesis by Fks Glucan Synthase
    treatment_effect: INHIBITS
    description: >-
      Echinocandins are non-competitive inhibitors of the beta-1,3-glucan
      synthase complex, depleting the wall polymer.
  evidence:
  - reference: PMID:31138565
    reference_title: "Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Despite their limited antifungal activity against Aspergillus spp.,
      echinocandins are considered an alternative option for the treatment of
      invasive aspergillosis (IA).
    explanation: >-
      States both the limited activity and the alternative-option role that this
      treatment entry claims. Evidence source is OTHER because this is a review.
  - reference: PMID:31138565
    reference_title: "Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This drug class exhibits several advantages, such as excellent
      tolerability and its potential for synergistic interactions with some
      other antifungals.
    explanation: >-
      Supports the tolerability and combination rationale that keeps the class
      in use despite limited monotherapy activity. Evidence source is OTHER
      because this is a review.
- name: Amphotericin B
  description: >-
    Polyene that binds and sequesters membrane ergosterol, forming pores that
    release intracellular ions, and that additionally drives reactive oxygen
    species accumulation. Because it acts on ergosterol itself rather than on
    the biosynthetic enzyme the azoles inhibit, a cyp51A target-site
    substitution does not by itself confer polyene cross-resistance — which is
    the basis for its role in azole-resistant disease, alongside use where
    triazoles are contraindicated. This is not a claim of universal polyene
    activity against Aspergillus: A. terreus is characteristically amphotericin
    B resistant by an unrelated oxidative-stress-response mechanism.
    Nephrotoxicity limits the deoxycholate formulation; lipid formulations are
    used in practice.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: amphotericin B
      term:
        id: CHEBI:2682
        label: amphotericin B
  target_mechanisms:
  - target: Ergosterol-Enriched Aspergillus Plasma Membrane
    treatment_effect: INHIBITS
    description: >-
      Amphotericin B binds membrane ergosterol directly, forming pores and
      permeabilising the fungal plasma membrane.
  evidence:
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      First, several molecules of AMB incorporate into the fungal lipid bilayer
      and bind to ergosterol. By ergosterol sequestration, pores are formed, and
      both the ions (K+, Mg2+, Ca2+, and Cl−) and electrolyte glucose are
      released.
    explanation: >-
      Gives the ergosterol-binding, pore-forming mechanism of action, which is
      the target the description says is distinct from the azoles' enzyme
      target. Evidence source is OTHER because this is a review.
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Second, AMB induces the accumulation of reactive oxygen species (ROS),
      resulting in DNA, protein, mitochondrial, and membrane damage
    explanation: >-
      Sources the second mechanism named in the description. Evidence source is
      OTHER because this is a review.
  - reference: PMID:32178468
    reference_title: Antifungal Drugs.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the higher activity of catalase and superoxide dismutase and the more
      intense stress response through heat shock proteins 70 and 90 (Hsp70,
      Hsp90) contribute to the intrinsic resistance of A. terreus
    explanation: >-
      Sources the A. terreus caveat, and identifies its mechanism as an
      oxidative-stress response unrelated to azole target-site resistance.
      Evidence source is OTHER because this is a review.
  - reference: PMID:12167683
    reference_title: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with invasive aspergillosis, initial therapy with voriconazole
      led to better responses and improved survival and resulted in fewer severe
      side effects than the standard approach of initial therapy with
      amphotericin B.
    explanation: >-
      Establishes that amphotericin B is no longer first-line for invasive
      aspergillosis. Graded PARTIAL because it supports the agent's demotion
      rather than its remaining indications.
- name: Posaconazole antifungal prophylaxis in prolonged neutropenia
  description: >-
    Primary prevention rather than treatment: in patients neutropenic from
    chemotherapy for acute myelogenous leukaemia or myelodysplastic syndrome,
    posaconazole prophylaxis cut invasive aspergillosis from 7% to 1% versus
    fluconazole or itraconazole and improved overall survival. Fluconazole is
    inactive against Aspergillus, so part of this effect is simply the switch to
    a mould-active agent — the intrinsic-resistance gate modelled in the
    pathophysiology, applied prospectively.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: posaconazole
      term:
        id: CHEBI:64355
        label: posaconazole
  target_mechanisms:
  - target: Fungal Ergosterol Biosynthesis via Cyp51 Sterol 14-alpha-Demethylase
    treatment_effect: INHIBITS
    description: >-
      Posaconazole inhibits fungal lanosterol 14-alpha-demethylase, suppressing
      fungal growth during the period of maximal host susceptibility.
  evidence:
  - reference: PMID:17251531
    reference_title: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significantly fewer patients in the posaconazole group had invasive
      aspergillosis (2 [1%] vs. 20 [7%], P<0.001).
    explanation: >-
      The randomised result establishing prophylactic efficacy specifically
      against invasive aspergillosis.
  - reference: PMID:17251531
    reference_title: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survival was significantly longer among recipients of posaconazole than
      among recipients of fluconazole or itraconazole (P=0.04).
    explanation: >-
      Establishes that the prophylactic benefit extends to overall survival, not
      only to infection incidence.
- name: Surgical excision of simple aspergilloma
  description: >-
    For a single fungal ball in a resectable cavity, excision is the definitive
    treatment and is preferred over prolonged antifungal therapy, ideally by
    video-assisted thoracic surgery. This is the clearest point at which the
    subtype distinction changes management: the same organism in the same lung
    is treated by resection here and by months of oral azole in chronic cavitary
    disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Saprophytic Cavity Colonisation and Fungal Ball Formation
    treatment_effect: INHIBITS
    description: >-
      Resection removes the colonised cavity and the fungal ball within it,
      eliminating the lesion rather than suppressing the organism.
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surgical excision of simple aspergilloma is recommended, if technically
      possible, and preferably via video-assisted thoracic surgery technique.
    explanation: >-
      The guideline recommendation for surgical management of simple
      aspergilloma, including the preferred approach. Evidence source is OTHER
      because this is a guideline review.
- name: Tranexamic acid for haemoptysis
  description: >-
    Antifibrinolytic used to control bleeding from the bronchial circulation
    around a colonised or destroyed cavity. Symptomatic rather than antifungal.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
  target_phenotypes:
  - preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Haemoptysis may be controlled with tranexamic acid and bronchial artery
      embolisation, rarely surgical resection
    explanation: >-
      Names tranexamic acid as a haemoptysis-control option in chronic pulmonary
      aspergillosis. Evidence source is OTHER because this is a guideline review.
- name: Bronchial artery embolisation for haemoptysis
  description: >-
    Interventional-radiology occlusion of the hypertrophied bronchial arteries
    supplying a colonised or destroyed cavity. Together with tranexamic acid it
    is the intervention that most often decides whether a patient with chronic
    pulmonary aspergillosis survives an acute haemoptysis, and surgical resection
    is a last resort.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Embolization Therapy
    term:
      id: NCIT:C15230
      label: Embolization Therapy
  target_phenotypes:
  - preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:26699723
    reference_title: "Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Haemoptysis may be controlled with tranexamic acid and bronchial artery
      embolisation, rarely surgical resection
    explanation: >-
      Names bronchial artery embolisation as a haemoptysis-control option and
      places surgical resection behind it. Evidence source is OTHER because this
      is a guideline review.
clinical_trials:
- name: NCT00412893
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SECURE: phase 3 double-blind randomised non-inferiority trial of
    isavuconazole versus voriconazole for primary treatment of invasive mould
    disease, 527 patients randomised across seven years, with 42-day all-cause
    mortality as the primary endpoint.
  evidence:
  - reference: PMID:26684607
    reference_title: "Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study is registered with ClinicalTrials.gov, number NCT00412893.
    explanation: >-
      The trial publication records the registration identifier used here.
  - reference: clinicaltrials:NCT00412893
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to compare the efficacy and safety of
      isavuconazole versus voriconazole in the treatment of patients with
      invasive aspergillosis.
    explanation: >-
      The ClinicalTrials.gov registry record, from which the phase and status
      recorded in this entry were taken.
- name: NCT01259336
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    Prospective randomised controlled trial of itraconazole 400 mg daily for six
    months plus supportive therapy versus supportive therapy alone in chronic
    cavitary pulmonary aspergillosis.
  evidence:
  - reference: PMID:23496375
    reference_title: "Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Itraconazole was found to be superior to standard supportive treatment
      alone in stabilising cases of CCPA. (clinicaltrials.gov; NCT01259336)
    explanation: >-
      The trial publication records both the result and the registration
      identifier used here.
  - reference: clinicaltrials:NCT01259336
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to determine whether there itraconazole is
      effective in the treatment of chronic cavitary pulmonary aspergillosis
    explanation: >-
      The ClinicalTrials.gov registry record, from which the phase and status
      recorded in this entry were taken.
- name: NCT00044486
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Randomised multicentre trial of posaconazole versus fluconazole or
    itraconazole prophylaxis in 602 patients with prolonged neutropenia from
    chemotherapy for acute myelogenous leukaemia or myelodysplastic syndrome.
  evidence:
  - reference: PMID:17251531
    reference_title: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 304 patients were randomly assigned to receive posaconazole,
      and 298 patients were randomly assigned to receive fluconazole (240) or
      itraconazole (58).
    explanation: >-
      Describes the randomised allocation of the registered trial, establishing
      its design and enrolment.
  - reference: clinicaltrials:NCT00044486
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This trial is in high risk patients to determine the safety and efficacy of
      posaconazole vs. fluconazole in the prophylaxis against development of
      invasive fungal infections.
    explanation: >-
      The ClinicalTrials.gov registry record, from which the phase and status
      recorded in this entry were taken.
discussions:
- discussion_id: gliotoxin_virulence_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does gliotoxin production contribute materially to Aspergillus virulence in
    human disease, or is its measured virulence contribution specific to
    invertebrate infection models?
  attaches_to:
  - pathophysiology#Gliotoxin-Mediated Suppression of Host Phagocyte Function
  rationale: >-
    The direct evidence tying virulence to gliotoxin production rather than to
    growth rate or enzyme activity comes from Galleria mellonella, and the
    authors qualify the finding to that model. Galleria has no adaptive immunity
    and no neutrophils, so it cannot test the phagocyte suppression that the
    mechanism is proposed to act through in humans. Human aspergillosis is
    dominated by host-side phagocyte defects, which this entry models upstream.
    The gap matters because gliotoxin is periodically proposed as a therapeutic
    or diagnostic target on the strength of model-system data.
  evidence:
  - reference: PMID:15487324
    reference_title: Correlation between gliotoxin production and virulence of Aspergillus fumigatus in Galleria mellonella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      implicating a critical role for gliotoxin production rather than growth
      rate or enzymatic activity in the virulence of A. fumigatus in this model
    explanation: >-
      The authors themselves restrict the virulence conclusion to the Galleria
      model, which is the mismatch this discussion records.
notes: >-
  Concept decision (issue #9041): curated as a single root Disease with
  has_subtypes rather than as a kb/groupings/ Grouping. The forms share one
  conserved pathograph — inhalation of ubiquitous conidia, then a phagocyte
  gate whose state sets the branch — so they are specialisations of one
  mechanism rather than a union of mechanistically distinct diseases, which is
  the test a grouping would have to meet. The host-status axis is carried
  explicitly by the environmental block (corticosteroid exposure, severe viral
  critical illness) and the genetic block (CYBB, TLR4) rather than being
  implied by the subtype names.

  Related dismech entries: Cystic_Fibrosis and Hypersensitivity_Pneumonitis for
  the ABPA host context and the adjacent allergic lung disease;
  Chronic_Granulomatous_Disease for the phagocyte-defect host; Otomycosis for
  non-invasive Aspergillus disease outside the lung; and the
  fungal_cell_wall_glucan_synthesis_inhibition and
  antifungal_intrinsic_resistance_gating modules, both of which this entry
  conforms to.

  Deliberate omissions. ECTO has no term
  for exposure to Aspergillus, fungi, or airborne spores, so the conidial
  exposure is bound to the general ECTO:3000000 organism-exposure class. No
  datasets block is included: no Aspergillus-specific accession was verified for
  this entry, and an unverified accession is worse than none.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 21 citations 2026-08-28T15:21:15.593843

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Aspergillosis
MONDO ID: (if available)
Category: Infectious Disease

Research Objectives

Please provide a comprehensive research report on Aspergillosis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Aspergillosis: comprehensive disease-characteristics report

Executive summary and evidence scope

Aspergillosis is a family of diseases caused by Aspergillus spp., principally A. fumigatus, after inhalation of ubiquitous airborne conidia. Clinical expression is governed less by exposure alone than by the interaction among fungal strain, lung architecture, and host immunity: immune overactivity produces allergic disease; structural lung damage favors chronic infection and fungal balls; profound immune dysfunction permits tissue-invasive and disseminated disease. A 2024 European Respiratory Journal review identifies sensitization, allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, chronic pulmonary aspergillosis (CPA), and invasive pulmonary aspergillosis (IPA) as the major pulmonary phenotypes (jaggi2024fungallungdisease pages 3-4, jaggi2024fungallungdisease pages 1-3).

The evidence below is chiefly aggregated disease-level evidence from guidelines, reviews, clinical cohorts, functional experiments, and trial registries—not individual-level EHR data. Exact PMIDs were not exposed for most retrieved 2023–2024 papers; DOI URLs and dates are therefore supplied rather than inventing PMID values. Proposed ontology mappings should be verified against the current ontology release before production ingestion.

The principal clinical spectrum is summarized here:

Form	Dominant host state/risk	Mechanism	Hallmark phenotype/imaging/biomarker	Typical course	Core treatment
ABPA	Asthma or cystic fibrosis; also reported with COPD/bronchiectasis	Allergic/type-2 immune reaction to Aspergillus colonization/sensitization	A. fumigatus-specific IgE ≥0.35 kUA/L; total IgE ≥500 IU/mL; often eosinophils ≥500/µL; suggestive CT findings and/or mucus plugging/bronchiectasis	Relapsing exacerbations; can progress to bronchiectasis or pleuropulmonary fibrosis	Oral prednisolone or itraconazole monotherapy for acute disease; combination prednisolone+itraconazole for recurrent exacerbations; biologics/nebulized amphotericin in selected cases
Aspergillus bronchitis / sensitization	Chronic airway disease, especially severe asthma or cystic fibrosis; risk increased by inhaled corticosteroids, antibiotics, prior exacerbations	Persistent superficial airway infection or immune sensitization without invasive tissue disease	Sensitization: fungus-specific IgE ≥0.35 kUA/L; bronchitis: positive sputum/BAL culture or PCR with elevated Aspergillus IgG	Chronic or recurrent airway symptoms	Itraconazole-based antifungal therapy in selected bronchitis; airway-disease optimization
Aspergilloma / CPA	Structural lung disease, especially pulmonary cavitation; COPD, prior TB or other chronic lung damage	Chronic colonization/infection of cavities with local tissue destruction but no deep invasion	CT cavitary disease or fungal ball; Aspergillus IgG positive; hemoptysis common (∼50%)	Chronic, progressive over months to years; high long-term mortality	Oral azoles first line (itraconazole/voriconazole; alternatives posaconazole/isavuconazole) with prolonged therapy >6 months and often ≥12 months; surgery for localized/simple aspergilloma; bronchial artery embolization for major hemoptysis
Invasive pulmonary aspergillosis	Prolonged severe neutropenia, graft-versus-host disease, hematologic malignancy, transplant, prolonged corticosteroids/immunosuppressants; also severe viral critical illness	Inhaled conidia germinate to hyphae with tissue invasion, angioinvasion, thrombosis, necrosis, and hemorrhage	CT dense well-circumscribed lesion ± halo sign, air-crescent sign, cavity, or wedge-shaped consolidation; serum or BAL galactomannan ≥1.0; Aspergillus PCR positivity; culture/microscopy supportive	Acute/subacute, rapidly progressive, high mortality if delayed diagnosis	Triazoles first choice, individualized (voriconazole or isavuconazole commonly used); adjunctive immune optimization/immunomodulation when feasible
Extrapulmonary / disseminated aspergillosis	Usually profoundly immunocompromised patients following pulmonary invasion and hematogenous spread	Dissemination from a primary focus with organ invasion outside lung	Evidence of Aspergillus in extrapulmonary tissue or compatible multisite disease; no single universal biomarker threshold established here	Acute, severe, often life-threatening	Systemic antifungal therapy centered on triazoles; organ-directed management and reduction of immunosuppression when possible

Table: This table summarizes the major clinical forms of aspergillosis across host states, mechanisms, hallmark findings, course, and core treatments. It is useful as a quick disease-spectrum reference built only from gathered evidence. (jaggi2024fungallungdisease pages 8-9, tashiro2024chronicpulmonaryaspergillosis pages 1-2, heylen2024acuteinvasivepulmonary pages 1-2, jaggi2024fungallungdisease pages 4-5, jaggi2024fungallungdisease pages 5-7, heylen2024acuteinvasivepulmonary pages 6-7)

1. Disease information

Definition and forms

Aspergillosis: infection, colonization-associated disease, or hypersensitivity caused by Aspergillus.
Allergic disease: Aspergillus sensitization and ABPA, generally complicating asthma, cystic fibrosis (CF), bronchiectasis, or COPD.
Airway disease: Aspergillus bronchitis or tracheobronchitis.
Chronic disease: simple aspergilloma, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive aspergillosis.
Invasive disease: acute IPA, invasive tracheobronchial disease, extrapulmonary focal infection, or hematogenously disseminated aspergillosis.

Identifiers and synonyms

MONDO: aspergillosis MONDO:0005657; ABPA MONDO:0015243; pulmonary aspergilloma MONDO:0000266 (OpenTargets Search: aspergillosis).
MeSH: Aspergillosis; subordinate concepts include pulmonary, allergic bronchopulmonary, and invasive forms.
ICD-10-CM: B44 family—B44.0 invasive pulmonary, B44.1 other pulmonary, B44.2 tonsillar, B44.7 disseminated, B44.81 ABPA, B44.89 other, B44.9 unspecified. Coding should be checked against the jurisdictional release.
ICD-11: fungal-disease chapter contains aspergillosis and clinical extensions; the precise current URI/code should be resolved directly from the ICD-11 release.
OMIM/Orphanet: no single Mendelian disease entry appropriately represents all aspergillosis. Host immunodeficiencies predisposing to disease have separate entries.
Synonyms: aspergillus infection; invasive aspergillosis; IPA; chronic pulmonary aspergillosis/CPA; aspergilloma or fungus ball; ABPA; invasive fungal tracheobronchitis.

2. Etiology, risk, protection, and gene–environment interaction

Causal agent and exposure

The immediate cause is exposure to viable conidia followed by fungal persistence, germination, or antigen-driven inflammation. Humans may inhale roughly 100–1,000 conidia daily. Normal mucociliary and innate defenses usually remove them; failed clearance permits germination into hyphae (heylen2024acuteinvasivepulmonary pages 1-2).

Important species are A. fumigatus worldwide, with A. flavus, A. terreus, A. niger, and cryptic species contributing regionally. A. flavus may be relatively prominent in hot/arid regions and was particularly common in one pediatric hematology cohort. Geography, climate, environment, fungal genotype, and host comorbidities materially alter disease distribution (jaggi2024fungallungdisease pages 3-4, jaggi2024fungallungdisease pages 4-5).

Clinical risk factors

IPA: neutrophils below 0.5×10⁹/L for more than 10 days; acute leukemia; hematopoietic-cell or solid-organ transplantation; graft-versus-host disease; inherited severe immunodeficiency; T- or B-cell immunosuppressants; corticosteroids at approximately ≥0.3 mg/kg/day for ≥3 weeks in the preceding 60 days; and critical illness with severe influenza or COVID-19 (heylen2024acuteinvasivepulmonary pages 1-2, heylen2024acuteinvasivepulmonary pages 6-7).
CPA: a pre-existing cavity is the strongest anatomical risk. Prior tuberculosis or nontuberculous mycobacterial disease, COPD/emphysema, bronchiectasis, sarcoidosis, lung cancer, and previous thoracic procedures are typical substrates (tashiro2024chronicpulmonaryaspergillosis pages 1-2).
ABPA: asthma and CF are classical; bronchiectasis and COPD are now recognized predisposing conditions. Repeated fungal exposure, impaired mucociliary clearance, inhaled corticosteroids, and antibiotic-associated airway-ecology changes may contribute (jaggi2024fungallungdisease pages 8-9, jaggi2024fungallungdisease pages 4-5).
Other: diabetes, prolonged ICU care, chemotherapy/radiotherapy, and systemic immunosuppression increase risk (harliza2024diagnosisandtreatment pages 1-2).

Genetic susceptibility and protection

Aspergillosis itself is not a single-gene inherited disorder. Reported host susceptibility involves CFTR dysfunction and variants affecting epithelial recognition, Toll-like receptors, surfactant proteins, mannose-binding lectin, MHC, IL4R, and IL13/type-2 signaling. These are susceptibility or modifier associations, not sufficient causes of disease (jaggi2024fungallungdisease pages 5-7, jaggi2024fungallungdisease pages 17-18).

Rare primary immunodeficiencies—especially chronic granulomatous disease and defects of antifungal innate immunity—can confer large risks, but penetrance is exposure- and treatment-dependent. No clinically validated universal “protective variant,” carrier frequency, anticipation, founder effect, or germline-mosaicism framework exists for aspergillosis. Population allele frequencies and ACMG classifications should therefore be attached to the underlying immunodeficiency, not to aspergillosis as though it were Mendelian.

Protective factors

Effective mucociliary clearance, intact alveolar macrophages and neutrophils, avoidance of unnecessary immunosuppression, control of structural lung disease, HEPA-filtered protective environments during profound neutropenia, and indicated mold-active prophylaxis reduce risk. Evidence does not support a specific protective diet or routine population supplement. Vitamin D has been investigated in ABPA, but it is not an established preventive intervention.

Gene–environment interaction

The clearest interaction is ubiquitous inhalational exposure × host defense phenotype. CFTR/mucus-clearance defects increase airway residence time; innate-recognition variants alter fungal sensing; corticosteroids suppress phagocyte and lymphocyte function; and cavities furnish an ecological niche. Agricultural azole fungicides select resistant environmental A. fumigatus, allowing azole-naïve people to inhale resistant conidia—an important One Health interaction.

3. Phenotypes

Phenotype	Type, course, and approximate frequency	Suggested HPO term
Cough, sputum	Symptom; chronic in CPA/bronchitis, episodic in ABPA, acute in IPA	Cough (HP:0012735); productive cough
Dyspnea/wheeze	Symptom; fluctuating in ABPA/asthma, progressive in CPA/IPA	Dyspnea (HP:0002094); wheezing
Fever	Symptom; common but nonspecific in IPA, especially neutropenic disease	Fever (HP:0001945)
Hemoptysis	Symptom; about 50% in CPA and may be life-threatening	Hemoptysis (HP:0002105)
Fatigue/weight loss	Symptoms; common in chronic or disseminated disease	Fatigue (HP:0012378); weight loss (HP:0001824)
Bronchiectasis	Structural sign; central/proximal pattern supports ABPA; chronic	Bronchiectasis (HP:0002110)
Pulmonary cavity/fungal ball	Imaging sign; hallmark of CPA/aspergilloma	Pulmonary cavity; abnormal lung morphology
Halo sign, wedge-shaped consolidation, air-crescent sign	CT signs of IPA/angioinvasion; evolve over days to weeks	Abnormal pulmonary imaging finding
Eosinophilia	Laboratory abnormality in ABPA; threshold commonly ≥500 cells/µL	Eosinophilia (HP:0001880)
Elevated total and fungus-specific IgE	Laboratory abnormality in ABPA	Increased circulating IgE (HP:0003212)
Cerebral, sinus, ocular, cutaneous, bone, or cardiac invasion	Extrapulmonary signs, usually severe	Map to organ-specific infection/lesion terms

ABPA severity is variable and relapsing; untreated recurrent mucus impaction can lead to bronchiectasis and chronic pleuropulmonary fibrosis. CPA progresses over months or years. IPA can progress over days and may be muted in neutropenia. Quality-of-life effects include breathlessness, fatigue, reduced exercise capacity, recurrent hospitalization, treatment toxicity, anxiety related to hemoptysis, and impaired work/daily function. Robust phenotype-specific EQ-5D or SF-36 frequencies were not available in the retrieved evidence.

4. Genetic and molecular information

Human genetics

There is no universal causal human gene, chromosome abnormality, somatic driver, or diagnostic pathogenic-variant panel for aspergillosis. Genetic testing is appropriate when unusually early, recurrent, refractory, or disseminated disease suggests an underlying immunodeficiency. Candidate testing can include genes responsible for chronic granulomatous disease and other phagocyte, CARD9/lectin-pathway, or combined-immunodeficiency disorders; interpretation must be tied to that syndrome.

OpenTargets identifies NR3C1, the glucocorticoid receptor, as a treatment-associated target for aspergillosis/ABPA. This reflects corticosteroid pharmacology rather than proof that NR3C1 mutations cause aspergillosis (OpenTargets Search: aspergillosis).

Pathogen genetics and resistance

Azoles inhibit fungal lanosterol 14α-demethylase, encoded principally by cyp51A. Promoter tandem repeats and coding substitutions can cause resistance; environmental and patient-selected routes both occur. Susceptibility testing is clinically important because resistant invasive disease carries poorer outcomes. These are fungal, not human, variants and are not classified under human ACMG/AMP criteria.

Functional genomics and epigenetic regulation

In combined A549 human epithelial-cell and RAW264.7 murine-macrophage transcriptomics, 140 fungal genes were commonly upregulated; 13 remained concordant with an in-vivo dataset. Disrupting fungal maiA, part of phenylalanine degradation, increased pyomelanin, reduced cell-wall β-glucan, dampened macrophage inflammation, and reduced virulence in neutropenic mice (published January 2024; DOI: https://doi.org/10.3389/fcimb.2024.1327299) (guruceaga2024theaspergillusfumigatus pages 1-2).
The fungal deacetylase SirE regulates histone/non-histone acetylation, cell-wall integrity, thermotolerance, secondary metabolism, and virulence. Deletion attenuated disease in murine and Galleria mellonella models, making fungal epigenetic enzymes experimental drug targets.
CotA–SsdA couples host-relevant carbon-source sensing to hyphal morphogenesis and invasive growth, illustrating pathogen metabolic plasticity.
These are experimental pathogen targets; none currently constitutes a validated human diagnostic or approved therapeutic biomarker.

5. Environmental and infectious-agent information

Aspergillus is ubiquitous in soil, compost, decaying vegetation, dust, stored grain, construction aerosols, and indoor/outdoor air. Exposure is principally airborne and environmental; routine person-to-person transmission is not characteristic. Construction, gardening/compost handling, agriculture, grain/poultry work, and heavily contaminated buildings can raise inoculum.

Smoking is not a direct infectious cause but promotes COPD, emphysema, cavitation, and impaired airway clearance. Broad antibiotics and corticosteroids alter airway ecology or host immunity. Agricultural/horticultural triazole fungicides are a major environmental selection pressure for medical azole resistance. Environmental control should therefore combine occupational protection, hospital engineering, antifungal stewardship, and agricultural One Health surveillance.

Agent taxonomy: genus Aspergillus; major pathogen A. fumigatus (NCBI Taxonomy ID 746128 for the commonly referenced species entry; verify strain-level IDs), followed by A. flavus, A. terreus, and A. niger complex.

6. Mechanism and pathophysiology

Causal chains

Invasive disease: inhaled conidium → deposition in terminal airway/alveolus → failed macrophage killing → germination → neutrophil failure permits hyphal extension → epithelial/endothelial penetration → angioinvasion → thrombosis, ischemic infarction, necrosis, hemorrhage → pulmonary failure or hematogenous dissemination (heylen2024acuteinvasivepulmonary pages 1-2).
CPA: damaged lung/cavity → persistent fungal growth and biofilm/fungal ball → chronic local inflammation and progressive cavitation/fibrosis → vessel erosion and hemoptysis. Deep angioinvasion is generally absent from classic CPA (tashiro2024chronicpulmonaryaspergillosis pages 1-2).
ABPA: impaired clearance and persistent airway antigen → epithelial/innate sensing → Th2/IL-4/IL-5/IL-13 signaling → fungus-specific IgE, mast-cell activation, eosinophilia and mucus hypersecretion → mucus plugs, exacerbations and bronchiectasis (jaggi2024fungallungdisease pages 5-7).

Cells, pathways, and ontology suggestions

Alveolar macrophage (CL:0000583): conidial uptake; GO suggestions—phagocytosis (GO:0006909), innate immune response (GO:0045087).
Neutrophil (CL:0000775): hyphal damage, oxidative burst and extracellular traps; GO—respiratory burst (GO:0045730), neutrophil activation (GO:0042119).
Airway/alveolar epithelial cells: mucociliary clearance, barrier and cytokine signaling; GO—epithelial barrier establishment and response to fungus.
Eosinophil (CL:0000771), mast cell (CL:0000097), type-2 helper T cell: ABPA inflammation; GO—type 2 immune response and cytokine production.
Endothelial cells: targets of hyphal invasion; GO—blood coagulation, cell death, response to hypoxia.
NK cell (CL:0000623): human CD56 binds fungal galactosaminogalactan (GAG), inducing activation, degranulation, chemokines and cytotoxic effectors; conditioned supernatants enhance polymorphonuclear antifungal activity (published June 2024; DOI: https://doi.org/10.1371/journal.ppat.1012315) (heilig2024cd56mediatedactivationof pages 1-2).

Cellular, metabolic, and molecular profiling

Key processes include cell-wall remodeling, thermotolerance, iron acquisition, hypoxia adaptation, oxidative-stress resistance, secondary metabolites, nutritional plasticity, biofilm matrix production, autophagy/stress responses, and host immunometabolism. Current RNA-seq, dual-transcriptomic, proteomic, metabolomic, and CRISPR studies have identified candidate fungal vulnerabilities, but none has replaced culture, antigen detection, PCR, imaging, or histopathology in routine diagnosis. Single-cell and spatial methods are promising for resolving macrophage, neutrophil, epithelial, and lymphocyte heterogeneity, but remain research technologies.

7. Anatomical structures affected

Primary: respiratory tract—nasal/paranasal sinuses, tracheobronchial tree, bronchi, bronchioles, alveoli, lung parenchyma, pleura, and pre-existing cavities. Suggested UBERON concepts include lung (UBERON:0002048), bronchus (UBERON:0002185), alveolus of lung, trachea (UBERON:0003126), and paranasal sinus.

Secondary/disseminated: brain/CNS, eye/orbit, skin/subcutis, bone, heart/endocardium, kidney, liver, and gastrointestinal tract. Pulmonary lesions are usually multifocal rather than consistently lateralized; aspergilloma can be unilateral or bilateral according to cavity distribution.

Tissue/cell: respiratory epithelium, alveolar interstitium, vascular endothelium, macrophages, neutrophils, eosinophils, lymphocytes, and fibroblasts. Subcellular fungal targets include cell wall, plasma membrane/ergosterol pathway, nucleus/chromatin, mitochondria, and secretory machinery; proposed GO cellular-component terms include fungal-type cell wall and plasma membrane.

8. Temporal development

ABPA: often begins in adolescents or adults with asthma and in children/adults with CF. It is episodic or relapsing; stages include acute disease, treatment response, remission, exacerbation, treatment-dependent disease, and advanced bronchiectatic/fibrotic disease.
CPA: generally adult or older-adult onset, insidious and chronic. Diagnostic frameworks require compatible disease over months; progression ranges from stable simple aspergilloma to enlarging cavities and chronic fibrosis. Relapse after stopping azoles is common.
IPA: acute or subacute, often developing during neutropenia, transplantation, high-dose steroid exposure, or severe viral critical illness. Early CT/biomarker detection is a critical intervention window; delay increases mortality.
Remission: ABPA commonly achieves treatment-induced remission but can relapse. CPA may stabilize on prolonged therapy; localized aspergilloma may be cured surgically. IPA recovery requires rapid antifungal therapy plus immune recovery where feasible.

9. Epidemiology, inheritance, and population

Global estimates are uncertain because diagnostics and surveillance are uneven. A 2024 synthesis reported approximately 1.84 million annual CPA cases in a 2020 model and about 340,000 first-year deaths; earlier modeling estimated 372,000 cases. CPA mortality ranges were 7–32% at one year and 38–52% at five years (tashiro2024chronicpulmonaryaspergillosis pages 1-2). These are modeled estimates rather than complete case registries.

Disease burden varies with tuberculosis prevalence, COPD, asthma/CF, hematologic malignancy, transplantation, intensive-care populations, access to diagnostics, and azole resistance. Invasive-disease incidence is therefore best reported within a risk cohort rather than as one general-population rate. Age is not causal but a 2024 meta-analysis of 55 retrospective studies and 13,983 patients found patients with IA averaged about 2.5 years older than controls; residual confounding is likely.

No fixed male:female ratio exists. A 2024 CPA cohort of 106 patients had mean age 60.3 years and 69.8% were male, probably reflecting underlying smoking-related and structural lung disease rather than sex-linked inheritance. Aspergillosis has no Mendelian inheritance pattern, anticipation, carrier state, or routine reproductive genetic-screening indication.

10. Diagnostics

Invasive aspergillosis

Diagnosis integrates host factors + compatible imaging/clinical disease + mycological evidence. Proven disease requires histopathologic demonstration of tissue invasion and/or recovery from a normally sterile site. Probable disease uses validated consensus combinations; these definitions were developed principally for research and should not delay treatment.

CT: dense circumscribed nodule/lesion with or without halo; wedge-shaped consolidation; cavity; later air-crescent sign. Findings are host- and timing-dependent.
Microscopy/histopathology: acute-angle branching, septate hyphae with tissue or vascular invasion; morphology is not completely species-specific.
Culture: enables identification and susceptibility testing but lacks sensitivity and may represent colonization in respiratory specimens.
Galactomannan (GM): EORTC/MSGERC-compatible thresholds include serum/plasma index ≥1.0 and BAL index ≥1.0 in appropriate hosts; interpretation varies with prophylaxis and population (heylen2024acuteinvasivepulmonary pages 6-7).
PCR: repeated blood positivity or duplicate BAL positivity can satisfy mycological criteria. Standardization led to inclusion of blood and respiratory Aspergillus PCR in revised EORTC/MSGERC definitions.
β-D-glucan: supports invasive fungal disease but is not Aspergillus-specific.
Pediatric cohort performance: among 100 hematologic-malignancy patients, serum GM at 0.67 yielded sensitivity 82.3%, specificity 97.4%, PPV 98.1%, and NPV 77.1%; at 0.5, sensitivity was 87.1% and NPV 80.5%. These estimates are cohort-specific, not universal.

CPA and aspergilloma

Diagnosis requires compatible chronic symptoms/radiology, exclusion of alternatives, and microbiological or immunological evidence. Chest CT plus serum Aspergillus IgG are central; sputum culture/PCR and histology increase specificity (tashiro2024chronicpulmonaryaspergillosis pages 1-2). Differential diagnoses include recurrent/active tuberculosis, nontuberculous mycobacterial disease, lung cancer, bacterial abscess, endemic mycoses, cavitating vasculitis, and other fungal balls.

ABPA

The 2024 ISHAM guideline recommends diagnosis in a predisposing condition or compatible clinico-radiological presentation with mandatory fungal sensitization and total IgE ≥500 IU/mL, plus at least two of fungus-specific IgG, eosinophilia, or suggestive imaging. A. fumigatus-specific IgE ≥0.35 kUA/L and eosinophils ≥500/µL are commonly used thresholds (jaggi2024fungallungdisease pages 8-9, jaggi2024fungallungdisease pages 5-7, serpa2024allergicbronchopulmonaryaspergillosis pages 19-21). The guideline’s abstract states: “We do not routinely recommend treating asymptomatic ABPA patients” and recommends prednisolone or itraconazole monotherapy for acute ABPA.

Genetic and omics testing

WES/WGS, immunodeficiency panels, single-gene testing, or functional neutrophil assays are indicated only when the phenotype suggests inherited immune dysfunction. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing have no routine role. mNGS may detect fungi missed by culture but requires contamination-aware interpretation; it remains adjunctive rather than a stand-alone criterion (jaggi2024fungallungdisease pages 1-3).

No population screening program exists. Targeted surveillance—serial GM/PCR and prompt CT—is used in selected high-risk hematology/transplant settings.

11. Outcome and prognosis

IPA remains highly lethal; a 2024 diagnostic review reported mortality up to 70%, while early diagnosis may reduce mortality by as much as 30%. Rates depend strongly on host, certainty category, species/resistance, dissemination, and immune recovery. One multicenter AML population cited approximately 30% mortality (heylen2024acuteinvasivepulmonary pages 1-2).

CPA has approximately 38–52% five-year mortality. Poor prognostic factors include advanced age/frailty, low BMI or albumin, extensive bilateral/cavitary disease, COPD/emphysema, lung cancer, nontuberculous mycobacterial coinfection, azole resistance, and inability to tolerate therapy. In a 106-patient cohort, emphysema had adjusted HR 4.107 and lung cancer HR 8.511 for mortality; three-year survival with versus without emphysema was 64.9% versus 85.9%.

ABPA is seldom directly fatal but causes repeated exacerbations, mucus plugging, bronchiectasis, loss of lung function, steroid toxicity, and occasionally chronic fibrosis. Prognosis improves with early recognition, control of type-2 inflammation, reduced fungal burden, and prevention of recurrent exacerbations.

12. Treatment and current applications

IPA

First line: systemic mold-active triazole, commonly voriconazole or isavuconazole; selection depends on susceptibility, hepatic function, QT effects, interactions, CNS involvement, and prior prophylaxis (heylen2024acuteinvasivepulmonary pages 1-2).
Alternatives/salvage: liposomal amphotericin B; posaconazole or another active triazole; echinocandin-containing combinations in selected refractory or resistant cases. Echinocandin monotherapy is generally not preferred initially.
Support: reduce immunosuppression where feasible, recover neutrophils, manage drug interactions, perform therapeutic drug monitoring (especially voriconazole/itraconazole/posaconazole), and surgically control selected focal lesions or hemorrhage.
Duration: individualized, usually at least 6–12 weeks and longer until clinical/radiographic improvement and reversal of immunosuppression.

Suggested NCIT concepts: Voriconazole, Isavuconazole, Liposomal Amphotericin B, Posaconazole, Antifungal Therapy, Therapeutic Drug Monitoring, Surgical Resection.

CPA/aspergilloma

Itraconazole or voriconazole with drug monitoring is first-line; posaconazole or isavuconazole are alternatives. At least 6 months is recommended, while 12 months or longer produces better control and fewer relapses (tashiro2024chronicpulmonaryaspergillosis pages 1-2, jaggi2024fungallungdisease pages 8-9). Reported response ranges are itraconazole 43–76%, voriconazole 32–80%, posaconazole 44–61%, isavuconazole 82.7%, echinocandins 42–77%, and liposomal amphotericin B 52–73%; cross-study comparisons are confounded by differing populations and endpoints (tashiro2024chronicpulmonaryaspergillosis pages 1-2).

Localized simple aspergilloma may be cured by resection: postoperative mortality is 0–5%, although complications range from 11–63%. Bronchial-artery embolization controls major hemoptysis in 64–100%, but approximately 50% recur (tashiro2024chronicpulmonaryaspergillosis pages 1-2).

ABPA

The 2024 ISHAM experts recommend oral prednisolone or itraconazole monotherapy for newly diagnosed acute disease or an exacerbation, generally over about four months; combination prednisolone plus itraconazole is reserved for recurrent exacerbations. Asymptomatic disease is not routinely treated (jaggi2024fungallungdisease pages 5-7). Omalizumab, mepolizumab/benralizumab, and dupilumab are steroid-sparing options in treatment-dependent or severe type-2 disease, but evidence remains less mature than for steroids/azoles. Airway clearance, asthma/CF therapy, bronchodilators, and treatment of bacterial coinfection are important.

Pharmacology and adverse effects

Azoles: inhibit ergosterol biosynthesis; risks include hepatotoxicity, interactions through CYP enzymes, variable exposure, neuropathy/phototoxicity with prolonged voriconazole, and QT effects. Isavuconazole shortens rather than prolongs QT.
Polyenes: bind ergosterol; nephrotoxicity and electrolyte loss remain important, reduced with liposomal formulation.
Echinocandins: inhibit β-1,3-glucan synthesis; generally intravenous and relatively well tolerated.
Glucocorticoids: suppress ABPA inflammation but increase infection, diabetes, osteoporosis, adrenal suppression, and IPA risk. Up to 30% of CPA patients experience azole adverse effects (jaggi2024fungallungdisease pages 8-9).

No universally accepted host pharmacogenomic dosing algorithm replaces therapeutic drug monitoring. CYP2C19 genotype affects voriconazole exposure, but implementation is institution- and guideline-dependent.

Trials and emerging treatment

NCT05653193: adjunctive interferon-γ for CPA; randomized phase II feasibility study, 50 participants, active but not recruiting at retrieval.
NCT00531479: voriconazole plus anidulafungin versus voriconazole; phase III, 459 participants, completed.
NCT00263315: weekly inhaled liposomal amphotericin B prophylaxis in neutropenic hematology patients; randomized phase II/III, 320 participants, completed. The trial targeted reduction in IPA from about 7% to 1% and used twice-weekly serum GM plus CT for persistent fever (NCT00263315 chunk 1).
New agents in development include olorofim, fosmanogepix, ibrexafungerp, and inhaled triazoles such as opelconazole/PC945. Their roles in resistant, refractory, or localized pulmonary disease remain investigational.

13. Prevention

Primary: no licensed human vaccine exists. Minimize unnecessary corticosteroids and antibiotics; optimize asthma/CF/COPD and cavity-producing diseases; use respirators or avoid compost, construction dust, soil, and renovation aerosols during profound immunosuppression. Hospitals should use HEPA filtration, positive-pressure protective rooms, dust barriers, and construction-risk controls for high-risk units.

Secondary: stratify AML/HCT and other high-risk patients; use mold-active prophylaxis according to specialty guidelines and local resistance; monitor with symptom assessment, biomarkers, and early CT where appropriate. The preventive-amphotericin trial illustrates targeted rather than population prophylaxis (NCT00263315 chunk 1).

Tertiary: therapeutic drug monitoring, susceptibility testing, adherence support, serial CT/IgG or IgE monitoring as syndrome-appropriate, embolization for bleeding, surgery for selected localized lesions, and pulmonary rehabilitation prevent progression and complications.

Public-health priorities are improved mycology laboratories, resistance surveillance, antifungal stewardship, regulation/stewardship of agricultural azoles, and One Health linkage of environmental, veterinary, and clinical isolates. Genetic counseling is relevant only for an identified underlying inherited immunodeficiency, not for routine aspergillosis.

14. Other species and natural disease

Natural aspergillosis occurs widely in birds and mammals. Birds—poultry, raptors, waterfowl, penguins, parrots, and other captive/wild species—are especially susceptible to respiratory disease involving air sacs and lungs. Young birds are often at higher risk. Mammalian manifestations include sinonasal/orbital disease in dogs and cats, guttural-pouch mycosis and keratitis in horses, and pneumonia, mastitis, or rhinitis in sheep and goats.

A 2023 household study in Kazakhstan found median incidence risk/fatality of 39%/26% in chickens, 42%/22% in turkeys, and 37%/33% in geese; egg production fell a median 58.3%. These data demonstrate substantial veterinary and economic impact but should not be generalized globally.

Human aspergillosis is ordinarily acquired from the shared environment rather than directly from diseased animals. Thus, conventional zoonotic transmission is not a dominant mechanism. Birds may nevertheless disperse environmental and azole-resistant strains, making avian disease a potential sentinel in One Health surveillance.

Suggested taxonomy includes domestic chicken Gallus gallus (NCBI Taxon 9031), turkey Meleagris gallopavo (9103), goose Anser anser (8843), dog Canis lupus familiaris (9615), cat Felis catus (9685), and horse Equus caballus (9796). Breed-specific VBO susceptibility is insufficiently established.

15. Model organisms and experimental systems

Mouse IPA models: immunosuppression is induced with cyclophosphamide/neutropenia, corticosteroids, or targeted genetic defects, followed by intranasal/intratracheal conidia. They reproduce germination, lung invasion, inflammation, angioinvasion, fungal burden, and mortality. Limitations include artificial immune suppression, inoculum, route, murine pharmacokinetics, and immune differences.
Chronic/allergic mouse models: repeated airway challenge can reproduce eosinophilia, IgE, mucus and airway remodeling, but not the full decades-long human history or structural lung disease.
Galleria mellonella: inexpensive, high-throughput innate-immunity model used for fungal virulence and drug screening; lacks adaptive immunity and mammalian lung anatomy.
Zebrafish/larval systems: permit live imaging of phagocyte–fungus interactions, but temperature and organ differences constrain translation.
Cell systems: A549 epithelial cells, primary airway/alveolar cells, RAW264.7 or primary macrophages, neutrophils, NK cells, air–liquid-interface cultures, organoids, and lung-on-chip models isolate cell-specific mechanisms. They omit systemic immunity and full tissue architecture.
Fungal CRISPR/knockout models: deletion of maiA, sirE, or components of the CotA–SsdA axis links genotype to cell-wall/metabolic adaptation and virulence. The maiA evidence combines in-vitro transcriptomics with a neutropenic mouse model, providing stronger causal support than expression alone (guruceaga2024theaspergillusfumigatus pages 1-2).

Evidence-quality interpretation

Human guidelines and clinical cohorts most directly support diagnostic and treatment recommendations. Mouse, insect, and cell studies establish biological plausibility and target function but do not establish clinical efficacy. Computational/global burden estimates are essential where surveillance is absent but carry substantial uncertainty. The authoritative 2024 position is therefore that rapid syndrome-specific diagnosis, local resistance knowledge, antifungal exposure optimization, and correction of the host defect remain more clinically actionable than any single emerging omics marker (jaggi2024fungallungdisease pages 3-4, heylen2024acuteinvasivepulmonary pages 1-2, jaggi2024fungallungdisease pages 8-9).

References

(jaggi2024fungallungdisease pages 3-4): Tavleen Kaur Jaggi, Ritesh Agarwal, Pei Yee Tiew, Anand Shah, Emily C. Lydon, Chadi A. Hage, Grant W. Waterer, Charles R. Langelier, Laurence Delhaes, and Sanjay H. Chotirmall. Fungal lung disease. The European Respiratory Journal, 64:2400803, Oct 2024. URL: https://doi.org/10.1183/13993003.00803-2024, doi:10.1183/13993003.00803-2024. This article has 56 citations.
(jaggi2024fungallungdisease pages 1-3): Tavleen Kaur Jaggi, Ritesh Agarwal, Pei Yee Tiew, Anand Shah, Emily C. Lydon, Chadi A. Hage, Grant W. Waterer, Charles R. Langelier, Laurence Delhaes, and Sanjay H. Chotirmall. Fungal lung disease. The European Respiratory Journal, 64:2400803, Oct 2024. URL: https://doi.org/10.1183/13993003.00803-2024, doi:10.1183/13993003.00803-2024. This article has 56 citations.
(jaggi2024fungallungdisease pages 8-9): Tavleen Kaur Jaggi, Ritesh Agarwal, Pei Yee Tiew, Anand Shah, Emily C. Lydon, Chadi A. Hage, Grant W. Waterer, Charles R. Langelier, Laurence Delhaes, and Sanjay H. Chotirmall. Fungal lung disease. The European Respiratory Journal, 64:2400803, Oct 2024. URL: https://doi.org/10.1183/13993003.00803-2024, doi:10.1183/13993003.00803-2024. This article has 56 citations.
(tashiro2024chronicpulmonaryaspergillosis pages 1-2): Masato Tashiro, Takahiro Takazono, and Koichi Izumikawa. Chronic pulmonary aspergillosis: comprehensive insights into epidemiology, treatment, and unresolved challenges. Therapeutic Advances in Infectious Disease, Jan 2024. URL: https://doi.org/10.1177/20499361241253751, doi:10.1177/20499361241253751. This article has 59 citations.
(heylen2024acuteinvasivepulmonary pages 1-2): Jannes Heylen, Yuri Vanbiervliet, Johan Maertens, Bart Rijnders, and Joost Wauters. Acute invasive pulmonary aspergillosis: clinical presentation and treatment. Seminars in Respiratory and Critical Care Medicine, 45:069-087, Jan 2024. URL: https://doi.org/10.1055/s-0043-1777769, doi:10.1055/s-0043-1777769. This article has 49 citations and is from a peer-reviewed journal.
(jaggi2024fungallungdisease pages 4-5): Tavleen Kaur Jaggi, Ritesh Agarwal, Pei Yee Tiew, Anand Shah, Emily C. Lydon, Chadi A. Hage, Grant W. Waterer, Charles R. Langelier, Laurence Delhaes, and Sanjay H. Chotirmall. Fungal lung disease. The European Respiratory Journal, 64:2400803, Oct 2024. URL: https://doi.org/10.1183/13993003.00803-2024, doi:10.1183/13993003.00803-2024. This article has 56 citations.
(jaggi2024fungallungdisease pages 5-7): Tavleen Kaur Jaggi, Ritesh Agarwal, Pei Yee Tiew, Anand Shah, Emily C. Lydon, Chadi A. Hage, Grant W. Waterer, Charles R. Langelier, Laurence Delhaes, and Sanjay H. Chotirmall. Fungal lung disease. The European Respiratory Journal, 64:2400803, Oct 2024. URL: https://doi.org/10.1183/13993003.00803-2024, doi:10.1183/13993003.00803-2024. This article has 56 citations.
(heylen2024acuteinvasivepulmonary pages 6-7): Jannes Heylen, Yuri Vanbiervliet, Johan Maertens, Bart Rijnders, and Joost Wauters. Acute invasive pulmonary aspergillosis: clinical presentation and treatment. Seminars in Respiratory and Critical Care Medicine, 45:069-087, Jan 2024. URL: https://doi.org/10.1055/s-0043-1777769, doi:10.1055/s-0043-1777769. This article has 49 citations and is from a peer-reviewed journal.
(OpenTargets Search: aspergillosis): Open Targets Query (aspergillosis, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(harliza2024diagnosisandtreatment pages 1-2): Baiq Fanindya Harliza and Prima Belia Fathana. Diagnosis and treatment of aspergillosis. Jurnal Biologi Tropis, 24:386-392, Oct 2024. URL: https://doi.org/10.29303/jbt.v24i4.7682, doi:10.29303/jbt.v24i4.7682. This article has 4 citations.
(jaggi2024fungallungdisease pages 17-18): Tavleen Kaur Jaggi, Ritesh Agarwal, Pei Yee Tiew, Anand Shah, Emily C. Lydon, Chadi A. Hage, Grant W. Waterer, Charles R. Langelier, Laurence Delhaes, and Sanjay H. Chotirmall. Fungal lung disease. The European Respiratory Journal, 64:2400803, Oct 2024. URL: https://doi.org/10.1183/13993003.00803-2024, doi:10.1183/13993003.00803-2024. This article has 56 citations.
(guruceaga2024theaspergillusfumigatus pages 1-2): Xabier Guruceaga, Uxue Perez-Cuesta, Adela Martin-Vicente, Eduardo Pelegri-Martinez, Harrison I. Thorn, Saioa Cendon-Sanchez, Jinhong Xie, Ashley V. Nywening, Andoni Ramirez-Garcia, Jarrod R. Fortwendel, and Aitor Rementeria. The aspergillus fumigatus maia gene contributes to cell wall homeostasis and fungal virulence. Frontiers in Cellular and Infection Microbiology, Jan 2024. URL: https://doi.org/10.3389/fcimb.2024.1327299, doi:10.3389/fcimb.2024.1327299. This article has 7 citations.
(heilig2024cd56mediatedactivationof pages 1-2): Linda Heilig, Fariha Natasha, Nora Trinks, Vishukumar Aimanianda, Sarah Sze Wah Wong, Thierry Fontaine, Ulrich Terpitz, Lea Strobel, François Le Mauff, Donald C. Sheppard, Sascha Schäuble, Oliver Kurzai, Kerstin Hünniger, Esther Weiss, Mario Vargas, P. Lynne Howell, Gianni Panagiotou, Sebastian Wurster, Hermann Einsele, and Juergen Loeffler. Cd56-mediated activation of human natural killer cells is triggered by aspergillus fumigatus galactosaminogalactan. Jun 2024. URL: https://doi.org/10.1371/journal.ppat.1012315, doi:10.1371/journal.ppat.1012315. This article has 17 citations and is from a highest quality peer-reviewed journal.
(serpa2024allergicbronchopulmonaryaspergillosis pages 19-21): Faradiba Sarquis Serpa, Gustavo Falbo Wandalsen, Solange Oliveira Rodrigues Valle, Adelmir Souza Machado, Alfeu Tavares França, Álvaro Augusto Cruz, Antonio Carlos Pastorino, José Angelo Rizzo, José Elabras-Filho, Luane Marques de-Mello, Patricia Polles de Oliveira Jorge, Pedro Giavina-Bianchi, Ekaterini Simões Goudoris, and Fabio Chigres Kuschnir. Allergic bronchopulmonary aspergillosis: brazilian association of allergy and immunology guidelines for diagnosis and management. Jan 2024. URL: https://doi.org/10.5935/2526-5393.20240033-en, doi:10.5935/2526-5393.20240033-en. This article has 0 citations.
(NCT00263315 chunk 1): Inhalation of Liposomal Amphotericin B to Prevent Invasive Aspergillosis. Erasmus Medical Center. 2000. ClinicalTrials.gov Identifier: NCT00263315

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	7
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	24
Resolved	24
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	11
Terms named correctly	8
Terms named as a different term	0
Terms whose name is worth a second look	3

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001880 (1 mention) - the report calls it "Eosinophilia"; HP calls it Increased total eosinophil count, and lists "Eosinophilia" among its other names
HP:0003212 (1 mention) - the report calls it "Increased circulating IgE"; HP calls it Increased circulating IgE concentration, and lists "Increased circulating IgE level" among its other names
CL:0000623 (1 mention) - the report calls it "NK cell"; CL calls it natural killer cell, and lists "NK cell" among its other names

Every term resolved, and every label the report gave matched.

Ask OpenScientist

OpenScientist Report

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Imaging Findings

Progression

Prevalence

Infectious Agent

Transmission

Clinical Burden

Differential Diagnoses

Clinical Trials

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Aspergillosis: comprehensive disease-characteristics report

Executive summary and evidence scope

1. Disease information

Definition and forms

Identifiers and synonyms

2. Etiology, risk, protection, and gene–environment interaction

Causal agent and exposure

Clinical risk factors

Genetic susceptibility and protection

Protective factors

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Human genetics

Pathogen genetics and resistance

Functional genomics and epigenetic regulation

5. Environmental and infectious-agent information

6. Mechanism and pathophysiology

Causal chains

Cells, pathways, and ontology suggestions

Cellular, metabolic, and molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Epidemiology, inheritance, and population

10. Diagnostics

Invasive aspergillosis

CPA and aspergilloma

ABPA

Genetic and omics testing

11. Outcome and prognosis

12. Treatment and current applications

IPA

CPA/aspergilloma

ABPA

Pharmacology and adverse effects

Trials and emerging treatment