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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0005706 coccidioidomycosis

Primary MONDO disease identifier for coccidioidomycosis.

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Definitions

1

Clinical case definition

Coccidioidomycosis is a systemic fungal infection caused by inhalation of arthroconidia from the dimorphic soil fungi Coccidioides immitis or Coccidioides posadasii. The disease spectrum ranges from asymptomatic seroconversion (approximately half of infections) to acute self-limited pneumonia, chronic progressive pulmonary disease, or disseminated extrapulmonary infection involving skin, bones, joints, and meninges. Diagnosis is established by serologic testing (IgM and IgG antibodies, complement fixation titers), culture isolation of Coccidioides species, or histopathologic identification of characteristic spherules containing endospores in tissue specimens.

CASE_DEFINITION

Show evidence (2 references)

PMID:38535182 SUPPORT Human Clinical

"only half of infected, immunologically intact people develop symptomatic pneumonia; most symptomatic infections resolve spontaneously, although some resolve very slowly."

Supports the clinical definition by documenting the disease spectrum from asymptomatic to symptomatic pneumonia.

PMID:39452676 SUPPORT Human Clinical

"Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."

Confirms the causative agents and their genetic distinction.

◆

Subtypes

3

Primary pulmonary coccidioidomycosis

Acute pulmonary infection that is often self-limited, presenting as community-acquired pneumonia in endemic areas. Most symptomatic infections resolve spontaneously.

Show evidence (2 references)

PMID:39452676 SUPPORT Human Clinical

"Clinically, the infection ranges from asymptomatic to fatal disease due to pneumonia or disseminated states. The recognition of coccidioidomycosis can be challenging, as it frequently mimics bacterial community-acquired pneumonia."

Confirms that primary pulmonary coccidioidomycosis mimics community-acquired pneumonia and ranges from asymptomatic to severe.

PMID:38535182 SUPPORT Human Clinical

"only half of infected, immunologically intact people develop symptomatic pneumonia; most symptomatic infections resolve spontaneously, although some resolve very slowly."

Confirms that most primary pulmonary infections are self-limited.

Disseminated coccidioidomycosis

Extrapulmonary spread of infection to skin, bones, joints, meninges, and other organs. Occurs in a minority of infected individuals. Immunocompromised patients are at significantly higher risk.

Show evidence (2 references)

PMID:39189034 SUPPORT Human Clinical

"41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement)."

Documents the spectrum of extrapulmonary dissemination sites in critically ill patients.

PMID:38535182 SUPPORT Human Clinical

"People who are immunocompromised are much more likely to develop disseminated infection."

Confirms that immunocompromise is a major risk factor for dissemination.

Coccidioidal meningitis

The most serious complication of disseminated disease, involving chronic basilar meningitis that is associated with very high mortality without antifungal treatment and requires lifelong antifungal therapy.

Show evidence (1 reference)

PMID:39189034 SUPPORT Human Clinical

"41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). Seventy patients (48%) died during hospitalization"

Documents meningitis as a significant form of extrapulmonary disease with high mortality in ICU patients.

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Mechanistic Hypotheses

2

Coccidioidal Granuloma Composition and Maintenance Model

granuloma_composition_containment_model EMERGING

Evidence balance 8 support

A hypothesis about the cellular and signaling composition of the coccidioidal granuloma, and about which features of it determine containment versus progression to cavitation and dissemination. The model proposed here is that the spherule's resistance to phagocytosis obliges a specific, sustained macrophage-transformation program - epithelioid differentiation and giant-cell fusion under Th1/Th17 and TNF drive - and that the identity of the recruited cells, the signals that maintain the structure, and the immune microenvironment inside the granuloma are what distinguish a contained lesion from one that necroses and disseminates. The status is EMERGING rather than CANONICAL because the intermediate steps are borrowed rather than measured. Granuloma biology in coccidioidomycosis is currently modeled largely by analogy to tuberculosis: morphologies have been described, but the cells recruited, the maintenance signals, and the interior microenvironment are explicitly unresolved in the primary literature. This entry's conformance to the `granuloma_formation` module therefore rests on two causal edges (Th1/Th17 -> epithelioid transformation, and epithelioid transformation -> organized granuloma) whose evidence is PARTIAL for exactly this reason; those edges are tagged into this hypothesis group so the dependency is explicit rather than implied. Two comparators already in the knowledge base bear on the same question through the shared module: Sarcoidosis (`antigen_persistence_granuloma_chronicity_model`) and Chronic_Beryllium_Disease. The mouse scRNA-seq time course (GSE274766) and Visium spatial transcriptomics (GSE274767) recorded in this entry's `datasets` block are the matched data most directly capable of addressing the cell-identity and spatial-organization components.

Pathograph links

Th1/Th17 cell-mediated adaptive immunity -> Epithelioid transformation and multinucleated giant cell formation INDIRECT KNOWN INTERMEDIATES The IFN-gamma- and TNF-activated macrophage milieu is what licenses the defining epithelioid and multinucleated-giant-cell transformations of the granulomatous response to Coccidioides.

Epithelioid transformation and multinucleated giant cell formation -> Granuloma formation and containment DIRECT Epithelioid and giant-cell transformation converts a diffuse macrophage infiltrate into the organized cellular core of a coccidioidal granuloma.

Deep research

OpenScientist 2026-08-08T19:41:08.421952

Show evidence (8 references)

PMID:33262956 SUPPORT Other

"we do not know what cells are recruited to the granuloma, what signals form and maintain the granuloma structure, nor details on the immune microenvironment within the granuloma interior"

States the open question this hypothesis group exists to resolve, in the authors' own words: granuloma cell composition, maintenance signals, and interior microenvironment are all unresolved for Coccidioides.

PMID:33262956 SUPPORT Other

"Exploring granuloma immunity is imperative for understanding infection chronicity as Coccidioides infection often presents with granuloma formation."

Motivates the hypothesis: granuloma immunity is framed as the route to understanding why some infections become chronic rather than resolving.

PMID:37367586 SUPPORT Other

"However, very little is known about granulomas during Coccidioides infection."

Independent confirmation from a review dedicated to coccidioidal granulomas that the disease-specific granuloma biology is largely uncharacterized.

+ 5 more references

Neutrophil and Inflammasome Immunopathology Model

neutrophil_inflammasome_immunopathology_model ALTERNATIVE

Evidence balance 4 support

The competing account of what determines outcome in coccidioidomycosis. Instead of outcome being set by the quality of the macrophage epithelioid/giant-cell containment program, this model holds that it is set by inflammasome-driven immunopathology: spherule rupture engages NLRP3 and pyrin inflammasomes, IL-1beta drives neutrophil recruitment, and the resulting neutrophilic response damages tissue and impairs the protective Th1/Th17 arm. It is registered as ALTERNATIVE rather than as a component of the granuloma model because two independent loss-of-function experiments run the opposite way to a protective reading: CXCR2-deficient mice have fewer neutrophils and *fewer* organisms with higher Ifng/Il17a, and caspase-1-deficient mice show improved tolerance at *equivalent* fungal burden. A model in which neutrophil influx and inflammasome signaling are protective effectors of containment does not predict either result. The two models are not mutually exclusive and share a trigger: both descend from the phagocytosis-resistant spherule, diverging at rupture. Where they make different predictions is the composition of the destructive lesion, and there the available human evidence favours this model - the wall of the established human cavity shows no granulomas, and its lining is neutrophils and caseous necrosis (PMID:24321524). Curated as ALTERNATIVE rather than promoted because the two decisive experiments are murine, the human evidence is descriptive pathology rather than perturbation, and the IL-1/IL-18 axis also has documented protective functions in this infection.

Pathograph links

Phagocytosis-resistant spherule persistence -> Spherule rupture-triggered inflammasome activation and neutrophil recruitment DIRECT The same persistent spherule that cannot be phagocytosed eventually ruptures, and rupture is the specific trigger of the alternative inflammasome/neutrophil axis. This is the branch point at which the two curated models diverge from a shared trigger.

Spherule rupture-triggered inflammasome activation and neutrophil recruitment -> Pulmonary cavitary disease INDIRECT KNOWN INTERMEDIATES Under this model the neutrophilic, inflammasome-driven response is what destroys tissue: the lining of the established human cavity is neutrophils and caseous necrosis rather than granulomatous tissue.

Show evidence (4 references)

PMID:33106296 SUPPORT Model Organism

"IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice."

Loss of the neutrophil-recruiting receptor improves fungal control, which a protective-neutrophil model does not predict.

PMID:42386736 SUPPORT Model Organism

"Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens"

Disentangles immunopathology from fungal control: outcome improves with inflammasome signaling removed while burden is unchanged.

PMID:42386736 SUPPORT In Vitro

"A TLR2-NLRP3-pyrin-IL-18 axis in macrophages promotes spherule growth."

Adds a direct pathogen-benefit arm to this model - inflammasome signaling promoting spherule growth. Support is PARTIAL because it is a cell-culture result and does not by itself establish the organism-level outcome.

+ 1 more reference

?

Discussions and Knowledge Gaps

3

Do dust storms specifically cause measurable subsequent increases in coccidioidomycosis incidence, or is dust-storm exposure one of several aerosolization routes whose population-level contribution is unresolved?

CONTROVERSY OPEN controversy_dust_storms_vs_incidence

Attached to

environmental#Dust storm and windblown dust events pathophysiology#Arthroconidia inhalation and spherule morphogenesis

This is a live, published disagreement rather than an absence of evidence, and the two positions were argued in the same journal. Tong et al. (2017) reconstructed a long-term dust climatology and reported that dust storm frequency correlates with Valley Fever incidence in Maricopa and Pima Counties at least as strongly as other accepted controls of the disease. Comrie (2021) applied superposed-epoch analysis to all recorded dust storms from 2006 to 2020 near Phoenix and Bakersfield and found no difference in monthly or weekly case patterns following dust storms versus non-dust-storm conditions, noting that arthroconidia also travel in low-wind conditions and that an earlier study measuring airborne arthroconidia likewise found no consistent wind/dust link. Tong et al. (2022) replied that the crowdsourced NOAA Storm Events dust records are unsuitable for the question, that "dust storm" is not consistently defined across communities, and that exposure must account for event frequency, magnitude, and duration. The disagreement is partly about measurement rather than biology: nobody disputes that dust events aerosolize and transport arthroconidia, and the entry's mechanism edge is scoped to that transport route only. What is unresolved is whether discrete, catalogued dust storms are a quantitatively important driver of incidence relative to chronic low-wind aerosolization and to soil disturbance by construction and agriculture. This matters practically, because dust-storm advisories are a public-health lever only if the attribution holds, and it matters for the entry because a climate-change-driven increase in dust events is repeatedly cited as a reason to expect rising Valley Fever incidence.

Proposed experiments

Co-located airborne Coccidioides DNA sampling and incidence surveillance across defined dust events

exp_dust_storm_arthroconidia_incidence_coupling

Pair continuous air sampling with quantitative Coccidioides PCR at fixed endemic sites against a dust-event catalogue built to a single explicit definition (rather than aggregated storm reports), recording event frequency, magnitude, and duration. Link airborne arthroconidia concentration to laboratory-confirmed incidence at an appropriate incubation lag and individual residence location, so that exposure and outcome are measured on the same spatial scale instead of being compared across county-level aggregates. This addresses both the exposure misclassification Tong et al. raise and the null result Comrie reports.

Show evidence (3 references)

PMID:30166741 SUPPORT Human Clinical

"The frequency of dust storms is found to be correlated with Valley fever incidences, with a coefficient (r) comparable to or stronger than that with other factors believed to control the disease in two endemic centers (Maricopa and Pima County, Arizona)."

The position asserting a dust-storm/incidence association. Tagged HUMAN_CLINICAL to match the identical snippet on the dust-storm mechanism edge: this quote is the paper's county-level epidemiological correlation, which CLAUDE.md classifies as HUMAN_CLINICAL. The separate OTHER-tagged item from this paper quotes its atmospheric dust-climatology finding, a genuinely different evidence type.

PMID:34877441 REFUTE Human Clinical

"there is no reliable evidence that all or most dust storms consistently lead to subsequent increases in coccidioidomycosis cases"

The opposing position, from the superposed-epoch reanalysis.

PMID:35949254 SUPPORT Other

"The dust data from National Oceanic and Atmospheric Administration Storm Events Database are from diverse sources, unsuitable for assessing dust-coccidioidomycosis relationships."

Published reply contesting the refuting study on exposure-measurement grounds, which is why the controversy is recorded as open rather than settled in either direction.

Has anyone shown, in Coccidioides-infected tissue, that Th1/Th17 and TNF signalling drives macrophages into the epithelioid and multinucleated giant-cell program, and that this transformation is what organizes and maintains the granuloma rather than being a bystander marker of it?

KNOWLEDGE GAP OPEN gap_epithelioid_transformation_edges_unmeasured

Attached to

pathophysiology#Epithelioid transformation and multinucleated giant cell formation pathophysiology#Granuloma formation and containment mechanistic_hypotheses#granuloma_composition_containment_model

The two module-conforming edges at the centre of this entry are the ones with no Coccidioides measurement behind them. Both ends of the chain are documented in this disease: the spherule genuinely resists phagocytosis, the Th1/Th17 and TNF requirement is established by human genetic defects and by TNF blockade, and organized granulomas track with containment across mouse strains while the human cavity is neutrophilic and non-granulomatous. What is missing is the middle. The mechanistic cascade in which IFN-gamma primes macrophages to make TNF and IL-1 and thereby produces epithelioid and giant-cell differentiation was worked out in hypersensitivity pneumonitis and in antigen-bead granulomas, not in coccidioidomycosis, and no study has perturbed macrophage differentiation in a Coccidioides model to ask whether granuloma organization and containment are lost when fungal burden is held constant. This is a gap in evidence, not a suspected error: the entry's giant-cell node is anchored on human tissue histopathology showing spherules inside multinucleated giant cells, so the transformation demonstrably occurs. The open question is whether it is driven by the signals the model names and whether it does the containing. It matters because the entry's conformance to `granuloma_formation` rests on these two edges, and because the field's default move - reasoning from tuberculosis - is exactly what the hypothesis flags as unvalidated. Note what would not close this gap. Etiology-comparative granuloma transcriptomics is sometimes cited as already showing that granuloma programs diverge by cause; the study most often invoked here (PMID:33276795) compares tissue sites within sarcoidosis, includes only three coccidioidomycosis subjects, and makes no direct coccidioidomycosis-versus-tuberculosis comparison, so it motivates the caution without measuring the edges.

Proposed experiments

Spatial transcriptomic coupling of macrophage differentiation state to local Th1/Th17 cytokine fields in contained versus necrotic coccidioidal lesions

exp_spatial_coupling_macrophage_state_to_cytokine_niche

Apply spatially resolved transcriptomics and single-cell profiling to coccidioidal lesions stratified by architecture - organized granuloma versus neutrophilic or caseous lesion - and ask whether epithelioid and giant-cell macrophage signatures are spatially coupled to local IFN-gamma, IL-17, and TNF fields, and whether that coupling separates contained from progressive lesions. The mouse datasets already recorded in this entry (GSE274766 and GSE274767) are matched to the question but were generated in lethal acute infection, so contained lesions and human tissue would have to be added for the contrast to exist.

Would support

pathophysiology#Epithelioid transformation and multinucleated giant cell formation

Would refute

mechanistic_hypotheses#granuloma_composition_containment_model

Supporting outcome

Epithelioid and giant-cell macrophage signatures localize to Th1/Th17-cytokine-rich niches and are enriched in contained lesions relative to necrotic ones.

Refuting outcome

Macrophage differentiation state is unrelated to local cytokine fields, or lesion outcome tracks neutrophil and inflammasome signatures irrespective of macrophage state, which would favour the alternative neutrophil/inflammasome model over this one.

Conditional blockade of macrophage fusion and epithelioid programming in a murine Coccidioides model

exp_block_giant_cell_fusion_at_constant_burden

Interrupt giant-cell fusion or epithelioid differentiation - for example by targeting the fusion machinery - during established murine coccidioidal infection, and measure granuloma architecture, containment, and dissemination while holding fungal burden constant. This is the perturbation that separates a driver from a marker, and it is the experiment no published Coccidioides study has performed.

Decision criterion

Loss of organized granuloma architecture and of containment at unchanged fungal burden distinguishes a causal maintenance role from an incidental morphological correlate.

Would support

pathophysiology#Granuloma formation and containment

Would refute

mechanistic_hypotheses#granuloma_composition_containment_model

Supporting outcome

Blocking the transformation disorganizes the granuloma and degrades containment without altering the organism load.

Refuting outcome

Granuloma organization and containment are preserved despite loss of epithelioid and giant-cell differentiation, making the transformation a marker rather than the maintaining mechanism.

Show evidence (2 references)

PMID:33262956 SUPPORT Other

"we do not know what cells are recruited to the granuloma, what signals form and maintain the granuloma structure, nor details on the immune microenvironment within the granuloma interior"

The gap stated by the field in its own words: recruited cells, maintenance signals, and the interior microenvironment are all recorded as unknown for Coccidioides.

PMID:37367586 SUPPORT Other

"Granulomas are best defined in TB, providing clues that may be leveraged to understand Coccidioides infections."

Documents that the working model for these edges is transferred from tuberculosis, which is what makes the transfer a gap rather than a conclusion.

Do regulatory T cells and B-cell or ectopic-lymphoid structures govern whether a coccidioidal granuloma contains the organism or injures the lung, as they do in comparator granulomatous diseases?

KNOWLEDGE GAP OPEN gap_regulatory_and_b_cell_granuloma_maintenance

Attached to

pathophysiology#Granuloma formation and containment mechanistic_hypotheses#granuloma_composition_containment_model

The curated model for this entry describes granuloma maintenance almost entirely as drive: Th1 and Th17 cytokines and TNF licensing a macrophage transformation. In the two granulomatous comparators this entry already names through the shared `granuloma_formation` module, the decisive variables include regulation as well as drive. In an HLA-DP2 transgenic model of chronic beryllium disease, depleting regulatory T cells worsened lung inflammation and increased granuloma formation, and depleting B cells dissolved the lymphoid aggregates and granulomas while increasing lung injury, with B cells found at the granuloma periphery in human disease too. No equivalent measurement exists for coccidioidomycosis. Neither cell type has been depleted, expanded, or systematically enumerated in a Coccidioides granuloma, so the entry cannot say whether the regulatory arm is absent from this disease or merely unstudied. That distinction is the gap. Deliberately not curated as pathophysiology nodes. Both supporting results come from a sterile particulate exposure in transgenic mice, and adding regulatory T cell or B cell nodes to this entry on that basis would assert a coccidioidal mechanism nobody has measured. The comparator evidence is recorded here, where its provenance stays visible, until Coccidioides-specific data exist.

Proposed experiments

Timed regulatory T cell and B cell depletion in murine pulmonary coccidioidomycosis

exp_treg_and_b_cell_depletion_in_murine_coccidioidomycosis

Deplete regulatory T cells, or B cells, at defined phases of established murine Coccidioides infection and read out granuloma architecture, lymphoid aggregate formation, fungal burden, lung injury, and dissemination. Running both arms against the same infection separates a regulatory contribution to containment from a regulatory contribution to tissue tolerance, and pairs the disease with the comparator results that motivate the question.

Would support

pathophysiology#Granuloma formation and containment

Supporting outcome

Depletion changes lesion architecture or lung injury without a proportional change in fungal burden, establishing a regulatory arm in coccidioidal granuloma maintenance analogous to the comparator diseases.

Refuting outcome

Depletion leaves granuloma organization, injury, and burden unchanged, indicating that the comparator finding does not transfer and that this entry's drive-centred model is adequate.

Show evidence (2 references)

PMID:24912188 SUPPORT Model Organism

"Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation."

Comparator-disease evidence that regulatory T cells modulate the granulomatous response. Cited to establish that the question is live in granuloma biology generally; it says nothing about Coccidioides, which is the gap.

PMID:31094704 SUPPORT Model Organism

"B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice."

Comparator-disease evidence that B cells are required for granuloma and lymphoid-aggregate formation and are protective against lung injury. Again chronic beryllium disease, not coccidioidomycosis; recorded to scope the gap rather than to assert the mechanism here.

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Pathophysiology

8

Arthroconidia inhalation and spherule morphogenesis

Coccidioides exists as a mycelial form in soil. When soil is disturbed, arthroconidia (barrel-shaped spores 2-5 micrometers in size) become airborne and are inhaled into the lungs, reaching terminal bronchioles. In host tissues at 37 degrees C, arthroconidia undergo a morphological transition to spherules, which are large round structures that undergo internal division to produce hundreds of endospores. Developing spherules secrete a metalloproteinase that contributes to immune masking. Rupture of mature spherules releases endospores that trigger rapid immune cell influx and can spread hematogenously.

alveolar macrophage CL:0000583 neutrophil CL:0000775 dendritic cell CL:0000451

innate immune response GO:0045087

lung UBERON:0002048

Downstream

Cough Pulmonary Coccidioides infection after inhalation commonly presents with cough.

Pleuritic chest pain Pulmonary coccidioidomycosis can involve pleuritic inflammation and chest pain.

Fever Developing Coccidioides infection produces flu-like systemic symptoms, including fever.

Fatigue Symptomatic coccidioidomycosis commonly includes fatigue during pulmonary infection.

Dyspnea Pulmonary and pleural involvement can present with shortness of breath.

Headache Developing Coccidioides infection produces flu-like systemic symptoms, including headache.

Erythema nodosum Coccidioidomycosis can trigger the desert-rheumatism symptom complex with erythema nodosum.

Arthralgia Coccidioidomycosis can trigger the desert-rheumatism symptom complex with arthralgia.

Night sweats Established Coccidioides infection produces the constitutional symptoms of a chronic pulmonary/disseminated mycosis, including night sweats.

Weight loss Chronic and disseminated Coccidioides infection produces a wasting constitutional response with unintentional weight loss.

Phagocytosis-resistant spherule persistence Morphogenesis from the small, readily phagocytosed arthroconidium into the large tissue-phase spherule is what converts the organism into a stimulus that an individual phagocyte cannot clear.

Show evidence (2 references)

PMID:39452676 SUPPORT Human Clinical

"Coccidioidomycosis is transmitted through the inhalation of fungal spores, arthroconidia, which can cause disease in susceptible mammalian hosts, including humans."

Confirms the inhalation route of arthroconidia transmission.

PMID:33262956 SUPPORT Other

"In the spherule state, Coccidioides secretes metalloproteinase 1 (Mep1) which digests an immunodominant antigen spherical outer wall glycoprotein (SOWgp) on the fungal surface"

Describes spherule morphogenesis and the Mep1 metalloproteinase that digests SOWgp to evade immune detection.

Phagocytosis-resistant spherule persistence

The mature spherule is the disease-specific substitution for the generic persistent indigestible stimulus of the granuloma module. At 20-200 micrometers it exceeds the phagocytic capacity of macrophages and neutrophils, which engulf endospores readily but can only partially engulf spherules ("frustrated phagocytosis"). Because no individual phagocyte can eliminate it, the spherule sustains a chronic, organized macrophage response rather than a self-limited acute one - the entry condition for granuloma formation.

Neutrophil and Inflammasome Immunopathology Model

macrophage CL:0000235 neutrophil CL:0000775

chronic inflammatory response GO:0002544 ↑ INCREASED

lung UBERON:0002048

Downstream

Spherule rupture-triggered inflammasome activation and neutrophil recruitment The same persistent spherule that cannot be phagocytosed eventually ruptures, and rupture is the specific trigger of the alternative inflammasome/neutrophil axis. This is the branch point at which the two curated models diverge from a shared trigger.

Th1/Th17 cell-mediated adaptive immunity A stimulus that cannot be cleared by innate phagocytosis obliges the host to mount the sustained Th1/Th17 and TNF-driven macrophage-activating response that organizes a granuloma.

Show evidence (4 references)

PMID:33262956 SUPPORT Other

"Mature spherules are too large for most host phagocytic activity, allowing Coccidiodes to evade early immune detection"

States that mature spherules exceed host phagocytic capacity, which is the module's persistent-indigestible-stimulus criterion applied to Coccidioides. Evidence source is OTHER because this is a review.

PMID:33262956 SUPPORT In Vitro

"human neutrophils readily phagocytose Coccidioides endospores and exhibit partial phagocytosis of larger spherules"

Documents that human phagocytes clear endospores but can only partially engulf spherules, the cellular basis of spherule persistence. Evidence source is IN_VITRO because the underlying observation is a neutrophil-fungus co-incubation assay.

PMID:6300253 SUPPORT In Vitro

"Arthroconidia possess an antiphagocytic surface derived from the original hyphal outer wall layer. Only 20%-30% of arthroconidia or endospores that are ingested by PMNs are killed."

Primary-literature anchor for the two components of this node that the review evidence above asserts without quantifying: the fungal surface is actively antiphagocytic, and even the organisms that are successfully ingested are mostly not killed. Together these make phagocyte-mediated clearance insufficient in principle, which is the module's persistent-indigestible-stimulus criterion. Evidence source is IN_VITRO because the quoted killing fraction comes from phagocyte-fungus killing assays.

+ 1 more reference

Spherule rupture-triggered inflammasome activation and neutrophil recruitment

The alternative, macrophage-independent axis of this entry. Rupture of the mature spherule - not the intact spherule - engages NLRP3 and pyrin inflammasomes with GSDMD/GSDME pore formation, releasing IL-1beta and recruiting neutrophils, which in human tissue congregate in and around rupturing spherules. Two loss-of-function results make this a genuine competitor to the macrophage/granuloma containment model rather than an elaboration of it, because in both the host does BETTER with less of this response: CXCR2 (IL-8R2)-deficient mice have fewer lung neutrophils and, unexpectedly, fewer organisms, with higher Ifng/Il17a - the authors' interpretation being that neutrophils interfere with development of the protective Th1/Th17 response; and caspase-1-deficient mice show improved disease tolerance at equivalent fungal burden. Under this model, outcome is set by inflammasome-driven immunopathology rather than by the quality of the epithelioid/giant-cell program, and the neutrophil-and-caseous-necrosis lining of the human cavity is its destructive end point. This node deliberately carries no downstream edge to Th1/Th17: the claim there is that neutrophil influx *impairs* the protective response, and `CausalEdge` has no polarity slot, so an edge would misread as promotion.

Neutrophil and Inflammasome Immunopathology Model

neutrophil CL:0000775 macrophage CL:0000235

canonical inflammasome complex assembly GO:0140632 ↑ INCREASED NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED

Downstream

Pulmonary cavitary disease Under this model the neutrophilic, inflammasome-driven response is what destroys tissue: the lining of the established human cavity is neutrophils and caseous necrosis rather than granulomatous tissue.

Show evidence (5 references)

PMID:42386736 SUPPORT In Vitro

"only ruptured spherules-not intact ones-trigger IL-1β production through NLRP3-pyrin inflammasomes and GSDMD-GSDME pores"

Establishes spherule rupture as the specific trigger of inflammasome activation, distinguishing this axis from generic fungal sensing. Evidence source is IN_VITRO because the mechanism was dissected in bone marrow-derived macrophages.

PMID:42386736 SUPPORT Model Organism

"Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens"

The load-bearing loss-of-function result: removing inflammasome signaling improves outcome without changing fungal burden, which separates immunopathology from fungal control and is what makes this an alternative model rather than a component of the containment model.

PMID:33106296 SUPPORT Model Organism

"IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice."

Blocking neutrophil recruitment improves fungal control, the opposite of what a purely protective role for neutrophils would predict.

+ 2 more references

Pulmonary cavitary disease

The destructive arm of the module's double-edged consequence node, specialized to Coccidioides. Where the granulomatous response contains the organism the infection resolves or leaves a quiescent nodule; where it fails to contain it, the granulomatous focus necroses and cavitates, and the cavity can rupture into the pleural space or bleed. Cavitary disease may be detected incidentally or during evaluation of cough or hemoptysis. Important qualifier on this conformance: the established cavity is where containment has already been lost, and human surgical pathology shows the cavity wall itself is characteristically NOT granulomatous - it shows chronic inflammation and occasional giant cells but no granulomas, with the lining composed of neutrophils and caseous necrosis, while granulomas persist in the adjacent lung as satellite lesions. The node therefore conforms to the module's destruction arm as the outcome of granulomatous containment failing, not as a granulomatous lesion in its own right. That same lining of neutrophils and necrosis is what the `neutrophil_inflammasome_immunopathology_model` hypothesis group proposes is doing the damage.

lung UBERON:0002048

Downstream

Hemoptysis Cavitary lung disease in coccidioidomycosis can present when hemoptysis is investigated.

Show evidence (4 references)

PMID:37233271 SUPPORT Other

"Subsequent pulmonary complications as well as extrapulmonary metastatic infection may occur, either of which may be the presenting disease manifestation. Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis."

Human clinical review evidence documents cavitary lung disease as a pulmonary complication of coccidioidomycosis.

PMID:24613568 SUPPORT Human Clinical

"Pleuritis is a recognized complication of ruptured cavitary infections"

Documents cavity rupture and pleural extension, the tissue-destruction arm of the module's containment-versus-destruction consequence node.

PMID:24321524 SUPPORT Human Clinical

"The cavity wall showed chronic inflammation and occasional giant cells but no granulomas and no microorganisms."

Human surgical pathology of 21 consecutive resected cavities. Support is PARTIAL and deliberately qualifying: it confirms the destructive end state this node represents while establishing that the cavity wall itself is not a granulomatous lesion. It therefore bounds what the conformance to `granuloma_formation#Tissue Containment versus Destruction and Fibrosis` may be read as claiming - the cavity is the consequence of containment failing, not a granuloma.

+ 1 more reference

Innate immune recognition via pattern recognition receptors

Initial recognition of Coccidioides involves pattern recognition receptors including Toll-like receptors and C-type lectin receptors. Dectin-1 (CLEC7A) is the primary receptor for fungal beta-1,3-glucan exposed on spherule surfaces. Dectin-1 signals through CARD9 via the Syk kinase pathway, activating NF-kB and promoting pro-inflammatory cytokine production. Deficiency in Dectin-1 or CARD9 leads to impaired Th17/Th1 responses and increased susceptibility to disseminated disease. Arthroconidia can initially bias macrophage differentiation toward a noninflammatory state and induce limited dendritic cell activation.

macrophage CL:0000235 dendritic cell CL:0000451

CLEC7A hgnc:14558 CARD9 hgnc:16391

pattern recognition receptor signaling pathway GO:0002221 cytokine production GO:0001816

Downstream

Th1/Th17 cell-mediated adaptive immunity CARD9-coupled C-type lectin receptor signaling on innate cells is the upstream requirement for polarizing the protective Th17 (and Th1) response.

Show evidence (2 references)

PMID:32358020 SUPPORT Model Organism

"the GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways."

Demonstrates that innate immune recognition of Coccidioides involves CARD9-associated Dectin-1 and Dectin-2 C-type lectin receptor signaling pathways.

PMID:33262956 SUPPORT Other

"Macrophages and neutrophils detect Coccidioides arthroconidia and immature spherules via receptors Dectin-1, Dectin-2, and Mincle interacting with SOWgp"

Identifies the specific pattern recognition receptors (Dectin-1, Dectin-2, Mincle) and their fungal ligand (SOWgp) involved in innate immune recognition of Coccidioides.

Th1/Th17 cell-mediated adaptive immunity

Protective immunity against Coccidioides depends on robust Th1 and Th17 CD4+ T cell responses. IFN-gamma produced by Th1 cells activates macrophages to kill fungal organisms. IL-17 from Th17 cells recruits neutrophils and supports mucosal immunity. The IL-12/IFN-gamma signaling axis is critical; genetic defects in IL12RB1, STAT4, or STAT3 impair these responses and increase susceptibility to severe disseminated disease. TNF-alpha is essential for granuloma formation and maintenance. Th2 skewing or immunosuppression (particularly TNF-alpha blockade) predisposes to dissemination. This is the coccidioidomycosis-specific substitution for the module's Th1/TNF-driven macrophage recruitment and activation step: the cytokine-rich milieu that licenses the epithelioid and giant-cell transformations downstream.

Coccidioidal Granuloma Composition and Maintenance Model

T-helper 1 cell CL:0000545 T-helper 17 cell CL:0000899 CD4-positive, alpha-beta T cell CL:0000624 macrophage CL:0000235

STAT4 hgnc:11365 STAT3 hgnc:11364 IL12RB1 hgnc:5971

T-helper 1 type immune response GO:0042088 T-helper 17 type immune response GO:0072538 macrophage activation GO:0042116 ↑ INCREASED

Downstream

Epithelioid transformation and multinucleated giant cell formation The IFN-gamma- and TNF-activated macrophage milieu is what licenses the defining epithelioid and multinucleated-giant-cell transformations of the granulomatous response to Coccidioides.

Fungal meningitis Failure of protective cell-mediated immunity can permit disseminated infection, including meningitis.

Osteomyelitis Disseminated coccidioidomycosis can involve skeletal infection, including osteomyelitis.

Show evidence (2 references)

PMID:38535182 SUPPORT Human Clinical

"the host response to this organism is very effective at resolving the infection in most cases and immunizing to prevent second infections. People who are immunocompromised are much more likely to develop disseminated infection."

Confirms the effectiveness of cell-mediated immunity and the role of immunocompromise in dissemination.

PMID:38667927 SUPPORT Human Clinical

"Specific genetic variants, sex, and immune suppression by TNF inhibitors have been validated in later cohort studies, confirming the original hypotheses."

Validates genetic susceptibility factors and TNF-alpha blockade as risk factors, supporting the importance of the Th1/TNF-alpha axis.

Epithelioid transformation and multinucleated giant cell formation

In the activated milieu, lung macrophages undergo the module's defining transformations: they differentiate into interdigitated epithelioid cells and fuse into multinucleated giant cells. In coccidioidomycosis the giant cells are the compartment in which spherules are characteristically found on tissue histopathology, so this step is simultaneously the granuloma-forming transformation and the containment of the organism the host could not phagocytose as a single cell.

Coccidioidal Granuloma Composition and Maintenance Model

epithelioid macrophage CL:0002150 multinucleated giant cell CL:0000647

syncytium formation by cell-cell fusion GO:0000768 ↑ INCREASED

Downstream

Granuloma formation and containment Epithelioid and giant-cell transformation converts a diffuse macrophage infiltrate into the organized cellular core of a coccidioidal granuloma.

Show evidence (2 references)

PMID:28857979 SUPPORT Human Clinical

"scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells"

Human tissue histopathology places Coccidioides spherules predominantly inside multinucleated giant cells, directly documenting the giant-cell transformation in this disease.

PMID:24613568 SUPPORT Human Clinical

"All cases showed granulomatous pleuritis."

A 36-case surgical-pathology series in which every case showed granulomatous inflammation. Support is PARTIAL because the snippet establishes a uniformly granulomatous tissue response without itself resolving the epithelioid/giant-cell cytology.

Granuloma formation and containment

The host attempts to contain Coccidioides infection through granuloma formation, a hallmark of the tissue response. Granulomas consist of epithelioid macrophages, multinucleated giant cells, and a surrounding cuff of lymphocytes. TNF-alpha is essential for granuloma formation and maintenance. CD14-positive macrophages localize to granuloma cores while CD206-positive macrophages are present internally and peripherally. Effective granuloma formation correlates with disease containment, while failure to form organized granulomas (as in immunocompromise or TNF-alpha blockade) is associated with dissemination and mortality.

macrophage CL:0000235

granuloma formation GO:0002432

Downstream

Pulmonary cavitary disease When the granulomatous focus fails to contain the organism, the assembled granuloma is also the lesion that necroses and cavitates, and the resulting cavity may rupture into the pleural space.

Granulomatosis Granuloma formation is the tissue-response mechanism underlying the granulomatous phenotype.

Show evidence (6 references)

PMID:37367586 SUPPORT Other

"One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."

Directly supports granuloma formation as a key containment mechanism in coccidioidomycosis.

PMID:33262956 SUPPORT Other

"Host responses sometimes control infections through granuloma formation in the lung as fungi is walled off instead of destroyed"

Confirms that granuloma formation in the lung is a containment mechanism where fungi are walled off rather than destroyed.

PMID:24613568 SUPPORT Human Clinical

"All cases showed granulomatous pleuritis."

Surgical-pathology series confirming that the organized granulomatous tissue response is the invariable histology of coccidioidal disease at this site.

+ 3 more references

⬡

Pathograph

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Phenotypes

14

Blood 1

Granulomatosis HP:0002955

Granuloma formation is a hallmark of the host tissue response to Coccidioides infection.

Show evidence (1 reference)

PMID:37367586 SUPPORT Other

"One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."

Confirms granuloma formation as a key feature of coccidioidomycosis.

Immune 3

Erythema nodosum HP:0012219

Occurs in a subset of patients, more frequently in women. Associated with a robust immune response and generally favorable prognosis. Part of the classic desert rheumatism triad.

Show evidence (2 references)

PMID:38196429 SUPPORT Other

"A common triad of symptoms of coccidioidomycosis, also called "desert rheumatism," include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem."

Erythema nodosum is identified as part of the classic symptom triad of coccidioidomycosis.

PMID:38667927 SUPPORT Human Clinical

"some risk factors, such as ABO blood group, Filipino ancestry, or lack of erythema nodosum among black individuals, are repeated in the literature despite the lack of supporting studies or biologic plausibility."

Discusses erythema nodosum in the context of coccidioidomycosis risk assessment.

Fungal meningitis HP:0032159

The most serious complication; requires lifelong antifungal therapy.

Show evidence (1 reference)

PMID:39189034 SUPPORT Human Clinical

"41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement)."

Documents meningitis as one of the most common extrapulmonary manifestations in critically ill patients.

Osteomyelitis HP:0002754

Bones are a common site of dissemination, particularly vertebrae, ribs, and skull.

Show evidence (1 reference)

PMID:21791226 SUPPORT Human Clinical

"Systemic MRI evaluation revealed osteomyelitis of his right foot; and lesions involving the vertebral bodies of the thoracic, and lumbar spine, sacrum, bilateral iliac wings, ribs, skull, and long bones of the legs bilaterally."

Documents osteomyelitis in disseminated coccidioidomycosis.

Metabolism 1

Fever VERY_FREQUENT HP:0001945

Present in the majority of symptomatic infections as part of the classic desert rheumatism triad.

Show evidence (1 reference)

PMID:33262956 SUPPORT Other

"the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress"

Identifies fever as one of the flu-like symptoms of coccidioidomycosis.

Nervous System 1

Headache HP:0002315

Prominent symptom in coccidioidal meningitis; may present with hydrocephalus.

Show evidence (1 reference)

PMID:33262956 SUPPORT Other

"the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress"

Documents headache as part of the symptomatic presentation of coccidioidomycosis.

Respiratory 3

Cough VERY_FREQUENT HP:0012735

Cough is a common symptom in symptomatic primary pulmonary coccidioidomycosis.

Show evidence (1 reference)

PMID:26904326 SUPPORT Human Clinical

"Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."

Identifies cough as one of the usual presenting symptoms of coccidioidomycosis.

Hemoptysis HP:0002105

May occur with cavitary pulmonary disease.

Show evidence (1 reference)

PMID:37233271 SUPPORT Other

"Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis."

Identifies hemoptysis as a presenting symptom that prompts investigation of cavitary coccidioidomycosis.

Dyspnea HP:0002094

Present in patients with pneumonia or diffuse pulmonary involvement.

Show evidence (2 references)

PMID:24613568 SUPPORT Human Clinical

"Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%)."

Documents dyspnea in 39% of patients with pleural coccidioidomycosis.

PMID:28857979 SUPPORT Human Clinical

"a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats"

Documents dyspnea on exertion as a presenting symptom in disseminated coccidioidomycosis.

Constitutional 4

Pleuritic chest pain HP:0033771

Pleuritic chest pain is common in acute pulmonary coccidioidomycosis.

Show evidence (2 references)

PMID:24613568 SUPPORT Human Clinical

"Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%)."

Documents chest pain in 44% of patients with pleural coccidioidomycosis.

PMID:26904326 SUPPORT Human Clinical

"Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."

Confirms pleurisy (pleuritic chest pain) as a common symptom of coccidioidomycosis.

Fatigue FREQUENT HP:0012378

Show evidence (2 references)

PMID:21791226 SUPPORT Human Clinical

"His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias."

Documents fatigue as a presenting symptom in a patient with disseminated coccidioidomycosis.

PMID:26904326 SUPPORT Human Clinical

"Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."

Confirms fatigue as a common symptom of coccidioidomycosis.

Night sweats HP:0030166

Show evidence (2 references)

PMID:28857979 SUPPORT Human Clinical

"a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats"

Documents night sweats as a presenting symptom in a patient with disseminated coccidioidomycosis.

PMID:21791226 SUPPORT Human Clinical

"His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias."

Confirms night sweats as part of the clinical presentation of disseminated coccidioidomycosis.

Arthralgia HP:0002829

Desert rheumatism refers to the triad of fever, erythema nodosum, and arthralgias.

Show evidence (1 reference)

PMID:38196429 SUPPORT Other

"A common triad of symptoms of coccidioidomycosis, also called "desert rheumatism," include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem."

Arthralgia is part of the classic desert rheumatism triad.

Growth 1

Weight loss HP:0001824

Observed in chronic or disseminated forms of coccidioidomycosis.

Show evidence (2 references)

PMID:28857979 SUPPORT Human Clinical

"a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats"

Documents weight loss as a presenting symptom in disseminated coccidioidomycosis.

PMID:21791226 SUPPORT Human Clinical

"Pain progressed over the ensuing weeks, refractory to analgesics, and then accompanied by fevers, night sweats, and unintentional (15-pound) weight loss prompting further evaluation."

Documents significant unintentional weight loss in a patient with disseminated coccidioidomycosis.

🧬

Genetic Associations

5

CLEC7A (Dectin-1 receptor for beta-glucan sensing; mutations associated with disseminated disease)

Gene: CLEC7A hgnc:14558

Show evidence (2 references)

PMID:18418396 SUPPORT Model Organism

"These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules."

Demonstrates that truncated Dectin-1 (Clec7a) splice variant in C57BL/6 mice contributes to coccidioidomycosis susceptibility.

PMID:35071044 SUPPORT Model Organism

"Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice."

Identifies Dectin-1 (CLEC7A) deficiency as a primary immunodeficiency associated with disseminated coccidioidomycosis.

CARD9 (Adaptor protein downstream of Dectin-1; essential for Th17 immunity)

Gene: CARD9 hgnc:16391

Show evidence (1 reference)

PMID:32358020 SUPPORT Model Organism

"The GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways."

Demonstrates that CARD9-associated signaling through Dectin-1 and Dectin-2 is required for protective Th17 immunity against Coccidioides.

STAT4 (Transcription factor for IL-12 signaling; E626G mutation increases susceptibility)

Gene: STAT4 hgnc:11365

Show evidence (2 references)

PMID:35149520 SUPPORT Model Organism

"All affected family members had a single heterozygous base change in STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/+ ). A knockin mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-type mice."

Identifies the STAT4 E626G mutation in a family with disseminated coccidioidomycosis and validates its effect in a mouse model.

PMID:35149520 SUPPORT Model Organism

"defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans."

Confirms that STAT4 deficiency impairs IFN-gamma and adaptive immune responses critical for controlling coccidioidomycosis.

STAT3 (Transcription factor for Th17 differentiation; mutations linked to disseminated disease)

Gene: STAT3 hgnc:11364

Show evidence (3 references)

PMID:35071044 SUPPORT Model Organism

"Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice."

Identifies STAT3 mutations as a primary immunodeficiency associated with disseminated coccidioidomycosis.

PMID:35071044 SUPPORT Model Organism

"Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease."

Demonstrates that unvaccinated mice with STAT3 and other PID-associated mutations develop disseminated disease, and that vaccination can mitigate this susceptibility.

PMID:28098554 SUPPORT Human Clinical

"We identified 8 patients with disseminated coccidioidomycosis who had defects in the interleukin-12/interferon-γ and STAT3 axes, indicating that these are critical host defense pathways."

The human evidence behind this record, which previously rested on mouse models alone. A systematic review of published disseminated cases found eight patients with proven primary immunodeficiency, whose defects fell in the IL-12/IFN-gamma and STAT3 pathways; several improved on exogenous IFN-gamma. Consistent with the subtype scope noted above, all eight had disseminated rather than contained infection.

IL12RB1 (IL-12 receptor subunit; deficiency impairs IFN-gamma production)

Gene: IL12RB1 hgnc:5971

Show evidence (1 reference)

PMID:21258095 SUPPORT Human Clinical

"We report a family with disseminated coccidioidomycosis due to a novel homozygous C186Y mutation in interleukin (IL)-12 receptor β1. This family confirms the centrality of the IL-12/IFN-γ axis to human immunity to Coccidioides spp."

Documents a family with IL12RB1 deficiency (C186Y mutation) presenting with disseminated coccidioidomycosis, confirming the gene's role in host defense.

💊

Medical Actions

3

Fluconazole

Action: fluconazole therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: fluconazole CHEBI:46081

Platform: Small molecule

First-line azole antifungal for most forms of coccidioidomycosis, including meningitis. Standard drug of choice for treatment of symptomatic disease.

Show evidence (1 reference)

PMID:11074900 SUPPORT Human Clinical

"fluconazole and itraconazole were effective therapy for progressive forms of coccidioidomycosis."

Randomized double-blind trial confirms fluconazole as effective therapy for progressive coccidioidomycosis.

Itraconazole

Action: itraconazole therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: itraconazole CHEBI:6076

Platform: Small molecule

Alternative azole antifungal used for non-meningeal disseminated disease and chronic pulmonary infection.

Show evidence (2 references)

PMID:11074900 SUPPORT Human Clinical

"50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 8 months of treatment with fluconazole and itraconazole, respectively"

Randomized double-blind trial of 198 patients showing itraconazole had a 63% response rate in nonmeningeal coccidioidomycosis.

PMID:11074900 SUPPORT Human Clinical

"Patients with skeletal infections responded twice as frequently to itraconazole as to fluconazole."

Demonstrates itraconazole's particular efficacy in skeletal coccidioidomycosis compared to fluconazole.

Amphotericin B

Action: amphotericin B therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: amphotericin B CHEBI:2682

Platform: Small molecule

Used for severe or rapidly progressive disease, including diffuse pneumonia and life-threatening dissemination. Often used as initial therapy before transitioning to azoles.

Show evidence (2 references)

PMID:21791226 SUPPORT Human Clinical

"Treatment was initiated with liposomal amphotericin and posaconazole (400-mg bid) with fatty meals."

Documents use of liposomal amphotericin B as initial induction therapy for severe disseminated coccidioidomycosis.

PMID:39189034 SUPPORT Human Clinical

"most (91%) received antifungal therapy during hospitalization."

Documents that the vast majority of critically ill patients received antifungal therapy.

🌍

Environmental Factors

3

Arid and semi-arid soil exposure

Coccidioides is endemic to the southwestern United States (Arizona, California, New Mexico, Texas), northern Mexico, and parts of Central and South America. The fungus thrives in alkaline, sandy soils with hot summers and mild winters. Disturbance of soil by construction, earthquakes, or agricultural activities releases arthroconidia into the air; wind-driven disturbance is curated separately as "Dust storm and windblown dust events", because the population-level attribution of cases to discrete dust storms is contested in a way the general soil-exposure claim is not. Cases have been increasing, with reported incidence surging notably in California and Arizona.

Show evidence (3 references)

PMID:39452676 SUPPORT Human Clinical

"Coccidioidomycosis is endemic to the western part of the United States of America, including the central valley of California, Arizona, New Mexico, and parts of western Texas."

Confirms the endemic geography of coccidioidomycosis in the southwestern United States.

PMID:39365073 SUPPORT Human Clinical

"Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."

Confirms the association with arid regions across the Americas.

PMID:39710556 SUPPORT Human Clinical

"The number of clinically recognized coccidioidomycosis cases continues to increase yearly including in regions outside the traditional regions of endemicity."

Documents expanding geographic range and increasing case numbers.

Mechanism Target:

TRIGGERS Arthroconidia inhalation and spherule morphogenesis — Disturbing arid soil aerosolizes the arthroconidia that the fungus forms in it, and inhaling those spores is the initiating event of infection.

Show evidence (1 reference)

PMID:39365073 SUPPORT Human Clinical

"Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."

Establishes that these fungal pathogens are prevalent in arid regions of the Americas, the soil reservoir from which inhaled arthroconidia originate.

Dust storm and windblown dust events

Haboobs and strong regional wind events lift large volumes of semi-desert subsoil, the reservoir in which Coccidioides grows as mycelium, and are the most visible route by which arthroconidia become airborne over populated areas. Dust storm frequency in the American Southwest has risen sharply (reported as a 240% increase from the 1990s to the 2000s), and is a prominent mechanism in climate-change projections of expanding Valley Fever incidence. Scope caveat - two claims must be kept apart here. That a dust event aerosolizes and transports arthroconidia is not in dispute, and is what the mechanism edge below asserts. Whether dust storms *specifically* drive measurable subsequent increases in coccidioidomycosis cases is actively disputed: a superposed-epoch analysis of all recorded 2006-2020 dust storms near Phoenix and Bakersfield found no difference in case patterns after dust storms versus non-dust-storm conditions, and arthroconidia are also transported in low-wind conditions. That disagreement is recorded as a CONTROVERSY discussion rather than being resolved in favour of either side.

Show evidence (2 references)

PMID:30166741 SUPPORT Other

"The frequency of windblown dust storms has increased 240% from 1990s to 2000s."

Documents the rising dust storm activity that motivates treating dust events as an exposure of growing importance in the endemic region.

PMID:39432997 SUPPORT Other

"The intensified onset of climate change has caused frequencies and possibly intensities of natural hazard events like dust storms and drought to increase, which has been correlated with greater prevalence of VF."

Review linking climate-driven increases in dust storm frequency to rising Valley Fever prevalence. Stated as correlation, matching the strength of the underlying literature.

Mechanism Target:

TRIGGERS Arthroconidia inhalation and spherule morphogenesis — Windblown dust events are a route by which arthroconidia are lifted from subsoil and carried into the breathing zone, which is the initiating step of infection. This edge asserts the aerosolization and transport route only; it does not assert a quantified population-level attribution of cases to dust storms, which the refuting evidence below contests.

Show evidence (3 references)

PMID:34877441 SUPPORT Other

"Fungal arthroconidia can be transported in low-wind conditions as well as in individual dust events"

Even the study arguing against a consistent dust-storm/case link accepts that individual dust events transport arthroconidia, which is the transport route this edge asserts. It simultaneously bounds the claim by noting low-wind transport also occurs, so dust storms are one route rather than the route.

PMID:30166741 SUPPORT Human Clinical

"The frequency of dust storms is found to be correlated with Valley fever incidences, with a coefficient (r) comparable to or stronger than that with other factors believed to control the disease in two endemic centers (Maricopa and Pima County, Arizona)."

Ecological correlation between dust storm frequency and Valley Fever incidence in two endemic Arizona counties. This is a county-level time-series correlation, not an individual-level exposure study.

PMID:34877441 REFUTE Human Clinical

"Analyses of monthly and weekly disease case data showed no statistical differences in the patterns of coccidioidomycosis cases following dust storms versus non-dust storm conditions"

Superposed-epoch analysis of all recorded 2006-2020 dust storms near Phoenix and Bakersfield found no post-dust-storm excess of cases, refuting a general dust-storm-to-incidence link at the population level. Retained deliberately: the edge is curated with its refutation attached rather than dropped or asserted unqualified.

TNF-alpha inhibitor therapy

Iatrogenic exposure rather than a natural-environment one. TNF is non-redundantly required to initiate and maintain the granuloma, so pharmacological TNF neutralization for an unrelated inflammatory indication removes the cytokine arm on which coccidioidal containment depends. This is the coccidioidomycosis instance of the granuloma-module drug pattern read in reverse: what is therapeutic in sterile granulomatous disease is a dissemination risk when a live, contained fungus is present.

Show evidence (1 reference)

PMID:38667927 SUPPORT Human Clinical

"Specific genetic variants, sex, and immune suppression by TNF inhibitors have been validated in later cohort studies, confirming the original hypotheses."

Establishes TNF-inhibitor immune suppression as a validated risk factor for coccidioidomycosis.

Mechanism Target:

PREDISPOSES Th1/Th17 cell-mediated adaptive immunity — TNF blockade acts directly on the Th1/TNF-driven macrophage-activation step that licenses granuloma formation, degrading containment of the organism.

Show evidence (1 reference)

PMID:38667927 SUPPORT Human Clinical

"immune suppression by TNF inhibitors have been validated in later cohort studies"

Cohort-validated evidence that TNF-inhibitor immunosuppression is a susceptibility factor for coccidioidomycosis, the exposure this edge asserts.

🔬

Diagnosis

2

Coccidioides serology (IgM and IgG)

Serologic testing with enzyme immunoassay (EIA) for IgM and IgG antibodies and complement fixation (CF) titers is the primary diagnostic method. CF titers correlate with disease severity and are used to monitor treatment response.

Show evidence (1 reference)

PMID:21791226 SUPPORT Human Clinical

"positive coccidioides serology (the ELISA was positive for both IgG and IgM, and presenting complement-fixation (CF) titer was 1:8). Titers less than or equal to 1:2 are considered negative."

Documents the use of IgM/IgG ELISA and complement fixation titers for diagnosis of disseminated coccidioidomycosis.

Histopathologic identification of spherules

Identification of characteristic large thick-walled spherules (20-200 micrometers) containing endospores in tissue specimens is diagnostic. May be visualized with H&E, PAS, or GMS staining.

Show evidence (1 reference)

PMID:28857979 SUPPORT Human Clinical

"Skin biopsy of the lesion revealed prominent squamous epithelial hyperplasia with basal keratinocytic atypia and associated mixed inflammatory infiltrate and scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells."

Describes histopathologic identification of characteristic spherules with endospores in tissue.

📊

Prevalence

1

United States

Annual Incidence 45.0 per 100,000 1–9 per 10,000 per year

Normalized from the cited estimate of ~150,000 new infections per year, against a US population of ~330 million (150,000 / 330,000,000 x 100,000 = ~45 per 100,000 per year); the source states the absolute count, not a rate, so the denominator is this entry's assumption and the band follows from that arithmetic. This is estimated *infections*, not reported cases: roughly half of infections never become symptomatic pneumonia, so the notifiable-disease case rate is substantially lower. The national figure also averages over a sharply focal endemic distribution - incidence in endemic counties of Arizona and California is far above the national number and near zero outside the endemic range.

Show evidence (2 references)

PMID:32358020 SUPPORT Other

"An estimated 150,000 new infections occur each year in the US."

Source for the annual US infection estimate this rate is normalized from. Evidence source is OTHER, not HUMAN_CLINICAL: the cited publication is a mouse vaccine study and this figure is background epidemiology it reports rather than a human clinical finding of its own.

PMID:38535182 SUPPORT Human Clinical

"only half of infected, immunologically intact people develop symptomatic pneumonia"

Supports the caveat that estimated infections substantially exceed clinically recognized and reported cases.

🌍

Epidemiology

1

Incidence in the United States

Estimated 150,000 infections per year in the US. 10,000-20,000 reported cases yearly, concentrated in Arizona and California. Incidence has been rising; Arizona reported 144.1/100,000 in 2019. ICU mortality rate of 48% in culture-proven critically ill patients.

Show evidence (2 references)

PMID:32358020 SUPPORT Human Clinical

"An estimated 150,000 new infections occur each year in the US."

Provides the estimated annual incidence of coccidioidomycosis in the United States.

PMID:39452676 SUPPORT Human Clinical

"The incidence of reported cases of coccidioidomycosis has notably increased since it became reportable in 1995."

Documents the increasing incidence trend.

🦠

Infectious Agent

2

Coccidioides immitis

Coccidioides immitis NCBITaxon:5501

Show evidence (2 references)

PMID:39452676 SUPPORT Human Clinical

"Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."

Identifies C. immitis as one of two causative species, primarily associated with California isolates.

PMID:39365073 SUPPORT Human Clinical

"Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."

Confirms both Coccidioides species as causative agents of systemic mycoses.

Coccidioides posadasii

Coccidioides posadasii NCBITaxon:199306

Show evidence (2 references)

PMID:39452676 SUPPORT Human Clinical

"Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."

Identifies C. posadasii as the species found outside California.

PMID:39365073 SUPPORT Human Clinical

"While C. immitis mainly occurs in California and Washington, C. posadasii is widely distributed across North and South America."

Confirms the geographic distribution of C. posadasii.

📊

Related Datasets

3

scRNA-seq time-course of Coccidioides posadasii infected lungs geo:GSE274766

Single-cell RNA-seq time course of murine lung during Coccidioides posadasii infection, comparing uninfected lung (D0) with infected lung at 5, 9, and 14 days post-infection. Resolves the cellular composition of the pulmonary response over the interval in which containment is established or lost.

house mouse SINGLE CELL RNA SEQ n=1

PMID:39611685

Identified by GEO DataSets index search for Coccidioidomycosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities. Title, sample count, and organism are GEO's own values. No evidence block: bulk-discovered dataset records carry repository provenance rather than a quoted abstract.

Spatial Transcriptomics of Lungs Infected with Coccidioides posadasii geo:GSE274767

10x Visium spatial transcriptomics of murine lung, comparing non-infected lung (D0) with lung at 14 days post-infection with Coccidioides posadasii. Spatially resolved counterpart to GSE274766 from the same study, relevant to the organization of the granulomatous lesion.

house mouse SPATIAL TRANSCRIPTOMICS n=2

PMID:39611685

Identified by GEO DataSets index search for Coccidioidomycosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities. Title, sample count, and organism are GEO's own values.

Functional characterization of the transcription programs underlying phase transition in the BSL3 pathogen Coccidioides immitis geo:GSE179468

Capped small RNA-seq of Coccidioides immitis across the mycelium-to-spherule phase transition, profiling the transcriptional reprogramming that underlies the morphogenesis step at the head of this entry's pathograph. Includes comparator fungal species used in the analysis.

Coccidioides immitis BULK RNA SEQ n=27

PMID:35076277

Identified by GEO DataSets index search for Coccidioidomycosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities. GEO lists four organisms for this series (Schizosaccharomyces pombe; Saccharomyces cerevisiae; Agaricus bisporus; Coccidioides immitis); the pathogen of interest is recorded here.

🔬

Clinical Trials

2

NCT02663674 PHASE_IV COMPLETED

FLEET-Valley Fever: Randomized, double-blind, placebo-controlled trial of 1000 adults evaluating early empiric fluconazole (400 mg/day for 42 days) for coccidioidomycosis pneumonia in patients presenting with community-acquired pneumonia in endemic areas.

Target Phenotypes: Cough HP:0012735 Dyspnea HP:0002094

Show evidence (1 reference)

clinicaltrials:NCT02663674 SUPPORT Human Clinical

"This study is designed to provide data on the effectiveness of early antifungal treatment (Fluconazole, 400 mg/day) for coccidioidomycosis pneumonia (also referred to as Valley Fever (VF) Pneumonia or acute onset valley fever) vs. placebo in subjects with coccidioidomycosis pneumonia."

Phase IV trial evaluating early fluconazole treatment for Valley Fever pneumonia.

NCT07385638 PHASE_II RECRUITING

Open-label evaluation of olorofim, a novel dihydroorotate dehydrogenase inhibitor, for treatment of early coccidioidal meningitis in 10-12 participants diagnosed within 4-8 weeks and without VP shunt.

Target Phenotypes: Fungal meningitis HP:0032159

Show evidence (1 reference)

clinicaltrials:NCT07385638 SUPPORT Human Clinical

"This research study is being conducted to learn more about the use of olorofim in Coccidioidal (Cocci) meningitis, a rare but serious fungal infection that affects the brain and spinal cord."

Phase II trial evaluating olorofim for early coccidioidal meningitis.

🐁

Animal Models

1

Mus musculus

C57BL/6 mice are susceptible to coccidioidomycosis due to expression of a truncated Dectin-1 (Clec7a) splice variant. DBA/2 mice with intact Dectin-1 are resistant. Various knockout models (Stat4, Stat3, Ifngr1, Clec7a, Rag-1) are used to study immunodeficiency-associated disseminated disease and vaccine efficacy.

Species

Mus musculus

Show evidence (2 references)

PMID:18418396 SUPPORT Model Organism

"These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules."

Establishes the C57BL/6 mouse as a susceptible model for coccidioidomycosis due to truncated Dectin-1.

PMID:35071044 SUPPORT Model Organism

"mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain."

Documents the use of multiple immunodeficient mouse models for studying coccidioidomycosis vaccine protection.

{ }

Source YAML

click to show

name: Coccidioidomycosis
creation_date: "2026-03-07T00:00:00Z"
synonyms:
- Valley Fever
- San Joaquin Valley Fever
- Desert Rheumatism
- Coccidioides infection
description: >-
  Coccidioidomycosis (Valley Fever) is a fungal infection caused by the dimorphic
  soil fungi Coccidioides immitis and Coccidioides posadasii, endemic to arid
  regions of the southwestern United States, Mexico, and Central and South
  America. Infection begins when inhaled arthroconidia convert in the lung into
  tissue-phase spherules that rupture and release endospores, propagating the
  organism. Host control depends on Th1/Th17 cell-mediated immunity and
  granuloma formation; most infections are self-limited pulmonary disease, but
  impaired cellular immunity permits cavitary lung disease, dissemination, and
  coccidioidal meningitis.
categories:
- Infectious Disease
- Fungal Disease
disease_term:
  preferred_term: coccidioidomycosis
  term:
    id: MONDO:0005706
    label: coccidioidomycosis
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:39452676
      reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."
      explanation: Confirms coccidioidomycosis is an infectious disease caused by fungal pathogens.
    - reference: PMID:39365073
      reference_title: "From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."
      explanation: Confirms coccidioidomycosis is a systemic mycosis (fungal infectious disease).
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005706
      label: coccidioidomycosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for coccidioidomycosis.
has_subtypes:
- name: Primary pulmonary coccidioidomycosis
  description: >
    Acute pulmonary infection that is often self-limited, presenting as community-acquired
    pneumonia in endemic areas. Most symptomatic infections resolve spontaneously.
  evidence:
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, the infection ranges from asymptomatic to fatal disease due to pneumonia or disseminated states. The recognition of coccidioidomycosis can be challenging, as it frequently mimics bacterial community-acquired pneumonia."
    explanation: Confirms that primary pulmonary coccidioidomycosis mimics community-acquired pneumonia and ranges from asymptomatic to severe.
  - reference: PMID:38535182
    reference_title: "The Host Response to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only half of infected, immunologically intact people develop symptomatic pneumonia; most symptomatic infections resolve spontaneously, although some resolve very slowly."
    explanation: Confirms that most primary pulmonary infections are self-limited.
- name: Disseminated coccidioidomycosis
  description: >
    Extrapulmonary spread of infection to skin, bones, joints, meninges, and other organs.
    Occurs in a minority of infected individuals. Immunocompromised patients are
    at significantly higher risk.
  evidence:
  - reference: PMID:39189034
    reference_title: "Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement)."
    explanation: Documents the spectrum of extrapulmonary dissemination sites in critically ill patients.
  - reference: PMID:38535182
    reference_title: "The Host Response to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "People who are immunocompromised are much more likely to develop disseminated infection."
    explanation: Confirms that immunocompromise is a major risk factor for dissemination.
- name: Coccidioidal meningitis
  description: >
    The most serious complication of disseminated disease, involving chronic basilar meningitis
    that is associated with very high mortality without antifungal treatment and requires lifelong antifungal therapy.
  evidence:
  - reference: PMID:39189034
    reference_title: "Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement). Seventy patients (48%) died during hospitalization"
    explanation: Documents meningitis as a significant form of extrapulmonary disease with high mortality in ICU patients.
prevalence:
- population: United States
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 45.0
  notes: >-
    Normalized from the cited estimate of ~150,000 new infections per year,
    against a US population of ~330 million (150,000 / 330,000,000 x 100,000 =
    ~45 per 100,000 per year); the source states the absolute count, not a rate,
    so the denominator is this entry's assumption and the band follows from that
    arithmetic. This is estimated *infections*, not reported cases: roughly half
    of infections never become symptomatic pneumonia, so the notifiable-disease
    case rate is substantially lower. The national figure also averages over a
    sharply focal endemic distribution - incidence in endemic counties of
    Arizona and California is far above the national number and near zero
    outside the endemic range.
  evidence:
  - reference: PMID:32358020
    reference_title: "CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "An estimated 150,000 new infections occur each year in the US."
    explanation: >-
      Source for the annual US infection estimate this rate is normalized from.
      Evidence source is OTHER, not HUMAN_CLINICAL: the cited publication is a
      mouse vaccine study and this figure is background epidemiology it reports
      rather than a human clinical finding of its own.
  - reference: PMID:38535182
    reference_title: "The Host Response to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only half of infected, immunologically intact people develop symptomatic pneumonia"
    explanation: >-
      Supports the caveat that estimated infections substantially exceed
      clinically recognized and reported cases.
infectious_agent:
- name: Coccidioides immitis
  infectious_agent_term:
    preferred_term: Coccidioides immitis
    term:
      id: NCBITaxon:5501
      label: Coccidioides immitis
  evidence:
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."
    explanation: Identifies C. immitis as one of two causative species, primarily associated with California isolates.
  - reference: PMID:39365073
    reference_title: "From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."
    explanation: Confirms both Coccidioides species as causative agents of systemic mycoses.
- name: Coccidioides posadasii
  infectious_agent_term:
    preferred_term: Coccidioides posadasii
    term:
      id: NCBITaxon:199306
      label: Coccidioides posadasii
  evidence:
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."
    explanation: Identifies C. posadasii as the species found outside California.
  - reference: PMID:39365073
    reference_title: "From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While C. immitis mainly occurs in California and Washington, C. posadasii is widely distributed across North and South America."
    explanation: Confirms the geographic distribution of C. posadasii.
mechanistic_hypotheses:
- hypothesis_group_id: granuloma_composition_containment_model
  hypothesis_label: Coccidioidal Granuloma Composition and Maintenance Model
  status: EMERGING
  description: >-
    A hypothesis about the cellular and signaling composition of the
    coccidioidal granuloma, and about which features of it determine containment
    versus progression to cavitation and dissemination. The model proposed here
    is that the spherule's resistance to phagocytosis obliges a specific,
    sustained macrophage-transformation program - epithelioid differentiation
    and giant-cell fusion under Th1/Th17 and TNF drive - and that the identity
    of the recruited cells, the signals that maintain the structure, and the
    immune microenvironment inside the granuloma are what distinguish a
    contained lesion from one that necroses and disseminates.

    The status is EMERGING rather than CANONICAL because the intermediate steps
    are borrowed rather than measured. Granuloma biology in coccidioidomycosis
    is currently modeled largely by analogy to tuberculosis: morphologies have
    been described, but the cells recruited, the maintenance signals, and the
    interior microenvironment are explicitly unresolved in the primary
    literature. This entry's conformance to the `granuloma_formation` module
    therefore rests on two causal edges (Th1/Th17 -> epithelioid transformation,
    and epithelioid transformation -> organized granuloma) whose evidence is
    PARTIAL for exactly this reason; those edges are tagged into this hypothesis
    group so the dependency is explicit rather than implied.

    Two comparators already in the knowledge base bear on the same question
    through the shared module: Sarcoidosis
    (`antigen_persistence_granuloma_chronicity_model`) and
    Chronic_Beryllium_Disease. The mouse scRNA-seq time course (GSE274766) and
    Visium spatial transcriptomics (GSE274767) recorded in this entry's
    `datasets` block are the matched data most directly capable of addressing
    the cell-identity and spatial-organization components.
  evidence:
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we do not know what cells are recruited to the granuloma, what signals form and maintain the granuloma structure, nor details on the immune microenvironment within the granuloma interior"
    explanation: >-
      States the open question this hypothesis group exists to resolve, in the
      authors' own words: granuloma cell composition, maintenance signals, and
      interior microenvironment are all unresolved for Coccidioides.
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Exploring granuloma immunity is imperative for understanding infection chronicity as Coccidioides infection often presents with granuloma formation."
    explanation: >-
      Motivates the hypothesis: granuloma immunity is framed as the route to
      understanding why some infections become chronic rather than resolving.
  - reference: PMID:37367586
    reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, very little is known about granulomas during Coccidioides infection."
    explanation: >-
      Independent confirmation from a review dedicated to coccidioidal
      granulomas that the disease-specific granuloma biology is largely
      uncharacterized.
  - reference: PMID:37367586
    reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Granulomas are best defined in TB, providing clues that may be leveraged to understand Coccidioides infections."
    explanation: >-
      Documents that the current model is an extrapolation from tuberculosis.
      Support is PARTIAL because this justifies the analogy rather than
      establishing that it holds for Coccidioides - which is the substance of
      what makes this hypothesis EMERGING.
  - reference: PMID:33276795
    reference_title: "Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level."
    explanation: >-
      Micro-dissected human granuloma transcriptomics across sarcoidosis,
      coccidioidomycosis, and tuberculosis, bearing on whether granuloma
      biology can be transferred between etiologies by histological analogy -
      the assumption this hypothesis flags as unmeasured. Support is PARTIAL and
      the claim is bounded: the study is sarcoidosis-centred with only three
      coccidioidomycosis subjects, it reports commonalities as well as
      divergences, and it performs no direct comparison between
      coccidioidomycosis and tuberculosis, which is the specific analogy at
      issue. It
      motivates the EMERGING status without settling it.
  - reference: PMID:39611685
    reference_title: "Spatiotemporal analysis of lung immune dynamics in lethal Coccidioides posadasii infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We identified monocyte-derived Spp1-expressing macrophages as potential mediators of tissue remodeling and fibrosis, marked by high expression of profibrotic and proinflammatory transcripts."
    explanation: >-
      The publication behind GSE274766 and GSE274767, the two datasets this
      hypothesis names as the instruments most capable of resolving its
      cell-identity component. It supplies a first answer: the dominant
      macrophage state recovered from infected lung is a monocyte-derived,
      Spp1-expressing profibrotic population rather than the epithelioid and
      giant-cell program the hypothesis borrows from tuberculosis. This does not
      settle the hypothesis - the model is lethal acute murine infection, not a
      contained human granuloma, and a profibrotic remodeling state and an
      epithelioid state are not mutually exclusive - but it moves the
      cell-identity question from unaddressed to partially addressed.
  - reference: PMID:39611685
    reference_title: "Spatiotemporal analysis of lung immune dynamics in lethal Coccidioides posadasii infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Additionally, we observed significant neutrophil infiltration and defective lymphocyte responses, indicating severe adaptive immunity dysregulation in lethal, acute infection."
    explanation: >-
      Bears on which of this entry's two curated models describes the failing
      lesion. In lethal infection the single-cell and spatial data show
      neutrophil influx together with a failing lymphocyte response, which is
      what the `neutrophil_inflammasome_immunopathology_model` predicts and what
      the Th1/Th17-driven containment model requires to be intact. It is recorded
      here because it bounds this hypothesis rather than supporting it.
  - reference: PMID:40704794
    reference_title: "Early immune response to Coccidioides is characterized by robust neutrophil and fibrotic macrophage recruitment and differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "At 24 h post-infection, robust immune infiltration is detected in the lung, marked by high levels of inflammatory PD-L1+ neutrophils and fungal-contact-dependent pro-fibrotic Spp1+ macrophages."
    explanation: >-
      An independent single-cell run recovering the same two populations at the
      earliest timepoint, and adding that the Spp1-expressing macrophage state is
      induced by contact with the fungus. Relevant to this hypothesis because the
      cellular program the infection actually induces is being characterized
      directly now, so the borrowed tuberculosis chain is testable rather than
      merely unproven. Scope: attenuated high-dose murine challenge at 24 hours,
      which is upstream of granuloma assembly.
- hypothesis_group_id: neutrophil_inflammasome_immunopathology_model
  hypothesis_label: Neutrophil and Inflammasome Immunopathology Model
  status: ALTERNATIVE
  description: >-
    The competing account of what determines outcome in coccidioidomycosis.
    Instead of outcome being set by the quality of the macrophage
    epithelioid/giant-cell containment program, this model holds that it is set
    by inflammasome-driven immunopathology: spherule rupture engages NLRP3 and
    pyrin inflammasomes, IL-1beta drives neutrophil recruitment, and the
    resulting neutrophilic response damages tissue and impairs the protective
    Th1/Th17 arm.

    It is registered as ALTERNATIVE rather than as a component of the granuloma
    model because two independent loss-of-function experiments run the opposite
    way to a protective reading: CXCR2-deficient mice have fewer neutrophils and
    *fewer* organisms with higher Ifng/Il17a, and caspase-1-deficient mice show
    improved tolerance at *equivalent* fungal burden. A model in which
    neutrophil influx and inflammasome signaling are protective effectors of
    containment does not predict either result.

    The two models are not mutually exclusive and share a trigger: both descend
    from the phagocytosis-resistant spherule, diverging at rupture. Where they
    make different predictions is the composition of the destructive lesion, and
    there the available human evidence favours this model - the wall of the
    established human cavity shows no granulomas, and its lining is neutrophils
    and caseous necrosis (PMID:24321524). Curated as ALTERNATIVE rather than
    promoted because the two decisive experiments are murine, the human evidence
    is descriptive pathology rather than perturbation, and the IL-1/IL-18 axis
    also has documented protective functions in this infection.
  evidence:
  - reference: PMID:33106296
    reference_title: "Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice."
    explanation: >-
      Loss of the neutrophil-recruiting receptor improves fungal control, which
      a protective-neutrophil model does not predict.
  - reference: PMID:42386736
    reference_title: "Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens"
    explanation: >-
      Disentangles immunopathology from fungal control: outcome improves with
      inflammasome signaling removed while burden is unchanged.
  - reference: PMID:42386736
    reference_title: "Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A TLR2-NLRP3-pyrin-IL-18 axis in macrophages promotes spherule growth."
    explanation: >-
      Adds a direct pathogen-benefit arm to this model - inflammasome signaling
      promoting spherule growth. Support is PARTIAL because it is a cell-culture
      result and does not by itself establish the organism-level outcome.
  - reference: PMID:24321524
    reference_title: "Cavitary pulmonary coccidioidomycosis: pathologic and clinical correlates of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cavity wall showed chronic inflammation and occasional giant cells but no granulomas and no microorganisms."
    explanation: >-
      The human observation that most discriminates the two models: at the
      destructive end state the lesion is not granulomatous.
pathophysiology:
- name: Arthroconidia inhalation and spherule morphogenesis
  biological_scale: CELLULAR
  description: >
    Coccidioides exists as a mycelial form in soil. When soil is disturbed, arthroconidia
    (barrel-shaped spores 2-5 micrometers in size) become airborne and are inhaled into the
    lungs, reaching terminal bronchioles. In host tissues at 37 degrees C, arthroconidia undergo
    a morphological transition to spherules, which are large round structures that undergo
    internal division to produce hundreds of endospores. Developing spherules secrete a
    metalloproteinase that contributes to immune masking. Rupture of mature spherules releases
    endospores that trigger rapid immune cell influx and can spread hematogenously.
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
  evidence:
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioidomycosis is transmitted through the inhalation of fungal spores, arthroconidia, which can cause disease in susceptible mammalian hosts, including humans."
    explanation: Confirms the inhalation route of arthroconidia transmission.
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the spherule state, Coccidioides secretes metalloproteinase 1 (Mep1) which digests an immunodominant antigen spherical outer wall glycoprotein (SOWgp) on the fungal surface"
    explanation: Describes spherule morphogenesis and the Mep1 metalloproteinase that digests SOWgp to evade immune detection.
  downstream:
  - target: Cough
    description: >
      Pulmonary Coccidioides infection after inhalation commonly presents with
      cough.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26904326
      reference_title: "Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."
      explanation: >
        Human clinical evidence identifies cough as a usual symptom of
        coccidioidomycosis.
  - target: Pleuritic chest pain
    description: >
      Pulmonary coccidioidomycosis can involve pleuritic inflammation and chest
      pain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26904326
      reference_title: "Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."
      explanation: >
        Human clinical evidence identifies pleurisy as a usual symptom of
        coccidioidomycosis.
  - target: Fever
    description: >
      Developing Coccidioides infection produces flu-like systemic symptoms,
      including fever.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33262956
      reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "As fungi develop, the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress"
      explanation: >
        Review evidence connects fungal development in the host to fever among
        flu-like manifestations.
  - target: Fatigue
    description: >
      Symptomatic coccidioidomycosis commonly includes fatigue during pulmonary
      infection.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26904326
      reference_title: "Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."
      explanation: >
        Human clinical evidence identifies fatigue as a usual symptom of
        coccidioidomycosis.
  - target: Dyspnea
    description: >
      Pulmonary and pleural involvement can present with shortness of breath.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24613568
      reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%)."
      explanation: >
        Human clinical evidence documents dyspnea among common symptoms of
        pleural coccidioidomycosis.
  - target: Headache
    description: >
      Developing Coccidioides infection produces flu-like systemic symptoms,
      including headache.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33262956
      reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "As fungi develop, the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress"
      explanation: >
        Review evidence connects fungal development in the host to headache
        among flu-like manifestations.
  - target: Erythema nodosum
    description: >
      Coccidioidomycosis can trigger the desert-rheumatism symptom complex with
      erythema nodosum.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38196429
      reference_title: "Valley Fever: Pathogenesis and Evolving Treatment Options."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A common triad of symptoms of coccidioidomycosis, also called \"desert rheumatism,\" include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem."
      explanation: >
        Human clinical review evidence identifies erythema nodosum as part of
        the coccidioidomycosis symptom triad.
  - target: Arthralgia
    description: >
      Coccidioidomycosis can trigger the desert-rheumatism symptom complex with
      arthralgia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38196429
      reference_title: "Valley Fever: Pathogenesis and Evolving Treatment Options."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A common triad of symptoms of coccidioidomycosis, also called \"desert rheumatism,\" include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem."
      explanation: >
        Human clinical review evidence identifies arthralgia as part of the
        coccidioidomycosis symptom triad.
  - target: Night sweats
    description: >
      Established Coccidioides infection produces the constitutional symptoms of
      a chronic pulmonary/disseminated mycosis, including night sweats.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21791226
      reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias."
      explanation: >
        Human clinical evidence documents night sweats in the presenting
        symptom complex of established Coccidioides infection.
  - target: Weight loss
    description: >
      Chronic and disseminated Coccidioides infection produces a wasting
      constitutional response with unintentional weight loss.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21791226
      reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pain progressed over the ensuing weeks, refractory to analgesics, and then accompanied by fevers, night sweats, and unintentional (15-pound) weight loss prompting further evaluation."
      explanation: >
        Human clinical evidence documents unintentional weight loss developing
        as Coccidioides infection progresses.
  - target: Phagocytosis-resistant spherule persistence
    description: >
      Morphogenesis from the small, readily phagocytosed arthroconidium into the
      large tissue-phase spherule is what converts the organism into a stimulus
      that an individual phagocyte cannot clear.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33262956
      reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Lifecycle transition allows vulnerable, easily phagocytosed, arthroconidia to develop into phagocytosis-resistant spherules"
      explanation: >
        Directly links the arthroconidium-to-spherule transition to the
        acquisition of phagocytosis resistance.
- name: Phagocytosis-resistant spherule persistence
  role: trigger
  biological_scale: CELLULAR
  conforms_to: "granuloma_formation#Persistent Indigestible Stimulus"
  description: >-
    The mature spherule is the disease-specific substitution for the generic
    persistent indigestible stimulus of the granuloma module. At 20-200
    micrometers it exceeds the phagocytic capacity of macrophages and
    neutrophils, which engulf endospores readily but can only partially engulf
    spherules ("frustrated phagocytosis"). Because no individual phagocyte can
    eliminate it, the spherule sustains a chronic, organized macrophage response
    rather than a self-limited acute one - the entry condition for granuloma
    formation.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: chronic inflammatory response
    term:
      id: GO:0002544
      label: chronic inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mature spherules are too large for most host phagocytic activity, allowing Coccidiodes to evade early immune detection"
    explanation: >-
      States that mature spherules exceed host phagocytic capacity, which is the
      module's persistent-indigestible-stimulus criterion applied to
      Coccidioides. Evidence source is OTHER because this is a review.
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "human neutrophils readily phagocytose Coccidioides endospores and exhibit partial phagocytosis of larger spherules"
    explanation: >-
      Documents that human phagocytes clear endospores but can only partially
      engulf spherules, the cellular basis of spherule persistence. Evidence
      source is IN_VITRO because the underlying observation is a neutrophil-fungus
      co-incubation assay.
  - reference: PMID:6300253
    reference_title: "Coccidioidomycosis: factors affecting the host-parasite interaction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Arthroconidia possess an antiphagocytic surface derived from the original hyphal outer wall layer. Only 20%-30% of arthroconidia or endospores that are ingested by PMNs are killed."
    explanation: >-
      Primary-literature anchor for the two components of this node that the
      review evidence above asserts without quantifying: the fungal surface is
      actively antiphagocytic, and even the organisms that are successfully
      ingested are mostly not killed. Together these make phagocyte-mediated
      clearance insufficient in principle, which is the module's
      persistent-indigestible-stimulus criterion. Evidence source is IN_VITRO
      because the quoted killing fraction comes from phagocyte-fungus killing
      assays.
  - reference: PMID:21129481
    reference_title: "Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These live, first-generation parasitic cells of Coccidioides, referred to as spherule initials, suppressed NO production as well as iNOS mRNA expression by activated macrophages."
    explanation: >-
      Adds an active-suppression arm to the persistence of the spherule: the
      parasitic-phase organism does not merely resist ingestion, it releases a
      soluble factor that shuts down nitric oxide and iNOS output in
      IFN-gamma/LPS-activated macrophages, and phagocytosis is not required for
      the effect. This is the one direct Coccidioides measurement bearing on the
      granuloma interior microenvironment that the
      `granuloma_composition_containment_model` hypothesis names as unresolved.
      Scope caveat: the same study found macrophages from iNOS-deficient mice
      killed Coccidioides as efficiently as wild-type ones, so the suppression is
      documented but its contribution to containment is not established, and the
      fungal factor is unidentified.
  downstream:
  - target: Spherule rupture-triggered inflammasome activation and neutrophil recruitment
    description: >
      The same persistent spherule that cannot be phagocytosed eventually
      ruptures, and rupture is the specific trigger of the alternative
      inflammasome/neutrophil axis. This is the branch point at which the two
      curated models diverge from a shared trigger.
    causal_link_type: DIRECT
    hypothesis_groups:
    - neutrophil_inflammasome_immunopathology_model
    evidence:
    - reference: PMID:42386736
      reference_title: "Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "only ruptured spherules-not intact ones-trigger IL-1β production through NLRP3-pyrin inflammasomes and GSDMD-GSDME pores"
      explanation: >
        Rupture, not the intact spherule, is what engages the inflammasome,
        making this edge conditional on the rupture step rather than on
        spherule persistence alone.
  - target: Th1/Th17 cell-mediated adaptive immunity
    description: >
      A stimulus that cannot be cleared by innate phagocytosis obliges the host
      to mount the sustained Th1/Th17 and TNF-driven macrophage-activating
      response that organizes a granuloma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33262956
      reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Host responses sometimes control infections through granuloma formation in the lung as fungi is walled off instead of destroyed"
      explanation: >
        Establishes that when the fungus is not destroyed outright the host
        falls back on walling it off, i.e. the granulomatous route.
- name: Spherule rupture-triggered inflammasome activation and neutrophil recruitment
  biological_scale: CELLULAR
  description: >-
    The alternative, macrophage-independent axis of this entry. Rupture of the
    mature spherule - not the intact spherule - engages NLRP3 and pyrin
    inflammasomes with GSDMD/GSDME pore formation, releasing IL-1beta and
    recruiting neutrophils, which in human tissue congregate in and around
    rupturing spherules.

    Two loss-of-function results make this a genuine competitor to the
    macrophage/granuloma containment model rather than an elaboration of it,
    because in both the host does BETTER with less of this response: CXCR2
    (IL-8R2)-deficient mice have fewer lung neutrophils and, unexpectedly, fewer
    organisms, with higher Ifng/Il17a - the authors' interpretation being that
    neutrophils interfere with development of the protective Th1/Th17 response;
    and caspase-1-deficient mice show improved disease tolerance at equivalent
    fungal burden. Under this model, outcome is set by inflammasome-driven
    immunopathology rather than by the quality of the epithelioid/giant-cell
    program, and the neutrophil-and-caseous-necrosis lining of the human cavity
    is its destructive end point.

    This node deliberately carries no downstream edge to Th1/Th17: the claim
    there is that neutrophil influx *impairs* the protective response, and
    `CausalEdge` has no polarity slot, so an edge would misread as promotion.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: canonical inflammasome complex assembly
    term:
      id: GO:0140632
      label: canonical inflammasome complex assembly
    modifier: INCREASED
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  evidence:
  - reference: PMID:42386736
    reference_title: "Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "only ruptured spherules-not intact ones-trigger IL-1β production through NLRP3-pyrin inflammasomes and GSDMD-GSDME pores"
    explanation: >-
      Establishes spherule rupture as the specific trigger of inflammasome
      activation, distinguishing this axis from generic fungal sensing. Evidence
      source is IN_VITRO because the mechanism was dissected in bone
      marrow-derived macrophages.
  - reference: PMID:42386736
    reference_title: "Dual activation of NLRP3 and pyrin inflammasomes mediates host responses to the human fungal pathogen Coccidioides."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Caspase-1-deficient mice show improved disease tolerance to coccidioidomycosis despite equivalent fungal burdens"
    explanation: >-
      The load-bearing loss-of-function result: removing inflammasome signaling
      improves outcome without changing fungal burden, which separates
      immunopathology from fungal control and is what makes this an alternative
      model rather than a component of the containment model.
  - reference: PMID:33106296
    reference_title: "Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice."
    explanation: >-
      Blocking neutrophil recruitment improves fungal control, the opposite of
      what a purely protective role for neutrophils would predict.
  - reference: PMID:33106296
    reference_title: "Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We postulate that neutrophils in the lung directly or indirectly interfere with the development of a protective Th1/Th17 immune response"
    explanation: >-
      States the proposed antagonism between this axis and the Th1/Th17
      containment arm. Recorded as the authors' postulate, which is how it is
      framed in the source, rather than as a demonstrated mechanism.
  - reference: PMID:33106296
    reference_title: "Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathology of human coccidioidomycosis is granulomatous inflammation with many neutrophils surrounding ruptured spherules"
    explanation: >-
      Human-tissue framing establishing that neutrophils around ruptured
      spherules are a real feature of the disease, not a mouse artifact.
      Evidence source is OTHER because this is background characterization
      rather than a finding of the reported experiments.
  downstream:
  - target: Pulmonary cavitary disease
    description: >
      Under this model the neutrophilic, inflammasome-driven response is what
      destroys tissue: the lining of the established human cavity is neutrophils
      and caseous necrosis rather than granulomatous tissue.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - neutrophil_inflammasome_immunopathology_model
    evidence:
    - reference: PMID:24321524
      reference_title: "Cavitary pulmonary coccidioidomycosis: pathologic and clinical correlates of disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the cavity lining showed neutrophils and caseous necrosis"
      explanation: >
        Human surgical pathology showing the destructive lesion is lined by
        neutrophils and necrosis, the composition this axis predicts.
- name: Pulmonary cavitary disease
  role: consequence
  biological_scale: TISSUE
  conforms_to: "granuloma_formation#Tissue Containment versus Destruction and Fibrosis"
  description: >
    The destructive arm of the module's double-edged consequence node, specialized
    to Coccidioides. Where the granulomatous response contains the organism the
    infection resolves or leaves a quiescent nodule; where it fails to contain it,
    the granulomatous focus necroses and cavitates, and the cavity can rupture into
    the pleural space or bleed. Cavitary disease may be detected incidentally or
    during evaluation of cough or hemoptysis.

    Important qualifier on this conformance: the established cavity is where
    containment has already been lost, and human surgical pathology shows the
    cavity wall itself is characteristically NOT granulomatous - it shows chronic
    inflammation and occasional giant cells but no granulomas, with the lining
    composed of neutrophils and caseous necrosis, while granulomas persist in the
    adjacent lung as satellite lesions. The node therefore conforms to the
    module's destruction arm as the outcome of granulomatous containment failing,
    not as a granulomatous lesion in its own right. That same lining of
    neutrophils and necrosis is what the
    `neutrophil_inflammasome_immunopathology_model` hypothesis group proposes is
    doing the damage.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:37233271
    reference_title: "Coccidioidal Pulmonary Cavitation: A New Age."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Subsequent pulmonary complications as well as extrapulmonary metastatic infection may occur, either of which may be the presenting disease manifestation. Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis."
    explanation: >
      Human clinical review evidence documents cavitary lung disease as a
      pulmonary complication of coccidioidomycosis.
  - reference: PMID:24613568
    reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pleuritis is a recognized complication of ruptured cavitary infections"
    explanation: >
      Documents cavity rupture and pleural extension, the tissue-destruction
      arm of the module's containment-versus-destruction consequence node.
  - reference: PMID:24321524
    reference_title: "Cavitary pulmonary coccidioidomycosis: pathologic and clinical correlates of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cavity wall showed chronic inflammation and occasional giant cells but no granulomas and no microorganisms."
    explanation: >-
      Human surgical pathology of 21 consecutive resected cavities. Support is
      PARTIAL and deliberately qualifying: it confirms the destructive end state
      this node represents while establishing that the cavity wall itself is not
      a granulomatous lesion. It therefore bounds what the conformance to
      `granuloma_formation#Tissue Containment versus Destruction and Fibrosis`
      may be read as claiming - the cavity is the consequence of containment
      failing, not a granuloma.
  - reference: PMID:24321524
    reference_title: "Cavitary pulmonary coccidioidomycosis: pathologic and clinical correlates of disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the cavity lining showed neutrophils and caseous necrosis"
    explanation: >-
      Identifies the cellular composition of the destructive lesion as
      neutrophilic and necrotic, the human anchor for the alternative
      neutrophil/inflammasome immunopathology model curated in this entry.
  downstream:
  - target: Hemoptysis
    description: >
      Cavitary lung disease in coccidioidomycosis can present when hemoptysis is
      investigated.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37233271
      reference_title: "Coccidioidal Pulmonary Cavitation: A New Age."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis."
      explanation: >
        Human clinical review evidence links coccidioidal cavitary lung disease
        with hemoptysis as a presenting symptom.
- name: Innate immune recognition via pattern recognition receptors
  biological_scale: CELLULAR
  description: >
    Initial recognition of Coccidioides involves pattern recognition receptors including
    Toll-like receptors and C-type lectin receptors. Dectin-1 (CLEC7A) is the primary
    receptor for fungal beta-1,3-glucan exposed on spherule surfaces. Dectin-1 signals through
    CARD9 via the Syk kinase pathway, activating NF-kB and promoting pro-inflammatory
    cytokine production. Deficiency in Dectin-1 or CARD9 leads to impaired Th17/Th1
    responses and increased susceptibility to disseminated disease. Arthroconidia can initially
    bias macrophage differentiation toward a noninflammatory state and induce limited dendritic
    cell activation.
  genes:
  - preferred_term: CLEC7A
    term:
      id: hgnc:14558
      label: CLEC7A
  - preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: pattern recognition receptor signaling pathway
    term:
      id: GO:0002221
      label: pattern recognition receptor signaling pathway
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
  evidence:
  - reference: PMID:32358020
    reference_title: "CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways."
    explanation: Demonstrates that innate immune recognition of Coccidioides involves CARD9-associated Dectin-1 and Dectin-2 C-type lectin receptor signaling pathways.
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Macrophages and neutrophils detect Coccidioides arthroconidia and immature spherules via receptors Dectin-1, Dectin-2, and Mincle interacting with SOWgp"
    explanation: Identifies the specific pattern recognition receptors (Dectin-1, Dectin-2, Mincle) and their fungal ligand (SOWgp) involved in innate immune recognition of Coccidioides.
  downstream:
  - target: Th1/Th17 cell-mediated adaptive immunity
    description: >
      CARD9-coupled C-type lectin receptor signaling on innate cells is the
      upstream requirement for polarizing the protective Th17 (and Th1) response.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32358020
      reference_title: "CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways."
      explanation: >
        Demonstrates that Th17 immunity to Coccidioides is generated through
        CARD9-associated Dectin-1/Dectin-2 innate signaling.
- name: Th1/Th17 cell-mediated adaptive immunity
  role: amplifier
  biological_scale: CELLULAR
  conforms_to: "granuloma_formation#Th1 and TNF-Driven Macrophage Recruitment and Activation"
  description: >
    Protective immunity against Coccidioides depends on robust Th1 and Th17 CD4+ T cell
    responses. IFN-gamma produced by Th1 cells activates macrophages to kill fungal organisms.
    IL-17 from Th17 cells recruits neutrophils and supports mucosal immunity. The IL-12/IFN-gamma
    signaling axis is critical; genetic defects in IL12RB1, STAT4, or STAT3 impair these
    responses and increase susceptibility to severe disseminated disease. TNF-alpha is essential
    for granuloma formation and maintenance. Th2 skewing or immunosuppression (particularly
    TNF-alpha blockade) predisposes to dissemination. This is the
    coccidioidomycosis-specific substitution for the module's Th1/TNF-driven
    macrophage recruitment and activation step: the cytokine-rich milieu that
    licenses the epithelioid and giant-cell transformations downstream.
  genes:
  - preferred_term: STAT4
    term:
      id: hgnc:11365
      label: STAT4
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  - preferred_term: IL12RB1
    term:
      id: hgnc:5971
      label: IL12RB1
  cell_types:
  - preferred_term: T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: T-helper 1 type immune response
    term:
      id: GO:0042088
      label: T-helper 1 type immune response
  - preferred_term: T-helper 17 type immune response
    term:
      id: GO:0072538
      label: T-helper 17 type immune response
  - preferred_term: macrophage activation
    term:
      id: GO:0042116
      label: macrophage activation
    modifier: INCREASED
  evidence:
  - reference: PMID:38535182
    reference_title: "The Host Response to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the host response to this organism is very effective at resolving the infection in most cases and immunizing to prevent second infections. People who are immunocompromised are much more likely to develop disseminated infection."
    explanation: Confirms the effectiveness of cell-mediated immunity and the role of immunocompromise in dissemination.
  - reference: PMID:38667927
    reference_title: "The Known and Unknown \"Knowns\" of Human Susceptibility to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specific genetic variants, sex, and immune suppression by TNF inhibitors have been validated in later cohort studies, confirming the original hypotheses."
    explanation: Validates genetic susceptibility factors and TNF-alpha blockade as risk factors, supporting the importance of the Th1/TNF-alpha axis.
  downstream:
  - target: Epithelioid transformation and multinucleated giant cell formation
    description: >
      The IFN-gamma- and TNF-activated macrophage milieu is what licenses the
      defining epithelioid and multinucleated-giant-cell transformations of the
      granulomatous response to Coccidioides.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - granuloma_composition_containment_model
    evidence:
    - reference: PMID:37367586
      reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."
      explanation: >
        Attributes granuloma formation in coccidioidomycosis to the host immune
        response. Support is PARTIAL because the snippet establishes the
        immune-response-to-granuloma link generically without resolving the
        macrophage-activation-to-epithelioid-transformation step; the review
        itself notes how little is known about Coccidioides granulomas
        specifically.
  - target: Fungal meningitis
    description: >
      Failure of protective cell-mediated immunity can permit disseminated
      infection, including meningitis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38535182
      reference_title: "The Host Response to Coccidioidomycosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "People who are immunocompromised are much more likely to develop disseminated infection."
      explanation: >
        Human clinical review evidence connects impaired host immunity with
        disseminated coccidioidomycosis.
    - reference: PMID:39189034
      reference_title: "Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement)."
      explanation: >
        Human ICU cohort evidence identifies meningitis as an extrapulmonary
        manifestation of coccidioidomycosis.
  - target: Osteomyelitis
    description: >
      Disseminated coccidioidomycosis can involve skeletal infection, including
      osteomyelitis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21791226
      reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic MRI evaluation revealed osteomyelitis of his right foot; and lesions involving the vertebral bodies of the thoracic, and lumbar spine, sacrum, bilateral iliac wings, ribs, skull, and long bones of the legs bilaterally."
      explanation: >
        Human clinical evidence documents osteomyelitis in disseminated
        coccidioidomycosis.
- name: Epithelioid transformation and multinucleated giant cell formation
  role: central_effector
  biological_scale: CELLULAR
  conforms_to: "granuloma_formation#Epithelioid Transformation and Multinucleated Giant Cell Formation"
  description: >-
    In the activated milieu, lung macrophages undergo the module's defining
    transformations: they differentiate into interdigitated epithelioid cells and
    fuse into multinucleated giant cells. In coccidioidomycosis the giant cells
    are the compartment in which spherules are characteristically found on tissue
    histopathology, so this step is simultaneously the granuloma-forming
    transformation and the containment of the organism the host could not
    phagocytose as a single cell.
  cell_types:
  - preferred_term: epithelioid macrophage
    term:
      id: CL:0002150
      label: epithelioid macrophage
  - preferred_term: multinucleated giant cell
    term:
      id: CL:0000647
      label: multinucleated giant cell
  biological_processes:
  - preferred_term: syncytium formation by cell-cell fusion
    term:
      id: GO:0000768
      label: syncytium formation by cell-cell fusion
    modifier: INCREASED
  evidence:
  - reference: PMID:28857979
    reference_title: "Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells"
    explanation: >-
      Human tissue histopathology places Coccidioides spherules predominantly
      inside multinucleated giant cells, directly documenting the giant-cell
      transformation in this disease.
  - reference: PMID:24613568
    reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All cases showed granulomatous pleuritis."
    explanation: >-
      A 36-case surgical-pathology series in which every case showed
      granulomatous inflammation. Support is PARTIAL because the snippet
      establishes a uniformly granulomatous tissue response without itself
      resolving the epithelioid/giant-cell cytology.
  downstream:
  - target: Granuloma formation and containment
    description: >
      Epithelioid and giant-cell transformation converts a diffuse macrophage
      infiltrate into the organized cellular core of a coccidioidal granuloma.
    causal_link_type: DIRECT
    hypothesis_groups:
    - granuloma_composition_containment_model
    evidence:
    - reference: PMID:37367586
      reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."
      explanation: >
        Establishes granuloma formation as the host-response structure that the
        macrophage transformations assemble into. Support is PARTIAL because the
        review explicitly notes that the assembly steps of Coccidioides
        granulomas remain poorly characterized.
- name: Granuloma formation and containment
  role: effector
  biological_scale: TISSUE
  conforms_to: "granuloma_formation#Organized Granuloma Assembly"
  description: >
    The host attempts to contain Coccidioides infection through granuloma formation, a hallmark
    of the tissue response. Granulomas consist of epithelioid macrophages, multinucleated giant
    cells, and a surrounding cuff of lymphocytes. TNF-alpha is essential for granuloma formation
    and maintenance. CD14-positive macrophages localize to granuloma cores while CD206-positive
    macrophages are present internally and peripherally. Effective granuloma formation correlates
    with disease containment, while failure to form organized granulomas (as in immunocompromise
    or TNF-alpha blockade) is associated with dissemination and mortality.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: granuloma formation
    term:
      id: GO:0002432
      label: granuloma formation
  evidence:
  - reference: PMID:37367586
    reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."
    explanation: Directly supports granuloma formation as a key containment mechanism in coccidioidomycosis.
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Host responses sometimes control infections through granuloma formation in the lung as fungi is walled off instead of destroyed"
    explanation: Confirms that granuloma formation in the lung is a containment mechanism where fungi are walled off rather than destroyed.
  - reference: PMID:24613568
    reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All cases showed granulomatous pleuritis."
    explanation: >-
      Surgical-pathology series confirming that the organized granulomatous
      tissue response is the invariable histology of coccidioidal disease at
      this site.
  - reference: PMID:18852250
    reference_title: "Vaccine-induced cellular immune responses differ from innate responses in susceptible and resistant strains of mice infected with Coccidioides posadasii."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Resistant Swiss-Webster mice developed prominent perivascular/peribronchiolar lymphocytic cuffing and well-formed granulomas with few fungal elements and debris in the necrotic center, surrounded by a mantle of macrophages, lymphocytes, and fibrocytes."
    explanation: >-
      The containment arm of the strain-comparison histopathology, and the most
      direct evidence in this entry that an organized granuloma accompanies
      control of the organism. It also supplies the cellular composition this
      node's description asserts - a macrophage and lymphocyte mantle - which the
      review evidence above states without documenting.
  - reference: PMID:18852250
    reference_title: "Vaccine-induced cellular immune responses differ from innate responses in susceptible and resistant strains of mice infected with Coccidioides posadasii."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Susceptible C57BL/6 mice became moribund between 14 and 18 days postinfection, with overwhelming numbers of neutrophils and spherules and very few T cells, the drastic reduction of which was associated with failure and death"
    explanation: >-
      The failure arm of the same comparison: where the organized granuloma is
      not formed, the lesion is neutrophilic, the organism is abundant, T cells
      collapse, and the animal dies. This is the model-organism counterpart of
      the human containment-versus-cavitation dichotomy, and it is the observation
      that makes granuloma organization a candidate determinant of outcome rather
      than an incidental morphology. It remains correlational - no architecture
      was perturbed - so it does not establish that the organized structure is
      what causes containment.
  - reference: PMID:20930107
    reference_title: "T-lymphocyte predominance in lesions of canine coccidioidomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In nearly all lesions, T lymphocytes were more numerous than B lymphocytes and were distributed throughout the lesion with concentration in the periphery of granulomas, whereas B lymphocytes were mostly confined to the periphery of granulomas."
    explanation: >-
      Immunohistochemistry of naturally acquired coccidioidomycosis, addressing
      the "which cells are recruited" component of the
      `granuloma_composition_containment_model` hypothesis directly rather than by
      analogy. Species scope matters here and the source insists on it: the same
      paper reports that human coccidioidal pulmonary granulomas carried roughly
      equivalent numbers of T and B lymphocytes, and describes its own canine
      result as distinct from both human and mouse lesions. Cited as
      MODEL_ORGANISM evidence for the peripheral T-cell organization of the
      lesion, not as a statement of human granuloma composition.
  downstream:
  - target: Pulmonary cavitary disease
    description: >
      When the granulomatous focus fails to contain the organism, the assembled
      granuloma is also the lesion that necroses and cavitates, and the resulting
      cavity may rupture into the pleural space.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24613568
      reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All cases showed granulomatous pleuritis."
      explanation: >
        In a series assembled overwhelmingly from ruptured cavitary infections,
        the tissue response is uniformly granulomatous. Support is PARTIAL and
        the claim is scoped to the pleura: this observation is of granulomatous
        pleuritis at the site of rupture, not of the cavity wall, which
        PMID:24321524 shows is characteristically non-granulomatous. The edge
        asserts that cavitation arises where granulomatous disease is present,
        not that the cavity wall is itself a granuloma.
  - target: Granulomatosis
    description: >
      Granuloma formation is the tissue-response mechanism underlying the
      granulomatous phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37367586
      reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."
      explanation: >
        Review evidence directly identifies granuloma formation as a host
        response mechanism in coccidioidomycosis.
phenotypes:
- category: Respiratory
  name: Cough
  frequency: VERY_FREQUENT
  notes: Cough is a common symptom in symptomatic primary pulmonary coccidioidomycosis.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:26904326
    reference_title: "Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."
    explanation: Identifies cough as one of the usual presenting symptoms of coccidioidomycosis.
- category: Respiratory
  name: Pleuritic chest pain
  notes: Pleuritic chest pain is common in acute pulmonary coccidioidomycosis.
  phenotype_term:
    preferred_term: Pleuritic chest pain
    term:
      id: HP:0033771
      label: Pleuritic chest pain
  evidence:
  - reference: PMID:24613568
    reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%)."
    explanation: Documents chest pain in 44% of patients with pleural coccidioidomycosis.
  - reference: PMID:26904326
    reference_title: "Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."
    explanation: Confirms pleurisy (pleuritic chest pain) as a common symptom of coccidioidomycosis.
- category: Constitutional
  name: Fever
  frequency: VERY_FREQUENT
  notes: Present in the majority of symptomatic infections as part of the classic desert rheumatism triad.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress"
    explanation: Identifies fever as one of the flu-like symptoms of coccidioidomycosis.
- category: Constitutional
  name: Fatigue
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:21791226
    reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias."
    explanation: Documents fatigue as a presenting symptom in a patient with disseminated coccidioidomycosis.
  - reference: PMID:26904326
    reference_title: "Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptoms are nonspecific yet usually involve fatigue, cough, and pleurisy."
    explanation: Confirms fatigue as a common symptom of coccidioidomycosis.
- category: Constitutional
  name: Night sweats
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
  evidence:
  - reference: PMID:28857979
    reference_title: "Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats"
    explanation: Documents night sweats as a presenting symptom in a patient with disseminated coccidioidomycosis.
  - reference: PMID:21791226
    reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His initial presentation included a non-productive cough, dyspnea, fatigue, night sweats, myalgias, and arthralgias."
    explanation: Confirms night sweats as part of the clinical presentation of disseminated coccidioidomycosis.
- category: Constitutional
  name: Weight loss
  notes: Observed in chronic or disseminated forms of coccidioidomycosis.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:28857979
    reference_title: "Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats"
    explanation: Documents weight loss as a presenting symptom in disseminated coccidioidomycosis.
  - reference: PMID:21791226
    reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pain progressed over the ensuing weeks, refractory to analgesics, and then accompanied by fevers, night sweats, and unintentional (15-pound) weight loss prompting further evaluation."
    explanation: Documents significant unintentional weight loss in a patient with disseminated coccidioidomycosis.
- category: Dermatologic
  name: Erythema nodosum
  notes: >
    Occurs in a subset of patients, more frequently in women. Associated with a robust
    immune response and generally favorable prognosis. Part of the classic desert rheumatism triad.
  phenotype_term:
    preferred_term: Erythema nodosum
    term:
      id: HP:0012219
      label: Erythema nodosum
  evidence:
  - reference: PMID:38196429
    reference_title: "Valley Fever: Pathogenesis and Evolving Treatment Options."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A common triad of symptoms of coccidioidomycosis, also called \"desert rheumatism,\" include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem."
    explanation: Erythema nodosum is identified as part of the classic symptom triad of coccidioidomycosis.
  - reference: PMID:38667927
    reference_title: "The Known and Unknown \"Knowns\" of Human Susceptibility to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "some risk factors, such as ABO blood group, Filipino ancestry, or lack of erythema nodosum among black individuals, are repeated in the literature despite the lack of supporting studies or biologic plausibility."
    explanation: Discusses erythema nodosum in the context of coccidioidomycosis risk assessment.
- category: Musculoskeletal
  name: Arthralgia
  notes: Desert rheumatism refers to the triad of fever, erythema nodosum, and arthralgias.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:38196429
    reference_title: "Valley Fever: Pathogenesis and Evolving Treatment Options."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A common triad of symptoms of coccidioidomycosis, also called \"desert rheumatism,\" include fever, erythema nodosum, and arthralgia, often accompanied by a respiratory problem."
    explanation: Arthralgia is part of the classic desert rheumatism triad.
- category: Respiratory
  name: Hemoptysis
  notes: May occur with cavitary pulmonary disease.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:37233271
    reference_title: "Coccidioidal Pulmonary Cavitation: A New Age."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cavitary lung disease may be found incidentally or when investigating symptoms such as cough or hemoptysis."
    explanation: Identifies hemoptysis as a presenting symptom that prompts investigation of cavitary coccidioidomycosis.
- category: Respiratory
  name: Dyspnea
  notes: Present in patients with pneumonia or diffuse pulmonary involvement.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:24613568
    reference_title: "Surgical pathology of pleural coccidioidomycosis: a clinicopathological study of 36 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common symptoms (median, 5 weeks) included cough (47%), chest pain (44%), and dyspnea (39%)."
    explanation: Documents dyspnea in 39% of patients with pleural coccidioidomycosis.
  - reference: PMID:28857979
    reference_title: "Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 42-year-old male farmer from the west Texas who presented with an approximately 2-month history of progressive shortness of breath and dyspnea on exertion, weight loss, and night sweats"
    explanation: Documents dyspnea on exertion as a presenting symptom in disseminated coccidioidomycosis.
- category: Neurological
  name: Headache
  notes: Prominent symptom in coccidioidal meningitis; may present with hydrocephalus.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the host presents generic flu-like symptoms including headache, fever, body ache, coughing, and respiratory distress"
    explanation: Documents headache as part of the symptomatic presentation of coccidioidomycosis.
- category: Neurological
  name: Fungal meningitis
  notes: The most serious complication; requires lifelong antifungal therapy.
  phenotype_term:
    preferred_term: Fungal meningitis
    term:
      id: HP:0032159
      label: Fungal meningitis
  evidence:
  - reference: PMID:39189034
    reference_title: "Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "41 had extrapulmonary disease (17 meningitis, 13 fungemia, 10 musculoskeletal disease, and 4 pericardial or aortic involvement)."
    explanation: Documents meningitis as one of the most common extrapulmonary manifestations in critically ill patients.
- category: Musculoskeletal
  name: Osteomyelitis
  notes: Bones are a common site of dissemination, particularly vertebrae, ribs, and skull.
  phenotype_term:
    preferred_term: Osteomyelitis
    term:
      id: HP:0002754
      label: Osteomyelitis
  evidence:
  - reference: PMID:21791226
    reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic MRI evaluation revealed osteomyelitis of his right foot; and lesions involving the vertebral bodies of the thoracic, and lumbar spine, sacrum, bilateral iliac wings, ribs, skull, and long bones of the legs bilaterally."
    explanation: Documents osteomyelitis in disseminated coccidioidomycosis.
- category: Histopathologic
  name: Granulomatosis
  notes: Granuloma formation is a hallmark of the host tissue response to Coccidioides infection.
  phenotype_term:
    preferred_term: Granulomatosis
    term:
      id: HP:0002955
      label: Granulomatosis
  evidence:
  - reference: PMID:37367586
    reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One mechanism by which the host immune system attempts to control and eliminate Coccidioides is through granuloma formation."
    explanation: Confirms granuloma formation as a key feature of coccidioidomycosis.
genetic:
- name: CLEC7A
  gene_term:
    preferred_term: CLEC7A
    term:
      id: hgnc:14558
      label: CLEC7A
  association: Dectin-1 receptor for beta-glucan sensing; mutations associated with disseminated disease
  notes: >
    Primary C-type lectin receptor for fungal beta-1,3-glucan on spherule surfaces. Deficiency
    leads to impaired Th17/Th1 responses and increased susceptibility to dissemination. WES
    studies in disseminated disease cohorts show enrichment for CLEC7A mutations.
  evidence:
  - reference: PMID:18418396
    reference_title: "Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules."
    explanation: Demonstrates that truncated Dectin-1 (Clec7a) splice variant in C57BL/6 mice contributes to coccidioidomycosis susceptibility.
  - reference: PMID:35071044
    reference_title: "Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice."
    explanation: Identifies Dectin-1 (CLEC7A) deficiency as a primary immunodeficiency associated with disseminated coccidioidomycosis.
- name: CARD9
  gene_term:
    preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  association: Adaptor protein downstream of Dectin-1; essential for Th17 immunity
  notes: >
    Critical for vaccine-induced protection and Th17 immunity against Coccidioides. CARD9
    deficiency impairs antifungal defense through disrupted CLR signaling.
  evidence:
  - reference: PMID:32358020
    reference_title: "CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The GCP-rCpa1 vaccine stimulates a robust Th17 immunity against Coccidioides infection through activation of the CARD9-associated Dectin-1 and Dectin-2 signal pathways."
    explanation: Demonstrates that CARD9-associated signaling through Dectin-1 and Dectin-2 is required for protective Th17 immunity against Coccidioides.
- name: STAT4
  gene_term:
    preferred_term: STAT4
    term:
      id: hgnc:11365
      label: STAT4
  association: Transcription factor for IL-12 signaling; E626G mutation increases susceptibility
  notes: >
    STAT4 E626G dominant-negative mutation reduces IFN-gamma responses to IL-12/IL-18 stimulation,
    increasing susceptibility to disseminated coccidioidomycosis. Subtype scope: the
    human genetic evidence for the Th1 axis comes from patients with DISSEMINATED
    disease, so it speaks to what prevents dissemination and should not be read as
    explaining severity within primary pulmonary infection.
  evidence:
  - reference: PMID:35149520
    reference_title: "Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "All affected family members had a single heterozygous base change in STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/+ ). A knockin mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-type mice."
    explanation: Identifies the STAT4 E626G mutation in a family with disseminated coccidioidomycosis and validates its effect in a mouse model.
  - reference: PMID:35149520
    reference_title: "Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans."
    explanation: Confirms that STAT4 deficiency impairs IFN-gamma and adaptive immune responses critical for controlling coccidioidomycosis.
- name: STAT3
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  association: Transcription factor for Th17 differentiation; mutations linked to disseminated disease
  notes: >
    Involved in Th17 differentiation; mutations (as in Hyper-IgE syndrome) are associated with
    increased susceptibility to disseminated coccidioidomycosis. Subtype scope: as for
    STAT4 and IL12RB1, the human evidence is drawn from disseminated cases.
  evidence:
  - reference: PMID:35071044
    reference_title: "Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice."
    explanation: Identifies STAT3 mutations as a primary immunodeficiency associated with disseminated coccidioidomycosis.
  - reference: PMID:35071044
    reference_title: "Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease."
    explanation: Demonstrates that unvaccinated mice with STAT3 and other PID-associated mutations develop disseminated disease, and that vaccination can mitigate this susceptibility.
  - reference: PMID:28098554
    reference_title: "Risk Factors for Disseminated Coccidioidomycosis, United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 8 patients with disseminated coccidioidomycosis who had defects in the interleukin-12/interferon-γ and STAT3 axes, indicating that these are critical host defense pathways."
    explanation: >-
      The human evidence behind this record, which previously rested on mouse
      models alone. A systematic review of published disseminated cases found
      eight patients with proven primary immunodeficiency, whose defects fell in
      the IL-12/IFN-gamma and STAT3 pathways; several improved on exogenous
      IFN-gamma. Consistent with the subtype scope noted above, all eight had
      disseminated rather than contained infection.
- name: IL12RB1
  gene_term:
    preferred_term: IL12RB1
    term:
      id: hgnc:5971
      label: IL12RB1
  association: IL-12 receptor subunit; deficiency impairs IFN-gamma production
  notes: >
    IL12RB1 deficiency causes impaired IL-12 signaling and severe disseminated infection.
    Clinical improvement has been reported with IFN-gamma treatment and dupilumab (IL-4/IL-13 blockade).
    Subtype scope: as for STAT4 and STAT3, the human evidence is drawn from disseminated
    cases. Note also that Mendelian defects of this axis explain only a small minority of
    disseminated disease overall.
  evidence:
  - reference: PMID:21258095
    reference_title: "Interleukin-12 receptor β1 deficiency predisposing to disseminated Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a family with disseminated coccidioidomycosis due to a novel homozygous C186Y mutation in interleukin (IL)-12 receptor β1. This family confirms the centrality of the IL-12/IFN-γ axis to human immunity to Coccidioides spp."
    explanation: Documents a family with IL12RB1 deficiency (C186Y mutation) presenting with disseminated coccidioidomycosis, confirming the gene's role in host defense.
environmental:
- name: Arid and semi-arid soil exposure
  exposure_term:
    preferred_term: arid soil exposure
    term:
      id: ECTO:7000012
      label: exposure to soil
  influences_mechanisms:
  - target: Arthroconidia inhalation and spherule morphogenesis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Disturbing arid soil aerosolizes the arthroconidia that the fungus forms
      in it, and inhaling those spores is the initiating event of infection.
    evidence:
    - reference: PMID:39365073
      reference_title: "From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."
      explanation: >-
        Establishes that these fungal pathogens are prevalent in arid regions
        of the Americas, the soil reservoir from which inhaled arthroconidia
        originate.
  description: >
    Coccidioides is endemic to the southwestern United States (Arizona, California, New Mexico,
    Texas), northern Mexico, and parts of Central and South America. The fungus thrives in
    alkaline, sandy soils with hot summers and mild winters. Disturbance of soil by construction,
    earthquakes, or agricultural activities releases arthroconidia into the air; wind-driven
    disturbance is curated separately as "Dust storm and windblown dust events", because the
    population-level attribution of cases to discrete dust storms is contested in a way the
    general soil-exposure claim is not. Cases have been increasing, with reported incidence
    surging notably in California and Arizona.
  evidence:
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioidomycosis is endemic to the western part of the United States of America, including the central valley of California, Arizona, New Mexico, and parts of western Texas."
    explanation: Confirms the endemic geography of coccidioidomycosis in the southwestern United States.
  - reference: PMID:39365073
    reference_title: "From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioides immitis and Coccidioides posadasii are fungal pathogens that cause systemic mycoses and are prevalent in arid regions in the Americas."
    explanation: Confirms the association with arid regions across the Americas.
  - reference: PMID:39710556
    reference_title: "Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The number of clinically recognized coccidioidomycosis cases continues to increase yearly including in regions outside the traditional regions of endemicity."
    explanation: Documents expanding geographic range and increasing case numbers.
- name: Dust storm and windblown dust events
  exposure_term:
    preferred_term: exposure to windblown dust from a dust storm
    term:
      id: ECTO:7000001
      label: exposure to dust
  environment_context:
    preferred_term: dust
    term:
      id: ENVO:00002008
      label: dust
  description: >
    Haboobs and strong regional wind events lift large volumes of semi-desert
    subsoil, the reservoir in which Coccidioides grows as mycelium, and are the
    most visible route by which arthroconidia become airborne over populated
    areas. Dust storm frequency in the American Southwest has risen sharply
    (reported as a 240% increase from the 1990s to the 2000s), and is a
    prominent mechanism in climate-change projections of expanding Valley Fever
    incidence.

    Scope caveat - two claims must be kept apart here. That a dust event
    aerosolizes and transports arthroconidia is not in dispute, and is what the
    mechanism edge below asserts. Whether dust storms *specifically* drive
    measurable subsequent increases in coccidioidomycosis cases is actively
    disputed: a superposed-epoch analysis of all recorded 2006-2020 dust storms
    near Phoenix and Bakersfield found no difference in case patterns after dust
    storms versus non-dust-storm conditions, and arthroconidia are also
    transported in low-wind conditions. That disagreement is recorded as a
    CONTROVERSY discussion rather than being resolved in favour of either side.
  effect: >-
    Aerosolizes soil arthroconidia over populated areas; population-level
    attribution of case increases to dust storms is contested.
  influences_mechanisms:
  - target: Arthroconidia inhalation and spherule morphogenesis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Windblown dust events are a route by which arthroconidia are lifted from
      subsoil and carried into the breathing zone, which is the initiating step
      of infection. This edge asserts the aerosolization and transport route
      only; it does not assert a quantified population-level attribution of
      cases to dust storms, which the refuting evidence below contests.
    evidence:
    - reference: PMID:34877441
      reference_title: "No Consistent Link Between Dust Storms and Valley Fever (Coccidioidomycosis)."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Fungal arthroconidia can be transported in low-wind conditions as well as in individual dust events"
      explanation: >-
        Even the study arguing against a consistent dust-storm/case link accepts
        that individual dust events transport arthroconidia, which is the
        transport route this edge asserts. It simultaneously bounds the claim by
        noting low-wind transport also occurs, so dust storms are one route
        rather than the route.
    - reference: PMID:30166741
      reference_title: "Intensified dust storm activity and Valley fever infection in the southwestern United States."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The frequency of dust storms is found to be correlated with Valley fever incidences, with a coefficient (r) comparable to or stronger than that with other factors believed to control the disease in two endemic centers (Maricopa and Pima County, Arizona)."
      explanation: >-
        Ecological correlation between dust storm frequency and Valley Fever
        incidence in two endemic Arizona counties. This is a county-level
        time-series correlation, not an individual-level exposure study.
    - reference: PMID:34877441
      reference_title: "No Consistent Link Between Dust Storms and Valley Fever (Coccidioidomycosis)."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "Analyses of monthly and weekly disease case data showed no statistical differences in the patterns of coccidioidomycosis cases following dust storms versus non-dust storm conditions"
      explanation: >-
        Superposed-epoch analysis of all recorded 2006-2020 dust storms near
        Phoenix and Bakersfield found no post-dust-storm excess of cases,
        refuting a general dust-storm-to-incidence link at the population level.
        Retained deliberately: the edge is curated with its refutation attached
        rather than dropped or asserted unqualified.
  evidence:
  - reference: PMID:30166741
    reference_title: "Intensified dust storm activity and Valley fever infection in the southwestern United States."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The frequency of windblown dust storms has increased 240% from 1990s to 2000s."
    explanation: >-
      Documents the rising dust storm activity that motivates treating dust
      events as an exposure of growing importance in the endemic region.
  - reference: PMID:39432997
    reference_title: "Valley fever under a changing climate in the United States."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The intensified onset of climate change has caused frequencies and possibly intensities of natural hazard events like dust storms and drought to increase, which has been correlated with greater prevalence of VF."
    explanation: >-
      Review linking climate-driven increases in dust storm frequency to rising
      Valley Fever prevalence. Stated as correlation, matching the strength of
      the underlying literature.
- name: TNF-alpha inhibitor therapy
  description: >
    Iatrogenic exposure rather than a natural-environment one. TNF is
    non-redundantly required to initiate and maintain the granuloma, so
    pharmacological TNF neutralization for an unrelated inflammatory indication
    removes the cytokine arm on which coccidioidal containment depends. This is
    the coccidioidomycosis instance of the granuloma-module drug pattern read in
    reverse: what is therapeutic in sterile granulomatous disease is a
    dissemination risk when a live, contained fungus is present.
  effect: Predisposes to symptomatic and disseminated coccidioidomycosis.
  influences_mechanisms:
  - target: Th1/Th17 cell-mediated adaptive immunity
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      TNF blockade acts directly on the Th1/TNF-driven macrophage-activation step
      that licenses granuloma formation, degrading containment of the organism.
    evidence:
    - reference: PMID:38667927
      reference_title: "The Known and Unknown \"Knowns\" of Human Susceptibility to Coccidioidomycosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "immune suppression by TNF inhibitors have been validated in later cohort studies"
      explanation: >-
        Cohort-validated evidence that TNF-inhibitor immunosuppression is a
        susceptibility factor for coccidioidomycosis, the exposure this edge
        asserts.
  evidence:
  - reference: PMID:38667927
    reference_title: "The Known and Unknown \"Knowns\" of Human Susceptibility to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specific genetic variants, sex, and immune suppression by TNF inhibitors have been validated in later cohort studies, confirming the original hypotheses."
    explanation: >-
      Establishes TNF-inhibitor immune suppression as a validated risk factor
      for coccidioidomycosis.
epidemiology:
- name: Incidence in the United States
  notes: >
    Estimated 150,000 infections per year in the US. 10,000-20,000 reported cases yearly,
    concentrated in Arizona and California. Incidence has been rising; Arizona reported
    144.1/100,000 in 2019. ICU mortality rate of 48% in culture-proven critically ill patients.
  evidence:
  - reference: PMID:32358020
    reference_title: "CARD9-Associated Dectin-1 and Dectin-2 Are Required for Protective Immunity of a Multivalent Vaccine against Coccidioides posadasii Infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An estimated 150,000 new infections occur each year in the US."
    explanation: Provides the estimated annual incidence of coccidioidomycosis in the United States.
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of reported cases of coccidioidomycosis has notably increased since it became reportable in 1995."
    explanation: Documents the increasing incidence trend.
treatments:
- name: Fluconazole
  therapeutic_modality: SMALL_MOLECULE
  description: >
    First-line azole antifungal for most forms of coccidioidomycosis, including meningitis.
    Standard drug of choice for treatment of symptomatic disease.
  treatment_term:
    preferred_term: fluconazole therapy
    therapeutic_agent:
    - preferred_term: fluconazole
      term:
        id: CHEBI:46081
        label: fluconazole
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:11074900
    reference_title: "Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fluconazole and itraconazole were effective therapy for progressive forms of coccidioidomycosis."
    explanation: Randomized double-blind trial confirms fluconazole as effective therapy for progressive coccidioidomycosis.
- name: Itraconazole
  therapeutic_modality: SMALL_MOLECULE
  description: Alternative azole antifungal used for non-meningeal disseminated disease and chronic pulmonary infection.
  treatment_term:
    preferred_term: itraconazole therapy
    therapeutic_agent:
    - preferred_term: itraconazole
      term:
        id: CHEBI:6076
        label: itraconazole
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:11074900
    reference_title: "Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "50% of patients (47 of 94) and 63% of patients (61 of 97) responded to 8 months of treatment with fluconazole and itraconazole, respectively"
    explanation: Randomized double-blind trial of 198 patients showing itraconazole had a 63% response rate in nonmeningeal coccidioidomycosis.
  - reference: PMID:11074900
    reference_title: "Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with skeletal infections responded twice as frequently to itraconazole as to fluconazole."
    explanation: Demonstrates itraconazole's particular efficacy in skeletal coccidioidomycosis compared to fluconazole.
- name: Amphotericin B
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Used for severe or rapidly progressive disease, including diffuse pneumonia and
    life-threatening dissemination. Often used as initial therapy before transitioning to azoles.
  treatment_term:
    preferred_term: amphotericin B therapy
    therapeutic_agent:
    - preferred_term: amphotericin B
      term:
        id: CHEBI:2682
        label: amphotericin B
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:21791226
    reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment was initiated with liposomal amphotericin and posaconazole (400-mg bid) with fatty meals."
    explanation: Documents use of liposomal amphotericin B as initial induction therapy for severe disseminated coccidioidomycosis.
  - reference: PMID:39189034
    reference_title: "Clinical Characteristics and Mortality Risks Among Patients With Culture-Proven Coccidioidomycosis Who Are Critically Ill: A Multicenter Study in an Endemic Region."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most (91%) received antifungal therapy during hospitalization."
    explanation: Documents that the vast majority of critically ill patients received antifungal therapy.
clinical_trials:
- name: NCT02663674
  phase: PHASE_IV
  status: COMPLETED
  description: >
    FLEET-Valley Fever: Randomized, double-blind, placebo-controlled trial of 1000 adults
    evaluating early empiric fluconazole (400 mg/day for 42 days) for coccidioidomycosis
    pneumonia in patients presenting with community-acquired pneumonia in endemic areas.
  target_phenotypes:
  - preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  - preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: clinicaltrials:NCT02663674
    reference_title: "A Randomized, Double-blind, Placebo-controlled Clinical Trial of Fluconazole as Early Empiric Treatment of Coccidioidomycosis Pneumonia (Valley Fever) in Adults Presenting With Community Acquired Pneumonia (CAP) in Endemic Areas (FLEET-Valley Fever)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study is designed to provide data on the effectiveness of early antifungal treatment (Fluconazole, 400 mg/day) for coccidioidomycosis pneumonia (also referred to as Valley Fever (VF) Pneumonia or acute onset valley fever) vs. placebo in subjects with coccidioidomycosis pneumonia."
    explanation: Phase IV trial evaluating early fluconazole treatment for Valley Fever pneumonia.
- name: NCT07385638
  phase: PHASE_II
  status: RECRUITING
  description: >
    Open-label evaluation of olorofim, a novel dihydroorotate dehydrogenase inhibitor,
    for treatment of early coccidioidal meningitis in 10-12 participants diagnosed
    within 4-8 weeks and without VP shunt.
  target_phenotypes:
  - preferred_term: Fungal meningitis
    term:
      id: HP:0032159
      label: Fungal meningitis
  evidence:
  - reference: clinicaltrials:NCT07385638
    reference_title: "Phase 2, Open-label Evaluation of Olorofim in Early Coccidioidal Meningitis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This research study is being conducted to learn more about the use of olorofim in Coccidioidal (Cocci) meningitis, a rare but serious fungal infection that affects the brain and spinal cord."
    explanation: Phase II trial evaluating olorofim for early coccidioidal meningitis.
definitions:
- name: Clinical case definition
  definition_type: CASE_DEFINITION
  description: >-
    Coccidioidomycosis is a systemic fungal infection caused by inhalation of
    arthroconidia from the dimorphic soil fungi Coccidioides immitis or
    Coccidioides posadasii. The disease spectrum ranges from asymptomatic
    seroconversion (approximately half of infections) to acute self-limited pneumonia,
    chronic progressive pulmonary disease, or disseminated extrapulmonary
    infection involving skin, bones, joints, and meninges. Diagnosis is
    established by serologic testing (IgM and IgG antibodies, complement
    fixation titers), culture isolation of Coccidioides species, or
    histopathologic identification of characteristic spherules containing
    endospores in tissue specimens.
  evidence:
  - reference: PMID:38535182
    reference_title: "The Host Response to Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "only half of infected, immunologically intact people develop symptomatic pneumonia; most symptomatic infections resolve spontaneously, although some resolve very slowly."
    explanation: Supports the clinical definition by documenting the disease spectrum from asymptomatic to symptomatic pneumonia.
  - reference: PMID:39452676
    reference_title: "Overview of the Current Challenges in Pulmonary Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coccidioidomycosis is a disease caused by soil fungi of the genus Coccidioides, divided genetically into Coccidioides immitis (California isolates) and Coccidioides posadasii (isolates outside California)."
    explanation: Confirms the causative agents and their genetic distinction.
diagnosis:
- name: Coccidioides serology (IgM and IgG)
  description: >
    Serologic testing with enzyme immunoassay (EIA) for IgM and IgG antibodies and
    complement fixation (CF) titers is the primary diagnostic method. CF titers
    correlate with disease severity and are used to monitor treatment response.
  evidence:
  - reference: PMID:21791226
    reference_title: "Two cases illustrating successful adjunctive interferon-γ immunotherapy in refractory disseminated coccidioidomycosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "positive coccidioides serology (the ELISA was positive for both IgG and IgM, and presenting complement-fixation (CF) titer was 1:8). Titers less than or equal to 1:2 are considered negative."
    explanation: Documents the use of IgM/IgG ELISA and complement fixation titers for diagnosis of disseminated coccidioidomycosis.
- name: Histopathologic identification of spherules
  description: >
    Identification of characteristic large thick-walled spherules (20-200 micrometers)
    containing endospores in tissue specimens is diagnostic. May be visualized with
    H&E, PAS, or GMS staining.
  evidence:
  - reference: PMID:28857979
    reference_title: "Coccidioidomycosis Involving Lungs and Skin: A Mimicker of Metastatic Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin biopsy of the lesion revealed prominent squamous epithelial hyperplasia with basal keratinocytic atypia and associated mixed inflammatory infiltrate and scattered large thick-walled spherules containing variable-sized endospores, predominantly within the multinucleated giant cells."
    explanation: Describes histopathologic identification of characteristic spherules with endospores in tissue.
animal_models:
- species: Mus musculus
  description: >
    C57BL/6 mice are susceptible to coccidioidomycosis due to expression of a truncated
    Dectin-1 (Clec7a) splice variant. DBA/2 mice with intact Dectin-1 are resistant.
    Various knockout models (Stat4, Stat3, Ifngr1, Clec7a, Rag-1) are used to study
    immunodeficiency-associated disseminated disease and vaccine efficacy.
  evidence:
  - reference: PMID:18418396
    reference_title: "Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of Dectin-1 (Clec7a)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules."
    explanation: Establishes the C57BL/6 mouse as a susceptible model for coccidioidomycosis due to truncated Dectin-1.
  - reference: PMID:35071044
    reference_title: "Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain."
    explanation: Documents the use of multiple immunodeficient mouse models for studying coccidioidomycosis vaccine protection.
datasets:
- accession: geo:GSE274766
  title: scRNA-seq time-course of Coccidioides posadasii infected lungs
  description: >-
    Single-cell RNA-seq time course of murine lung during Coccidioides posadasii
    infection, comparing uninfected lung (D0) with infected lung at 5, 9, and 14
    days post-infection. Resolves the cellular composition of the pulmonary
    response over the interval in which containment is established or lost.
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 1
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:39611685
  notes: >-
    Identified by GEO DataSets index search for Coccidioidomycosis
    (scripts/discover_datasets.py); accession and metadata verified against NCBI
    E-utilities. Title, sample count, and organism are GEO's own values. No
    evidence block: bulk-discovered dataset records carry repository provenance
    rather than a quoted abstract.
- accession: geo:GSE274767
  title: Spatial Transcriptomics of Lungs Infected with Coccidioides posadasii
  description: >-
    10x Visium spatial transcriptomics of murine lung, comparing non-infected
    lung (D0) with lung at 14 days post-infection with Coccidioides posadasii.
    Spatially resolved counterpart to GSE274766 from the same study, relevant to
    the organization of the granulomatous lesion.
  data_type: SPATIAL_TRANSCRIPTOMICS
  sample_count: 2
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:39611685
  notes: >-
    Identified by GEO DataSets index search for Coccidioidomycosis
    (scripts/discover_datasets.py); accession and metadata verified against NCBI
    E-utilities. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE179468
  title: >-
    Functional characterization of the transcription programs underlying phase
    transition in the BSL3 pathogen Coccidioides immitis
  description: >-
    Capped small RNA-seq of Coccidioides immitis across the mycelium-to-spherule
    phase transition, profiling the transcriptional reprogramming that underlies
    the morphogenesis step at the head of this entry's pathograph. Includes
    comparator fungal species used in the analysis.
  data_type: BULK_RNA_SEQ
  sample_count: 27
  organism:
    preferred_term: Coccidioides immitis
    term:
      id: NCBITaxon:5501
      label: Coccidioides immitis
  publication: PMID:35076277
  notes: >-
    Identified by GEO DataSets index search for Coccidioidomycosis
    (scripts/discover_datasets.py); accession and metadata verified against NCBI
    E-utilities. GEO lists four organisms for this series (Schizosaccharomyces
    pombe; Saccharomyces cerevisiae; Agaricus bisporus; Coccidioides immitis);
    the pathogen of interest is recorded here.
discussions:
- discussion_id: controversy_dust_storms_vs_incidence
  prompt: >-
    Do dust storms specifically cause measurable subsequent increases in
    coccidioidomycosis incidence, or is dust-storm exposure one of several
    aerosolization routes whose population-level contribution is unresolved?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - environmental#Dust storm and windblown dust events
  - pathophysiology#Arthroconidia inhalation and spherule morphogenesis
  rationale: >-
    This is a live, published disagreement rather than an absence of evidence,
    and the two positions were argued in the same journal. Tong et al. (2017)
    reconstructed a long-term dust climatology and reported that dust storm
    frequency correlates with Valley Fever incidence in Maricopa and Pima
    Counties at least as strongly as other accepted controls of the disease.
    Comrie (2021) applied superposed-epoch analysis to all recorded dust storms
    from 2006 to 2020 near Phoenix and Bakersfield and found no difference in
    monthly or weekly case patterns following dust storms versus non-dust-storm
    conditions, noting that arthroconidia also travel in low-wind conditions and
    that an earlier study measuring airborne arthroconidia likewise found no
    consistent wind/dust link. Tong et al. (2022) replied that the crowdsourced
    NOAA Storm Events dust records are unsuitable for the question, that "dust
    storm" is not consistently defined across communities, and that exposure
    must account for event frequency, magnitude, and duration.

    The disagreement is partly about measurement rather than biology: nobody
    disputes that dust events aerosolize and transport arthroconidia, and the
    entry's mechanism edge is scoped to that transport route only. What is
    unresolved is whether discrete, catalogued dust storms are a quantitatively
    important driver of incidence relative to chronic low-wind aerosolization
    and to soil disturbance by construction and agriculture. This matters
    practically, because dust-storm advisories are a public-health lever only if
    the attribution holds, and it matters for the entry because a
    climate-change-driven increase in dust events is repeatedly cited as a
    reason to expect rising Valley Fever incidence.
  proposed_experiments:
  - experiment_id: exp_dust_storm_arthroconidia_incidence_coupling
    name: >-
      Co-located airborne Coccidioides DNA sampling and incidence surveillance
      across defined dust events
    description: >-
      Pair continuous air sampling with quantitative Coccidioides PCR at fixed
      endemic sites against a dust-event catalogue built to a single explicit
      definition (rather than aggregated storm reports), recording event
      frequency, magnitude, and duration. Link airborne arthroconidia
      concentration to laboratory-confirmed incidence at an appropriate
      incubation lag and individual residence location, so that exposure and
      outcome are measured on the same spatial scale instead of being compared
      across county-level aggregates. This addresses both the exposure
      misclassification Tong et al. raise and the null result Comrie reports.
  evidence:
  - reference: PMID:30166741
    reference_title: "Intensified dust storm activity and Valley fever infection in the southwestern United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of dust storms is found to be correlated with Valley fever incidences, with a coefficient (r) comparable to or stronger than that with other factors believed to control the disease in two endemic centers (Maricopa and Pima County, Arizona)."
    explanation: >-
      The position asserting a dust-storm/incidence association. Tagged
      HUMAN_CLINICAL to match the identical snippet on the dust-storm mechanism
      edge: this quote is the paper's county-level epidemiological correlation,
      which CLAUDE.md classifies as HUMAN_CLINICAL. The separate OTHER-tagged
      item from this paper quotes its atmospheric dust-climatology finding, a
      genuinely different evidence type.
  - reference: PMID:34877441
    reference_title: "No Consistent Link Between Dust Storms and Valley Fever (Coccidioidomycosis)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "there is no reliable evidence that all or most dust storms consistently lead to subsequent increases in coccidioidomycosis cases"
    explanation: The opposing position, from the superposed-epoch reanalysis.
  - reference: PMID:35949254
    reference_title: "Dust Storms, Valley Fever, and Public Awareness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The dust data from National Oceanic and Atmospheric Administration Storm Events Database are from diverse sources, unsuitable for assessing dust-coccidioidomycosis relationships."
    explanation: >-
      Published reply contesting the refuting study on exposure-measurement
      grounds, which is why the controversy is recorded as open rather than
      settled in either direction.
- discussion_id: gap_epithelioid_transformation_edges_unmeasured
  prompt: >-
    Has anyone shown, in Coccidioides-infected tissue, that Th1/Th17 and TNF
    signalling drives macrophages into the epithelioid and multinucleated
    giant-cell program, and that this transformation is what organizes and
    maintains the granuloma rather than being a bystander marker of it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Epithelioid transformation and multinucleated giant cell formation
  - pathophysiology#Granuloma formation and containment
  - mechanistic_hypotheses#granuloma_composition_containment_model
  rationale: >-
    The two module-conforming edges at the centre of this entry are the ones with
    no Coccidioides measurement behind them. Both ends of the chain are
    documented in this disease: the spherule genuinely resists phagocytosis, the
    Th1/Th17 and TNF requirement is established by human genetic defects and by
    TNF blockade, and organized granulomas track with containment across mouse
    strains while the human cavity is neutrophilic and non-granulomatous. What is
    missing is the middle. The mechanistic cascade in which IFN-gamma primes
    macrophages to make TNF and IL-1 and thereby produces epithelioid and
    giant-cell differentiation was worked out in hypersensitivity pneumonitis and
    in antigen-bead granulomas, not in coccidioidomycosis, and no study has
    perturbed macrophage differentiation in a Coccidioides model to ask whether
    granuloma organization and containment are lost when fungal burden is held
    constant.

    This is a gap in evidence, not a suspected error: the entry's giant-cell node
    is anchored on human tissue histopathology showing spherules inside
    multinucleated giant cells, so the transformation demonstrably occurs. The
    open question is whether it is driven by the signals the model names and
    whether it does the containing. It matters because the entry's conformance to
    `granuloma_formation` rests on these two edges, and because the field's
    default move - reasoning from tuberculosis - is exactly what the hypothesis
    flags as unvalidated.

    Note what would not close this gap. Etiology-comparative granuloma
    transcriptomics is sometimes cited as already showing that granuloma programs
    diverge by cause; the study most often invoked here (PMID:33276795) compares
    tissue sites within sarcoidosis, includes only three coccidioidomycosis
    subjects, and makes no direct coccidioidomycosis-versus-tuberculosis
    comparison, so it motivates the caution without measuring the edges.
  proposed_experiments:
  - experiment_id: exp_spatial_coupling_macrophage_state_to_cytokine_niche
    name: >-
      Spatial transcriptomic coupling of macrophage differentiation state to
      local Th1/Th17 cytokine fields in contained versus necrotic coccidioidal
      lesions
    description: >-
      Apply spatially resolved transcriptomics and single-cell profiling to
      coccidioidal lesions stratified by architecture - organized granuloma
      versus neutrophilic or caseous lesion - and ask whether epithelioid and
      giant-cell macrophage signatures are spatially coupled to local IFN-gamma,
      IL-17, and TNF fields, and whether that coupling separates contained from
      progressive lesions. The mouse datasets already recorded in this entry
      (GSE274766 and GSE274767) are matched to the question but were generated in
      lethal acute infection, so contained lesions and human tissue would have to
      be added for the contrast to exist.
    would_support:
    - pathophysiology#Epithelioid transformation and multinucleated giant cell formation
    would_refute:
    - mechanistic_hypotheses#granuloma_composition_containment_model
    supporting_outcome:
    - >-
        Epithelioid and giant-cell macrophage signatures localize to
        Th1/Th17-cytokine-rich niches and are enriched in contained lesions
        relative to necrotic ones.
    refuting_outcome:
    - >-
        Macrophage differentiation state is unrelated to local cytokine fields, or
        lesion outcome tracks neutrophil and inflammasome signatures irrespective
        of macrophage state, which would favour the alternative
        neutrophil/inflammasome model over this one.
  - experiment_id: exp_block_giant_cell_fusion_at_constant_burden
    name: >-
      Conditional blockade of macrophage fusion and epithelioid programming in a
      murine Coccidioides model
    description: >-
      Interrupt giant-cell fusion or epithelioid differentiation - for example by
      targeting the fusion machinery - during established murine coccidioidal
      infection, and measure granuloma architecture, containment, and
      dissemination while holding fungal burden constant. This is the perturbation
      that separates a driver from a marker, and it is the experiment no published
      Coccidioides study has performed.
    would_support:
    - pathophysiology#Granuloma formation and containment
    would_refute:
    - mechanistic_hypotheses#granuloma_composition_containment_model
    decision_criterion: >-
      Loss of organized granuloma architecture and of containment at unchanged
      fungal burden distinguishes a causal maintenance role from an incidental
      morphological correlate.
    supporting_outcome:
    - >-
        Blocking the transformation disorganizes the granuloma and degrades
        containment without altering the organism load.
    refuting_outcome:
    - >-
        Granuloma organization and containment are preserved despite loss of
        epithelioid and giant-cell differentiation, making the transformation a
        marker rather than the maintaining mechanism.
  evidence:
  - reference: PMID:33262956
    reference_title: "Host Response to Coccidioides Infection: Fungal Immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we do not know what cells are recruited to the granuloma, what signals form and maintain the granuloma structure, nor details on the immune microenvironment within the granuloma interior"
    explanation: >-
      The gap stated by the field in its own words: recruited cells, maintenance
      signals, and the interior microenvironment are all recorded as unknown for
      Coccidioides.
  - reference: PMID:37367586
    reference_title: "Coccidioidomycosis Granulomas Informed by Other Diseases: Advancements, Gaps, and Challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Granulomas are best defined in TB, providing clues that may be leveraged to understand Coccidioides infections."
    explanation: >-
      Documents that the working model for these edges is transferred from
      tuberculosis, which is what makes the transfer a gap rather than a
      conclusion.
- discussion_id: gap_regulatory_and_b_cell_granuloma_maintenance
  prompt: >-
    Do regulatory T cells and B-cell or ectopic-lymphoid structures govern
    whether a coccidioidal granuloma contains the organism or injures the lung,
    as they do in comparator granulomatous diseases?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Granuloma formation and containment
  - mechanistic_hypotheses#granuloma_composition_containment_model
  rationale: >-
    The curated model for this entry describes granuloma maintenance almost
    entirely as drive: Th1 and Th17 cytokines and TNF licensing a macrophage
    transformation. In the two granulomatous comparators this entry already names
    through the shared `granuloma_formation` module, the decisive variables
    include regulation as well as drive. In an HLA-DP2 transgenic model of
    chronic beryllium disease, depleting regulatory T cells worsened lung
    inflammation and increased granuloma formation, and depleting B cells
    dissolved the lymphoid aggregates and granulomas while increasing lung
    injury, with B cells found at the granuloma periphery in human disease too.

    No equivalent measurement exists for coccidioidomycosis. Neither cell type
    has been depleted, expanded, or systematically enumerated in a Coccidioides
    granuloma, so the entry cannot say whether the regulatory arm is absent from
    this disease or merely unstudied. That distinction is the gap.

    Deliberately not curated as pathophysiology nodes. Both supporting results
    come from a sterile particulate exposure in transgenic mice, and adding
    regulatory T cell or B cell nodes to this entry on that basis would assert a
    coccidioidal mechanism nobody has measured. The comparator evidence is
    recorded here, where its provenance stays visible, until Coccidioides-specific
    data exist.
  proposed_experiments:
  - experiment_id: exp_treg_and_b_cell_depletion_in_murine_coccidioidomycosis
    name: >-
      Timed regulatory T cell and B cell depletion in murine pulmonary
      coccidioidomycosis
    description: >-
      Deplete regulatory T cells, or B cells, at defined phases of established
      murine Coccidioides infection and read out granuloma architecture, lymphoid
      aggregate formation, fungal burden, lung injury, and dissemination. Running
      both arms against the same infection separates a regulatory contribution to
      containment from a regulatory contribution to tissue tolerance, and pairs
      the disease with the comparator results that motivate the question.
    would_support:
    - pathophysiology#Granuloma formation and containment
    supporting_outcome:
    - >-
        Depletion changes lesion architecture or lung injury without a proportional
        change in fungal burden, establishing a regulatory arm in coccidioidal
        granuloma maintenance analogous to the comparator diseases.
    refuting_outcome:
    - >-
        Depletion leaves granuloma organization, injury, and burden unchanged,
        indicating that the comparator finding does not transfer and that this
        entry's drive-centred model is adequate.
  evidence:
  - reference: PMID:24912188
    reference_title: "Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation."
    explanation: >-
      Comparator-disease evidence that regulatory T cells modulate the
      granulomatous response. Cited to establish that the question is live in
      granuloma biology generally; it says nothing about Coccidioides, which is
      the gap.
  - reference: PMID:31094704
    reference_title: "Protective role of B cells in sterile particulate-induced lung injury."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice."
    explanation: >-
      Comparator-disease evidence that B cells are required for granuloma and
      lymphoid-aggregate formation and are protective against lung injury. Again
      chronic beryllium disease, not coccidioidomycosis; recorded to scope the
      gap rather than to assert the mechanism here.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 35 citations 2026-03-07T05:30:53.936527

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 Pathophysiology Research Template

Target Disease

Disease Name: Coccidioidomycosis
MONDO ID: (if available)
Category:

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Coccidioidomycosis. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Disease Pathophysiology Research Report: Coccidioidomycosis (Valley fever)

Target disease metadata

Disease name: Coccidioidomycosis (Valley fever)
Etiologic agents: Coccidioides immitis and Coccidioides posadasii (lim2024clinicalcharacteristicsand pages 1-2, fayed2024overviewofthea pages 1-2)
MONDO ID: Not verified from retrieved sources in this run.
Category: Endemic dimorphic fungal infection (primary pulmonary infection with potential for extrapulmonary dissemination) (lim2024clinicalcharacteristicsand pages 1-2, fayed2024overviewofthea pages 1-2)

1) Key concepts & definitions (current understanding)

1.1 Core definition and clinical spectrum

Coccidioidomycosis is acquired by inhalation of airborne Coccidioides arthroconidia and ranges from asymptomatic infection to severe pulmonary disease and disseminated infection (hsu2024theknownand pages 2-4, fayed2024overviewofthea pages 1-2). In a 2024 ICU cohort paper, the authors summarize that “about two-thirds of cases are asymptomatic or have mild respiratory symptoms” and that “1% to 3% present as disseminated infection” (lim2024clinicalcharacteristicsand pages 1-2).

1.2 Central pathophysiology concept: host–pathogen interaction shaped by fungal morphogenesis and immune polarization

A key unifying concept across recent reviews is that disease outcome depends on (i) in-host fungal morphogenesis (arthroconidia → spherules → endospores) and (ii) whether host immunity develops protective Th1/Th17 responses and organized containment (e.g., granulomas), versus immune evasion, Th2 skewing, or immunosuppression leading to persistence/dissemination (miranda2023coccidioidomycosisgranulomasinformed pages 7-10, jackson2024fromsoilto pages 8-9, kirkland2024thehostresponse pages 14-16, fayed2024overviewofthea pages 2-6).

2) Core pathophysiology (molecular & cellular mechanisms)

2.1 Initiation: inhalation and morphogenesis in the lung

Trigger: inhalation of arthroconidia; incubation is reported as “one-to-three weeks” (Fayed et al., 2024; DOI:10.3390/jof10100724; published Oct 2024) (fayed2024overviewofthea pages 2-6).

Morphogenetic switch: Hsu (2024; DOI:10.3390/jof10040256; published Mar 2024) notes that inhaled “2–5 µm arthroconidia” can reach terminal bronchioles and “swell into spherules” that undergo endospore formation; developing spherules can secrete a metalloproteinase that contributes to immune masking, and “rupture of mature spherules triggers a rapid influx of immune cells” (hsu2024theknownand pages 1-2).

Phagocytosis constraint: spherules are largely extracellular, while “small round cells and endospores” are phagocytosed by neutrophils, dendritic cells, and macrophages (kirkland2024thehostresponsea pages 9-10).

2.2 Innate sensing and early immune programming

Pattern recognition: A 2024 clinical review summarizes that initial recognition involves PRRs including “Toll-like receptors (TLRs) and c-type lectin receptors (CLRs)” (fayed2024overviewofthea pages 2-6).

β-glucan sensing axis (Dectin-1/2 → CARD9): In the 2024 host-response review (Kirkland et al., 2024; DOI:10.3390/jof10030173; published Feb 2024), Dectin-1 (CLEC7A) is highlighted as required for pro-inflammatory cytokine responses to spherules and for controlling fungal burden and Th1/Th17 cytokines in murine infection models (kirkland2024thehostresponsea pages 4-5). The granuloma-focused 2023 review states that β-1,3-glucan and SOWgp are detected by Dectin-1 signaling via MyD88 and CARD9, activating NFAT/NF-κB and pro-inflammatory cytokine production (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).

Innate hyporesponsiveness to arthroconidia: Kirkland et al. (2024) report that arthroconidia can bias macrophage differentiation toward noninflammatory “M0” macrophages and induce little dendritic cell activation, suggesting early immune programming may be suboptimal before spherule exposure (kirkland2024thehostresponsea pages 4-5).

Oxidant biology beyond classical NADPH oxidase: Whole-exome sequencing (WES) of disseminated cases in Kirkland et al. (2024) identified β-glucan sensing pathway defects (including CLEC7A and PLCG2) and enrichment of DUOX1/DUOXA1 mutations associated with reduced epithelial H2O2 responses to Dectin-1 agonists (kirkland2024thehostresponsea pages 9-10).

2.3 Adaptive immunity: Th1/Th17 dominance and cytokine axes

Multiple 2023–2024 sources converge on Th1/Th17 dominance as the protective response.

Jackson et al. (2024; Microbiology and Molecular Biology Reviews; DOI:10.1128/mmbr.00161-23; published Dec 2024) notes that “a protective immune response is dominated by Th1/Th17 cells” and that loss of granuloma structure in immunocompromise can lead to fatal infection in mice (jackson2024fromsoilto pages 8-9).
Fayed et al. (2024; DOI:10.3390/jof10100724) states that “Th1 and Th17 subtypes is particularly critical,” and specifically that “TNF-α… is essential for granuloma formation,” while IL-6/IL-21/TGF-β drive Th17 differentiation and IL-17 production (fayed2024overviewofthea pages 2-6).

Human genetic evidence of Th1 axis importance: In Kirkland et al. (2024), a dominant-negative STAT4 E626G mutation is described as reducing IFN-γ responses to IL-12/IL-18 (kirkland2024thehostresponsea pages 9-10). IL12RB1 deficiency is described in the same review with impaired IL-12 signaling and clinical improvement after IFN-γ treatment and subsequent IL-4/IL-13 blockade (dupilumab), supporting pathogenic relevance of Th1:Th2 imbalance in severe disseminated disease (kirkland2024thehostresponse pages 14-16).

2.4 Granuloma biology: containment versus breakdown

Granulomas are repeatedly emphasized as a major containment strategy.

The 2023 granuloma review reports that granulomas form in “roughly 5% of infections” and can be necrotizing and cellularly complex, including neutrophils, macrophages, and lymphocytes (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).
Spatial immune architecture in patient granulomas is described with CD14+ macrophages localized to granuloma cores and CD206+ macrophages present inside and around granulomas; CD14/CD206/IL-10/TNF-α enriched within granulomas (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).
Jackson et al. (2024) highlights that immunocompromise can disrupt granuloma structure and lead to mortality in mice (jackson2024fromsoilto pages 8-9).

2.5 Immune evasion and immunopathology drivers

SOWgp and protease-mediated immune masking: Hsu (2024) reports a metalloproteinase secreted by developing spherules contributes to immune masking (hsu2024theknownand pages 1-2). The granuloma review emphasizes surface antigens such as SOWgp and their role in host recognition (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).

Urease-mediated microenvironmental modulation: The granuloma review describes urease/urea release competing with iNOS for L-arginine and promoting an alkalinized microenvironment, with downstream skewing toward anti-inflammatory cytokines (IL-10, IL-4, IL-13) and M2-like responses (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).

3) Key molecular players (host + fungal), cell types, tissues, chemicals

Entity	Type	Ontology/ID	Role in Coccidioidomycosis Pathophysiology	Evidence/Citation Context IDs
Dectin-1 (CLEC7A)	Host Gene/Protein	HGNC:14536	Primary C-type lectin receptor for fungal $\beta$-1,3-glucan; deficiency leads to dissemination; critical for Th17/Th1 responses.	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponsea pages 9-10, kirkland2024thehostresponse pages 4-5, kirkland2024thehostresponsea pages 4-5)
CARD9	Host Gene/Protein	HGNC:16391	Adaptor protein downstream of Dectin-1/2; essential for vaccine-induced protection and Th17 immunity.	(kirkland2024thehostresponse pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5)
STAT1	Host Gene/Protein	HGNC:11362	Transcription factor for IFN-$\gamma$ signaling; gain-of-function mutations modulate susceptibility.	(kirkland2024thehostresponse pages 9-10, hsu2024theknownand pages 18-20)
STAT3	Host Gene/Protein	HGNC:11364	Transcription factor involved in Th17 differentiation; mutations linked to disseminated disease (Hyper-IgE).	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponseb pages 9-10, jackson2024fromsoilto pages 8-9, hsu2024theknownand pages 18-20)
STAT4	Host Gene/Protein	HGNC:11365	Transcription factor for IL-12 signaling; E626G mutation reduces IFN-$\gamma$ response and increases susceptibility.	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponseb pages 9-10, jackson2024fromsoilto pages 8-9)
IL12RB1	Host Gene/Protein	HGNC:5970	Receptor for IL-12; deficiency impairs IFN-$\gamma$ production, leading to severe disseminated infection.	(kirkland2024thehostresponse pages 14-16, hsu2024theknownand pages 18-20)
IFN-$\gamma$ (IFNG)	Host Gene/Protein	HGNC:5438	Cytokine driving Th1 responses and macrophage activation; critical for fungal clearance.	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponseb pages 9-10, kirkland2024thehostresponse pages 14-16, hsu2024theknownand pages 18-20)
TNF-$\alpha$ (TNF)	Host Gene/Protein	HGNC:11892	Pro-inflammatory cytokine essential for granuloma formation and maintenance.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5, fayed2024overviewofthe pages 2-6)
IL-17 (IL17A)	Host Gene/Protein	HGNC:5981	Cytokine produced by Th17 cells; crucial for mucosal immunity and vaccine efficacy.	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponseb pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5, fayed2024overviewofthe pages 2-6)
SOWgp	Fungal Factor	-	Spherule Outer Wall Glycoprotein; major surface antigen recognized by host; can be degraded by fungal metalloproteinase (Mep1) to evade detection.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10)
Urease	Fungal Factor	-	Enzyme producing ammonia/urea; alkalizes microenvironment to inhibit phagolysosome fusion.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10)
Macrophage	Cell Type	CL:0000235	Phagocytes forming the core of granulomas; phenotype (M1 vs M2) influences clearance vs persistence.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5)
Th1 Cell	Cell Type	CL:0000545	CD4+ T cells producing IFN-$\gamma$; associated with effective disease resolution.	(kirkland2024thehostresponse pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 14-16)
Th17 Cell	Cell Type	CL:0000899	CD4+ T cells producing IL-17; associated with vaccine protection and fungal control.	(kirkland2024thehostresponse pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5, jackson2024fromsoilto pages 8-9)
Lung	Tissue	UBERON:0002048	Primary site of infection (pulmonary coccidioidomycosis); site of spherule development and granuloma formation.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5, lim2024clinicalcharacteristicsand pages 1-2)
Meninges	Tissue	UBERON:0002360	Major site of extrapulmonary dissemination (coccidioidal meningitis); high mortality.	(lim2024clinicalcharacteristicsand pages 1-2)
Meningitis	Phenotype	HP:0001287	Severe complication of disseminated infection; requires lifelong therapy.	(lim2024clinicalcharacteristicsand pages 1-2)
Granuloma	Phenotype	HP:0002955	Organized immune structure to contain fungus; failure leads to dissemination.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10, jackson2024fromsoilto pages 8-9, fayed2024overviewofthe pages 2-6)
Beta-1,3-glucan	Chemical	CHEBI:37671	Fungal cell wall component recognized by Dectin-1; PAMP triggering innate immune response.	(kirkland2024thehostresponse pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10)

Table: This table maps key genes, proteins, fungal factors, cell types, tissues, and phenotypes involved in Coccidioides infection to standard ontology identifiers (HGNC, CL, UBERON, HP, CHEBI) where available, summarizing their pathophysiological roles and supporting evidence.

3.1 Host genes/proteins implicated in susceptibility and protection (HGNC)

Evidence from WES and clinical immunogenetics in 2024 reviews implicates: - β-glucan sensing and CLR signaling: CLEC7A (Dectin-1) and downstream signaling intermediates (e.g., PLCG2), with disseminated disease enrichment for CLEC7A mutations (kirkland2024thehostresponsea pages 9-10). - CARD9 (CLR adaptor) as critical for vaccine-induced Th17/IFN-γ responses and protection (kirkland2024thehostresponsea pages 4-5). - STAT4, STAT3, STAT1 as key transcriptional nodes in Th polarization and IFN-γ signaling; STAT4 mutation linked to impaired IFN-γ response; STAT3 mutations observed in disseminated disease cohorts (kirkland2024thehostresponsea pages 9-10). - IL12RB1 as a causal susceptibility locus in severe disseminated disease with impaired IL-12 signaling (kirkland2024thehostresponse pages 14-16). - DUOX1/DUOXA1 variants associated with reduced epithelial H2O2 responses to Dectin-1 agonists in disseminated disease cohorts (kirkland2024thehostresponsea pages 9-10).

3.2 Fungal determinants

Recent reviews highlight fungal attributes that shape immune recognition and persistence: - SOWgp (spherule outer wall glycoprotein): a prominent surface antigen implicated in host recognition (miranda2023coccidioidomycosisgranulomasinformed pages 7-10). - Metalloproteinase-mediated masking: developing spherules secrete a metalloproteinase associated with immune masking (hsu2024theknownand pages 1-2). - Urease: linked to altered local pH and macrophage polarization effects (miranda2023coccidioidomycosisgranulomasinformed pages 7-10). - CPS1: Jackson et al. (2024) describes CPS1 as a virulence-associated gene; Δcps1 is avirulent and can protect mice as a live attenuated vaccine strain (jackson2024fromsoilto pages 8-9).

3.3 Key cell types (CL) and anatomical sites (UBERON)

Primary infection occurs in the lung (UBERON:0002048) with early involvement of alveolar macrophages, neutrophils, and dendritic cells, followed by adaptive Th1 and Th17 responses (kirkland2024thehostresponsea pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, fayed2024overviewofthea pages 2-6). Extrapulmonary dissemination targets include the meninges (UBERON:0002360) (coccidioidal meningitis) and musculoskeletal and other tissues (lim2024clinicalcharacteristicsand pages 1-2).

3.4 Chemical entities (CHEBI) and relevant small molecules/drugs

β-1,3-glucan (CHEBI:37671) is a key fungal PAMP sensed via Dectin-1 pathways (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).
TNF-α inhibitors and other immunosuppressive agents are repeatedly cited as increasing risk of severe/disseminated disease by suppressing critical antifungal defense mechanisms (fayed2024overviewofthea pages 2-6, hsu2024theknownand pages 18-20).
Dupilumab (IL-4/IL-13 blockade) is described in an IL12RB1-deficiency case as normalizing Th1:Th2 balance with “dramatic clinical improvement” (kirkland2024thehostresponse pages 14-16).

4) Biological processes disrupted (GO-oriented)

The following biological processes are supported by the retrieved evidence as central to pathophysiology (process names provided in a GO-compatible style; specific GO IDs not asserted here because they were not present in the retrieved text): - Pattern recognition receptor signaling (CLR/TLR-linked), including β-glucan sensing and downstream NF-κB-associated inflammatory gene programs (miranda2023coccidioidomycosisgranulomasinformed pages 7-10, fayed2024overviewofthea pages 2-6). - Cytokine-mediated signaling and T-helper cell differentiation, particularly Th1 (IFN-γ) and Th17 (IL-17) programs (fayed2024overviewofthea pages 2-6, jackson2024fromsoilto pages 8-9). - Granuloma organization / maintenance and chronic inflammatory response, with TNF-α as a key mediator (miranda2023coccidioidomycosisgranulomasinformed pages 7-10, fayed2024overviewofthea pages 2-6). - Reactive oxygen species (ROS) production in epithelial and immune contexts (DUOX-related H2O2) linked to disseminated disease genetics (kirkland2024thehostresponsea pages 9-10).

5) Cellular components (where key processes occur)

Based on the mechanistic descriptions retrieved: - Cell surface / plasma membrane: PRR engagement (e.g., Dectin-1/CLRs; TLRs) for sensing fungal PAMPs (miranda2023coccidioidomycosisgranulomasinformed pages 7-10, fayed2024overviewofthea pages 2-6). - Nuclear compartment: STAT transcription-factor signaling (STAT1/3/4) downstream of cytokine receptors shaping IFN-γ and Th differentiation programs (kirkland2024thehostresponsea pages 9-10, kirkland2024thehostresponse pages 14-16). - Extracellular space / tissue lesions: extracellular spherules in host tissues and granuloma microenvironments (kirkland2024thehostresponsea pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10).

6) Disease progression model (sequence of events)

Exposure and deposition in lung: inhalation of arthroconidia; incubation ~1–3 weeks (fayed2024overviewofthea pages 2-6).
Morphogenesis and immune masking: arthroconidia swell into spherules, undergo endospore development; developing spherules secrete a metalloproteinase associated with immune masking (hsu2024theknownand pages 1-2).
Innate sensing and early programming: arthroconidia may elicit weak dendritic cell activation and M0 macrophage bias; later spherule β-glucans and surface antigens are recognized via CLRs (Dectin-1/2) and CARD9-linked signaling, promoting pro-inflammatory cytokines (kirkland2024thehostresponsea pages 4-5, miranda2023coccidioidomycosisgranulomasinformed pages 7-10).
Spherule rupture and inflammatory influx: mature spherule rupture drives rapid recruitment of immune cells (hsu2024theknownand pages 1-2).
Adaptive immunity and containment: protective responses dominated by Th1/Th17; TNF-α supports granuloma formation and integrity; granulomas may form in ~5% of infections (miranda2023coccidioidomycosisgranulomasinformed pages 7-10, fayed2024overviewofthea pages 2-6).
Outcomes:
Resolution in most immunologically intact hosts (approximately two-thirds asymptomatic) (lim2024clinicalcharacteristicsand pages 1-2, hsu2024theknownand pages 2-4).
Chronic pulmonary disease in a subset; Hsu (2024) provides a conceptual breakdown (e.g., ~30% uncomplicated primary, ~5% chronic pulmonary, <1% extrapulmonary) (hsu2024theknownand pages 2-4).
Dissemination (skin/bone/CNS) when key immune axes fail (e.g., impaired CLR signaling, IL-12/IFN-γ axis defects, TNF blockade, low CD4 counts) (kirkland2024thehostresponsea pages 9-10, kirkland2024thehostresponse pages 14-16, hsu2024theknownand pages 18-20).

7) Phenotypic manifestations (HP-oriented) and mechanistic links

Key phenotypes include: - Primary pulmonary coccidioidomycosis (pneumonia-like illness) (fayed2024overviewofthea pages 1-2). - Chronic pulmonary disease (>12 months despite therapy) and complications such as cavitary disease (hsu2024theknownand pages 1-2, hsu2024theknownand pages 2-4). - Disseminated disease including meningitis (HP:0001287) and musculoskeletal disease (lim2024clinicalcharacteristicsand pages 1-2, hsu2024theknownand pages 2-4). - Granulomatous inflammation / granuloma (HP:0002955) as a tissue-level containment phenotype (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).

Mechanistic links: - Th1/IFN-γ deficiency or signaling impairment (e.g., STAT4, IL12RB1-related) is associated with severe/disseminated phenotypes (kirkland2024thehostresponsea pages 9-10, kirkland2024thehostresponse pages 14-16). - TNF-α suppression (biologics) undermines granuloma formation/maintenance and increases risk of severe disease (fayed2024overviewofthea pages 2-6, hsu2024theknownand pages 18-20).

8) Recent developments and latest research (prioritize 2023–2024)

8.1 Human genetics and “experiments of nature”

Kirkland et al. (Feb 2024) reports WES signals in disseminated disease implicating β-glucan sensing (CLEC7A/Dectin-1; PLCG2) and epithelial ROS pathways (DUOX1/DUOXA1) (kirkland2024thehostresponsea pages 9-10). These findings reinforce the mechanistic importance of early CLR signaling and mucosal oxidant biology in preventing dissemination (kirkland2024thehostresponsea pages 9-10).

8.2 Granuloma microenvironment and cellular ecology

The 2023 granuloma review compiles emerging human tissue evidence describing heterogeneous granuloma morphology and macrophage subset localization (CD14+ core; CD206+ internal/peripheral), and mixed cytokine enrichment within granulomas (miranda2023coccidioidomycosisgranulomasinformed pages 7-10). This supports a microenvironment-driven model in which macrophage polarization states and cytokine milieu influence containment versus persistence (miranda2023coccidioidomycosisgranulomasinformed pages 7-10).

8.3 Vaccine-relevant advances

Jackson et al. (Dec 2024) highlights virulence-associated genes and vaccine concepts including Δcps1 live attenuated strains (avirulent yet immunogenic) and emphasizes Th1/Th17 dominance for protective immunity (jackson2024fromsoilto pages 8-9). Kirkland et al. (Feb 2024) summarizes that spherule preparations and live attenuated mutants that form sterile spherules can be protective in animals (kirkland2024thehostresponse pages 14-16).

9) Current applications and real-world implementations (2024 emphasis)

9.1 Diagnostics and testing: current practice and performance

Serology as first line: Fayed et al. (Oct 2024) describes EIA IgM/IgG, immunodiffusion, and complement fixation as standard serologic modalities, noting IgM detectability “within roughly 1-to-3 weeks of symptom onset” and emphasizing that EIAs can vary and “should not be used for definitive assessment” (fayed2024overviewofthea pages 13-15, fayed2024overviewofthe pages 13-15).

Culture and histopathology: Culture is described as gold standard but with poor sensitivity “around 50%” and BSL-3 handling requirements (fayed2024overviewofthea pages 15-17). Histopathology can show spherules directly (fayed2024overviewofthe pages 15-17).

PCR and FDA-cleared BAL testing: Fayed et al. (2024) reports FDA approval of GenStat for detecting Coccidioides DNA from BAL/BW and describes a center’s PCR performance with “100% specificity” and sample-type dependent sensitivities (e.g., BAL 91%, sputum 94%, CSF 59%) (fayed2024overviewofthea pages 15-17).

Large-scale real-world testing statistics (commercial laboratory): Benedict et al. (Aug 2024; DOI:10.1093/ofid/ofae448) reports 2019–2024 volumes and positivity for Coccidioides EIAs: 154,989 IgM results (5% positive) and 154,968 IgG results (8% positive) (benedict2024testingforblastomycosis pages 1-2, benedict2024testingforblastomycosis pages 2-3). Turnaround time was median 1 day (IQR 1–3) overall, with regional variation (benedict2024testingforblastomycosis pages 2-3).

9.2 Severe disease management context: ICU outcomes

In a multicenter ICU cohort of 145 culture-proven cases (Arizona; 2017–2022), 48% died during hospitalization; 72% had pulmonary disease and 28% extrapulmonary disease including meningitis (n=17) and fungemia (n=13) (Lim et al., Aug 2024; DOI:10.1093/ofid/ofae454) (lim2024clinicalcharacteristicsand pages 1-2).

10) Relevant statistics and data (recent sources)

Estimated annual infections: ~150,000 infections/year are cited in Hsu (2024) (hsu2024theknownand pages 1-2).
Dissemination frequency (population-level estimate): Hsu (2024) reports dissemination in ~600–1000 cases/year (0.4–0.6%) (hsu2024theknownand pages 1-2).
Reported case burden: a 2024 clinical review cites CDC estimates of 10,000–20,000 reported U.S. cases yearly, mostly in Arizona and California (fayed2024overviewofthea pages 1-2).
Incidence trends: Hsu (2024) reports increases in reported incidence (e.g., 5.3/100,000 in 1998 to 42.6/100,000 in 2011; Arizona 84.4/100,000 in 2014 to 144.1/100,000 in 2019) (hsu2024theknownand pages 2-4).
Commercial-lab EIA positivity: IgM 5% positive; IgG 8% positive in 2019–2024 dataset (benedict2024testingforblastomycosis pages 1-2).
ICU mortality: 48% in culture-proven ICU cohort (lim2024clinicalcharacteristicsand pages 1-2).

11) Expert opinions and authoritative analysis (2023–2024)

Consensus immune model: Recent authoritative reviews emphasize that protective immunity is dominated by Th1/Th17 programs, and that immunosuppression (notably TNF-α blockade) increases risk of severe/disseminated disease by compromising granuloma formation and antifungal T-cell responses (jackson2024fromsoilto pages 8-9, fayed2024overviewofthea pages 2-6, hsu2024theknownand pages 18-20).
Genetic susceptibility framing: Hsu (2024) cautions that some historically repeated risk factors are not strongly supported, while specific genetic variants and TNF-inhibitor–associated immunosuppression have stronger validation in later cohort studies (hsu2024theknownand pages 1-2).

12) Knowledge-base-ready annotations (evidence-linked)

12.1 Pathophysiology description (narrative)

Coccidioidomycosis begins when inhaled 2–5 µm arthroconidia reach distal airways and, if not cleared, swell into spherules that form endospores; developing spherules may secrete a metalloproteinase linked to immune masking, while rupture of mature spherules triggers strong inflammatory influx (hsu2024theknownand pages 1-2). Early innate responses can be blunted by arthroconidia (limited DC activation and M0 macrophage bias), but spherules expose β-glucan and antigens sensed by CLRs (notably Dectin-1/2) and CARD9-linked signaling, supporting inflammatory cytokines that prime Th1/Th17 adaptive immunity (kirkland2024thehostresponsea pages 4-5, miranda2023coccidioidomycosisgranulomasinformed pages 7-10). Protective control is associated with Th1 and Th17 programs (IFN-γ, IL-17) and TNF-α-mediated granuloma formation; breakdown of granuloma structure in immunocompromise predisposes to progression and dissemination (jackson2024fromsoilto pages 8-9, fayed2024overviewofthea pages 2-6). Dissemination risk is amplified by immunosuppression and by inborn errors affecting CLR signaling and IL-12/IFN-γ pathways (e.g., CLEC7A, IL12RB1, STAT4), and by epithelial oxidant response defects (DUOX1/DUOXA1) (kirkland2024thehostresponsea pages 9-10, kirkland2024thehostresponse pages 14-16).

12.2 Evidence-linked mechanism summary

Mechanism / Stage	Key Host Pathways (Genes/Proteins)	Key Fungal Factors	Key Cell Types	Key Tissues	Evidence / Description	Key Citations
Innate Recognition	Dectin-1 (CLEC7A), Dectin-2 (CLEC6A), CARD9, MyD88, Syk-JNK, NLRP3, IL-1R1	$\beta$-1,3-glucan (exposed on spherules), SOWgp	Macrophages, Dendritic Cells (DCs), Neutrophils	Lung (Alveoli)	Dectin-1 is the primary receptor for spherule recognition; Dectin-2/CARD9 axis drives Th17 vaccine immunity; Arthroconidia often induce poor activation (M0 bias).	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponsea pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 4-5, kirkland2024thehostresponsea pages 4-5)
Fungal Morphogenesis & Evasion	iNOS (competed by fungal arginase)	SOWgp, Metalloproteinase (Mep1), Urease, CPS1	Neutrophils, Macrophages	Lung	Spherules grow too large for phagocytosis; Mep1 digests immunogenic SOWgp; Urease alkalizes local pH to inhibit phagolysosomes; CPS1 required for virulence.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10, jackson2024fromsoilto pages 8-9, hsu2024theknownand pages 1-2, fayed2024overviewofthe pages 2-6)
Adaptive Immunity (Control)	IFN-$\gamma$, IL-17, TNF-$\alpha$, IL-12/IL-23 axis, STAT1, STAT3, STAT4	Spherule antigens (e.g., Ag2/Prp2)	Th1 Cells, Th17 Cells, B cells	Lung, Lymph Nodes	Robust Th1 (IFN-$\gamma$) and Th17 (IL-17) responses are required for clearance; Th2 skewing or low CD4+ count increases dissemination risk.	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponseb pages 9-10, miranda2023coccidioidomycosisgranulomasinformed pages 7-10, kirkland2024thehostresponse pages 14-16, hsu2024theknownand pages 18-20)
Granuloma Formation	TNF-$\alpha$, IFN-$\gamma$	Persistent fungal antigens	Macrophages (CD14+ core, CD206+ mantle), T cells	Lung	Granulomas form in ~5% of infections to contain fungi; TNF-$\alpha$ is essential for maintenance; breakdown leads to reactivation/spread.	(miranda2023coccidioidomycosisgranulomasinformed pages 7-10, jackson2024fromsoilto pages 8-9, fayed2024overviewofthe pages 2-6)
Dissemination & Susceptibility	IL12RB1, IFNGR1, STAT1, STAT3, STAT4, CLEC7A, DUOX1/DUOXA1	Spherules/Endospores	Th1/Th17 Cells, Monocytes	Meninges, Skin, Bone, Liver	Genetic defects in IL-12/IFN-$\gamma$ loop or Dectin-1 increase dissemination; Biologic suppression (TNF blockers) is a major risk; Pregnancy and specific ancestries (Black, Filipino) elevate risk.	(kirkland2024thehostresponse pages 9-10, kirkland2024thehostresponsea pages 9-10, kirkland2024thehostresponsea pages 4-5, lim2024clinicalcharacteristicsand pages 1-2, hsu2024theknownand pages 18-20)

Table: Summary of key mechanisms, molecular players, and evidence underlying the host-pathogen interaction in Coccidioides infection.

12.3 Visual evidence from a 2024 source

Kirkland et al. (2024) includes a gene-expression network figure highlighting key inflammatory/signaling nodes (e.g., STAT1, TNF-α, IL-6, IRF1) relevant to the immune programs discussed above (kirkland2024thehostresponse media b6399fc9).

13) URLs and publication dates (for key 2023–2024 sources used)

Kirkland et al. “The Host Response to Coccidioidomycosis” (Journal of Fungi), Feb 2024, https://doi.org/10.3390/jof10030173 (kirkland2024thehostresponsea pages 9-10)
Hsu “The Known and Unknown ‘Knowns’ of Human Susceptibility to Coccidioidomycosis” (Journal of Fungi), Mar 2024, https://doi.org/10.3390/jof10040256 (hsu2024theknownand pages 1-2)
Jackson et al. “From soil to clinic: current advances in understanding Coccidioides and coccidioidomycosis” (Microbiology and Molecular Biology Reviews), Dec 2024, https://doi.org/10.1128/mmbr.00161-23 (jackson2024fromsoilto pages 8-9)
Fayed et al. “Overview of the Current Challenges in Pulmonary Coccidioidomycosis” (Journal of Fungi), Oct 2024, https://doi.org/10.3390/jof10100724 (fayed2024overviewofthea pages 1-2)
Lim et al. “Clinical Characteristics and Mortality Risks… Critically Ill” (Open Forum Infectious Diseases), Aug 2024, https://doi.org/10.1093/ofid/ofae454 (lim2024clinicalcharacteristicsand pages 1-2)
Benedict et al. “Testing for Blastomycosis, Coccidioidomycosis, and Histoplasmosis… 2019–2024” (Open Forum Infectious Diseases), Aug 2024, https://doi.org/10.1093/ofid/ofae448 (benedict2024testingforblastomycosis pages 1-2)
Miranda & Hoyer “Coccidioidomycosis Granulomas Informed by Other Diseases” (Journal of Fungi), Jun 2023, https://doi.org/10.3390/jof9060650 (miranda2023coccidioidomycosisgranulomasinformed pages 7-10)

Notes on PMIDs

The retrieved full-text excerpts did not expose PubMed identifiers (PMIDs) for most mechanistic claims. Where PMIDs are required for a downstream knowledge base, the DOIs above provide a reliable route to PubMed records; however, I did not extract PMIDs directly from the available evidence snippets in this run.

References

(lim2024clinicalcharacteristicsand pages 1-2): James Lim, Ashley M Scott, Rebecca Wig, Rachel V Tan, Emily R Harnois, Tirdad T Zangeneh, and Mohanad M Al-Obaidi. Clinical characteristics and mortality risks among patients with culture-proven coccidioidomycosis who are critically ill: a multicenter study in an endemic region. Open Forum Infectious Diseases, Aug 2024. URL: https://doi.org/10.1093/ofid/ofae454, doi:10.1093/ofid/ofae454. This article has 9 citations and is from a peer-reviewed journal.
(fayed2024overviewofthea pages 1-2): Mohamed A. Fayed, Timothy M. Evans, Eyad Almasri, Kathryn L. Bilello, Robert Libke, and Michael W. Peterson. Overview of the current challenges in pulmonary coccidioidomycosis. Journal of Fungi, 10:724, Oct 2024. URL: https://doi.org/10.3390/jof10100724, doi:10.3390/jof10100724. This article has 4 citations.
(hsu2024theknownand pages 2-4): Amy P. Hsu. The known and unknown “knowns” of human susceptibility to coccidioidomycosis. Journal of Fungi, 10:256, Mar 2024. URL: https://doi.org/10.3390/jof10040256, doi:10.3390/jof10040256. This article has 4 citations.
(miranda2023coccidioidomycosisgranulomasinformed pages 7-10): Nadia Miranda and Katrina K. Hoyer. Coccidioidomycosis granulomas informed by other diseases: advancements, gaps, and challenges. Journal of Fungi, 9:650, Jun 2023. URL: https://doi.org/10.3390/jof9060650, doi:10.3390/jof9060650. This article has 9 citations.
(jackson2024fromsoilto pages 8-9): Katrina M. Jackson, Marcus de Melo Teixeira, and Bridget M. Barker. From soil to clinic: current advances in understanding coccidioides and coccidioidomycosis. Microbiology and Molecular Biology Reviews, Dec 2024. URL: https://doi.org/10.1128/mmbr.00161-23, doi:10.1128/mmbr.00161-23. This article has 5 citations and is from a domain leading peer-reviewed journal.
(kirkland2024thehostresponse pages 14-16): TN Kirkland, CY Hung, LF Shubitz, S Beyhan, and J Fierer. The host response to coccidioidomycosis. j. fungi 2024, 10, 173. Unknown journal, 2024.
(fayed2024overviewofthea pages 2-6): Mohamed A. Fayed, Timothy M. Evans, Eyad Almasri, Kathryn L. Bilello, Robert Libke, and Michael W. Peterson. Overview of the current challenges in pulmonary coccidioidomycosis. Journal of Fungi, 10:724, Oct 2024. URL: https://doi.org/10.3390/jof10100724, doi:10.3390/jof10100724. This article has 4 citations.
(hsu2024theknownand pages 1-2): Amy P. Hsu. The known and unknown “knowns” of human susceptibility to coccidioidomycosis. Journal of Fungi, 10:256, Mar 2024. URL: https://doi.org/10.3390/jof10040256, doi:10.3390/jof10040256. This article has 4 citations.
(kirkland2024thehostresponsea pages 9-10): Theo N. Kirkland, Chiung-Yu Hung, Lisa F. Shubitz, Sinem Beyhan, and Joshua Fierer. The host response to coccidioidomycosis. Journal of Fungi, 10:173, Feb 2024. URL: https://doi.org/10.3390/jof10030173, doi:10.3390/jof10030173. This article has 5 citations.
(kirkland2024thehostresponsea pages 4-5): Theo N. Kirkland, Chiung-Yu Hung, Lisa F. Shubitz, Sinem Beyhan, and Joshua Fierer. The host response to coccidioidomycosis. Journal of Fungi, 10:173, Feb 2024. URL: https://doi.org/10.3390/jof10030173, doi:10.3390/jof10030173. This article has 5 citations.
(kirkland2024thehostresponse pages 9-10): TN Kirkland, CY Hung, LF Shubitz, S Beyhan, and J Fierer. The host response to coccidioidomycosis. j. fungi 2024, 10, 173. Unknown journal, 2024.
(kirkland2024thehostresponse pages 4-5): TN Kirkland, CY Hung, LF Shubitz, S Beyhan, and J Fierer. The host response to coccidioidomycosis. j. fungi 2024, 10, 173. Unknown journal, 2024.
(hsu2024theknownand pages 18-20): Amy P. Hsu. The known and unknown “knowns” of human susceptibility to coccidioidomycosis. Journal of Fungi, 10:256, Mar 2024. URL: https://doi.org/10.3390/jof10040256, doi:10.3390/jof10040256. This article has 4 citations.
(kirkland2024thehostresponseb pages 9-10): TN Kirkland, CY Hung, LF Shubitz, S Beyhan, and J Fierer. The host response to coccidioidomycosis. j. fungi 2024, 10, 173. Unknown journal, 2024.
(fayed2024overviewofthe pages 2-6): MA Fayed, TM Evans, E Almasri, KL Bilello, and R Libke. Overview of the current challenges in pulmonary coccidioidomycosis. j. fungi 2024, 10, 724. Unknown journal, 2024.
(fayed2024overviewofthea pages 13-15): Mohamed A. Fayed, Timothy M. Evans, Eyad Almasri, Kathryn L. Bilello, Robert Libke, and Michael W. Peterson. Overview of the current challenges in pulmonary coccidioidomycosis. Journal of Fungi, 10:724, Oct 2024. URL: https://doi.org/10.3390/jof10100724, doi:10.3390/jof10100724. This article has 4 citations.
(fayed2024overviewofthe pages 13-15): MA Fayed, TM Evans, E Almasri, KL Bilello, and R Libke. Overview of the current challenges in pulmonary coccidioidomycosis. j. fungi 2024, 10, 724. Unknown journal, 2024.
(fayed2024overviewofthea pages 15-17): Mohamed A. Fayed, Timothy M. Evans, Eyad Almasri, Kathryn L. Bilello, Robert Libke, and Michael W. Peterson. Overview of the current challenges in pulmonary coccidioidomycosis. Journal of Fungi, 10:724, Oct 2024. URL: https://doi.org/10.3390/jof10100724, doi:10.3390/jof10100724. This article has 4 citations.
(fayed2024overviewofthe pages 15-17): MA Fayed, TM Evans, E Almasri, KL Bilello, and R Libke. Overview of the current challenges in pulmonary coccidioidomycosis. j. fungi 2024, 10, 724. Unknown journal, 2024.
(benedict2024testingforblastomycosis pages 1-2): Kaitlin Benedict, Samantha L Williams, Dallas J Smith, Mark D Lindsley, Shawn R Lockhart, and Mitsuru Toda. Testing for blastomycosis, coccidioidomycosis, and histoplasmosis at a major commercial laboratory, united states, 2019-2024. Open forum infectious diseases, 11 8:ofae448, Aug 2024. URL: https://doi.org/10.1093/ofid/ofae448, doi:10.1093/ofid/ofae448. This article has 4 citations and is from a peer-reviewed journal.
(benedict2024testingforblastomycosis pages 2-3): Kaitlin Benedict, Samantha L Williams, Dallas J Smith, Mark D Lindsley, Shawn R Lockhart, and Mitsuru Toda. Testing for blastomycosis, coccidioidomycosis, and histoplasmosis at a major commercial laboratory, united states, 2019-2024. Open forum infectious diseases, 11 8:ofae448, Aug 2024. URL: https://doi.org/10.1093/ofid/ofae448, doi:10.1093/ofid/ofae448. This article has 4 citations and is from a peer-reviewed journal.
(kirkland2024thehostresponse media b6399fc9): Theo N. Kirkland, Chiung-Yu Hung, Lisa F. Shubitz, Sinem Beyhan, and Joshua Fierer. The host response to coccidioidomycosis. Journal of Fungi, 10:173, Feb 2024. URL: https://doi.org/10.3390/jof10030173, doi:10.3390/jof10030173. This article has 5 citations.

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OpenScientist Report

Classifications

Mappings

Definitions

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Epidemiology

Infectious Agent

Related Datasets

Clinical Trials

Animal Models

Source YAML

References & Deep Research

Deep Research

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format

Disease Pathophysiology Research Report: Coccidioidomycosis (Valley fever)

Target disease metadata

1) Key concepts & definitions (current understanding)

1.1 Core definition and clinical spectrum

1.2 Central pathophysiology concept: host–pathogen interaction shaped by fungal morphogenesis and immune polarization

2) Core pathophysiology (molecular & cellular mechanisms)

2.1 Initiation: inhalation and morphogenesis in the lung

2.2 Innate sensing and early immune programming

2.3 Adaptive immunity: Th1/Th17 dominance and cytokine axes

2.4 Granuloma biology: containment versus breakdown

2.5 Immune evasion and immunopathology drivers

3) Key molecular players (host + fungal), cell types, tissues, chemicals

3.1 Host genes/proteins implicated in susceptibility and protection (HGNC)

3.2 Fungal determinants

3.3 Key cell types (CL) and anatomical sites (UBERON)

3.4 Chemical entities (CHEBI) and relevant small molecules/drugs

4) Biological processes disrupted (GO-oriented)

5) Cellular components (where key processes occur)

6) Disease progression model (sequence of events)

7) Phenotypic manifestations (HP-oriented) and mechanistic links

8) Recent developments and latest research (prioritize 2023–2024)

8.1 Human genetics and “experiments of nature”

8.2 Granuloma microenvironment and cellular ecology

8.3 Vaccine-relevant advances

9) Current applications and real-world implementations (2024 emphasis)

9.1 Diagnostics and testing: current practice and performance

9.2 Severe disease management context: ICU outcomes

10) Relevant statistics and data (recent sources)

11) Expert opinions and authoritative analysis (2023–2024)

12) Knowledge-base-ready annotations (evidence-linked)

12.1 Pathophysiology description (narrative)

12.2 Evidence-linked mechanism summary

12.3 Visual evidence from a 2024 source

13) URLs and publication dates (for key 2023–2024 sources used)

Notes on PMIDs