🏷

Classifications

Harrison's Chapter

🔗

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.

⚙

Pathophysiology

4

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 link neutrophil link dendritic cell link

innate immune response link

lung link

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.

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 link dendritic cell link

pattern recognition receptor signaling pathway link cytokine production link

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.

T-helper 1 cell link T-helper 17 cell link CD4-positive, alpha-beta T cell link macrophage link

T-helper 1 type immune response link T-helper 17 type immune response link

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.

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 link

granuloma formation link

Show evidence (2 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.

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Phenotypes

14

Blood 1

Granulomatosis 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 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 Human Clinical

"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 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 Osteomyelitis (HP:0002754)

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

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)."

Musculoskeletal disease, including osteomyelitis, is documented as a form of extrapulmonary dissemination.

Metabolism 1

Fever VERY_FREQUENT Fever (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 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 Cough (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 Hemoptysis (HP:0002105)

May occur with cavitary pulmonary disease.

Show evidence (1 reference)

PMID:37233271 SUPPORT Human Clinical

"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 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 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 Fatigue (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 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 Arthralgia (HP:0002829)

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

Show evidence (1 reference)

PMID:38196429 SUPPORT Human Clinical

"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 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.

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Genetic Associations

5

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

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)

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)

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)

Show evidence (2 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.

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

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.

💊

Treatments

3

Fluconazole

Action: fluconazole therapy Ontology label: pharmacotherapy MAXO:0000058

Agent: fluconazole ↗

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 MAXO:0000058

Agent: itraconazole ↗

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 MAXO:0000058

Agent: amphotericin B ↗

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

1

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, dust storms, or agricultural activities releases arthroconidia into the air. 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.

🔬

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 ↗ Dyspnea ↗

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 ↗

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.

📚

Literature Summaries

1

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.

{ }

Source YAML

click to show

name: Coccidioidomycosis
creation_date: "2026-03-07T00:00:00Z"
updated_date: "2026-03-08T12:00:00Z"
synonyms:
- Valley Fever
- San Joaquin Valley Fever
- Desert Rheumatism
- Coccidioides infection
categories:
- Infectious Disease
- Fungal Disease
disease_term:
  preferred_term: coccidioidomycosis
  term:
    id: MONDO:0005706
    label: coccidioidomycosis
classifications:
  harrisons_chapter:
  - classification_value: infectious disease
    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.
  - classification_value: fungal infectious disease
    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: 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.
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.
pathophysiology:
- name: Arthroconidia inhalation and spherule morphogenesis
  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.
- name: Innate immune recognition via pattern recognition receptors
  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.
  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.
- name: Th1/Th17 cell-mediated adaptive immunity
  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.
  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
  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.
- name: Granuloma formation and containment
  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.
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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: HUMAN_CLINICAL
    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: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: Musculoskeletal disease, including osteomyelitis, is documented as a form of extrapulmonary dissemination.
- 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
  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
  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
  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.
  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
  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.
  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.
- name: 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).
  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
  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, dust storms, or agricultural activities releases arthroconidia into the air.
    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.
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
  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: MAXO:0000058
      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
  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: MAXO:0000058
      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
  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: MAXO:0000058
      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
    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
    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: