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Coccidioides immitis

Coccidioides immitis is a soil-dwelling, dimorphic fungus belonging to the Ascomycota phylum, Onygenales order, that causes coccidioidomycosis, commonly known as Valley fever, in humans and other mammals.^[1] This pathogen exists in two morphological forms: as septate hyphae producing infectious arthroconidia in the environment and as large spherules filled with endospores in the host.^[2] Endemic primarily to arid and semi-arid regions of the southwestern United States, particularly California, it thrives in alkaline desert soils and is responsible for an estimated 350,000 infections annually in the U.S., though most are asymptomatic. As of 2025, estimates suggest 206,000–360,000 annual infections in the U.S., with reported cases reaching over 21,000 in 2023.^[3]^[4]^[2] The life cycle of C. immitis begins in the soil, where it grows as a mold under environmental conditions, fragmenting into barrel-shaped arthroconidia (2–4 µm in size) that become airborne when soil is disturbed by wind, construction, or earthquakes.^[1] Upon inhalation by a susceptible host, these arthroconidia evade alveolar macrophages and differentiate into spherules (30–80 µm in diameter) within 48–72 hours at 37°C, which mature and rupture to release hundreds of endospores, perpetuating the infection.^[2] This dimorphic transition is a key virulence factor, enabling the fungus to evade immune responses and disseminate in about 1% of cases, particularly in immunocompromised individuals or certain ethnic groups like Filipinos and African Americans.^[1] Climate change and expanding human activity in endemic areas have contributed to a 10-fold increase in reported cases from 1998 to 2019.^[3] Clinically, Valley fever presents as an acute respiratory illness in 40% of infected individuals, with symptoms including fever, cough, fatigue, chest pain, and sometimes erythema nodosum or multiforme rash appearing 1–3 weeks post-exposure.^[2] Disseminated disease can involve skin, bones, joints, meninges, or other organs, leading to chronic complications, and is more frequent in the elderly or those with comorbidities like diabetes or HIV.^[3] Diagnosis relies on serologic tests, culture, or histopathology showing spherules, while treatment involves antifungal agents like fluconazole for severe or disseminated cases.^[2] C. immitis is genetically distinct from its sister species C. posadasii, which predominates outside California, but both cause indistinguishable disease and share similar ecology.^[1] Ongoing research focuses on vaccines, such as the promising Δcps1 candidate, which has shown efficacy in animal models and is advancing toward clinical trials as of 2025.^[3]^[5]

Taxonomy and nomenclature

Classification

Coccidioides immitis is classified within the kingdom Fungi, division Ascomycota, class Eurotiomycetes, order Onygenales, family Onygenaceae, genus Coccidioides, and species C. immitis.^[6] This species belongs to the order Onygenales, which encompasses various human and animal pathogens, including dermatophytes such as Trichophyton spp. and dimorphic fungi like Histoplasma capsulatum and Blastomyces dermatitidis.^[7] Phylogenetically, C. immitis is closely related to Coccidioides posadasii, its sibling species, with which it shares over 98% sequence identity in homologous nonrepetitive genomic regions and approximately 93.5% overall homology in aligned sequences.^[7] The genetic distinction between C. immitis and C. posadasii was established through multilocus sequence analysis of single nucleotide polymorphisms, microsatellites, and housekeeping genes, revealing a divergence of about 1-2% in coding regions and an estimated speciation event around 5 million years ago.^[7]^[8] The species was originally described in 1896 by Emmet Rixford and Thomas Caspar Gilchrist, based on a type specimen isolated from human subcutaneous tissue in a case of infection observed in San Francisco, California.^[9]

Etymology and synonyms

The genus name Coccidioides derives from the Greek words kokkis (little berry) and eidos (resembling), reflecting the berry-like appearance of the spherules produced by the organism, which initially led to its mistaken classification as a protozoan resembling members of the Coccidia.^[10] The specific epithet immitis comes from the Latin immītis, meaning harsh or unrelenting, alluding to the severe clinical manifestations of the disease it causes.^[10] The organism was first described in 1892 by Argentine medical student Alejandro Posadas, who observed granulomatous lesions in a patient and interpreted the causative agent as a coccidian protozoan, naming the condition "mycosis fungoides granulomatosa."^[11] In 1896, American physicians Ernest Rixford and Thomas C. Gilchrist reported similar cases in California and formally named the pathogen Coccidioides immitis, continuing to regard it as a protozoan based on its morphological features.^[10] However, in 1900, pathologist William Ophüls and colleague H.C. Moffitt reclassified C. immitis as a fungus after culturing it and observing mycelial growth, marking a pivotal shift in understanding its nature. Historical synonyms include Zymonema immitis, proposed by C.W. Stiles in 1897 based on early misinterpretations of its hyphal structures, and Mycoderma immite, a variant reflecting similar taxonomic confusion in the early 20th century.^[12] Additionally, populations outside California were long subsumed under C. immitis until 2002, when molecular analyses distinguished Coccidioides posadasii as a separate species, honoring Posadas for his initial discovery; this split clarified genetic and geographic distinctions without altering the core nomenclature of the California-endemic C. immitis.

Morphology

Saprophytic phase

In its saprophytic phase, Coccidioides immitis exists as a filamentous mold in the soil environment, characterized by extensive mycelial growth. The mycelium consists of septate hyphae that are typically 2–7 μm in diameter and branch at right angles, forming a network that facilitates nutrient absorption and expansion in arid, alkaline soils.^[13] When cultured on laboratory media such as Sabouraud dextrose agar, these hyphae produce white to buff, cottony colonies that develop a suede-like or floccose aerial mycelium within 3–7 days.^[14] Arthroconidia, the primary reproductive and dispersal structures in this phase, form through the fragmentation of mature hyphae. These barrel-shaped arthroconidia measure approximately 3–5 μm in length by 2–4 μm in width and alternate with thinner, empty disjunctor cells that undergo autolysis to enable separation and aerosolization.^[15]^[16] The disjunctor cells provide structural weakness, allowing the thick-walled, multinucleate arthroconidia to break off easily and serve as the infectious propagules that can remain viable in dry conditions for extended periods.^[17] Growth in the saprophytic phase occurs optimally at temperatures of 25–30°C on nutrient-rich media, supporting rapid mycelial extension and arthroconidia production in low-humidity, high-salinity environments.^[18] The transition to the parasitic phase is initiated by environmental cues mimicking host conditions, such as a shift to 37°C and elevated CO₂ levels (5–20%), which inhibit hyphal growth and promote spherule formation.^[1]

Parasitic phase

In the parasitic phase, Coccidioides immitis undergoes a dimorphic transformation within mammalian hosts, converting from inhaled arthroconidia—barrel-shaped spores produced in the saprophytic phase—into specialized tissue-invasive structures known as spherules.^[19] This shift occurs rapidly in vivo, with arthroconidia enlarging and developing into immature spherules within 24 hours of inhalation.^[19] Spherules are large, round structures measuring 20–100 μm in diameter, characterized by a thick double-walled envelope that encapsulates numerous endospores.^[19]^[20] The endospores, typically 2–5 μm in size, form through successive septation and cleavage of the spherule's protoplasm, filling the mature spherule without reversion to a hyphal form.^[19]^[20] Upon maturation, typically 4–5 days post-infection, the spherule ruptures, releasing 200–300 endospores into surrounding tissues, each capable of initiating a new spherule and perpetuating the infection.^[19] This dimorphism can be replicated in laboratory models by incubating arthroconidia at 37°C in an atmosphere enriched with 5–20% CO₂, mimicking host conditions and inducing spherule formation without mycelial growth.^[1]^[21]

Life cycle

Environmental reproduction

Coccidioides immitis primarily reproduces asexually in its environmental phase through the formation of arthroconidia, which are barrel-shaped, thick-walled spores produced by the fragmentation of hyphae within the soil mycelium.^[15] This process occurs without a known sexual cycle in nature, although population genetic analyses of mating type loci (MAT1-1 and MAT1-2) reveal a balanced distribution and evidence of recombination, suggesting rare meiotic events that contribute to genetic diversity.^[22] The absence of observed sexual structures underscores the dominance of this asexual mechanism for propagation in arid ecosystems. In the soil, the reproductive cycle is tightly linked to environmental cues, beginning with hyphal growth stimulated by increased moisture and nutrient availability following rainfall, particularly during winter and spring seasons.^[23] These septate hyphae extend and segment into chains of arthroconidia, alternating with empty disjunctor cells that facilitate separation.^[15] As conditions shift to dry, warm weather—often accompanied by wind— the mature arthroconidia detach and become airborne through soil disturbance, enabling dispersal over wide areas.^[24] Arthroconidia exhibit remarkable survival adaptations, remaining viable for months to years in desiccated soil and dust, which allows persistence through prolonged droughts.^[15] Their thick, multinucleated walls provide resistance to ultraviolet radiation and extreme desiccation, protecting the spores until favorable rehydration occurs for germination into new mycelia.^[25] This resilience ensures the fungus's endurance in harsh, alkaline semiarid soils.^[15]

Host infection process

Upon inhalation into the mammalian host, the arthroconidia of Coccidioides immitis rapidly undergo a dimorphic transformation in the warm, moist environment of the lung tissue, enlarging to form immature spherules within 48 to 72 hours.^[26] This initial development involves free nuclear division within the swelling arthroconidia, which evolve into rounded, multinucleated structures up to 80 µm in diameter, marking the shift to the parasitic phase.^[26]^[25] As spherules mature over 4 to 5 days (approximately 72 to 120 hours), they fill with hundreds to thousands of endospores through repeated internal divisions, eventually rupturing to release these smaller propagules (2–5 µm) into surrounding lung tissue.^[25]^[26] The released endospores infect adjacent cells locally, initiating new rounds of spherule formation and perpetuating the cycle without initial dissemination through the bloodstream.^[26]^[27] In immunocompetent hosts, this localized replication can be contained through granuloma formation, where immune cells wall off the infection site in the lungs to limit fungal spread.^[28]^[29]

Ecology and habitat

Geographic distribution

Coccidioides immitis is primarily endemic to the southwestern United States, with its core distribution centered in California, particularly the San Joaquin Valley.^[30] Within California, C. immitis is predominantly found west of the Tehachapi Mountains, distinguishing its range from broader areas occupied by related species.^[31] In 2002, genetic analyses revealed significant DNA polymorphisms that led to the speciation of the genus Coccidioides into two distinct species: C. immitis and C. posadasii. C. immitis represents the California population, with a relatively restricted biogeographic range compared to C. posadasii, which predominates in Arizona, Texas, New Mexico, and extends into Central and South America.^[30] This split was formalized based on phylogenetic evidence from multiple loci, confirming reproductive isolation between the two species dating back approximately 11-12 million years. Recent trends indicate an expansion of C. immitis beyond its traditional endemic zones, driven by climate change, which has created more favorable arid conditions as of 2024, as well as human activities like construction that disturb soil and aerosolize spores.^[32] For example, C. immitis has been isolated from soils in Washington State during the 2010–2011 outbreak, confirming local presence outside traditional ranges.^[33] In California, incidence rates in endemic regions have surged fivefold from 2001 to 2021, underscoring the role of environmental shifts in altering distribution patterns.^[34]

Soil and environmental factors

Coccidioides immitis thrives in alkaline soils with a pH typically ranging from 7 to 8.5, which supports its saprophytic growth in arid environments.^[35] These soils are predominantly sandy loams, characterized by a texture consisting of high proportions of sand and silt with limited clay content, and they generally contain low levels of organic matter, facilitating the fungus's survival in nutrient-sparse conditions.^[32]^[36] The fungus is most commonly found at depths of 10 to 30 cm below the surface, where conditions remain stable and protected from extreme surface fluctuations.^[37] Climatically, C. immitis is adapted to arid and semi-desert regions with annual rainfall between 10 and 50 cm, where precipitation patterns play a critical role in its lifecycle.^[38] Growth of the fungus peaks following winter and spring rains, which provide the necessary moisture for hyphal development in the soil, while subsequent dry summer conditions promote the formation and wind dispersal of arthroconidia.^[39] Optimal soil temperatures for growth range from 25°C to 35°C, aligning with the warm conditions of these habitats during active periods.^[40] In its natural habitat, C. immitis shows strong associations with biotic factors, including rodent burrows, which provide microenvironments enriched for fungal proliferation.^[41] It is frequently isolated near native vegetation such as creosote bush (Larrea tridentata), where soil disturbances enhance spore viability.^[41] Additionally, the presence of C. immitis correlates with higher soil microbial diversity, particularly fungal communities, suggesting interactions that may influence its distribution and persistence.^[42]

Epidemiology

Incidence and prevalence

Coccidioidomycosis, caused by Coccidioides immitis and related species, primarily affects the southwestern United States, where an estimated 150,000 to 350,000 infections occur annually, though only about 20,000 cases are reported through national surveillance each year.^[4]^[43] Approximately 60% of infections are asymptomatic, meaning the true burden is significantly underreported as many cases resolve without medical attention.^[44] In 2023, Arizona reported the highest number of cases among U.S. states, with 10,990 confirmed infections, underscoring its status as a key endemic hotspot.^[45] The disease exhibits marked seasonality, with incidence peaking from October to March, coinciding with the drying of soils following seasonal rains that promote fungal growth in the environment.^[46] Outbreaks are often triggered by environmental disturbances such as dust storms, which aerosolize fungal spores, or seismic events like earthquakes; for instance, the 1994 Northridge earthquake in California led to over 200 outbreak-associated cases and three fatalities in Ventura County due to dust from landslides.^[47]^[48] Incidence trends show a marked increase over recent decades, attributed to factors including climate change, which enhances spore dispersal through prolonged droughts followed by heavy rains, and population growth in endemic regions. In California, reported cases rose nearly 800% from 2000 (2.4 per 100,000 population) to 2018 (18.8 per 100,000), and continued to climb to a record nearly 12,500 cases in 2024 (as of 2024); Arizona reported over 14,000 cases in 2024, the highest in 13 years (as of 2024).^[49]^[50]^[51] Provisional data indicate over 5,500 cases in California through the first six months of 2025 (as of August 2025).^[50] Additionally, cases in non-endemic areas have emerged due to travel from endemic zones or fomite transmission, contributing to sporadic outbreaks beyond traditional boundaries.^[32]

Risk factors and transmission

Coccidioides immitis, the causative agent of coccidioidomycosis (also known as Valley fever), is primarily transmitted through inhalation of airborne arthroconidia, the infectious fungal spores released from the soil in endemic regions. These spores become aerosolized during activities that disturb dust-laden soil, such as windstorms, earthquakes, or human interventions like digging and excavation.^[2] There is no routine person-to-person transmission, though extremely rare cases have been documented via solid organ transplantation from an infected donor or transplacental maternal-fetal spread.^[52] Laboratory-acquired infections occur infrequently but are well-recognized risks for microbiology personnel handling cultures, due to accidental aerosolization or direct contact with viable arthroconidia.^[53] Fomite transmission, involving contaminated objects like clothing, shoes, or agricultural products, is also rare but has been reported in isolated incidents outside typical endemic zones.^[54] Occupational exposure significantly elevates the risk of infection in endemic areas, particularly for individuals engaged in dust-generating activities. Workers in construction, agriculture, archaeology, and military training face heightened odds, as these roles often involve soil disruption in regions like the southwestern United States. For instance, during a 2016–2017 outbreak at a solar power construction site in California, the incidence rate among workers reached 1,095 cases per 100,000 person-years, far exceeding local background rates by 4.4 to 210.6 times.^[55] Seroconversion rates among highly exposed groups, such as those near active construction sites, can approach 5–10% over a year, reflecting the direct correlation between dust exposure intensity and infection probability.^[56] Certain host characteristics predispose individuals to more severe or disseminated disease following exposure. Immunocompromised persons, including those with HIV/AIDS (especially CD4 counts below 250 cells/mm³), organ transplant recipients, or individuals on immunosuppressive therapies, exhibit substantially higher risks of progression beyond primary pulmonary infection.^[57] Racial and ethnic factors also play a role; people of Filipino or African American descent face elevated dissemination risks, potentially 10 times higher than in Caucasians, linked to genetic susceptibilities such as specific HLA types.^[58] Pregnant women, particularly in the third trimester, are at markedly increased risk for severe outcomes, with dissemination rates reported as 40–100 times higher than in non-pregnant adults due to pregnancy-associated immune modulation.^[59] Additionally, adults over 60 years of age experience higher rates of complicated or chronic disease, independent of other factors.^[60]

Pathogenesis

Inhalation and initial infection

Infection with Coccidioides immitis typically begins when airborne arthroconidia, the infectious propagules of the fungus, are inhaled from disturbed soil in endemic areas. These barrel-shaped arthroconidia measure 2–5 μm in length, a size that allows them to bypass upper respiratory defenses and deposit directly in the terminal bronchioles and alveoli.^[61]^[44] Due to their small dimensions, the arthroconidia evade effective mucociliary clearance in the proximal airways, facilitating deep lung penetration.^[62] Upon reaching the alveoli, the arthroconidia are rapidly encountered by resident immune cells, including alveolar macrophages and recruited neutrophils, which attempt to engulf them through phagocytosis.^[19] However, the fungus initiates a morphological transformation within 8–24 hours at mammalian body temperature (37°C), developing into multinucleated spherules that enlarge to 30–60 μm and resist further phagocytic killing.^[61]^[44] This early spherule formation disrupts the initial containment efforts, as the maturing structures become too large for complete engulfment by individual immune cells.^[19] The alveolar response to this initial invasion involves localized inflammation, characterized by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) from activated macrophages and epithelial cells.^[61] These cytokines promote the recruitment of additional neutrophils and monocytes to the site, amplifying the innate immune reaction.^[62] In cases of low inoculum—typically 10–50 arthroconidia—this early innate response is often sufficient to contain the infection, leading to subclinical or self-resolving primary pulmonary disease in approximately 60% of immunocompetent hosts.^[61]^[19]

Immune evasion and dissemination

_Coccidioides immitis employs several strategies to evade host immune clearance during infection. Mature spherules, measuring 30-60 μm in diameter, are too large to be phagocytosed by most immune cells such as neutrophils and macrophages, thereby avoiding early detection and destruction by the innate immune system.^[63] Upon spherule rupture, the released endospores, which are smaller (2-5 μm), express urease that generates ammonia to damage surrounding host tissues and promote fungal survival.^[64] Additionally, endospores secrete metalloproteinases like Mep1, which degrade the immunodominant spherule outer wall glycoprotein (SOWgp) on their surface, preventing recognition and opsonization by host antibodies and complement proteins.^[65] The SOWgp protein, a major cell wall component, also modulates adhesin activity and has been genetically linked to increased disease severity through its role in host cell interactions and immune modulation. Dissemination occurs primarily via hematogenous spread from the primary pulmonary site, affecting extrapulmonary sites such as the skin, bones, and meninges in less than 1% of infections overall, though rates can rise in susceptible populations.^[66] This progression is critically dependent on T-cell mediated immunity; deficiencies in CD4+ T cells, as seen in HIV/AIDS or immunosuppressive therapy, impair granuloma formation and containment, allowing endospores to breach vascular barriers and establish metastatic foci.^[44] Following initial alveolar infection by arthroconidia, these mechanisms enable the fungus to transition from localized containment to systemic spread in immunocompromised hosts.^[67] Recent transcriptomic studies as of 2024 have identified key regulators, such as the WOPR family protein Ryp1, that control gene expression during dimorphic development and contribute to virulence.^[68]

Clinical features

Primary pulmonary infection

The primary pulmonary infection represents the initial stage of coccidioidomycosis following inhalation of Coccidioides immitis arthroconidia, typically manifesting as a self-limited respiratory illness in immunocompetent individuals.^[2] This form accounts for the majority of infections, with an incubation period ranging from 7 to 21 days after exposure. Approximately 60% of infections remain asymptomatic, detected only through serologic conversion or incidental findings.^[69] Among the 40% of cases that become symptomatic, the presentation mimics influenza-like illness, characterized by fever (occurring in about 76% of patients), dry or productive cough (73%), fatigue (39%), and arthralgias or myalgias.^[70] Chest pain, dyspnea, headache, and night sweats may also occur, often prompting evaluation for community-acquired pneumonia.^[44] A distinctive feature in 20-25% of symptomatic cases, particularly in younger patients and during outbreaks, is the development of erythema nodosum or erythema multiforme, presenting as tender, red nodules on the shins or target-like lesions on extremities; these skin manifestations arise from a hypersensitivity or immune complex reaction to the fungal antigens and signify a robust cell-mediated immune response.^[71]^[72] While most primary infections resolve spontaneously, complications can arise in a subset of patients. Up to 30-40% of symptomatic individuals may develop radiographic evidence of pneumonia, with infiltrates visible on chest imaging, though severe cases requiring hospitalization are less common in otherwise healthy hosts.^[44] Residual pulmonary nodules form in approximately 5% of cases, and thin-walled cavities may develop in another 5%, often as sequelae of resolved infiltrates; these structures are usually asymptomatic but can mimic malignancy or tuberculosis on imaging.^[73] In the majority of uncomplicated cases, symptoms subside within weeks to months without residual scarring or long-term sequelae, supported by effective T-cell immunity. However, recent studies indicate that symptoms like fatigue, headache, and joint pain may persist for up to 12 months in some patients, as observed in commercially insured cohorts from 2017–2023.^[70]^[74] Certain host factors, such as immunosuppression or pregnancy, elevate the risk for progression from this localized pulmonary phase.^[2]

Extrapulmonary and disseminated forms

Extrapulmonary and disseminated forms of coccidioidomycosis represent severe progression from the initial pulmonary infection, occurring in approximately 0.5–2% of cases overall and up to 30–50% in heavily immunosuppressed individuals. These manifestations arise via hematogenous or lymphatic spread of Coccidioides immitis or C. posadasii spherules and endospores beyond the lungs, leading to chronic, multi-organ involvement that can be life-threatening without intervention.^[57] Dissemination is more frequent in high-risk groups, including those of African or Filipino descent, males, and pregnant women, often presenting months to years after primary exposure.^[66] Skin involvement occurs in about 10–15% of disseminated cases and is typically the most benign extrapulmonary site, manifesting as verrucous lesions, subcutaneous abscesses, or ulcerative nodules that may mimic other granulomatous conditions. These lesions often appear on the face, particularly the nasolabial fold, trunk, or extremities, and can become chronic and non-healing due to persistent fungal burden in the dermis.^[57] In severe instances, multiple lesions develop, reflecting widespread hematogenous seeding.^[75] Skeletal dissemination affects 20–50% of cases and commonly involves the axial skeleton, with vertebrae (especially lumbar and thoracic) being the most frequent sites, followed by the skull, ribs, and long bones. This leads to osteomyelitis characterized by lytic bone destruction, chronic pain, pathologic fractures, and potential deformity or epidural abscess formation compressing neural structures. Appendicular involvement may cause joint effusions or arthritis, contributing to long-term mobility impairment.^[76]^[77] Coccidioidal meningitis is among the most severe forms, occurring in 30–50% of disseminated infections, with basilar meninges predilection leading to hydrocephalus, cranial nerve palsies, and symptoms such as headache, vomiting, confusion, or focal neurologic deficits. Untreated, it carries nearly 100% mortality within two years, while even with treatment, 30% of patients succumb early due to complications like ventriculitis or infarction.^[57]^[78] Other extrapulmonary sites include the liver, adrenals, pericardium, and genitourinary tract, though these are less common, affecting 5–10% of disseminated cases each and often presenting with organ-specific dysfunction such as hepatosplenomegaly or adrenal insufficiency. Pregnancy markedly elevates dissemination risk, particularly in the third trimester, with reported fetal or infant mortality reaching 40% in affected cases due to transplacental spread and maternal immunosuppression.^[57]^[79]

Diagnosis

Clinical assessment

Clinical assessment of suspected coccidioidomycosis begins with a detailed history to identify potential exposure and risk factors. Patients should be questioned about recent travel or residence in endemic regions, such as the southwestern United States (including Arizona and California's San Joaquin Valley), northern Mexico, or parts of Central and South America, particularly within the preceding 1 to 3 months. Occupational or recreational activities involving soil disturbance, such as construction, agriculture, or hiking in dusty arid environments, increase the likelihood of inhalation of Coccidioides arthroconidia. Immunosuppression from conditions like HIV/AIDS, organ transplantation, diabetes, pregnancy, or use of corticosteroids or other immunomodulatory drugs is a critical risk factor for severe or disseminated disease. The typical incubation period ranges from 1 to 3 weeks after exposure, with symptoms often emerging acutely thereafter.^[44]^[80]^[2] Physical examination focuses on pulmonary and systemic signs, as primary infection primarily affects the lungs. Common findings include fever, often low-grade and persistent, accompanied by cough, dyspnea, and pleuritic chest pain. Auscultation may reveal rales or crackles indicating alveolar involvement, though the exam can be unremarkable in mild cases. Erythema nodosum, presenting as tender erythematous nodules on the anterior shins, occurs in up to 20-30% of cases and is more frequent in women, often alongside arthralgias and fever as part of the "desert rheumatism" triad, signifying a robust immune response. In disseminated forms, which affect less than 1% of immunocompetent individuals but up to 30-50% of immunocompromised patients, additional findings include peripheral lymphadenopathy, maculopapular or verrucous skin lesions, bone and joint tenderness from osteomyelitis or arthritis, and neurological deficits such as headache, meningismus, or focal signs from central nervous system involvement.^[44]^[80]^[81] Differential diagnosis for pulmonary symptoms includes community-acquired bacterial pneumonia, which may present similarly but often responds to antibiotics and lacks the exposure history. Tuberculosis should be considered in patients with chronic cough, weight loss, and cavitary lesions, particularly in endemic overlap areas, while histoplasmosis mimics the presentation in regions with shared environmental risks but typically involves Midwest river valleys. Travel or residence history in coccidioidal-endemic zones is pivotal for raising suspicion, as symptoms overlap broadly with these entities; laboratory confirmation via serology, culture, or imaging is essential to differentiate.^[44]^[80]^[2]

Laboratory and imaging techniques

Laboratory diagnosis of coccidioidomycosis caused by Coccidioides immitis relies on microbiological culture, histopathology, serology, antigen detection, and molecular methods to confirm the presence of the fungus in clinical specimens.^[2] Culture remains the gold standard for definitive identification, typically performed on respiratory specimens such as sputum or bronchoalveolar lavage fluid using Sabouraud dextrose agar or other fungal media, where colonies appear as white, cottony growth within 3-7 days at 25-30°C; however, this method carries significant biosafety risks due to aerosolization of arthroconidia, necessitating Biosafety Level 3 (BSL-3) laboratory conditions.^[82] Sensitivity of culture varies by specimen type, ranging from 44% for respiratory samples to 30% for cerebrospinal fluid, and false negatives are common in early or localized infections.^[82] Histopathological examination of tissue biopsies provides direct visualization of characteristic spherules (20-80 μm diameter) filled with endospores, best demonstrated using Gomori methenamine silver (GMS), periodic acid-Schiff (PAS), or hematoxylin and eosin (H&E) stains; this approach has a sensitivity ranging from 23% to 84% depending on the specimen type, staining method, and infection stage but requires invasive procedures and can be mimicked by other fungi.^[44]^[83] Serologic testing is the most commonly used initial diagnostic tool, detecting IgM antibodies (indicating acute infection) via tube precipitin or enzyme immunoassay (EIA) methods and IgG antibodies (indicating chronic or disseminated disease) via complement fixation (CF) or immunodiffusion (ID); EIA sensitivity for IgM is 59-88% with specificity of 68-96%, while CF titers greater than 1:16 often correlate with dissemination and poor prognosis.^[83]^[82] Confirmatory testing with ID or CF is recommended following positive EIA to reduce false positives, and repeat serology after 2-6 weeks is advised if initial results are negative but clinical suspicion persists.^[83] Antigen detection assays, available in serum, urine, and CSF, offer another non-invasive option with sensitivity of 51%–73% and high specificity, though they may cross-react with other dimorphic fungi; they are particularly useful for immunocompromised patients and monitoring coccidioidal meningitis.^[83]^[24] Molecular diagnostics, particularly polymerase chain reaction (PCR), offer rapid detection of C. immitis DNA in respiratory or tissue specimens, with FDA-approved assays showing sensitivity of 56-75% and specificity of 99-100%; these are particularly useful in immunocompromised patients or when culture is inconclusive, though availability may be limited.^[2]^[82] Imaging techniques support diagnosis by revealing characteristic patterns of pulmonary and extrapulmonary involvement, though they are nonspecific and must be correlated with laboratory findings. Chest radiography typically shows unilateral infiltrates, hilar lymphadenopathy, or thin-walled cavities in primary pulmonary infection, with cavities occurring in up to 8% of adult cases and often resolving spontaneously.^[44] Computed tomography (CT) of the chest enhances detection of subtle nodules, ground-glass opacities, or tree-in-bud patterns in acute disease and is preferred for evaluating persistent cavities or miliary dissemination in chronic or disseminated forms.^[57] For extrapulmonary manifestations, such as meningitis in disseminated disease, magnetic resonance imaging (MRI) demonstrates basal meningeal enhancement, hydrocephalus, or vasculitis with leptomeningeal thickening, aiding in early identification of central nervous system involvement.^[44]

Treatment

Pharmacological options

The primary pharmacological options for treating infections caused by Coccidioides immitis (coccidioidomycosis) consist of azole antifungals and polyene agents, with selection guided by disease severity, site of involvement, and patient factors.^[84] Azoles, such as fluconazole and itraconazole, are fungistatic agents that inhibit the fungal enzyme 14-α-demethylase, disrupting ergosterol biosynthesis in the cell membrane and thereby inhibiting fungal growth. Fluconazole serves as the first-line therapy for mild-to-moderate pulmonary and nonmeningeal disseminated disease due to its excellent oral bioavailability, safety profile, and cerebrospinal fluid (CSF) penetration of approximately 70-90%.^[84] The recommended dosage is 400 mg daily orally, though higher doses (up to 800-1200 mg daily) may be used for meningitis or refractory cases to achieve therapeutic levels.^[84] Itraconazole is an alternative first-line azole for mild-to-moderate pulmonary infections, administered at 200 mg twice daily orally, offering broad-spectrum activity against dimorphic fungi but with variable absorption requiring therapeutic monitoring.^[84] For refractory or severe nonmeningeal disease, triazole derivatives like voriconazole (200-400 mg every 12 hours orally or IV) or posaconazole (400 mg every 12 hours orally as suspension) are employed, providing enhanced potency against resistant strains through stronger inhibition of ergosterol synthesis.^[84] Amphotericin B, a polyene antifungal, is reserved for severe, rapidly progressive, or disseminated coccidioidomycosis, including meningitis unresponsive to azoles, due to its fungicidal activity.^[84] It binds to ergosterol in the fungal cell membrane, forming pores that increase permeability, leading to ion leakage and cell death. Lipid formulations, such as liposomal amphotericin B or amphotericin B lipid complex, are preferred over conventional deoxycholate to minimize nephrotoxicity, administered intravenously at 3-5 mg/kg daily for initial therapy in hospitalized patients with severe disease.^[85] These formulations are particularly indicated for disseminated infections involving bone, joints, or meninges, where they provide high tissue concentrations and are transitioned to oral azoles once the patient stabilizes.^[84] Intrathecal administration of conventional amphotericin B (starting at 0.025-0.1 mg, increasing gradually) may be added for refractory meningitis, though this route carries risks of arachnoiditis.^[84] Other agents play limited roles in coccidioidomycosis management. Echinocandins, such as caspofungin, micafungin, and anidulafungin, inhibit β-1,3-glucan synthase to disrupt fungal cell wall integrity but demonstrate limited efficacy against C. immitis due to poor in vitro and in vivo activity, particularly against the tissue-invasive spherule form.^[57] They are not recommended as monotherapy and are rarely used even in combination for salvage therapy. Terbinafine, an allylamine that inhibits squalene epoxidase to deplete ergosterol precursors, has shown some activity in experimental models of coccidioidal meningitis and may be considered adjunctively with azoles in refractory disseminated cases, though clinical evidence in humans remains anecdotal and it is not a standard option.^[86] Investigigational antifungals, such as the orotomide olorofim, which inhibits fungal pyrimidine biosynthesis, have demonstrated potent in vitro and in vivo activity against C. immitis, including azole-resistant strains, and have been used successfully in limited cases of refractory disseminated and central nervous system disease as of 2025.^[24] Overall, therapy duration varies by response and site but is addressed in separate guidelines.^[84]

Therapy guidelines and outcomes

The Infectious Diseases Society of America (IDSA) 2016 clinical practice guidelines recommend antifungal therapy for most symptomatic cases of coccidioidomycosis, with azole agents such as fluconazole (400–800 mg daily) or itraconazole (200 mg twice to three times daily) as first-line options for primary pulmonary infections in non-pregnant adults.^[84] Therapy duration is typically at least 3–6 months or until clinical, radiographic, and serologic resolution, extended longer for high-risk patients including those with diabetes, immunosuppression, or extensive disease.^[84] For disseminated non-meningeal infections, initial induction with lipid-formulated amphotericin B (0.5–1.5 mg/kg daily) may be used in severe cases, followed by oral azoles for 12 months or more after apparent cure.^[84] Coccidioidal meningitis requires lifelong azole suppression, often starting with high-dose fluconazole (up to 1200 mg daily) after initial amphotericin B induction if needed, due to high relapse rates upon discontinuation.^[84] Monitoring during therapy involves serial serologic testing (e.g., complement fixation titers every 3–6 months) to assess response and detect relapse, alongside chest imaging for pulmonary cases and cerebrospinal fluid analysis for meningitis.^[84] Therapeutic drug monitoring is advised for itraconazole to maintain trough levels of 1–2 mcg/mL, while fluconazole levels are less routinely checked due to its favorable pharmacokinetics.^[84] Patients should be screened regularly for adverse effects, including hepatotoxicity (via liver function tests every 1–3 months), QT prolongation (ECG monitoring for azoles), and skin rashes or gastrointestinal upset.^[84] With appropriate therapy, primary pulmonary coccidioidomycosis achieves cure rates exceeding 90% in immunocompetent individuals, often resolving without sequelae.^[69] Disseminated disease responds in 70–80% of cases with prolonged azole therapy, though relapse occurs in up to 25% upon early cessation.^[84] Mortality remains low at approximately 0.07% for primary infections but can reach 20–70% for disseminated forms, particularly up to 70% in immunocompromised patients. For coccidioidal meningitis, untreated cases approach 100% fatality, but treatment reduces it to 20–40%.^[69] Annual treatment costs range from $5,000 to $20,000, driven by prolonged azole use and monitoring.^[85]

Prevention

Environmental and public health measures

Environmental and public health measures for coccidioidomycosis focus on mitigating the spread of Coccidioides immitis spores through dust in endemic regions, primarily in the southwestern United States. Dust control strategies are implemented during construction and land disturbance activities to reduce airborne spore dispersal. In California, public health guidelines require developers to submit dust control plans that include soil wetting with water or stabilizers, paving of access roads, and application of gravel or vegetation covers to disturbed areas, aiming to suppress dust generation by at least 70% coverage.^[87] Similarly, in Arizona's endemic zones, vegetation barriers such as native plantings or re-vegetation efforts are promoted to stabilize soils and prevent wind erosion, particularly around high-risk sites like prisons and construction zones.^[87]^[88] Public health surveillance plays a critical role in monitoring and responding to coccidioidomycosis incidence. In the United States, the disease is a nationally notifiable disease, reportable in 28 states and the District of Columbia as of 2025, with data collected via the CDC's National Notifiable Diseases Surveillance System to track cases and identify trends.^[43]^[4]^[89] Enhanced surveillance includes annual serologic testing in high-risk populations, such as inmates in Arizona prisons, where exposure rates are elevated due to outdoor labor and soil disturbance.^[90] These efforts enable early detection of clusters and inform resource allocation in areas like Maricopa County, Arizona, where incidence exceeds 100 cases per 100,000 population annually.^[54] With rising cases linked to climate change, additional measures like advanced dust monitoring and community education programs are being integrated into prevention efforts.^[43] Outbreak response protocols are activated following environmental events that aerosolize spores, such as earthquakes. After the 1994 Northridge earthquake in California, public health authorities implemented intensified monitoring, including serologic screening of exposed residents and healthcare workers, leading to the identification of over 200 cases linked to dust from landslides.^[91]^[92] In response to such outbreaks, antifungal prophylaxis with fluconazole (typically 400 mg daily for 6 weeks) is recommended for heavily exposed groups, such as first responders or community members in dust-affected areas, to prevent primary infection.^[93]^[94] This approach, combined with public advisories on avoiding disturbed sites, has been effective in limiting dissemination in post-event scenarios.^[95]

Personal protective strategies

Individuals at risk for coccidioidomycosis, caused by Coccidioides immitis, can reduce inhalation of fungal spores through appropriate personal protective equipment (PPE) during high-exposure activities. The use of N95 respirators or higher-rated masks is recommended for dusty outdoor tasks such as construction, excavation, or gardening in endemic areas, as these filters effectively capture airborne particles containing the fungus.^[60] Fit-tested half-mask respirators can reduce exposure by approximately 90%, though some faceseal leakage may occur.^[96] Additionally, avoiding outdoor work during windy, dry seasons—when spore dispersal is highest—helps minimize risk.^[97] Behavioral modifications further protect vulnerable individuals from infection. Staying indoors during dust storms and keeping windows closed prevents spore entry into living spaces, while using HEPA air filtration indoors can capture any residual particles.^[60] Immunocompromised persons, such as those with HIV or on immunosuppressive therapy, should limit non-essential travel to endemic regions like the southwestern United States to avoid unnecessary exposure.^[80] For high-risk individuals following potential heavy exposure, such as archeologists or laboratory workers, post-exposure serologic testing for IgM and IgG antibodies is advised to detect early infection, typically 1-3 weeks after exposure.^[93] Prophylactic antifungal therapy with azoles, such as fluconazole, may be considered for severely immunocompromised patients in endemic zones, particularly solid organ transplant recipients. Short-term prophylaxis (e.g., 3-12 months post-transplant) has been associated with low rates of coccidioidomycosis in seronegative lung transplant patients relocating to high-risk areas.^[98] Routine prophylaxis is not universally recommended for all immunocompromised groups, such as those with HIV in endemic areas, due to limited evidence of benefit.^[99]

History and regulation

Discovery and research milestones

The pathogenic fungus Coccidioides immitis was first identified in 1892 by Argentine medical student Alejandro Posadas, who described spherical structures resembling coccidian protozoa in the granulomatous lesions of a 36-year-old soldier with disseminated skin and visceral disease in Buenos Aires; Posadas initially classified the organism as a protozoan infection, naming the condition "coccidioidal granuloma."^[100] This marked the initial recognition of coccidioidomycosis, though the fungal nature of the pathogen remained unrecognized for years. In 1896, American physicians Emmet Rixford and Thomas C. Gilchrist reported similar cases in California and formally named the organism Coccidioides immitis, deriving the genus from its resemblance to coccidia and the species epithet from the Greek for "not mild," reflecting the severe clinical course; they too presumed it was a protozoan but provided the first detailed morphological description based on tissue examinations.^[101] Key epidemiological insights emerged in the 1930s through studies in California's San Joaquin Valley, where influxes of migrant workers during the Dust Bowl era led to outbreaks of a self-limited respiratory illness known as "Valley Fever." Charles E. Smith and colleagues at Stanford University conducted skin testing with coccidioidin antigen in Kern and Tulare counties from 1937 to 1938, revealing high infection rates (up to 80% seropositivity) among residents and linking the mild febrile illness to C. immitis exposure via airborne soil spores, thus establishing the fungus's endemicity and dimorphic life cycle—mycelial in soil and spherule-forming in hosts.^[100] These investigations shifted perceptions from a rare, fatal disseminated disease to a common, often asymptomatic infection, informing early public health responses. Advancing molecular taxonomy, a 2002 study by Fisher et al. used multilocus genotyping to delineate two genetically distinct species within the Coccidioides genus: C. immitis, restricted to California, and the newly described C. posadasii, encompassing isolates from outside California, including Arizona, Texas, and Latin America; this speciation, based on DNA polymorphisms and microsatellite loci, clarified geographic distributions and evolutionary divergence estimated at approximately 5 million years ago.^[102] In 2005, the Broad Institute completed draft genome sequencing of C. immitis strain RS, assembling a 28.9 Mb haploid genome with approximately 9,900 protein-coding genes, which revealed insights into dimorphism, virulence factors like the SOWgp gene family, and comparative genomics with other dimorphic fungi, facilitating subsequent studies on host-pathogen interactions.^[103] In the 2020s, research has focused on environmental drivers of disease emergence, with climate modeling predicting expanded endemic ranges due to warming temperatures and altered precipitation patterns; for instance, ensemble models project northward shifts into states like Idaho and Wyoming by mid-century, correlating historical incidence spikes with drought conditions that favor sporulation and dust dispersal.^[104] Concurrently, vaccine development has progressed, with preclinical studies on recombinant antigens such as rCpa1 showing cross-protection against both C. immitis and C. posadasii in animal models. In August 2024, the National Institutes of Health awarded $33 million to the University of Arizona to advance a live attenuated gene-deletion mutant vaccine (Δcps3::DsRed) toward phase 1 clinical trials in humans, following successful protection in animal models against both species.^[105]

Biosafety and select agent status

Coccidioides immitis is classified as a Risk Group 3 pathogen due to its potential to cause serious or lethal human disease through inhalation of infectious arthroconidia, though it is not typically transmitted person-to-person. Routine handling of clinical specimens and identification of isolates can be performed under Biosafety Level 2 (BSL-2) conditions with appropriate personal protective equipment and biosafety cabinets to minimize aerosol generation.^[106] However, manipulation of cultures, especially procedures that may generate aerosols or involve high concentrations of spores, requires Biosafety Level 3 (BSL-3) facilities and practices to mitigate the risk of laboratory-acquired infections via inhalation.^[2]^[107] Prior to 2012, C. immitis was designated as a Category B select agent by the Centers for Disease Control and Prevention (CDC) and the U.S. Department of Health and Human Services (HHS) under the Federal Select Agent Program, reflecting its moderate ease of dissemination and potential for causing moderate morbidity or low mortality in a bioterrorism context.^[108] On October 5, 2012, it was removed from the HHS select agent list effective December 4, 2012, following a biennial review that considered advances in diagnostics and availability of effective antifungal treatments, which reduced concerns over its bioterrorism potential.^[109] As of 2025, C. immitis has not been re-listed as a select agent.^[110] Despite its delisting, coccidioidomycosis caused by C. immitis remains a nationally notifiable disease in the United States, requiring healthcare providers and laboratories to report confirmed cases to public health authorities for surveillance purposes.^[111] Transport of cultures or viable organisms of C. immitis within the United States must comply with U.S. Department of Transportation (DOT) regulations for shipping infectious substances to ensure safe handling and prevent unintended release. These regulations maintain oversight for laboratory and research activities involving the pathogen without the stringent security measures associated with select agent status.

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Surgical procedures are recommended in addition to antifungal drugs ... Withdrawal of immunosuppressive agents in the treatment of disseminated coccidioidomycosis.
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Coccidioidomycosis and Valley Fever Treatment & Management
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[PDF] Preventing Work-Related Coccidioidomycosis (Valley Fever)
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BSL. Blastomyces dermatitides, 2. Coccidioides immitis*, 2/3. Cryptococcus neoformans, 2. Epidermophyton – pathogenic sp. 2. Histoplasma capsulatum, 2/3.
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Possession, Use, and Transfer of Select Agents and Toxins; Biennial ...
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The following biological agents and toxins have been determined to have the potential to pose a severe threat to both human and animal health, to plant health,Missing: immitis 2012
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Importation of Infectious Specimens, Biological Agents, and Vectors ...
Jun 9, 2025 · Subsequent transfers of any infectious biological agent, infectious substance, or vector in the US will require an additional CDC import permit.Missing: Coccidioides immitis