CONTENTS

• Basics
• Epidemiology
• Evolution between different forms
• Different clinical manifestations:
  • Acute pulmonary coccidioidomycosis
  • Chronic pulmonary coccidioidomycosis
  • Disseminated infection
    • CNS involvement
• Diagnosis
  • Laboratory tests
  • Bronchoscopy
• Treatment
• Questions & discussion

abbreviations used in the pulmonary section: 2

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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basics

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• Most patients will experience a pulmonary infection. Dissemination beyond the lungs is uncommon in immunocompetent patients, but occurs in the majority of immunocompromised patients.

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epidemiology

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geography

• Endemic regions include:
  • Southwestern United States (e.g., California, Arizona, New Mexico, Texas, Utah, Nevada). (32000283)
    • California and Arizona account for >95% of reported infections (especially the Maricopa, Pinal, and Pina counties in Arizona). (32000283, 35233706) Coccidioidomycosis has been called “San Joaquin Valley Fever.”
  • Central Washington state.
  • Parts of Mexico and South America (e.g., Argentina, Paraguay, Bolivia, Brazil).
• Coccidioidomycosis may cause ~3,000 hospitalizations/year in the United States, so it's not terribly rare. (Murray 2022) In endemic areas, it may account for up to a quarter of community-acquired pneumonia. (25019431) 

acquisition

• Coccidiomycosis is acquired from the environment (there is no person-to-person transmission aside from organ transplantation). Coccidioides grows in the soil and is aerosolized during dry periods.
• Risk is greatest in the late summer and fall, when the soil is dry and wind may mobilize arthroconidia (spores).
• High-risk activities include anything that disrupts the soil:
  • Excavation.
  • Construction.
  • Agriculture.
  • Earthquakes, dust storms.
• Even a short trip to an endemic region may cause exposure.

risk factors for severe disease and complications

• Most patients with coccidioidomycosis are immunocompetent (even including most patients with disseminated disease). (30921084)
• The risk of dissemination is increased among patients with immunocompromise, as listed below. T-cell immunity seems to be most important. (32000283) Alternatively, immunoglobulin deficiency doesn't appear to increase risk. (35233706)
  • Pregnancy (third trimester and early post-partum period; may reflect a cytosolic estrogen receptor within Coccidioides). (34016286)
  • HIV, usually with CD4 count <50-100/uL. (Murray 2022)
  • Organ transplantation (reactivation may occur during the first post-transplant year). (35233706)
  • Immunosuppressive medications, especially: (35809963, 35233706)
    • Chronic steroid therapy (>20 mg/day for >2 weeks).
    • Anti-TNF medications.
  • Malignancy, chemotherapy (especially hematologic).
  • Diabetes, hyperglycemia. (31279380)
  • Age >50 years. (32000283)

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evolution between different disease forms

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(#0) incubation

• Incubation lasts ~1-4 weeks.

(#1) clinical manifestations begin with acute pulmonary coccidioidomycosis

• Most patients will start out with an acute pulmonary infection, following inhalation from the environment.
• Pulmonary infection may be severe, mildly symptomatic (flu-like illness), or asymptomatic.
  • Thus, patients are often unaware that they have developed acute pulmonary coccidioidomycosis.
• (Coccidioidomycosis may rarely be acquired via direct implantation into the skin, but this is much less common.)

Following acute pulmonary infection, three outcomes are possible:

(#2a) >90% of patients: resolution 

• >90% of patients will resolve their primary pulmonary infection without further clinical complications.
• Patients may be left with an asymptomatic pulmonary nodule or small thin-walled cavity. These entities are benign, but may cause diagnostic confusion (e.g., differentiation from lung cancer).

(#2b) ~5% of patients: chronic pulmonary coccidioidomycosis

• Chronic infection is defined roughly as infection persisting >6 weeks.
• Chronic pulmonary infection may resemble tuberculosis.

(#2c) ~1-3% of patients: disseminated disease

• ~1-3% of all patients progress to disease dissemination beyond the lungs.
• Progression to disseminated disease is much more common among patients with immunodeficiency (see the section above).
• Disseminated disease usually occurs within one year of initial infection, generally as a consequence of acute infection

(#3) reactivation of latent infection

• Coccidioidomycosis may cause a latent infection, with reactivation later in life.
• As long as the immune system remains intact, recurrent coccidioidomycosis shouldn't occur. (32000283)
• Reactivation may be triggered by immunosuppression (e.g., lymphoma, transplantation, or HIV).

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acute pulmonary coccidioidomycosis

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symptoms

• Severity ranges from a mild flu-like illness to severe pneumonia. This is influenced by the host immune system as well as by the inoculum dose. (32000283)
  • Typically, acute pulmonary coccidioidomycosis is a self-limited illness lasting 3-6 weeks. (25019431)
  • Severe pneumonia with ARDS may rarely occur following a massive exposure (e.g., during construction or excavation).
• (1) Constitutional symptoms:
  • Malaise, fever, arthralgias, headache.
  • Anorexia, weight loss.
• (2) Pulmonary symptoms:
  • Pleuritic chest pain, which can be severe.
  • Nonproductive cough.
  • Rarely, endobronchial involvement with airflow obstruction may occur. (28889900)
  • Dyspnea.
• (3) Erythema nodosum and/or erythema multiforme:
  • Occur in up to 20% of patients.
  • Reflect exuberant immune response to infection.
  • Generally a favorable prognostic sign suggesting containment of infection.
  • May also associate with arthralgias, conjunctivitis, episcleritis.
  • May mimic Lofgren syndrome in sarcoidosis. 📖

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radiology of acute pulmonary coccidioidomycosis

pulmonary parenchymal abnormalities

• Consolidation (75% of cases)
  • Solitary or multiple areas.
  • Consolidation may be segmental or lobar.
  • Distribution is often unilateral, with perihilar and basilar predominance.
  • Rapid progression to diffuse consolidation is occasionally seen. (25019431)
• Nodules (20% of cases)
  • Range in size from 0.5 – 3 cm.
  • Smaller surrounding satellite nodules may be seen.
  • Distribution often has a perihilar and basilar predominance.
  • Borders are often ill-defined (“shaggy nodule”).
• Cavitation can occur acutely in ~5% of hospitalized patients. (25019431)
  • Most resolve spontaneously over time.
  • Cavitation may be more common in nodular disease.

lymphadenopathy

• On CT scanning, ~40% of patients have lymphadenopathy. (25019431)
• Lymphadenopathy is usually seen in combination with parenchymal abnormalities. However, isolated lymphadenopathy may also occur (which can mimic lymphoma, sarcoidosis, metastatic disease, fungal infection, or mycobacterial infection). (25019431)
• This may involve unilateral or bilateral hilar lymphadenopathy, or paratracheal lymphadenopathy.
• Progression to lymphatic infection might precede dissemination. Thus, paratracheal or mediastinal lymphadenopathy may be a risk factor for disseminated disease. (25019431)

pleural effusion (15% of patients)

• Often associated with chest pain (up to 70%).
• Effusion is usually unilateral and small, but it may be large.
• Fluid is typically a lymphocyte predominant exudate. However, there is nearly always also eosinophilia. 20% have a positive smear or culture for coccidioidomycosis from the pleural fluid (indicative of empyema).
  • Coccidioidomycosis empyema should probably be treated similarly to bacterial empyema. However, in the acute phase, decortication with a goal of maximal lung re-expansion may increase the risk of bronchopleural fistula formation – so it could be wise to defer this when possible. (31279380)

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chronic pulmonary coccidioidomycosis

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Chronic pulmonary infection may assume roughly four distinctive forms. 

(#1/4) residual pulmonary nodule (coccidioidoma)

• Residual nodule is left behind in ~6% of patients.
• This generally appears as a solitary pulmonary nodule (<5 mm). However, it can present as a mass up to 6 cm in size. (25019431)
• Radiologic features vary (e.g., smooth, spiculated, lobulated, halo sign, satellite nodules, cavitation, calcification).

(#2/4) chronic coccidioidal cavity

• A chronic cavitary lesion may be seen on CT scan in ~10% of patients.
• Like coccidioidomas, these are usually solitary lesions that are found incidentally on CT scans.
• Clinical manifestations may include:
  • Hemoptysis.
  • Fungus ball formation (usually Aspergillus, less commonly Coccidioides), which may associate with low-grade fever, weight loss, and hemoptysis.
  • Lung abscess, due to superinfection.
  • Rupture into the pleura (leading to pyopneumothorax, bronchopleural fistula).

(#3/4) chronic fibrocavitary pneumonia

• Consolidation and/or lymphadenopathy may persist for >6 weeks, which qualifies as chronic infection (aka persistent coccidioidal pneumonia). This may resolve, or progress to chronic fibrocavitary pneumonia (mimicking tuberculosis or histoplasmosis). Chronic fibrocavitary pneumonia is marked by the following features.
• Symptoms may include:
  • Chronic cough with sputum production, hemoptysis.
  • Chronic inflammatory symptoms (e.g., weight loss, fever, night sweats).
• Radiology: may include
  • Multiple cavities, nodules.
  • Calcified lesions.
  • Fibrosis (e.g., traction bronchiectasis).
• Laboratory:
  • Sputum cultures may remain persistently positive.
  • Positive serologies may support ongoing active infection.
• If cavities are located in the peripheral lung, they may lead to bronchopleural fistula formation with a resulting pneumothorax and/or empyema. (Murray 2022) 

(#4/4) pleural effusion

• Chronic effusion is rare, but may occur in 3% of patients.
• Size may fluctuate over time.
• Empyema can occur.

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disseminated infection

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general concepts regarding disseminated disease

• Dissemination occurs in ~1-3% of patients. Virtually any organ system can be involved.
• Disease pace varies, depending on the patient's immune status:
  • Immunocompetent patients: Subacute or chronic process evolving over weeks to months.
  • Severely immunocompromised patients: May present acutely (e.g., with progressive pulmonary infiltrates causing ARDS).

extrapulmonary disseminated infection

• Skin or subcutaneous tissue (~50% of patients), which may include: (32000283)
  • Cutaneous granulomatous lesions (often nodular).
  • Subcutaneous soft tissue abscess.
  • Deep ulcers.
  • Note that diffuse skin rashes due to coccidioidomycosis are usually reactive rashes (e.g., erythema nodosum, erythema multiforme), rather than due to true disseminated infection.
• Neurologic manifestations (~33% of patients) – discussed further in the section below. (31378870)
• Bone and joint infection (~25% of patients).
  • Joint infection most often involves the knees > ankles > wrists. Actual infection of the joint causes effusions (unlike arthralgias that may be associated with systemic inflammation due to primary pulmonary infection). (35233706)
  • Bony involvement most often involves the axial skeleton. (35233706)

pulmonary manifestations – miliary infection

• Hematogenous dissemination may cause a micronodular infiltrate throughout all lung fields.
• Radiology: (25019431)
  • (a) 3-4 mm nodules may be indistinguishable from miliary tuberculosis. (Murray 2022) Micronodules may merge together into confluent opacities.
  • (b) The original focus of parenchymal consolidation may be visible.
  • (c) Hilar and mediastinal lymphadenopathy are usually present.
• Clinical presentation:
  • Clinically, this may produce an acute respiratory illness.
  • ARDS may occur, especially when nodules merge together to produce consolidation.

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CNS involvement

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clinical presentation

• Pneumonia is generally a central clinical finding.
• Chronic basilar meningitis occurs in about a third of patients with disseminated disease, which may lead to hydrocephalus and/or vasculitic infarcts:
  • Headache is common, but frank meningismus is rare.
  • Mental status changes are frequently seen.
  • Hearing or vision changes may occur.
  • An adhesive arachnoiditis may occur, leading to compressive myelopathy, spinal subarachnoid block, and/or hydrocephalus. (33522738)
  • May cause vasculitis or vasospasm, leading to ischemic stroke.
  • CVT (cerebral venous thrombosis) has also been reported.
• Intraparenchymal abscess may result from spread of infection from the leptomeninges into the brain parenchyma. (33516057) This may lead to mass lesions that cause focal neurological deficits (e.g., seizure). (31378870) Spinal cord mass lesions may likewise occur.

laboratory findings

• Routine screening lumbar puncture is not needed for patients with coccidioidomycosis who lack neurological symptoms (even if they are at risk for disseminated disease). (34016286) Also note that headache is common during acute presentation of acute pulmonary coccidioidomycosis, so in this context headache doesn't indicate the need for lumbar puncture unless the headache is persistent. (35233706)
• CSF studies:
  • Pleocytosis with mixed neutrophilic or lymphocytic predominance (including CSF eosinophilia in 15% of cases). (31378870)
  • Glucose is often low.
  • Protein is generally elevated (and in severe cases it may be markedly elevated). (34016286)
  • CSF serology may be positive for antibodies against Coccidioides.
  • CSF cultures are usually negative.
• Serum antibody is generally positive.

imaging

• Basilar meningitis is a central finding:
  • Diffuse leptomeningeal enhancement, and/or enhancement of the basal cisterns, Sylvian fissures, and craniocervical junction. (33516057)
  • Hydrocephalus may be seen in ~40% of patients. (23983881)
  • Spinal nerve root enhancement may be seen. (26633781)
• Ischemic areas occur in about a third of patients, typically in the deep cerebral matter. (33516057)
• Brain abscess(es) may be seen:
  • Solitary or multifocal, 0.5-4 cm large.
  • Most often in the posterior fossa, but they may also involve juxtacortical and subcortical structures. (31378870)

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laboratory tests

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general laboratory studies

• Peripheral eosinophilia is frequently seen in acute infection.
• C-reactive protein is often elevated. (35233706)
• Procalcitonin doesn't appear to be elevated. (32000283)

sputum culture and smear

• Culture and smear may be performed on sputum or purulent material from abscesses.
• Smear evaluation with calcofluor white stain or Papanicolaou stain may reveal spherules.
  • Sensitivity varies depending on the disease form and burden of organisms (e.g., higher in patients with immunosuppression and disseminated disease).
• Culture:
  • ☣️ This requires biohazard protection – so alert the lab.
  • Cultures may grow faster than Histoplasma or Blastomyces (e.g., within ~5-7 days on fungal media).
• (PCR testing may be available in some laboratories). (35809963)

serology

• Overall utility:
  • Serology may be useful in the diagnosis of disseminated disease. Serology is less sensitive among immunocompromised patients, or in the context of mild disease (e.g., solitary pulmonary nodule).
  • Antibody dynamics are unlike most other infections:
    • (1) Antibodies generally decrease to undetectable levels following infection, so detection implies a recent or persistent infection. (25019431)
    • (2) Rising antibody titers after completion of therapy suggests persistent or relapsing disease. (34016286)
• IgM:
  • IgM often peaks at approximately 14 days after symptom onset. Subsequently wanes within 4-6 months.
  • Sensitivity:
    • ~50-75% convert within three weeks of illness.
    • Sensitivity may be higher in patients with symptoms (~90%). (32000283)
  • Specificity:
    • False-positive results may occur.
    • Positive results may represent asymptomatic infection (that is unrelated to the patient's clinical problems).
• IgG:
  • IgG often peaks at 1-2 months, before waning. (32000283)
  • Sensitivity and specificity are usually superior to the IgM assay, but this takes longer to seroconvert.
  • Sensitivity:
    • 90% convert by three months after onset of symptoms.
    • Early treatment may lead to lack of IgG production. (32000283)

antigen tests

• 1,3-beta-D-glucan assay:
  • This evaluates for an antigen present in a broad range of fungal organisms.
  • Using a cutoff value of >80 pg/ml, beta-D-glucan has a sensitivity of ~50%. Sensitivity is likely higher among patients with a large infection burden.
  • Specificity of beta-D-glucan varies, depending on clinical context. A positive result often reflects the presence of some type of fungal pathogen. Importantly, beta-D-glucan is not specific for Coccidioides. More on beta-D-glucan here: 📖
• (Urine coccidioidomycosis antigen test)
  • Sensitivity depends on the severity of disease (e.g., ~75% sensitive in moderate to severe disease).
  • Specificity is high (~98%), but may cross-react with some other endemic fungi (e.g., Histoplasma, Blastomyces).
  • Unfortunately, this test seems to be restricted to very few laboratories.

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bronchoscopy

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bronchoalveolar lavage (BAL)

• Cytology may yield a rapid diagnosis in ~50% of patients.
  • Spherules are the classic finding (60-100 uM in diameter).
  • Endospores are much smaller (4-10 uM); they are released from spherules. Endospores may spread hematogenously or via lymphatics, thereby spreading disease within the body. (34016286)
  • Septate hyphae can rarely be seen in patients with chronic disease and tissue necrosis (especially in the context of diabetes).
• Culture may be positive in ~40% of patients (discussed further above in the section on sputum analysis). (28889900)
• Eosinophilia may occur.

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treatment

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selection of azoles for coccidioidomycosis

• Some rough MIC data:
  • Itraconazole: 0.06-0.5 ug/mL.
  • Fluconazole: 4-8 ug/mL.
  • Voriconazole: 0.06-0.5 ug/mL.
  • Isavuconazonium: 0.06-0.25 ug/mL.
  • Posaconazole: 0.06 ug/mL.
• Itraconazole:
  • Usually, itraconazole is the preferred agent for Coccidioidomycosis pneumonia. Despite reported poor CSF and bone penetration, itraconazole is effective in CNS and bone infection. (35233706)
  • One RCT on chronic cavitary coccidioidomycosis found itraconazole (200 mg BID) to be superior to fluconazole 400 mg/day. (11074900)
  • Itraconazole is not recommended in seriously ill patients due to variable oral bioavailability.
• Fluconazole:
  • For primary pneumonia, fluconazole may be slightly inferior to itraconazole. However, fluconazole may be better tolerated than itraconazole.
  • Advantages include high bioavailability (100% absorption), low side-effect profile, and good CNS penetration (superior to itraconazole or amphotericin). However, fluconazole usually has a significantly higher minimum inhibitory concentration than other azoles, suggesting that other mold-active azoles may be superior in serious infection (MIC data listed above). (34016286)
• Voriconazole, isavuconazonium, posaconazole:
  • Voriconazole and isavuconazole both have excellent in vitro activity. They are generally used in patients who are refractory or unable to tolerate itraconazole or fluconazole. (34016286)
  • Voriconazole has been effective in some patients with refractory chronic fibrocavitary disease. (34016286) Retrospective series have demonstrated efficacy in meningeal and non-meningeal infection. (34016286)
  • Isavuconazole is supported by less evidence. However, one case series did find efficacy for coccidioidal meningitis. (30559134)
  • Posaconazole is another option for cocciodomycosis that is refractory/intolerant to Amphotericin, itraconazole, or fluconazole. (32000291)

primary pulmonary disease

• Not all patients require therapy (95% of patients will resolve spontaneously). There is no clear evidence that treatment prevents dissemination. (34016286)
• Indications for treatment might include:
  • Immunocompromise.
  • Pregnancy or postpartum.
  • Persistent infection:
    • Symptoms >6-8 weeks.
    • Night sweats >3 weeks.
  • Severe infection:
    • Loss of >10% body weight.
    • Involvement of >half of a lung.
    • Multilobar disease (especially diffuse pneumonia).
    • Prominent or persistent hilar lymphadenopathy.
    • Inability to work.
  • ⚠️ Look carefully for any evidence of dissemination (e.g., headache, skin lesions, arthritis, bony involvement). (Fishman 2023)
• Treatment regimen?
  • In severe disease: treatment may start with amphotericin with a subsequent step down to an azole (fluconazole or itraconazole). In some cases, amphotericin may be combined simultaneously with a triazole antifungal agent. (32000283)
  • For patients with mild/moderate disease, fluconazole or itraconazole may be utilized initially.
• Treatment duration is individualized but may be in the range of ~3-6 months. Ongoing immunosuppression may require chronic suppressive therapy. (32000283)

chronic fibrocavitary pulmonary disease

• Fluconazole or itraconazole are generally utilized. However, amphotericin may be appropriate for some sicker patients.
• Infection is seldom cured.

disseminated disease

• Options may include amphotericin, itraconazole, or high-dose fluconazole.
• Itraconazole may be preferred in patients with bone and joint disease. (34016286) An RCT involving nonmeningeal disseminated disease found that patients with skeletal infection responded twice as frequently to itraconazole (200 mg BID) as compared to fluconazole (400 mg/d). (11074900)
• CNS involvement:
  • Fluconazole is the preferred front-line therapy due to high CNS penetration (800-1200 mg/day). (34016286) Delayed recurrence is common, so guidelines recommend lifelong azole suppressive therapy following initial therapy.
  • For patients with meningitis, hydrocephalus often requires interventional therapy (e.g., therapeutic lumbar punctures and shunt placement if intracranial pressure is refractory to multiple therapeutic lumbar punctures). (31378870)
  • Among patients with coccidioidal meningitis who developed a stroke, a retrospective study suggests that steroid therapy correlated with a reduced risk of recurrent stroke. (28419259)

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questions & discussion

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