Coccidioidomycosis

7 Interesting Facts of Coccidioidomycosis 

1. Coccidioidomycosis is a noncontagious, airborne, fungal disease caused by primary or disseminated infection with Coccidioides immitis and Coccidioides posadasii, soil-dwelling fungi endemic to semiarid desert regions of North, Central, and South America 
2. Coccidioidomycosis typically presents as a subclinical or mild pulmonary infection (primary pulmonary coccidioidomycosis) that resolves spontaneously within a few weeks or months in immunocompetent individuals 
3. Progressive disseminated disease of the skin, musculoskeletal system, or meninges is frequently observed in immunosuppressed individuals and is fatal if left untreated 
4. Direct detection and culture of Coccidioides organisms confirms an active infection; serum antibody titers to coccidioidal antigens support the diagnosis in a clinical context suggesting infection, are prognostic indicators, and may be used to track disease activity 
5. Severe primary infection is treated with a 3- to 6-month course of oral fluconazole; amphotericin B is prescribed for coccidioidomycosis in patients with immediately life-threatening infection, with refractory disease, and who are pregnant 
6. A few infected individuals will develop pulmonary cavities or sustain pleural tissue damage, which can result in chronic pulmonary dysfunction 
7. Patients with subclinical or mild to moderate influenzalike symptoms see significant improvement within 2 to 3 weeks, and mortality rates remain generally low, although people with diabetes and immunosuppressed patients have a worse prognosis 

Pitfalls

• Serologic testing is less sensitive in immunocompromised individuals; a negative test result in this population does not exclude the diagnosis of coccidioidomycosis 

• Coccidioidomycosis is a noncontagious, airborne, fungal infection caused by Coccidioides spores that thrive in the semiarid desert regions of the southwestern United States, Mexico, and Central and South America 
• Also known as desert rheumatism, valley fever, and San Joaquin Valley fever 

Classification

• Clinical manifestations of coccidioidomycosis are classified according to route of inoculation, extent, and duration of disease
• Primary pulmonary disease is the most common manifestation 
  • • Typically a subclinical infection or presents as mild, self-limiting community-acquired pneumonia 
    • Symptom severity correlates with the number of inhaled spores 
      • Rarely may present as diffuse progressive pneumonia, primarily in immunosuppressed patients; may be accompanied by sepsis syndrome 
    • May become chronic
      • May be indolent and relatively asymptomatic, but subject to reactivation with immunosuppression
      • May progress slowly, with development of fibrotic scarring, cavities, bronchopleural fistulae, and empyema
  • Extrapulmonary disseminated disease (approximately 1%-5% of all cases) is more common in immunosuppressed people 
    • Hematogenous dissemination typically becomes clinically apparent within the first year following primary infection 
      • Previously quiescent or unrecognized disseminated disease may become clinically apparent in patients who become immunosuppressed through HIV infection or immunosuppressive therapy
    • Skin, lymph nodes, musculoskeletal system, and meninges are the most common sites of disseminated infection 
      • Cutaneous infection manifests as polymorphous lesions that may resemble acne, rosacea, or warts; severe infection may result in abscess formation 
      • Osteoarticular infections manifest as osteomyelitis or synovitis, which primarily affect weight-bearing bones, especially the vertebral column 
        • Severe infection may result in the development of large abscesses, necrotic lesions, bony detachment, and joint instability 
      • Central nervous system involvement manifests as basilar meningitis 
        • Can also cause ventriculitis and hydrocephalus
  • Primary cutaneous infection is rare (approximately 1%-2% of all cases) and results from traumatic inoculation (eg, from skin abrasions, lacerations, or splinters) 

Diagnosis

Clinical Presentation

History

• Incubation period between exposure and onset of the acute phase of illness ranges from 1 to 3 weeks 
• History of travel to or residence in an endemic region
• Primary pulmonary infection
  • 60% of individuals with primary pulmonary infection are asymptomatic 
    • Symptomatic patients with primary pulmonary infection typically present with nonspecific symptoms similar to a lower respiratory tract infection 
      • Most common complaints are acute headache (20%), pleuritic chest pain (71%), mild to moderate cough (65%), fever (64%), and general malaise (41%) 
      • White women and men are more likely to report the presence of painful, red lesions (erythema nodosum), especially on the lower extremities 
    • Constitutional or systemic complaints may predominate over pulmonary symptoms; constellation of arthralgias, erythema nodosum, and fever is known as desert rheumatism
  • Carefully assess patients suspected of having primary pulmonary infection for symptoms suggesting disseminated disease
• Disseminated infection
  • In most cases of disseminated infection, symptomatic patients typically report fever, night sweats, and fatigue
  • Skin, meninges, bone, and joints are common sites for disseminated coccidioidomycosis 
    • Patients with cutaneous infection typically present with single or multiple skin eruptions, which can appear anywhere on the body
    • Patients with osteoarticular infection usually report tenderness and redness around the affected bone or joint
    • Patients with suspected coccidioidal meningitis typically report blurry vision, nausea, vomiting, confusion, and headaches 
      • Rarely, may present with symptoms resembling acute psychosis
• Primary cutaneous infection
  • Patients with suspected primary cutaneous infection present with a painless ulcerated lesion (usually on the extremities) and have no evidence of pulmonary or disseminated infection
• Occasionally chronic asymptomatic or previously unrecognized disease is discovered incidentally in the course of work-up for another condition (eg, pulmonary nodule or cavity on chest radiography)

Physical examination

• Primary pulmonary infection
  • Adventitious breath sounds (eg, rales) may or may not be present
  • Dullness to percussion is indicative of pleural effusion 
  • Erythema nodosum, maculopapular rash, or erythema multiforme may accompany infection; these are the result of a hypersensitivity reaction, distinct from cutaneous Coccidioides infection, and are a favorable prognostic indicator 
    • Generalized maculopapular rash is only present in 10% to 15% of symptomatic primary pulmonary infections and is more frequently observed in children 
    • Erythema multiforme appears as a generalized rash of confluent targetlike lesions 
    • Erythema nodosum consists of 1 or several red or brown nodules, typically localized to the anterior aspect of the lower extremities 
• Disseminated infection
  • May be suggested by presenting complaint, but evaluate for disseminated infection in patients with suspected or confirmed pulmonary Coccidioides infection
  • Cutaneous
    • Primary morphology and texture: lesions may appear as macules, papules, acneiform pustules, verrucous plaques, granulomatous nodules, abscesses, or scars
    • Distribution and location: singular or multiple skin lesions are typically localized to the face (especially the nasolabial fold), neck, and chest
  • Osteoarticular 
    • Signs include soft tissue swelling, joint effusion, and decreased range of motion
  • Lymph nodes
    • Hilar adenopathy is commonly seen on radiography
    • Palpable cervical and supraclavicular involvement is common
• Primary cutaneous infection
  • Chancriform lesions with regional lymphadenopathy are evident 

Causes

• Primary pulmonary disease is caused by inhalation of airborne Coccidioides spores 
  • Arthroconidia of Coccidioides immitis and Coccidioides posadasii are dispersed into the air and inhaled into the lungs of the host where they form endospore-producing spherules 
• Coccidioides is found in soils in areas with low rainfall, high summer temperatures, and moderate winter temperatures such as the San Joaquin Valley and other arid regions in Southern California; much of Arizona; the southern regions of Utah, Nevada, and New Mexico; western Texas; eastern Washington; and parts of Mexico and Central and South America 
• Disseminated disease results from hematogenous spread of Coccidioides spherules to a single remote focus or to multiple organs
• Primary cutaneous disease is caused by direct inoculation of skin abrasions or wounds with Coccidioides spores 

Risk factors and/or associations

Age

• Adults aged 60 years or older have higher incidence rates partially attributed to: 
  • Immunosenescence (gradual deterioration of the immune system due to age)
  • Migration to endemic regions (eg, southern Arizona, central California) of large elderly populations with no previous Coccidioides exposure

Sex

• Incidence rates are higher in men because they are traditionally more likely to engage in high-risk occupations and outdoor recreational activities

Genetics

• Individuals with B or AB blood types are predisposed to more severe clinical manifestations of coccidiodomycosis 

Ethnicity/race

• Disseminated, persistent infections requiring hospitalization are 10 to 175 times more likely to develop in African Americans (osteoarticular) and Filipinos (cutaneous or meningeal) 

Other risk factors/associations

• Coccidioides exposure is almost entirely limited to geographic area of endemicity (ie, semiarid desert regions of the southwestern United States, Mexico, and Central and South America) 
  • Risk increased by circumstances that facilitate growth and dispersion of Coccidioides (eg, rain followed by high temperatures and drought, dust storms, excavation, earthquakes) 
• Occupational exposure to Coccidioides is higher among military personnel, construction workers, agricultural workers, and archaeologists 
  • Laboratory workers can contract coccidioidomycosis through aerosolization of arthrospores from Coccidioides grown in culture 
• Recreational exposure to contaminated soil can occur through high-risk outdoor activities (eg, hunting, triathlons, hiking) in endemic regions
• Immunosuppression increases likelihood of progressive infection
  • Pregnant women are at greater risk of developing severe or disseminated infections; susceptibility increases in late gestation and immediately postpartum 
  • Use of immunosuppressants, corticosteroids, and tumor necrosis factor inhibitors increases risk of infection 
  • Individuals with HIV/AIDS are at greater risk if CD4⁺ T lymphocyte count is less than 250 cells/μL 
• Diabetes mellitus is a risk factor for severe pulmonary infection but not for disseminated infection
• Patients with cardiopulmonary disease or chronic structural lung disease are at higher risk for severe pulmonary infection

Diagnostic Procedures

Primary diagnostic tools

• In addition to clinical signs and symptoms, history of travel to or residence in an endemic region supports the diagnosis 
• Serology is the most widely used diagnostic tool for coccidioidomycosis 
  • Complement fixation, immunodiffusion assays, and enzyme immunoassays are used to detect IgM and IgG antibodies to coccidioidal antigens 
    • Enzyme immunoassays qualitatively measure both IgM and IgG antibodies and have the greatest sensitivity of all 3 serologic methods 
    • Immunodiffusion tube precipitin assay is a quantitative method for measuring IgM antibodies 
      • IgM antibodies are detectable within 1 to 3 weeks of disease onset 
    • Immunodiffusion complement fixation assay is a quantitative method for measuring IgG antibodies 
      • IgG antibodies are detectable 2 weeks to several months after disease onset 
      • Complement fixation assays carry prognostic significance because IgG titer correlates with disease severity
      • As a quantitative assay, sometimes measured serially to assess response to treatment
    • Testing can be performed on serum and other bodily fluids (eg, cerebrospinal fluid, joint fluid, pleural fluid); however, antibody titers are highest in serum 
  • Serologic testing for coccidioidomycosis in immunocompromised patients is unreliable and cannot be used as the sole diagnostic tool for this population 
  • Negative serologic results do not rule out infection even in immunocompetent hosts, especially early in the course of infection 
• When pulmonary infection is suspected, definitive diagnosis is made based on the results from the following combination of tests: 
  • Serologic testing, including serology of pleural fluid in individuals with pleural effusion 
  • Culture and microscopic analysis for spores in sputum, bronchial lavage fluid, or pleural fluid (in individuals with pleural effusion) 
    • Although uncommon, acute coccidioidal pneumonia may present with diffuse pneumonia with nodules that may require biopsy 
  • Thoracic imaging modalities to determine the extent of primary pulmonary lung infection 
    • Pulmonary infiltrates, nodules, and/or pleural effusion may be found
  • Additionally, results of CBC and erythrocyte sedimentation rate may provide additional evidence supportive of the diagnosis (eg, eosinophilia, marked erythrocyte sedimentation rate elevation)
• Diagnosis of disseminated infection is confirmed by results from the following tests:
  • Serologic testing of blood and other relevant body fluids (eg, synovial, cerebrospinal) 
    • Early neurosurgical consultation and MRI are recommended for patients with elevated opening pressure on lumbar puncture 
  • Microscopy and culture of clinically relevant body fluids or tissues
  • Skin punch or tissue biopsy for culture and microscopy for suspected disseminated infection 
  • Results of CBC and erythrocyte sedimentation rate may provide additional evidence supportive of the diagnosis (eg, marked eosinophilia, significant erythrocyte sedimentation rate elevation) 
• If primary cutaneous infection is suspected, diagnosis is confirmed by a combination of tools, including:
  • Skin punch or tissue biopsy for culture and microscopy 
  • Serologic testing 

Laboratory

• Hematology
  • CBC
    • Mild eosinophilia (ie, 5%-10% of peripheral WBC count) is a nonspecific finding that may be present in some cases of primary pulmonary coccidioidomycosis, but not in all; marked eosinophilia (21% or more of peripheral WBC count) suggests disseminated disease 
  • Erythrocyte sedimentation rate
    • Sedimentation rate may be markedly elevated in patients with coccidioidomycosis, but not in all cases 
• Direct detection via microscopic examination
  • Coccidioides spherules with endospores can be visualized microscopically in histologic preparations with hematoxylin-eosin stain, periodic acid–Schiff stain, or Grocott-Gomori methenamine–silver nitrate stain 
    • Spherules appear as double-walled structures ranging in size from 20 to 150 μm in diameter and contain endospores
• Culture
  • Isolation of Coccidioides in culture is the most definitive diagnostic tool 
• Serologic testing
  • Enzyme immunoassay
    • Maximal serologic sensitivity provided by enzyme immunoassay detection of coccidioidal IgM and IgG antibodies
    • Detection of coccidioidal IgM and IgG antibodies indicates positive serology; however, cross-reactivity with antigens from other fungi (ie, Histoplasma capsulatum and Paracoccidioides braziliensis) may reduce assay specificity
    • Isolated positive IgM result requires clinical correlation and either serial testing of serum (early and convalescent), immediate repeat of enzyme immunoassay for IgG and IgM, or tube precipitin immunodiffusion reaction for confirmation
  • Immunodiffusion assays
    • Tube precipitin immunodiffusion (IgM)
      • Presence of 120 kDa β-glucosidase band in agar indicates positive serology 
    • Complement fixation immunodiffusion (IgG)
      • Detection of chitinase band in agar indicates positive serology 
      • Levels appear to correlate with severity of disease and prognosis
        • Serum antibody titers greater than 1:16 may indicate disseminated disease 
          • However, a recent study showed 24% of patients with disseminated disease had titers of 1:16 or less, and 12% had higher titers without dissemination 
        • Serum antibody titers greater than 1:256 may indicate a higher risk for relapse 
• Coccidioides spores are easily airborne and inhaled; use biosafety level 3 containment procedures when handling samples to lower risk of infection

Imaging

• Perform chest radiography on all patients with suspected pulmonary disease 
• Obtain CT scans in select patients, such as high-risk patients (eg, probable pulmonary exposure with symptoms) with normal-appearing radiographs or subtle changes on plain radiography 
  • CT indicated for guidance for procedures such as thoracentesis
  • CT scanning useful in chronic disease to monitor residual nodules, effusions, cavities, intrathoracic adenopathy, and persistent pneumonia
• Chest radiography (plain radiographs or CT scan) findings consistent with a diagnosis of primary pulmonary coccidioidomycosis include: 
  • Focal or diffuse infiltrates
    • Multilobar diffuse pulmonary infiltrates with a hazy appearance 
    • Diffuse miliary infiltrates occur rarely; typically observed in immunosuppressed patients 
  • Pleural effusion 
  • Hilar lymphadenopathy 
  • Solitary nodule in approximately 5% of cases 
  • Cavitary disease is seen in a small proportion of patients
• Imaging of other areas (eg, bones, joints) may be helpful in diagnosing disseminated disease, based on symptoms

Procedures

• Collection of a sample of cells for identification, analysis, and culture
  • Excisional biopsy: an entire lump or suspicious area is removed
  • Incisional biopsy (also called core biopsy): a sample of tissue is removed with preservation of the histologic architecture of the sample tissue
  • Needle biopsy (also called aspiration biopsy): a sample of tissue or fluid is removed with a needle without preservation of the histologic architecture of the sample tissue cells
• Diffuse pneumonia with nodules (rare presentation of acute coccidioidal pneumonia) 
• Suspected cutaneous infection, primary or disseminated 
• Other sites of suspected disseminated infection (eg, bones, joints)
• Uncontrolled bleeding diathesis
• Bleeding at site of biopsy
• Hematoma formation
• Spread of infection (seeding) to adjacent infected tissue
• Microscopic identification of Coccidioides spherules with endospores or positive culture results confirm diagnosis of coccidioidomycosis 
  • Spherules appear as double-walled structures 20 to 150 μm in diameter and contain endospores 
• Bronchofiberscope is passed through the nose or mouth, down the trachea, and into the lung
• Lung tissue is visually examined
• Sterile saline is injected into the lung, then aspirated and collected for analysis
• Primary pulmonary infection
• Diffuse pneumonia with nodules (rare presentation of acute coccidioidal pneumonia)
  • Need for visual examination of tracheal and alveolar tissue
  • To obtain specimens of deep respiratory secretions and cells for microscopy and culture
    • Diagnostic yield is increased by obtaining high-quality specimen without contamination, especially in patients with a dry, nonproductive cough
• Patient inability to support ventilation during procedure 
• Hemodynamic instability
• Fever
• Bronchospasm or bronchoconstriction
• Hypoxia
• Hypotension related to sedation
• Epistaxis
• Vomiting
• Pneumothorax
• Cardiac arrhythmias
• Laryngeal edema, injury, or spasm
• Identification of Coccidioides microscopically or by culture confirms diagnosis of coccidioidomycosis 
• Insertion of a hollow-bore needle between the vertebral bodies into the subarachnoid space to do 1 of the following:
  • Obtain a specimen of cerebrospinal fluid
  • Measure cerebrospinal fluid opening pressure in the subarachnoid space
  • Introduce therapeutic agents into the spinal canal
• Patient is either in the lateral recumbent position (preferable for measuring opening pressure) or sitting upright
• To collect and examine cerebrospinal fluid and measure intracranial pressure in suspected cases of coccidioidal meningitis
  • Indicated by unusual, worsening, or persistent headaches; altered mental status; unexplained nausea or vomiting; or new focal neurologic deficits 
• For intrathecal placement of therapeutic agents (eg, intrathecal amphotericin B)
• Uncontrolled coagulopathy
• Skin infection at site of needle insertion
• Patient at risk of brain herniation
  • Best predictors of precipitating herniation (even with normal CT result) include: 
    • Deteriorating level of consciousness (particularly to a Glasgow Coma Scale score of 11 or less)
    • Signs of brainstem compression (eg, pupillary changes, abnormal posturing, irregular respirations)
    • Very recent seizure
• Post–dural puncture headache
• Back pain
• Radicular injury
• Infection
  • Epidural abscess
  • Meningitis
  • Diskitis
  • Vertebral osteomyelitis
• Epidural hematoma
• Cerebral herniation
• Epidermoid tumor formation
• Cerebrospinal fluid IgG titer of 1:2 or higher confirms diagnosis 
• Identification of Coccidioides microscopically or by culture confirms diagnosis of coccidioidomycosis, but results are negative in over 50% of patients with Coccidioides meningitis 
• Aspiration of synovial fluid for disease identification via microscopic examination, serology, or culture
• Suspected disseminated coccidioidal osteoarticular infection
• Cutaneous infection at the intended needle insertion site
• Infection
• Cartilage damage
• Hemarthrosis
• Identification of Coccidioides microscopically or by culture, or demonstration of antibodies to Coccidioides in fluid confirms diagnosis of coccidioidomycosis 
• Insertion of a small-gauge needle between the ribs, through the thorax, and into the pleural space to access pleural fluid for diagnostic or therapeutic purposes
  • Diagnostic: performed on small volumes of pleural fluid for analysis
  • Therapeutic: performed to remove large volumes of pleural fluid
• Procedure can be performed with or without ultrasonographic guidance
• Presence of pleural effusion on chest radiograph, CT scan, or other imaging
• No absolute contraindications
• Relative contraindications
  • Uncorrected coagulopathy
  • Small effusion with secure clinical diagnosis
  • Mechanically ventilated patient
  • Bilateral thoracentesis should be done only after ensuring absence of pneumothorax in the first side
• Bleeding (eg, hematoma, hemothorax, hemoperitoneum)
• Pneumothorax
• Reexpansion pulmonary edema
• Infection (eg, empyema, soft tissue infection)
• Spleen or liver puncture
• Vasovagal events
• Retained intrapleural catheter fragments
• Identification of Coccidioides microscopically or by culture, or demonstration of antibodies to the organism in fluid confirms diagnosis of coccidioidomycosis
• Fluid is usually exudative and may show prominent eosinophilia 

Differential Diagnosis

Most common

• Community-acquired bacterial or viral pneumonia (Related: Community-Acquired Pneumonia in Adults)
  • Pulmonary coccidioidomycosis and bacterial or viral community-acquired pneumonia are characterized by fever, cough, chest pain, and dyspnea
  • Similar to pulmonary coccidioidomycosis, lung examination in patients with bacterial or viral community-acquired pneumonia reveals adventitious breath sounds, dullness to percussion and radiographic evidence of infiltrates
  • Mucopurulent sputum production may distinguish community-acquired bacterial pneumonia from pulmonary coccidioidomycosis
  • Common causes of community-acquired pneumonia may be differentiated from pulmonary coccidioidomycosis by the following:
    • Typical community-acquired organisms identified on Gram stain and culture of sputum or bronchoalveolar lavage fluid
    • Identification of bacterial urinary antigens (eg, Streptococcus pneumoniae)
    • Identification of influenza A or B antigen from nasal swab
• Tuberculosis
  • Similar to coccidioidomycosis, tuberculosis infection typically manifests as primary pulmonary disease; hematogenous dissemination to the skin, musculoskeletal system, and brain is also possible 
    • Pulmonary tuberculosis
      • Pulmonary coccidioidomycosis and tuberculosis present with cough, fever, and similar radiographic features (eg, lung infiltrates, hilar lymphadenopathy, nodules) 
      • In patients with pulmonary tuberculosis, cough is productive and lasts for more than 2 weeks; hemoptysis, anorexia, and weight loss are also common 
    • Cutaneous tuberculosis
      • Cutaneous coccidioidomycosis and tuberculosis present with polymorphous lesions that resemble small papules, warts, ulcers, or plaques 
      • As in primary cutaneous coccidiomycosis, cutaneous tuberculosis infection can also result from direct inoculation of the pathogen through damaged tissue in rare cases 
      • Like cutaneous coccidioidomycosis, cutaneous tuberculosis is more common in immunocompromised individuals; however, cases are rarely reported in the United States 
      • Hypersensitivity reactions to Mycobacterium tuberculosis antigens manifest as moderately painful, erythematous purplish subcutaneous nodules (erythema induratum), not erythema nodosum as is commonly seen in white people with coccidioidomycosis 
    • Osteoarticular tuberculosis
      • Osteoarticular disease in patients with coccidioidomycosis and tuberculosis typically presents as arthritis of weight-bearing joints (especially the spine), accompanied by swelling and loss of function 
      • Incidence of osteoarticular tuberculosis is highest among children and young adults in endemic countries; cases are rarely reported in the United States 
    • Tuberculosis meningitis
      • Coccidioidal and tuberculosis meningitis present with classic meningitis symptoms (ie, fever, vomiting, neck stiffness, neurologic impairment)
        • May be clinically indistinguishable from each other
  • Tuberculosis is differentiated from coccidioidomycosis by: 
    • Identification of acid-fast Mycobacterium tuberculosis bacilli in stains of sputum, bronchoalveolar lavage fluid, synovial fluid, cerebrospinal fluid, or tissue biopsy
    • Appearance of caseating granulomas in biopsy specimens
    • Nucleic acid amplification testing to isolate Mycobacterium tuberculosis DNA from clinical specimens
    • Growth of Mycobacterium tuberculosis in culture
• Nocardiosis
  • Nocardiosis is a noncontagious bacterial infection caused by soil-dwelling, gram-positive bacteria of the genus Nocardia
  • Similar to coccidioidomycosis, nocardial infection typically manifests as primary pulmonary disease; hematogenous dissemination to the skin and brain is also possible, as is primary cutaneous disease
  • Pulmonary nocardiosis
    • Pulmonary coccidioidomycosis and nocardiosis present with fever, cough, chest pain, dyspnea, and similar radiographic features (eg, lung infiltrates, nodules)
    • Pulmonary nocardiosis is almost always associated with immunosuppression, unlike pulmonary coccidioidomycosis, which more commonly occurs in immunocompetent hosts
  • Cutaneous nocardiosis
    • Cutaneous coccidioidomycosis and nocardiosis typically present with nodular lesions and superficial abscesses
    • As in primary cutaneous coccidioidomycosis, primary cutaneous nocardiosis infection usually results from direct inoculation of contaminated soil through damaged tissue in immunocompromised hosts
    • Significant local lymphatic involvement distinguishes primary cutaneous nocardiosis from cutaneous coccidioidomycosis
    • Cutaneous lesions may also result from disseminated Nocardia infection and differ from Coccidioides skin lesions in that they are more likely to be fluctuant, whereas Coccidioides lesions tend to be ulcerated or verrucous
  • Nocardiosis of the central nervous system 
    • Both coccidioidal and nocardial central nervous system disease may present with fever, vomiting, headache, and neurologic impairment
    • Unlike in coccidioidal central nervous system infection, cerebral abscess—not meningitis—is the predominant clinical feature in patients with nocardial infection of the central nervous system
  • Nocardiosis is differentiated from coccidioidomycosis by identification of Nocardia in Gram stain and culture of samples from sputum, pleural fluid, bronchial lavage, wound swabs, or cerebral spinal fluid, or by histologic findings on biopsy (eg, pulmonary nodule)
• Histoplasmosis
  • Infection caused by a dimorphic fungus, Histoplasma capsulatum, that grows as yeast at body temperature in mammals
  • Similar signs and symptoms include fever, headache, malaise, cough, chest pain, erythema nodosum, erythema multiforme, and arthritis
  • Pulmonary histoplasmosis is difficult to distinguish clinically from coccidioidomycosis, but exposure history may differ
    • Histoplasmosis is more common in the eastern United States, especially in the Ohio and Mississippi River valleys; however, there are some areas of overlap in Central and South America
    • Exposure to bird or bat droppings also suggests histoplasmosis
  • Unlike coccidioidomycosis, disseminated histoplasmosis may manifest as oropharyngeal ulcers (involving the buccal mucosa, tongue, gingiva, and larynx) and as gastrointestinal ulcers and lesions
  • Differentiated from coccidioidomycosis by detecting antigens for histoplasmosis in specimens obtained from lavage and by results of biopsy of oropharyngeal ulcers, pulmonary lesions, or lymph nodes
• Blastomycosis
  • Infection caused by the inhalation of spores of Blastomyces dermatitidis
  • Similar features include influenzalike symptoms (eg, fever, headache, fatigue, nonproductive cough); acute blastomycosis may also present with pleuritic chest pain
  • Endemic regions are different, as blastomycosis occurs primarily in the Great Lakes region, the Ohio and Mississippi River valleys, and along the Saint Lawrence River
  • Blastomycosis may involve organs not usually affected by coccidioidomycosis, including the liver, breast, eye, thyroid, and adrenal gland
  • Differentiated from coccidioidomycosis by microscopic visualization and culture of Blastomyces dermatitidis from sputum or other clinically relevant specimens
• Primary or metastatic tumor
  • Pulmonary tumors
    • Chest pain, productive cough, and dyspnea are common manifestations of both pulmonary coccidioidomycosis and pulmonary tumors
    • History of travel to or living in endemic areas raises the likelihood of coccidioidal infection
  • Cerebral tumors
    • Severe headaches, nausea, vomiting, blurry vision, and sensorimotor impairment are common manifestations of coccidioidal meningitis and brain tumors
    • Unlike in coccidioidal meningitis, seizures are seen in half of all patients with brain tumors
  • Primary or metastatic tumors are differentiated from coccidioidomycosis by identification of tumor mass with CT or MRI and confirmed by tissue biopsy

Treatment Goals

• Treatment goals in patients with severe primary infection, disseminated disease, or immunosuppression include:
  • Control of infection
  • Restoration of organ function
  • Prevention of relapse upon discontinuation of therapy

Disposition

Admission criteria

General admission criteria

• Severe infection
  • Meningitis
  • Pneumonia with significant hypoxia or respiratory distress
  • Empyema
• Infection requiring surgical treatment
  • Osteoarticular infections resulting in the development of large abscesses, necrotic lesions, bony detachment, or joint instability
  • Disseminated cutaneous disease with large abscesses

Criteria for ICU admission

• Respiratory distress

Recommendations for specialist referral

• Refer to:
  • Infectious disease specialist for all patients with suspected or diagnosed coccidioidomycosis
  • Pulmonologist for pulmonary evaluation and bronchoscopy if pulmonary coccidioidomycosis is suspected
  • Orthopedic surgeon for surgical debridement in cases of disseminated osteoarticular disease; it is recommended that surgical consultation be obtained periodically during course of the disease 
  • Plastic surgeon for debridement of large lesions or abscesses on the skin

Treatment Options

Customize treatment regimens according to the patient’s immune status and the severity of infection 

• Oral triazoles, specifically fluconazole and itraconazole, are prescribed for most cases of coccidioidomycosis requiring antifungal drug therapy because they exhibit low toxicity 
  • Fluconazole is preferred over itraconazole because it is better tolerated and has superior systemic absorption
  • Triazoles can cause adverse hepatic effects
    • Monitor liver function
• When disease is refractory or imminently life-threatening, IV amphotericin B is the preferred drug to start; patient may be switched to an azole when clinical course stabilizes 
  • Amphotericin B can cause renal toxicity and electrolyte abnormalities
    • Monitor renal function and electrolytes; reduce the dose or stop therapy in case of toxicity
• Optimal duration of therapy has not been determined, but in general, recommendations vary with the site and extent of infection; courses of months to years are recommended for most indications, with some circumstances (eg, meningitis) requiring lifelong treatment 
  • Response to treatment may be monitored by radiographic improvement, decline in quantitative serologic titers, and clinical judgment 
• Surgical debridement or drainage may be necessary for large areas of soft tissue destruction, abscesses, and bone involvement

Primary pulmonary infection

• Acute pneumonia
  • Treatment of primary pulmonary infection is of unproven benefit when infection is mild, there is no evidence of extrapulmonary disease, and no poor prognostic risk factors; it may be considered for patients with significant systemic complaints (eg, weight loss) or with antibody titers greater than 1:16 
  • Antifungal drug therapy is indicated in patients with significantly debilitating illness, extensive pulmonary involvement, prolonged infection, or immunosuppression 
    • Aggressive treatment is required for immunosuppressed individuals, including: 
      • Solid organ transplant recipients
      • Pregnant women
      • Patients with diabetes
      • Individuals with end-stage liver disease
      • Patients using systemic corticosteroids
      • Patients with HIV
        • Treatment is warranted if CD4⁺ T lymphocyte counts are below 250 cells/μL 
  • When treatment is indicated, a 3- to 6-month course of fluconazole or itraconazole is recommended 
    • Treat pregnant women with amphotericin B
• Diffuse progressive pneumonia
  • More severe form of disease
    • Initiate treatment with an azole or amphotericin B, and supplement with maintenance azole therapy for at least 1 year; indefinite azole therapy may be indicated for patients with ongoing immunodeficiency 
  • Residual nodules, cavities, and chronic infiltrates
    • Asymptomatic nodules and cavities do not require treatment 
    • Antifungal treatment should be prescribed for symptomatic cavities or chronic fibrocavitary disease 
      • Cavities larger than 5 cm are likely to persist and require prolonged antifungal therapy
      • Fluconazole or itraconazole are often prescribed for durations of more than 1 year 
      • If the response is poor despite prolonged therapy, increase dosage or prescribe amphotericin B or another azole 
      • Surgery to resect nodules or heal cavities is the last resort 
    • Oral azole is recommended when ruptured coccidioidal cavity exists (with planned surgical resection); if 2 or more surgical procedures are required, IV amphotericin B is recommended 

Disseminated extrapulmonary disease

• Disseminated cutaneous disease
  • Requires prolonged antifungal treatment with fluconazole or itraconazole 
  • Surgical debridement may be necessary if large abscesses are present 
• Disseminated osteoarticular infection
  • Azole therapy is preferred for osseous coccidioidomycosis; in severe disease (eg, disease causes joint instability), amphotericin B is recommended 
    • In patients who do not respond to initial oral azole therapy, strategies include switching therapy to another azole, to lipid-based amphotericin B or its deoxycholate form, or to an azole in combination with amphotericin B 
    • Several years of antifungal treatment may be required to render the disease inactive 
  • Surgical debridement or stabilization may be necessary in severe cases of osteoarticular infection causing joint instability
    • Surgical treatment is crucial when the vertebral column is involved because associated neurologic deficits may occur 
    • A sequestered paraspinal abscess should also be managed surgically 
• Coccidioidal meningitis
  • Treatment with a higher dose of oral fluconazole or itraconazole is indicated in these cases 
    • Lifelong treatment with azoles is recommended because of an extremely high relapse rate 
  • Patients not responding to oral fluconazole or itraconazole are treated with intrathecal amphotericin B; dose from daily to weekly, increasing the dose until patient becomes intolerant (eg, vomits, has transient mental status changes) 
  • Patients with elevated opening pressure on lumbar puncture require neurosurgical consultation because the condition will not resolve itself; repeated lumbar punctures may be required as initial management, with shunt placement likely to follow 
    • Early neurosurgical consultation and MRI are recommended for patients with elevated opening pressure

Primary cutaneous infection

• Typically resolves spontaneously without treatment 
• Surgical debridement may be necessary if large abscesses are present 

Drug therapy

• Triazoles
  • Fluconazole
    • For the treatment of disseminated (non-meningeal) or pulmonary coccidioidomycosis
      • Oral
        • Fluconazole Oral suspension; Neonates: 6 to 12 mg/kg/dose PO once daily.
        • Fluconazole Oral suspension; Infants and Children: 6 to 12 mg/kg/dose (Max: 400 or 800 mg/dose) PO once daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
        • Fluconazole Oral tablet; Adolescents: 400 mg PO once daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
        • Fluconazole Oral tablet; Adults: 400 mg PO once daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
      • Intravenous
        • Fluconazole, Dextrose Solution for injection; Neonates: 6 to 12 mg/kg/dose IV once daily.
        • Fluconazole, Dextrose Solution for injection; Infants and Children: 6 to 12 mg/kg/dose (Max: 400 or 800 mg/dose) IV once daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
        • Fluconazole, Dextrose Solution for injection; Adolescents: 400 mg IV once daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
        • Fluconazole, Dextrose Solution for injection; Adults: 400 mg IV once daily. Duration of treatment varies with disease location and depends on clinical response; treatment may be necessary for 12 months or longer.
    • For coccidioidal meningitis
      • Fluconazole, Dextrose Solution for injection; Adults: doses of 800 to 1,200 mg IV daily have been used. 
    • For the treatment of disseminated (non-meningeal) or pulmonary coccidioidomycosis in patients with HIV
      • Oral
        • Fluconazole Oral tablet; Adolescents: 400 mg PO once daily in combination with amphotericin B deoxycholate or lipid amphotericin B. Continue fluconazole for at least 12 months.
        • Fluconazole Oral tablet; Adults: 400 mg PO once daily in combination with amphotericin B deoxycholate or lipid amphotericin B. Continue fluconazole for at least 12 months.
      • Intravenous
        • Fluconazole, Dextrose Solution for injection; Adolescents: 400 mg IV once daily in combination with amphotericin B deoxycholate or lipid amphotericin B. Continue fluconazole for at least 12 months.
        • Fluconazole, Dextrose Solution for injection; Adults: 400 mg IV once daily in combination with amphotericin B deoxycholate or lipid amphotericin B. Continue fluconazole for at least 12 months.
  • Itraconazole 
    • For treatment of severe, nonmeningeal coccidioidomycosis (diffuse pulmonary or severely ill patients with extrathoracic disseminated disease) 
      • Oral dosage (Sporanox capsule, solution, or equivalent)
      • Itraconazole Oral solution; Infants and Children: 2 to 5 mg/kg/dose (Max: 200 mg/dose) PO 3 times daily for 3 days, then 2 to 5 mg/kg/dose (Max: 200 mg/dose) PO twice daily thereafter, followed by chronic suppressive therapy, is recommended in HIV guidelines. Duration of therapy determined by clinical improvement and may take several weeks. Oral solution is preferred due to increased absorption.
      • Itraconazole Oral capsule; Adolescents: 200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily.
      • Itraconazole Oral capsule; Adults: 200 mg PO 3 times daily for 3 days, then 200 mg PO twice daily.
    • For the treatment of disseminated (non-meningeal) or pulmonary coccidioidomycosis in patients with HIV
      • Oral dosage (Sporanox capsule, solution, or equivalent)
        • Itraconazole Oral capsule; Adolescents: 200 mg PO twice daily in combination with amphotericin B deoxycholate or lipid amphotericin B. Continue itraconazole for at least 12 months.
        • Itraconazole Oral capsule; Adults: 200 mg PO twice daily in combination with amphotericin B deoxycholate or lipid amphotericin B. Continue itraconazole for at least 12 months.
• Polyene antifungal
  • For the treatment of severe disseminated (nonmeningeal) or diffuse pulmonary coccidioidomycosis 
    • Amphotericin B lipid complex
      • Amphotericin B Phospholipid Complex Suspension for injection; Neonates: 5 mg/kg/dose IV every 24 hours.
      • Amphotericin B Phospholipid Complex Suspension for injection; Infants, Children, and Adolescents: 5 mg/kg/dose IV every 24 hours.
      • Amphotericin B Phospholipid Complex Suspension for injection; Adults: 5 mg/kg/dose IV every 24 hours.
  • For the treatment of disseminated (non-meningeal) or pulmonary coccidioidomycosis in patients with HIV
    • Amphotericin B lipid complex
      • Amphotericin B Phospholipid Complex Suspension for injection; Infants and Children: 5 mg/kg/dose IV every 24 hours until clinical improvement, followed by fluconazole or itraconazole for a total of 12 months. May increase dose to 10 mg/kg/dose IV every 24 hours in patients with life-threatening infection. Some experts add fluconazole or itraconazole to amphotericin B at initiation of therapy and continue the triazole after stopping amphotericin B.
      • Amphotericin B Phospholipid Complex Suspension for injection; Adolescents: 3 to 5 mg/kg/dose IV every 24 hours until clinical improvement, followed by fluconazole or itraconazole for at least 12 months. Some experts add fluconazole or itraconazole to amphotericin B at initiation of therapy and continue the triazole after stopping amphotericin B.
      • Amphotericin B Phospholipid Complex Suspension for injection; Adults: 3 to 5 mg/kg/dose IV every 24 hours until clinical improvement, followed by fluconazole or itraconazole for at least 12 months. Some experts add fluconazole or itraconazole to amphotericin B at initiation of therapy and continue the triazole after stopping amphotericin B.

Nondrug and supportive care

Procedures

Surgical debridement 

General explanation

• Surgical removal of nonviable tissue
  • Removal of necrotic tissue promotes healing

Indication

• Management of severe cases of cutaneous or osteoarticular infection
• Recommended for large abscesses, destructive lesions, necrotic bone tissue, or fluid accumulation that impairs organ function

Contraindications

• Uncorrected coagulopathy

Complications

• Soft tissue defects and functional impairment if muscle or deeper tissue is removed
• Cosmetic disfigurement
• Bleeding

Surgical resection of pulmonary lesions and nodules

General explanation

• Resection of residual cavitary lesions or nodules
• Uses thoracotomy or video-assisted thoracoscopic surgery

Indication

• Pulmonary coccidioidomycosis with residual disease (lasting more than 2 years) resistant to antifungal therapy 
• Ruptured coccidioidal cavity

Contraindications

• Uncorrected coagulopathy

Complications

• Air leaks
• Bronchopleural fistula

Comorbidities

• HIV/AIDS
  • In addition to antifungals, use antiretroviral therapy to bring CD4⁺ T lymphocyte count above 250 cells/μL; when CD4⁺ T lymphocyte count is above 250 cells/μL, management of coccidioidomycosis is the same as for patients without HIV 
    • Active disease requires conventional course of therapy despite CD4⁺ T lymphocyte count 
    • Lifelong antifungal therapy may be required for patients with HIV, especially those with coccidioidal meningitis 
  • Prophylactic antifungal therapy in immunocompromised individuals, particularly patients with HIV/AIDS, has not been proven effective and is not recommended 
  • Yearly serologic testing and chest radiography is recommended for HIV-positive persons living in endemic areas, with preemptive treatment for coccidioidomycosis in those with newly positive serologic test results and a CD4⁺ T lymphocyte count less than 250 cells/μL 

Special populations

• Pregnant women are managed in the same manner as other patients, except for the following:
  • Avoid azoles during the first trimester as they are teratogenic; use amphotericin B instead where antifungal therapy is usually indicated 
    • Women who develop an initial nonmeningeal coccidioidal infection in the first trimester are treated with IV amphotericin B until reaching the second trimester, at which time oral azole is considered or IV amphotericin B is continued throughout pregnancy
    • Women who develop coccidioidal meningitis during the first trimester are treated with intrathecal amphotericin B, switching to an azole after the first trimester
  • Women with a history of coccidioidomycosis without active disease are at low risk of reactivation but should receive serologic testing every 6 to 12 weeks during pregnancy 
    • If titers increase or there is a positive serologic test result, reactivation is suggested and therapy should be considered
  • Severe coccidioidomycosis is more likely to develop in the postpartum period when patients are infected in the third trimester
    • Although an azole can be used, amphotericin B is the recommended initial treatment of choice
  • Breastfeeding is not recommended for mothers on azole therapy (except fluconazole therapy) 
• Neonates should not receive serologic testing during the first 3 months of life; use caution with interpretation of any positive test during the first year 
  • Treat infants suspected of having a coccidioidal infection with fluconazole until the diagnosis has been ruled out
• Patients on antiinflammatory medications (eg, prednisone, anti–tumor necrosis factor inhibitors)
  • May require lifelong antifungal therapy
• Patients who have received allogeneic or autologous hematopoietic stem cell transplant or solid organ transplant with acute or chronic pulmonary coccidioidomycosis: 
  • If patient is clinically stable and has normal renal function, standard dosing with fluconazole is recommended
  • If patient has very severe and/or rapidly progressing acute pulmonary or disseminated disease, amphotericin B is recommended; switch to fluconazole when stable
  • If patient has extrapulmonary coccidioidomycosis, treatment is the same as for nontransplant patients

Monitoring

• Follow-up visits every 3 to 6 months for up to 2 years are recommended to identify possible changes in condition, relapse, and disseminated disease based on radiographic studies, serial physical examinations and, in immunocompetent patients, serum antibody titers by complement fixation assay (which may return to negative with long-term control of disease) 
  • Monitor liver function in patients being treated with azoles 
  • Monitor renal function and electrolytes in patients being treated with amphotericin B 

Complications

• Development of pulmonary cavities
  • Cavities can cause discomfort and are susceptible to secondary infections by bacteria and other fungi
  • Pulmonary cavities can rupture, allowing pus and air to accumulate within the pleural cavity (pyopneumothorax)
  • Cavities less than 2.5 cm in diameter typically resolve within a year; those larger than 5 cm are likely to persist and require prolonged antifungal therapy 
• Immunosuppression can reactivate latent infections in individuals with a history of previous coccidioidomycosis 
• Chronic pulmonary dysfunction is observed in 5% to 10% of all cases and is associated with pleural tissue destruction and fibrosis 
• Intra-abdominal abscesses can develop even years after pulmonary exposure 

Prognosis

• Patients with subclinical or mild to moderate influenzalike symptoms see significant improvement within 2 to 3 weeks 
  • Profound fatigue lasting for weeks to months is not unusual
• Primary cutaneous infection typically heals spontaneously without treatment 
• Disseminated disease is typically fatal if not treated with systemic antifungals 
  • Relapse rate for cases of coccidioidal meningitis is extremely high (78%) 
• Overall, mortality rates are low (0.59 per 1 million persons-years) and have remained steady since 1997; an average of 200 coccidioidomycosis-related deaths annually were reported between 1990 and 2008 
• Primary infection confers lifelong immunity against subsequent exposure in healthy individuals 
• Men, people older than 65 years, inhabitants of endemic regions, and Hispanic, Filipino, and Native American populations have a higher risk of mortality 
• Erythema nodosum and erythema multiforme hypersensitivity reactions are a good prognostic indicator that disseminated or chronic disease will be unlikely 
• Infections in patients with diabetes who have uncontrolled blood glucose levels are less likely to resolve; relapses and chronic pulmonary dysfunction are more prevalent 
• Patients with HIV have a poorer prognosis, especially for disseminated disease, which has a reported fatality rate of 68% and a median survival of 54 days in this population 
• Relapse rates of 18% to 28% were reported after discontinuation of therapy with triazoles for nonmeningeal coccidioidomycosis 

Screening

At-risk populations

• HIV-infected persons living in endemic areas 

Screening tests

• Serologic testing (eg, enzyme immunoassay or immunodiffusion complement fixation) 

Prevention

• CDC recommendations to reduce coccidioidomycosis infection in immunocompromised individuals in regions where it is endemic include: 
  • Avoiding areas with lots of dust (eg, construction or excavation sites); if these areas cannot be avoided, wear an N95 respirator
  • Staying inside and closing windows during dust storms
  • Avoiding activities associated with close contact with dirt or dust (eg, yard work, digging, gardening)
  • Using air filtration systems while indoors
  • Cleaning skin injuries with soap and water, especially if wound exposed to dirt or dust
• Preemptively treat disease in HIV-infected persons with CD4⁺ T lymphocyte count less than 250 cells/μL and newly positive antibody test results 
• Patients undergoing organ transplant in an endemic area who do not have active coccidioidal disease are recommended to receive an oral azole for 6 to 12 months (eg, fluconazole 200 mg) 

References

DiCaudo DJ: Coccidioidomycosis: a review and update. J Am Acad Dermatol. 55(6):929-42; quiz 943-5, 2006