Coccidioides/Coccidioidomycosis

Coccidioidomycosis, commonly known as San Joaquin Valley fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia and can cause severe disease in the immunocompromised. Patients may present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, chills, cough, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, and shortness of breath. The diagnosis is supported by clinical history, radiology, microscopy, fungal culture, and serological data. Management involves antifungals and supportive care. In severe disease, addressing the etiology of immunosuppression is critical.

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General Characteristics and Epidemiology

Basic features of coccidioides

Taxonomy:

  • Order: Onygenales
  • Family: Onygenaceae
  • Genus: Coccidioides

Forms:

  • Dimorphic fungus
  • Exists as both mycelia or as spherules (asexual forms) 

Reproduction:

  • No sexual form has been found.
  • Mycelia and spherules undergo binary fission.
  • Arthroconidia are the infectious particles of the Coccidioides species.
    • Transform into spherules in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs and tissues
    • Spherules are filled with endospores that burst and amplify the infection.

Clinically relevant species

Coccidioidomycosis (also known as San Joaquin Valley fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever) can be caused by:

  • Coccidioides immitis 
  • Coccidioides posadasii

Epidemiology

  • In North America, Coccidioides is endemic to the southwestern United States:
    • California
    • Arizona
    • Utah
    • Nevada
    • New Mexico
  • Approximately 30%–60% of people who live in endemic areas are exposed at some point.
  • Incidence: approximately 42 cases per 100,000 people
    • Highest incidence in elderly
    • Can cause 15%–30% of community pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia in these areas

Pathogenesis

Reservoir

  • Soil in endemic regions
  • Rodents may serve as animal reservoirs (no reported zoonotic transmission to humans).

Transmission

Coccidioides arthroconidia can become airborne when soil is disturbed, allowing transmission via inhalation.

Host risk factors

  • Progressive coccidioidomycosis is uncommon in healthy people, and risk factors include:
    • AIDS infection
    • Use of immunosuppressant medications
    • Chronic steroid use
    • Elderly
    • Pregnant patients
    • History of diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus 
    • African American or Filipino ethnicity 
  • Those with high spore exposure are also at an increased risk:
    • Construction workers
    • Farmers
    • Archaeologists

Pathogenesis

  • Inhalation of arthroconidia → develop into tissue-invasive spherules 
    • Enlarge and rupture, releasing thousands of endospores → can form new spherules
    • Can be self-limiting or cause pulmonary disease
    • Can trigger local inflammatory response 
      • Infiltration of neutrophils and eosinophils
      • Granulomatous response with B and T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and macrophages
  • Disseminated disease occurs via hematogenous spread (particularly in immunocompromised and pregnant patients)
  • Cutaneous disease can result from either:
    • Dissemination
    • Direct inoculation

Clinical Presentation and Diagnosis

The clinical presentation can vary from asymptomatic to life-threatening. The incubation period is 1–4 weeks after exposure.

Constitutional symptoms

  • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Night sweats
  • Anorexia
  • Weight loss
  • Weakness
  • Chills

Pulmonary involvement

  • Chest pain
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Cough
    • Dry or with sputum 
    • May present with hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis

Cutaneous involvement

Cutaneous involvement may occur in conjunction with pulmonary involvement, with direct inoculation, or from disseminated disease.

  • Single or multiple granulomatous skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions
  • Abscesses
  • Draining sinus tracts
  • Immunologically induced eruptions:
    • Erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme
    • Erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum

Disseminated infection

Disseminated infection is defined as disease outside the thoracic cavity and is considered an AIDS-defining illness. Patients can present with the following (this list is not exhaustive):

  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis 
  • Muscle pain
  • Arthritis (particularly involving the knee)
  • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis

Classic triad of coccidioidomycosis

“Desert rheumatism” is often defined by the presence of:

  • Fever
  • Arthralgia
  • Erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum

Diagnosis

The diagnosis is made based on history and physical exam with supporting imaging and laboratory data.

Laboratory investigations

  • Fungal cultures
  • Microscopy for spherules in body fluid samples
  • Serologic testing
    • Enzyme immunoassay
    • Complement fixation (IgG antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins)
    • Immunodiffusion kit (IgM or IgG antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins)
  • PCR for lower respiratory tract samples (not widely available)
  • Urine antigen testing

Imaging modalities

  • Chest radiography
    • Pulmonary infiltrates, nodules, and cavities
    • Pleural effusions
    • Adenopathy
  • CT chest
    • Pleural infiltrates
      • Micronodular
      • Tree-in-bud sign
      • Multifocal ground-glass opacities
    • Pleural effusions
    • Hilar adenopathy
    • Cavities
    • Diffuse miliary pattern in immunosuppressed
Anteroposterior chest x-ray pulmonary fibrosis coccidioidomycosis

This anteroposterior chest X-ray revealed pulmonary changes indicative of pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis in a case of coccidioidomycosis, caused by fungal organisms of the genus Coccidioides:
Because these changes also resemble those seen in other lung infections, including tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, the findings uncovered with a chest X-ray need to be coupled with serologic testing as well as possible tissue biopsy. The degree of fibrotic changes, indicative of scarring found on X-ray, can be directly correlated to the severity of the fungal infection.

Image: “A case of pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis caused by coccidioidomycosis” by CDC/Dr. Lucille K. Georg. License: Public Domain

Invasive sampling

  • Bronchoscopy with bronchoalveolar lavage
  • Cerebral spinal fluid
  • Biopsy of infected site

Management

General treatment strategies

  • Mild asymptomatic cases do not require treatment.
  • Antimicrobials for symptomatic patients or risk factors for disseminated disease 
  • Manage etiology of immunosuppression.
  • Supportive care with respiratory adjuvants and hemodynamic support
  • Surgery may be needed for progressive cavitary disease.

Antimicrobial therapy

  • Fluconazole (preferred) or itraconazole for mild-to-moderate disease
  • Posaconazole and voriconazole are alternative therapies.
  • Amphotericin B:
    • Preferred for severe disease or persistent infections
    • Switch to oral azole therapy once stabilized.

Complications and Prevention

Complications

Listed complications are associated with being immunocompromised and/or delay in treatment:

  • Severe pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, progressing to ARDS ARDS Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome
  • Pulmonary cavities 
    • May require surgical resection
    • Secondary bacterial or other fungal pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia may result from an existing cavity.
    • Pyopneumothorax can result from a ruptured cavity.
    • Ruptured cavities can lead to bronchopleural fistulas.
  • Chronic fibrocavitary pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia 
  • Disseminated disease

Prevention

It is difficult to prevent coccidioidomycosis when living in an endemic area. General strategies include:

  • Avoiding areas of dust (e.g., construction sites or excavation sites)
  • Wearing a respirator if unable to avoid dust
  • Avoiding contact with dirt
  • Avoiding dust storms
  • Addressing etiology of the immunocompromised state

Differential Diagnosis

  • Bacterial pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: patients may present with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, shortness of breath, cough, and malaise. A thorough history should address risk factors for typical versus atypical bacterial pneumonias. Diagnosis is based on history, exam, imaging, cultures, and antigen testing. Treatments include supportive care, supplemental oxygenation, and antimicrobials. 
  • Blastomycosis Blastomycosis Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis: endemic to the Ohio and Mississippi River valleys and the Great Lakes regions of the United States. Blastomycosis Blastomycosis Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis can present with pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions, osteomyelitis, and meningitis. The diagnosis is made by identifying the organism in sputum or tissue samples, culture, PCR, or antigen testing. Antifungals are used for treatment.
  • Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis: endemic to the Mississippi and Ohio River valleys. Patients can present with pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia, lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, hepatosplenomegaly, and oral ulcerations. Diagnosis is made with fungal cultures, serology, and antigen testing. Treatment is with antifungals and supportive care.
  • Tuberculosis: an infectious disease caused by the Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis complex bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview. Pulmonary disease presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, night sweats, cough, hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis, fatigue, and weight loss. Extrapulmonary manifestations can include pleurisy, meningitis, Pott disease, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis, and miliary disease. The diagnosis is established with tuberculin skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin test, sputum culture, and lung imaging. The mainstay of management is anti-mycobacterial drugs.
  • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis: an inflammatory disorder characterized by noncaseating granulomas in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, brain, eyes, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin. Diagnosis may be suggested radiographically and confirmed by biopsy. Treatment is with corticosteroids and other immunosuppressive agents.

References

  1. Akram, SM. (2021). Coccidioidomycosis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK448161/
  2. Ampel, NM, & Hoover, SE. (2015). Pathogenesis of coccidioidomycosis. Current Fungal Infection Reports, 9(4), 253–258. https://doi.org/10.1007/s12281-015-0242-1
  3. Centers for Disease Control and Prevention. (2020). About valley fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Centers for Disease Control and Prevention. https://www.cdc.gov/fungal/diseases/coccidioidomycosis/definition.html
  4. Galgiani, JN, Ampel, NM, Blair, JE, Catanzaro, A, Johnson, RH, Stevens, DA, & Williams, PL. (2005). Coccidioidomycosis. Clinical Infectious Diseases, 41(9), 1217–1223. https://doi.org/10.1086/496991
  5. Revankar, SG. (2021). Coccidioidomycosis (San Joaquin fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever; Valley fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever). MSD Manual Professional Version. Retrieved June 11, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/fungi/coccidioidomycosis
  6. Blair, JE, & Ampel, NM. (2020). Primary pulmonary coccidioidal infection. In Mitty, J. (Ed.), UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/primary-pulmonary-coccidioidal-infection
  7. Blair, JE, & Ampel, NM. (2020). Coccidioidomycosis: Laboratory diagnosis and screening. In Mitty, J. (Ed.), UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/coccidioidomycosis-laboratory-diagnosis-and-screening
  8. Jaroszewski, D, Blair, JE, & Ampel, NM. (2019). Management of pulmonary sequelae and complications of coccidioidomycosis. In Mitty, J. (Ed.), UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/management-of-pulmonary-sequelae-and-complications-of-coccidioidomycosis
  9. Hospenthal, DR, Thompson III, GR, Oppenheimer, AP, and Arsura, EL. (2019). Coccidioidomycosis and valley fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. In Bronze, M.S. (Ed.), Medscape. Retrieved June 11, 2021, from https://emedicine.medscape.com/article/215978-overview

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