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Chapter 219 | Coccidioidomycosis

Part 5 | Infectious Diseases · Part 5 – Infectious Diseases: Fungal

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Coccidioidomycosis (Valley fever) is caused by dimorphic soil-dwelling fungi of the genus Coccidioides (C. immitis and C. posadasii).
  2. Endemic in the Western Hemisphere (US: CA, AZ, NV, NM, UT, TX; Mexico, Central/South America).
  3. 60% of infected individuals are asymptomatic; 40% develop primary pulmonary infection.
  4. Robust cellular immune response is critical for control; necrotizing granulomas indicate resolved infection.
  5. Dissemination occurs in approximately 1% of infected individuals and is associated with lack of cellular immunity.
  6. Coccidioidal meningitis is uniformly fatal if untreated and requires lifelong triazole therapy.
  7. Triazole antifungals (fluconazole, itraconazole) are principal drugs; amphotericin B reserved for severe cases.
  8. High-dose triazole therapy may be teratogenic during the first trimester of pregnancy.
  9. Erythema nodosum and symmetrical arthralgias ('desert rheumatism') are common immunologic manifestations.
  10. Diagnosis relies on serology (EIA, CF, TP) and culture; antigenuria/antigenemia useful in immunosuppressed patients.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Life cycle of Coccidioides, including the mycelial phase in the environment and...

1. DEFINITION & OVERVIEW

📖 Harrison's defines this as:

Coccidioidomycosis, commonly known as Valley fever (see “Epidemiology,” below), is caused by dimorphic soil-dwelling fungi of the genus Coccidioides.

  • Coccidioidomycosis, commonly known as Valley fever, is caused by dimorphic soil-dwelling fungi of the genus Coccidioides.
  • Genetic analysis has demonstrated the existence of at least two species, C. immitis and C. posadasii.
  • These species are indistinguishable with regard to the clinical disease they cause and their appearance on routine laboratory media, although C. posadasii may grow more quickly at higher temperatures.
  • Thus, the organisms will be referred to simply as Coccidioides for the remainder of this chapter.

1.1 Fungal Biology

  • The fungus is known to inhabit the native soils within the endemic regions.
  • Because of the difficulty in isolating Coccidioides from environmental sites, the precise characteristics of potentially infectious soil are not known.
  • Alluvial alkaline deposits in regions of relative aridity with moderate temperature ranges are most closely associated with endemicity.
  • In the United States, several outbreaks of coccidioidomycosis have been associated with soil from archeologic excavations of Amerindian sites both within and outside of the recognized endemic region.
  • When isolated from the soil, Coccidioides is found no more than 2–20 cm below the surface, nor is it usually isolated from cultivated soil.
  • In addition to its saphrophytic soil phase, Coccidioides appears to have an endozoan life cycle, likely infecting burrowing rodents.
  • This would suggest that the organisms are concentrated in these rodents and their burrows rather than extant in the soil.

2. EPIDEMIOLOGY

  • Coccidioidomycosis is confined to the Western Hemisphere between the latitudes of 40°N and 40°S.
  • In the United States, areas of high endemicity include the southern San Joaquin Valley of California (hence the sobriquet “Valley fever”) and the south-central region of Arizona.
  • However, infection may be acquired in other areas of the southwestern United States, including the other southern counties in California, southern Nevada, southwestern Utah, southern New Mexico, and western Texas.
  • Cases acquired well outside the recognized endemic region have also been described, and a recent climate model suggests that the endemic range may expand further east and north over time.
  • Outside the United States, coccidioidomycosis is endemic to northern Mexico as well as to localized regions of Central America.
  • In South America, there are endemic foci in Colombia, Venezuela, northeastern Brazil, Paraguay, Bolivia, and north-central Argentina.
  • The number of reported cases of coccidioidomycosis has been steadily increasing over the past two decades.
  • In 2019, a total of 20,003 cases were reported.
  • The majority of these were either from Arizona or California, in approximately equal numbers, with Nevada, New Mexico, and Utah reporting a small fraction of cases.
  • The factors associated with these increases have not been elucidated but likely include an influx of older individuals without prior coccidioidal infection into endemic areas, construction activity, increased reporting, and changing climate.
  • Periods of aridity following rainy seasons are associated with increases in the number of symptomatic infections.

2.1 Risk Factors

  • Most cases of human coccidioidomycosis occur without obvious soil or dust exposure.
  • Climatic factors may increase the risk of infection.
  • Dissemination is more likely to occur in male patients, particularly those of African and perhaps Filipino ancestry.
  • Dissemination is more likely in persons with depressed cellular immunity, including patients with HIV-1 infection and peripheral blood CD4 counts of <250/μL.
  • Dissemination is more likely in those receiving chronic glucocorticoid therapy.
  • Dissemination is more likely in those with allogeneic solid-organ transplants.
  • Dissemination is more likely in those being treated with tumor necrosis factor-α antagonists or other biological response modifiers.
  • Women who acquire new coccidioidal infection during the second or third trimester of pregnancy or postpartum also are at significant risk for disseminated disease.

3. ETIOLOGY & PATHOPHYSIOLOGY

  • Clinical observations and data from animal studies strongly support the critical role of a robust cellular immune response in the host’s control of coccidioidomycosis.
  • Necrotizing granulomas containing spherules are typically identified in patients with resolved pulmonary infection.
  • In disseminated disease in which infection is not controlled, granulomas are generally poorly formed or do not develop at all, and a polymorphonuclear leukocyte response is frequently seen.
  • In patients who are asymptomatic or in whom the initial pulmonary infection has resolved, delayed-type hypersensitivity to coccidioidal skin antigens has been routinely documented and T-cell activation has been observed in peripheral blood stimulated with coccidioidal antigens.
  • In persons who have developed protective cellular immunity, spherules exist in the lungs for prolonged periods, possibly lifelong, in a latent state.
  • This results in the persistence of protective immunity but also places those infected at risk of recurrent active disease if that immunity should wane.

3.1 Life Cycle

  • On agar media and in the environment, Coccidioides organisms exist as filamentous molds or mycelia.
  • Individual filaments (hyphae) elongate and branch, some growing upward.
  • Portions of these aerial hyphae thicken and septate, and alternating cells then degenerate by autolysis, leaving barrel-shaped viable spores called arthroconidia.
  • Measuring approximately 2 μm by 5 μm, individual arthroconidia can easily dislodge from the hypha and become airborne.
  • These may persist in the air for prolonged periods.
  • When arthroconidia are inhaled by a susceptible host, their small size allows them to evade initial mechanical mucosal defenses and reach deep into the bronchial tree, where infection is initiated.
  • Once within a susceptible host, the individual arthroconidia enlarge, become rounded, and develop internal septations.
  • The resulting structures, called spherules, may attain sizes up to 200 μm and are unique to Coccidioides.
  • The septations encompass uninuclear elements called endospores.
  • Spherules may rupture and release packets of endospores that can themselves develop into new spherules, thus propagating infection locally.
  • If returned to artificial media or the soil, the fungus reverts to its mycelial stage.

3.2 Immune Response

  • In patients who are asymptomatic or in whom the initial pulmonary infection has resolved, delayed-type hypersensitivity to coccidioidal skin antigens has been routinely documented.
  • T-cell activation has been observed in peripheral blood stimulated with coccidioidal antigens.
  • In persons who have developed protective cellular immunity, spherules exist in the lungs for prolonged periods, possibly lifelong, in a latent state.
  • This results in the persistence of protective immunity but also places those infected at risk of recurrent active disease if that immunity should wane.

4. CLINICAL FEATURES

  • After infection, 60% of individuals are completely asymptomatic.
  • The other 40% have symptoms that are related primarily to pulmonary infection, including fever, cough, and pleuritic chest pain.
  • Symptoms generally occur from several days to up to 3 weeks after inhalation of arthroconidia.
  • The risk of symptomatic illness increases with age.
  • In addition to these local symptoms indicative of infection, there are several manifestations of primary pulmonary coccidioidomycosis that are due to an immunologic response.
  • Most prominent among these are cutaneous reactions.
  • A diffuse, erythematous maculopapular rash, known as toxic erythema, has been noted in some cases.
  • Erythema nodosum (see Fig. A1-39)—typically over the lower extremities—and erythema multiforme (see Fig. A1-24)—usually in a necklace distribution—may occur.
  • Lesions consistent with Sweet syndrome have also been reported (Chap. 21).
  • Cutaneous manifestations are especially common in women.
  • Symmetrical arthralgias (“desert rheumatism”), often involving the ankles, knees, and hips, may also occur with or without cutaneous manifestations.
  • Primary pulmonary coccidioidomycosis is often misdiagnosed as a community-acquired bacterial pneumonia.
  • However, the diagnosis of primary pulmonary coccidioidomycosis is strongly suggested by the findings of rash or symmetrical arthralgias in a patient with an appropriate exposure history.
  • The finding of any of the following is also strongly suggestive of coccidioidomycosis: a history of night sweats, marked fatigue, peripheral-blood eosinophilia, failure to improve with antibacterial therapy, and an upper lobe infiltrate or hilar or mediastinal lymphadenopathy on chest imaging.
  • In most patients, primary pulmonary coccidioidomycosis resolves without sequelae over several weeks.
  • However, several pneumonic complications may arise.
  • Pulmonary nodules are residua of the primary pneumonia.
  • Generally single, frequently located in the upper lobes, and usually ≤4 cm in diameter, nodules are often discovered on routine chest radiograph in asymptomatic patients.
  • Calcification is uncommon.
  • Coccidioidal pulmonary nodules can be difficult to distinguish radiographically from pulmonary malignancies.
  • Like malignancies, coccidioidal nodules often enhance on positron emission tomography.
  • However, unlike malignancies, routine computed tomography (CT) imaging often demonstrates multiple nodules and there may be microsatellite lesions, scattered smaller nodules surrounding the larger one.
  • These findings are not specific, and biopsy may be required to distinguish between these two entities.
  • Pulmonary cavities occur when a nodule extrudes its contents into the bronchial tree, resulting in a thin-walled shell.
  • Frequently asymptomatic, these cavities may on occasion be associated with persistent cough, hemoptysis, and pleuritic chest pain.
  • They may also become secondarily infected with bacterial oral flora, environmental fungi such as Aspergillus species, or even with Coccidioides growing from the cavity wall.
  • Rarely, a cavity may rupture into the pleural space, causing pyopneumothorax.
  • In such cases, patients present with acute dyspnea, and the chest radiograph reveals a collapsed lung with a pleural air-fluid level.
  • Chronic or persistent pulmonary coccidioidomycosis manifests with prolonged fever, cough, and weight loss and is radiographically associated with pulmonary scarring, fibrosis, and cavities.
  • It is most common in patients who already have chronic lung disease due to other etiologies.
  • In some cases, primary pneumonia presents as a diffuse reticulonodular pulmonary process in association with dyspnea and fever.
  • This manifestation of pulmonary coccidioidomycosis may occur in settings of intense environmental exposure or in those with profoundly suppressed cellular immunity, such as persons with untreated HIV-1 infection and markedly depressed peripheral blood CD4 cell count.
  • In the latter case, this picture is associated with unrestrained fungal growth and is frequently associated with fungemia.

4.1 Disseminated Disease

  • Clinical dissemination occurs in approximately 1% of infected individuals and is defined as finding the fungus outside the thoracic cavity.
  • Dissemination is more likely to occur in male patients, particularly those of African and perhaps Filipino ancestry, and in persons with depressed cellular immunity.
  • Dissemination may follow symptomatic or asymptomatic pulmonary infection and may involve only one site or multiple anatomic foci.
  • When it occurs, clinical dissemination is usually evident within the first 6 months after primary pulmonary infection and is generally associated with a lack of cellular immunity to Coccidioides.
  • Of the disseminated syndromes, coccidioidal meningitis is the most dire and is uniformly fatal if untreated.
  • Patients usually present with a persistent dull headache, often accompanied by lethargy, and confusion.
  • Nuchal rigidity, if present, is not severe.
  • Examination of cerebrospinal fluid (CSF) demonstrates lymphocytic pleocytosis with profound hypoglycorrhachia and elevated protein levels.
  • CSF eosinophilia is occasionally observed.
  • The diagnosis is usually established by finding coccidioidal complement-fixing antibody (see below) in the CSF in association with the CSF inflammatory pattern described above.
  • The fungus is isolated from the CSF in fewer than one-third of cases.
  • Magnetic resonance imaging with gadolinium frequently demonstrates enhancement in the basilar meninges.
  • With or without appropriate therapy, patients may develop hydrocephalus, usually communicating, which presents clinically as a marked decline in mental status, often with gait disturbances.
  • An elevated opening CSF pressure on lumbar puncture and dilated ventricles on brain imaging are hallmarks of this condition.

4.2 Complications

  • Pulmonary nodules are residua of the primary pneumonia.
  • Generally single, frequently located in the upper lobes, and usually ≤4 cm in diameter, nodules are often discovered on routine chest radiograph in asymptomatic patients.
  • Calcification is uncommon.
  • Pulmonary cavities occur when a nodule extrudes its contents into the bronchial tree, resulting in a thin-walled shell.
  • Frequently asymptomatic, these cavities may on occasion be associated with persistent cough, hemoptysis, and pleuritic chest pain.
  • They may also become secondarily infected with bacterial oral flora, environmental fungi such as Aspergillus species, or even with Coccidioides growing from the cavity wall.
  • Rarely, a cavity may rupture into the pleural space, causing pyopneumothorax.
  • Chronic or persistent pulmonary coccidioidomycosis manifests with prolonged fever, cough, and weight loss and is radiographically associated with pulmonary scarring, fibrosis, and cavities.
  • It is most common in patients who already have chronic lung disease due to other etiologies.

5. DIFFERENTIAL DIAGNOSIS

  • Primary pulmonary coccidioidomycosis is often misdiagnosed as a community-acquired bacterial pneumonia.
  • Coccidioidal pulmonary nodules can be difficult to distinguish radiographically from pulmonary malignancies.
  • Like malignancies, coccidioidal nodules often enhance on positron emission tomography.
  • However, unlike malignancies, routine computed tomography (CT) imaging often demonstrates multiple nodules and there may be microsatellite lesions, scattered smaller nodules surrounding the larger one.
  • These findings are not specific, and biopsy may be required to distinguish between these two entities.
  • False-positive results may occur in cases of histoplasmosis or blastomycosis.

5.1 Distinguishing Features

  • Community-acquired bacterial pneumonia: Often misdiagnosis, but diagnosis strongly suggested by rash or symmetrical arthralgias.
  • Pulmonary malignancy: Nodules often enhance on PET; coccidioidal nodules often show multiple nodules and microsatellite lesions on CT.
  • Histoplasmosis/Blastomycosis: False-positive results may occur in coccidioidomycosis serology.
  • Aspergillus species: May secondarily infect pulmonary cavities.

6. INVESTIGATIONS & DIAGNOSIS

  • Serology is the most common method to establish the diagnosis of coccidioidomycosis.
  • Several techniques are available, including the traditional tube-precipitin (TP) and complement-fixation (CF) assays, immunodiffusion TP and CF (IDTP and IDCF), and enzyme immunoassay (EIA) to detect IgM and IgG antibodies.
  • TP and IgM antibodies are found in serum soon after infection and persist for weeks to months.
  • They are not useful for gauging severity of disease.
  • The CF and IgG antibodies occur later in the course of the disease and persist longer than TP and IgM antibodies.
  • Rising CF titers are a reflection of fungal growth and are associated with clinical progression, and the presence of CF antibody in CSF is indicative of coccidioidal meningitis.
  • Antibodies disappear over time in persons whose clinical illness resolves and the presence of coccidioidal antibodies in the serum does not indicate immunity or control of coccidioidomycosis.
  • Because of its commercial availability, relatively rapid turnaround time, and higher sensitivity than other tests, EIAs for IgM and IgG are recommended for the initial diagnosis of coccidioidomycosis.
  • Both tests, but particularly the IgM EIA, are occasionally falsely positive, and results should be interpreted cautiously when used for screening purposes in asymptomatic individuals.
  • If either the IgM or IgG EIA serology is positive, immunodiffusion tests (IDTP and IDCF) or traditional TP and CF assays should be performed for confirmation.
  • If the IDCF or traditional CF assays are qualitatively positive, a CF titer should be requested.
  • The optical density obtained from the EIA IgG does not correlate with the serologic titer of either the IDCF or traditional CF assay and should not be used as a surrogate for a titer.
  • The CF titer is an important prognostic tool.
  • High titers, for example, those ≥1:32, suggest unrestrained fungal growth, predict disease activity, and suggest the possibility of extrathoracic dissemination.
  • Coccidioides grows within 3–7 days at 37°C on a variety of artificial media, including blood agar.
  • Therefore, it is always useful to obtain samples of sputum or other respiratory fluids and tissue for culture in suspected cases of coccidioidomycosis.
  • The clinical laboratory should always be alerted to the possibility of this diagnosis, since Coccidioides poses a significant laboratory hazard if it is inadvertently inhaled.
  • The organism can also be identified directly.
  • While treatment of samples with potassium hydroxide is rarely fruitful, examination of sputum or other respiratory fluids after Papanicolaou, Gomori methenamine silver, or calcofluor white staining may reveal spherules in a significant proportion of patients with pulmonary coccidioidomycosis.
  • For fixed tissues (e.g., those obtained from biopsy specimens), spherules with surrounding inflammation can be demonstrated with hematoxylin-eosin or Gomori methenamine silver staining.
  • A commercially available test for coccidioidal antigenuria and antigenemia has been developed and appears to be useful in immunosuppressed patients with severe or disseminated disease.
  • It is also useful when the CSF is assayed in cases of suspected coccidioidal meningitis.
  • Some laboratories offer genomic detection by polymerase chain reaction; this assay does not appear to be more sensitive than culture but can be more rapid.

6.1 Diagnostic Algorithm

  • Step 1: Initial Screening
  • If suspected: Obtain serum EIA for IgM and IgG.
  • If positive: Proceed to Step 2.
  • If negative in symptomatic patient: Consider culture or antigen testing.
  • Step 2: Confirmation
  • Perform immunodiffusion tests (IDTP and IDCF) or traditional TP and CF assays.
  • If IDCF or traditional CF assays are qualitatively positive: Request CF titer.
  • Do not use EIA IgG optical density as surrogate for titer.
  • Step 3: Prognosis & Dissemination Assessment
  • High CF titers (≥1:32): Suggest unrestrained fungal growth and extrathoracic dissemination.
  • CSF CF antibody: Indicative of coccidioidal meningitis.
  • Step 4: Culture & Staining
  • Obtain sputum or respiratory fluids for culture.
  • Alert laboratory to Coccidioides hazard.
  • Stain with Papanicolaou, Gomori methenamine silver, or calcofluor white.
  • For fixed tissues: Hematoxylin-eosin or Gomori methenamine silver staining.

6.2 Laboratory Hazards

  • Coccidioides poses a significant laboratory hazard if it is inadvertently inhaled.
  • The clinical laboratory should always be alerted to the possibility of this diagnosis.
  • The organism can also be identified directly.

7. MANAGEMENT & TREATMENT

  • Currently, two classes of antifungal agents are useful for the treatment of coccidioidomycosis.
  • While once prescribed routinely, amphotericin B in all its formulations is now reserved for only the most severe cases of dissemination and for intrathecal or intraventricular administration in patients with coccidioidal meningitis in whom other antifungal therapy has failed.
  • The original formulation of amphotericin B, which is dispersed with deoxycholate, is usually administered intravenously in doses of 0.7–1.0 mg/kg either daily or three times per week.
  • The newer lipid-based formulations are associated with less renal toxicity, but there are no studies indicating whether they lead to better improvement than the deoxycholate formulation in coccidioidomycosis.
  • The lipid dispersions are administered intravenously at doses of 3–5 mg/kg daily or three times per week.
  • Triazole antifungals are currently the principal drugs used to treat most cases of coccidioidomycosis.
  • Clinical trials have demonstrated the usefulness of both fluconazole and itraconazole as initial treatment.
  • Fluconazole has been the triazole of choice for the treatment of coccidioidomycosis in the past because of availability, cost, predictable oral absorption, and perceived lack of severe adverse events.
  • However, there are no studies demonstrating its superiority over other triazole antifungals, and evidence indicates that itraconazole is more effective against bone and joint disease and may be more effective for other forms of coccidioidomycosis.
  • For both drugs, a minimal oral adult dosage of 400 mg/d should be used.
  • The maximum dose of itraconazole is 200 mg three times daily, but higher doses of fluconazole may be given and 800 mg is frequently prescribed for coccidioidal meningitis.
  • The newer triazole antifungals, voriconazole and posaconazole, are useful for all types of clinical disease, including meningitis, and should be considered in cases where fluconazole or itraconazole therapy has failed.
  • To date, isavuconazole has been used in limited circumstances in coccidioidomycosis but also appears to be effective, including for meningitis.
  • High-dose triazole therapy may be teratogenic during the first trimester of pregnancy, and triazole therapy should be avoided in pregnant women during this period.
  • There are several new antifungal agents that are promising for the treatment of coccidioidomycosis in the future.
  • These include olorofim, oteseconazole, ibrexafungerp, fosmanogepix, and oral liquid nanocrystal amphotericin B.
  • At this time, only olorofim has been studied in human coccidioidomycosis, and none are currently approved for use in coccidioidomycosis.
  • However, olorofim has been studied in human coccidioidomycosis and has received U.S. Food and Drug Administration breakthrough therapy designation for difficult-to-treat Coccidioides meningitis.

7.1 Treatment by Clinical Presentation

  • Asymptomatic infection: None.
  • Primary pneumonia (focal): In most cases, none.
  • Diffuse pneumonia: Amphotericin B followed by prolonged oral triazole therapy.
  • Pulmonary sequelae (Nodule): None.
  • Pulmonary sequelae (Cavity): In most cases, none.
  • Chronic pneumonia: Prolonged triazole therapy.
  • Disseminated disease: Prolonged triazole therapy.
  • Skin, bone, joint, soft tissue disease: Prolonged triazole therapy.
  • Meningitis: Lifelong triazole therapy.
  • Note: See text for dosages and durations.

7.2 Drug Therapy Details

  • Amphotericin B (Deoxycholate):
  • Dose: 0.7–1.0 mg/kg.
  • Frequency: Daily or three times per week.
  • Route: Intravenously.
  • Use: Reserved for severe cases of dissemination and intrathecal/intraventricular administration in meningitis.
  • Amphotericin B (Lipid-based):
  • Dose: 3–5 mg/kg.
  • Frequency: Daily or three times per week.
  • Route: Intravenously.
  • Use: Associated with less renal toxicity.
  • Fluconazole:
  • Dose: 400 mg/d (minimal adult dosage).
  • Higher doses may be given.
  • Meningitis dose: 800 mg.
  • Use: Principal triazole of choice (availability, cost, absorption).
  • Itraconazole:
  • Dose: 200 mg three times daily (maximum dose).
  • Use: More effective against bone and joint disease.
  • Voriconazole/Posaconazole:
  • Use: Useful for all types of clinical disease, including meningitis.
  • Indication: Considered in cases where fluconazole or itraconazole therapy has failed.
  • Isavuconazole:
  • Use: Limited circumstances in coccidioidomycosis.
  • Efficacy: Appears to be effective, including for meningitis.
  • Olorofim:
  • Status: Studied in human coccidioidomycosis.
  • Approval: None currently approved for use.
  • Designation: U.S. FDA breakthrough therapy designation for difficult-to-treat Coccidioides meningitis.

7.3 Pregnancy Considerations

  • High-dose triazole therapy may be teratogenic during the first trimester of pregnancy.
  • Triazole therapy should be avoided in pregnant women during this period.

8. PROGNOSIS & COMPLICATIONS

  • In most patients, primary pulmonary coccidioidomycosis resolves without sequelae over several weeks.
  • Coccidioidal meningitis is the most dire and is uniformly fatal if untreated.
  • With or without appropriate therapy, patients may develop hydrocephalus, usually communicating, which presents clinically as a marked decline in mental status, often with gait disturbances.
  • An elevated opening CSF pressure on lumbar puncture and dilated ventricles on brain imaging are hallmarks of this condition.
  • Hydrocephalus may occur, requiring a cerebrospinal fluid shunt.

8.1 Prognostic Indicators

  • Rising CF titers are a reflection of fungal growth and are associated with clinical progression.
  • The presence of CF antibody in CSF is indicative of coccidioidal meningitis.
  • High titers (≥1:32) suggest unrestrained fungal growth, predict disease activity, and suggest the possibility of extrathoracic dissemination.
  • Antibodies disappear over time in persons whose clinical illness resolves.
  • The presence of coccidioidal antibodies in the serum does not indicate immunity or control of coccidioidomycosis.

9. SPECIAL CONSIDERATIONS

  • Dissemination is more likely to occur in male patients, particularly those of African and perhaps Filipino ancestry.
  • Dissemination is more likely in persons with depressed cellular immunity, including patients with HIV-1 infection and peripheral blood CD4 counts of 250/μL), and HIV suppression with viral load <50 copies/mL on antiretroviral therapy.
  • Fibrosing mediastinitis, which represents a chronic fibrotic reaction to past mediastinal histoplasmosis rather than an active infection, does not respond to antifungal therapy.
  • Often patients with mediastinal granuloma have chronic or progressive courses and receive treatment with itraconazole and corticosteroids to reduce disease progression.

9.1 Immunocompromised Hosts

  • Patients with HIV-1 infection and peripheral blood CD4 counts of <250/μL.
  • Patients receiving chronic glucocorticoid therapy.
  • Patients with allogeneic solid-organ transplants.
  • Patients being treated with tumor necrosis factor-α antagonists or other biological response modifiers.
  • Patients with persistently suppressed immunity: Lifelong itraconazole maintenance therapy recommended.
  • Patients with immune recovery: Maintenance therapy may not be necessary if clinical findings cleared, antigen levels <2 ng/mL, and immunosuppression substantially reduced.

9.2 Pregnancy

  • Women who acquire new coccidioidal infection during the second or third trimester of pregnancy or postpartum also are at significant risk for disseminated disease.
  • High-dose triazole therapy may be teratogenic during the first trimester of pregnancy.
  • Triazole therapy should be avoided in pregnant women during this period.

10. KEY PEARLS & CLINICAL TRAPS

  • Valley fever is the common name for coccidioidomycosis.
  • Desert rheumatism refers to symmetrical arthralgias involving ankles, knees, and hips.
  • Coccidioidal meningitis is uniformly fatal if untreated.
  • Erythema nodosum typically occurs over the lower extremities.
  • Erythema multiforme usually occurs in a necklace distribution.
  • Upper lobe infiltrate or hilar or mediastinal lymphadenopathy on chest imaging is strongly suggestive of coccidioidomycosis.
  • Failure to improve with antibacterial therapy is strongly suggestive of coccidioidomycosis.
  • Peripheral-blood eosinophilia is a suggestive finding.
  • Night sweats are a suggestive finding.
  • Marked fatigue is a suggestive finding.
  • Coccidioides poses a significant laboratory hazard if it is inadvertently inhaled.

10.1 Diagnostic Clues

  • History of night sweats.
  • Marked fatigue.
  • Peripheral-blood eosinophilia.
  • Failure to improve with antibacterial therapy.
  • Upper lobe infiltrate or hilar or mediastinal lymphadenopathy on chest imaging.
  • Rash or symmetrical arthralgias in a patient with an appropriate exposure history.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Life cycle of Coccidioides, including the mycelial phase in the...

Caption: FIGURE 219-1 Life cycle of Coccidioides, including the mycelial phase in the environment and the spherule phase in the host. — Figure 219-1: Life cycle of Coccidioides, including the mycelial phase in the environment and the spherule phase in the host. Arthroconidia (2 μm by 5 μm) are inhaled and develop into spherules (up to 200 μm) containing endospores within the host. Spherules rupture to release endospores that propagate infection locally or revert to mycelial stage in the environment.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.