Dermatology

Coccidioidomycosis (Valley fever)

Are You Confident of the Diagnosis?

Coccidioidomycosis is a deep fungal infection associated with diverse cutaneous findings. Dermatologic manifestations may be the initial signs of the infection and are important clues to the diagnosis.

What you should be alert for in the history?

A key point in the patient's history is travel to or residence within an endemic area, specifically Arizona, central or southern California, southern New Mexico, west Texas, or less commonly, other arid regions of the western United States, Central America, and South America. The history occasionally includes an event that may have resulted in exposure to air-borne dust (for example, participation in an archeological expedition or hiking during a dust storm in Arizona); however, most patients living in endemic areas do not recall a specific time of exposure. The incubation period is typically 2 weeks with a range of 1 to 4 weeks.

Patients complain of influenza-like symptoms, especially cough, fever, and arthralgias. Some patients may have cutaneous manifestations with no associated systemic complaints.

Coccidioidomycosis primarily involves the lungs. Patients develop pneumonia or pulmonary nodules.

Pulmonary coccidioidomycosis induces a variety of reactive, immunologically mediated cutaneous eruptions. Rarely, the organisms spread hematogenously to the skin from the lungs, or are inoculated into the skin directly from the environment. Well-recognized cutaneous manifestations of coccidioidomycosis are listed in Table I. An individual patient typically presents with just one of the various manifestations, but occasional patients may sequentially develop two or more.

Table I.

Cutaneous manifestations of coccidioidomycosis
Acute exanthem
Erythema nodosum
Reactive interstitial granulomatous dermatitis
Sweet's syndrome
Disseminated coccidioidomycosis
Primary cutaneous coccidioidomycosis

ACUTE EXANTHEM

Characteristic features on physical examination

The acute exanthem of coccidioidomycosis is a generalized florid eruption occurring early in the course of the illness, often within 2 days after the onset of systemic symptoms (Figure 1). In some instances, the exanthem is the initial sign of illness. The eruption is symmetrically distributed and widespread. The most severely affected areas are often the flanks, back, and extremities.

Figure 1.

Acute exanthem of coccidioidomycosis. A florid generalized morbilliform eruption.

The eruption is typically morbilliform, but target-like features are often also present. There is frequently a clinical resemblance to erythema multiforme with target lesions on the palms and soles. Generalized pruritus may be associated and is sometimes severe. A mild oral enanthem is occasionally also present.

  • Expected results of diagnostic studies

The acute exanthem demonstrates nonspecific histopathologic findings. Mild epidermal spongiosis (Figure 2) or subtle interface dermatitis is present. A mild perivascular inflammatory infiltrate contains a mixed population of inflammatory cells, including lymphocytes, neutrophils, and eosinophils. Focal karyorrhectic debris may be present, but diagnostic features of vasculitis are not seen.

Figure 2.

Acute exanthem of coccidioidomycosis. Epidermal spongiosis (arrow) and mild perivascular inflammation. (H&E , X200).

In contrast to erythema multiforme, prominent necrotic keratinocytes are not a feature of the acute exanthem. Thus, biopsy may be helpful in ruling out erythema multiforme. Other entities in the differential diagnosis are more difficult to distinguish histopathologically from the acute exanthem, but may be ruled out by laboratory findings.

Serologic testing for Coccidioides is usually the single most helpful diagnostic test. However, seroconversion may not occur until 2 weeks after the onset of the exanthem. Repetition of serologic testing may be needed in 2 or 3 weeks if the initial result is negative. In coccidioidomycosis, even low titers, such as 1:2, may be indicative of active infection. In addition, chest radiograph is indicated, when the diagnosis of coccidioidomycosis is being considered.

The eruption subsides spontaneously over a period of weeks with or without treatment of the pulmonary infection.

Diagnosis confirmation

The clinical differential diagnosis of the acute exanthem includes an allergic drug eruption, viral exanthem, erythema multiforme, or severe generalized allergic contact dermatitis.

ERYTHEMA NODOSUM

Erythema nodosum occurs in association with a wide variety of systemic illnesses, including coccidioidomycosis. Erythema nodosum, when associated with coccidioidomycosis, is clinically similar to erythema nodosum arising in other clinical settings.

Characteristic findings on physical examination

Patients present with red tender subcutaneous nodules with a predilection for the anterior legs (Figure 3). The onset of erythema nodosum is typically one to three weeks after the development of systemic symptoms and is more delayed than other reactive manifestations.

Figure 3.

Erythema nodosum. Red nodules on the lower extremities.

Expected results of diagnostic studies

The diagnosis of erythema nodosum is usually established by the clinical features, but incisional skin biopsy may be considered if the diagnosis is unclear. If a patient with erythema nodosum lives in or has recently traveled to an endemic area, chest radiograph and serologic tests for Coccidioides are indicated.

Diagnosis confirmation

The clinical differential diagnosis may include other forms of panniculitis, polyarteritis nodosa, or subcutaneous lymphoma. The histopathologic pattern of granulomatous septal panniculitis is distinctive and may assist in ruling out the other entities.

REACTIVE INTERSTITIAL GRANULOMATOUS DERMATITIS

Characteristic findings on physical examination

Interstitial granulomatous dermatitis occurs as a reactive eruption in association with diverse inflammatory, autoimmune, neoplastic, and infectious diseases, including coccidioidomycosis. In cases associated with coccidioidomycosis, patients present with firm red dermal plaques asymmetrically distributed over widespread areas. Common sites of involvement are the knees, hands, wrists, ankles, and trunk (Figure 4). The plaques are usually non-tender.

Figure 4.

Reactive interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis.

Expected results of diagnostic studies

Skin biopsy reveals an interstitial dermal infiltrate of histiocytes admixed with variable numbers of neutrophils, multinucleate giant cells and eosinophils (Figure 5). Karyorrhectic debris may be present within the inflammatory infiltrate. Subepidermal edema is often present.

Figure 5.

Reactive interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. Interstitial infiltrate of histiocytes and multinucleate giant cells. (H&E , X400).

Diagnosis confirmation

In patients with pulmonary coccidioidomycosis, reactive interstitial granulomatous dermatitis must be distinguished from the granulomatous infiltrates of disseminated coccidioidomycosis. The key distinguishing feature is the absence of detectable organisms in reactive interstitial granulomatous dermatitis. Specials stains for fungi are negative, and fungal cultures of the skin yield no growth.

If the serologic results are not yet known, the differential diagnosis includes other systemic diseases that may induce a granulomatous reaction pattern in the dermis. Infections reported in association with an interstitial granulomatous dermatitis include Epstein Barr virus, Hepatitis C, Mycoplasma, HIV, and Parvovirus. Idiopathic granuloma annulare may also be considered in the differential diagnosis histopathologically and sometimes clinically.

Serologic tests for Coccidioides are often the key to the diagnosis. Because interstitial granulomatous dermatitis occurs early in the course of the illness, initial serologic tests may be negative. Repeat serologies in two or three weeks are recommended if the initial results are negative. Chest radiograph is also indicated.

SWEET'S SYNDROME

Characteristic findings on physical examination

In highly endemic areas, such as Phoenix, Arizona, coccidioidomycosis is one of the most common underlying causes of Sweet's syndrome. Patients present with asymmetrically distributed painful boggy red plaques on the trunk, extremities, and face (Figure 6). The plaques may have a clinically pustular quality in their central portions. Annular features are common. The patient often has associated fever and peripheral blood neutrophilic.

Figure 6.

Sweet's syndrome associated with pulmonary coccidioidomycosis.

Expected results of diagnostic studies

Skin biopsy reveals a diffuse dermal neutrophilic infiltrate with admixed histiocytes and abundant leukocytoclastic debris. Subepidermal edema is prominent.

Diagnosis confirmation

Sweet's syndrome, when associated with coccidioidomycosis, is clinically similar to Sweet's syndrome arising in other clinical settings. Sweet's syndrome is classically associated with a nonspecific respiratory infection, presumably of viral origin. A variety of other systemic diseases, especially myeloproliferative disorders and acute myeloid leukemia, may be associated with Sweet's syndrome.

In a patient with coccidioidomycosis, the plaques of Sweet's syndrome must be distinguished from the neutrophilic abscesses that are sometimes seen in disseminated coccidioidomycosis. Special stains for fungi and cultures of the biopsied tissue should be performed to rule out disseminated coccidioidomycosis.

In some cases, Sweet's syndrome may be very similar clinically and histopathologically to interstitial granulomatous dermatitis. In such cases, the predominance of neutrophils and the absence of multinucleate giant cells favor Sweet's syndrome.

ERYTHEMA MULTIFORME

Although classic descriptions of coccidioidomycosis include erythema multiforme as a common reactive manifestation of the infection, no published cases fulfill the current histopathologic criteria for erythema multiforme. Previous reports most likely constituted examples of the acute exanthem (with target-like lesions) or an annular variant of Sweet's syndrome. True erythema multiforme, as currently defined, has not been histopathologically described in coccidioidomycosis. The reactive eruptions that are associated with coccidioidomycosis lack the prominent keratinocytic apoptosis of erythema multiforme.

DISSEMINATED COCCIDIOIDOMYCOSIS

Dissemination of the infection occurs in less than 1% of patients with pulmonary coccidioidomycosis. The primary site of infection is nearly always the lungs, from which the organisms may disseminate hematogenously. The skin is the most common site of dissemination. Cutaneous sites on the trunk, head, and extremities all may be involved.

What you should be alert for in the history?

Dissemination to the skin typically occurs several weeks or months after the onset of pulmonary coccidioidomycosis. Patients with dissemination are often systemically ill and complain of fever, cough, and dyspnea. Occasionally, however, disseminated lesions of coccidioidomycosis may occur in a healthy-appearing patient who does not recall any recent respiratory infection.

Characteristic features on physical examination

Disseminated cutaneous lesions may be solitary or multiple, and are morphologically diverse (Figure 7, Figure 8). Papules, pustules, vesicles, nodules, plaques, subcutaneous abscesses, or sinus tracts may occur, with or without ulceration. The surface of the lesions may be verrucous or smooth. In cases of disseminated coccidioidomycosis involving the skin, up to 90% have dissemination to other organs, especially to the lymph nodes, meninges, or bones.

Figure 7.

Disseminated coccidioidomycosis. Infiltrative plaques involving the ear, scalp and cheek.

Figure 8.

Disseminated coccidioidomycosis. Ulcerated nodule on the chest.

Expected results of diagnostic studies

In a patient who is confirmed to have coccidioidomycosis, disseminated lesions must be distinguished from the reactive manifestations of coccidioidomycosis, especially Sweet's syndrome and reactive interstitial granulomatous dermatitis. The key to the diagnosis of dissemination is identification of the organisms within the skin.

Skin biopsies reveal the diagnostic spherules of coccidioidomycosis. The organisms are usually readily visualized with standard hematoxylin-eosin stains, but special stains for fungi, such as periodic acid-Schiff (PAS) and methenamine silver stains may also assist in identification of spherules. The organism usually ranges in size from from 10 to 80 microns and are most commonly identified in the upper dermis (Figure 9). Numerous endospores are sometimes identified within the largest and most mature spherules.

Figure 9.

Disseminated coccidioidomycosis. Coccidioidal spherules within the dermis. Endospores (arrow) are evident within the largest spherules. (H&E , X400).

Other histopathologic features may include epidermal ulceration or pseudo-epitheliomatous hyperplasia. Transepidermal elimination of organisms sometimes occurs and appears histopathologically as spherules within the overlying crust. Granulomatous inflammation is consistently present, at least focally, but the overall composition of the infiltrate is highly variable. The predominant pattern of inflammation may consist of suppurative granulomas, lymphoplasmacytic infiltrates, sarcoid-type granulomas, neutrophilic abscesses, or rarely, eosinophil-predominant infiltrates.

The organism may also be identified by culture of skin biopsy specimens. If coccidioidomycosis is suspected, the laboratory should be alerted to the possibility, since cultures of coccidioidomycosis require special handing and potentially present a danger to laboratory personnel. Coccidioides species may also be specifically identified in tissue sections by polymerase chain reaction techniques or by in situ hybridization.

In disseminated coccidioidomycosis, the serologic titer often correlates with the severity of the infection. When dissemination is present, Coccidioides titers of 1:16 or greater are often obtained. In some cases of limited dissemination, lower titers (such as 1:2 or 1:4) are occasionally encountered. Immunosuppressed patients and patients with mild self-limited infections may not show evidence of seroconversion. In most patients, sequential serologic titers are helpful in monitoring the course of the infection. A falling titer is typically seen as the infection resolves.

Diagnosis confirmation

Clinically, disseminated coccidioidomycosis may resemble other infections such as blastomycosis, histoplasmosis, or cutaneous tuberculosis or may resemble a cutaneous lymphoma. Histopathologically, the large size of the organism is distinctive and assists in differentiating it from other deep fungal infections.

The closest consideration in the histopathologic differential diagnosis is blastomycosis. The smallest spherules of coccidioidomycosis overlap in size with the spores of blastomycosis. However, Blastomyces species show broad-based budding, a feature not seen in coccidioidomycosis. Mature spherules of Coccidioides species occasionally contain numerous endospores, a feature not seen in blastomycosis. Geographic location and travel history can also assist in differentiating these two infections in most cases. Serological testing alone may not necessarily differentiate the two infections, since serological cross-reactivity may occur with Coccidioides and Blastomyces.

In disseminated coccidioidomycosis, the serologic titer often correlates with the severity of the infection. When dissemination is present, Coccidioides titers of 1:16 or greater are often obtained. In some cases of limited dissemination, lower titers (such as 1:2 or 1:4) are occasionally encountered. Immunosuppressed patients and patients with mild self-limited infections may not show evidence of seroconversion. In most patients, sequential serologic titers are helpful in monitoring the course of the infection. A falling titer is typically seen as the infection resolves.

PRIMARY CUTANEOUS COCCIDIOIDOMYCOSIS

Primary cutaneous coccidioidomycosis is exceedingly rare. Approximately 20 cases have been reported in the literature. The infection is transmitted to the skin by direct inoculation from the environment. Some reported cases have occurred following injury from a wooden splinter or from a broken laboratory pipette. In the skin, the infection typically gives rise to an ulcer or nodule. Sporotrichoid spread may occur in a linear pattern along the pathway of lymphatics, and lymph nodes may become secondarily involved.

Primary cutaneous coccidioidomycosis is histopathologically similar to disseminated coccidioidomycosis. Organisms may be identified by histopathology or by culture. Clinical correlation is needed to distinguish primary from secondary involvement of the skin. Disseminated infection can present as a single cutaneous lesion. Radiographic evaluation of the chest may be helpful in determining whether the primary infection originated in the lungs. High complement fixation titers (> 1:16) are suggestive of dissemination, rather than primary cutaneous infection.

Who is at Risk for Developing this Disease?

All exposed persons, either healthy or immunocompromised, are potentially at risk for developing coccidioidomycosis, unless the person has developed immunity from prior infection. Persons of all ages are affected. The severity of the clinical course, however, is greatly influenced by host factors. Immunosuppressed patients, including allograft recipients, other patients receiving immunosuppressant therapies, and HIV-infected patients, have a particularly high risk of fulminant disease and dissemination.

Genetic factors also contribute significantly to the host's immune response. Otherwise healthy Filipinos and African Americans have a markedly increased risk of a severe clinical course. Pregnant woman of all ethnic backgrounds, particularly during the third trimester and post-partum period, also have an increased risk of severe infection.

The severity of the clinical course also correlates directly with the number of inhaled organisms, even in healthy persons with no specific risk factors. A heavy concentration of inhaled organisms (as encountered by archeological excavators) may be associated with more severe pneumonia.

What is the Cause of the Disease?

Pathophysiology

Coccidioides species are the dimorphic fungi that cause coccidioidomycosis. C immitis is limited mostly to California. C posadasii is the non-Californian species found in Arizona and in most other endemic areas. Both species have a similar life cycle and similar clinical manifestations.

The organisms exist in a filamentous (hyphal) form in the soil. Under certain environmental conditions, the hyphae give rise to arthrospores, which are carried by the wind. Arthrospores may implant in favorable soil and give rise to additional hyphae. However, if arthrospores are inhaled by a host, they implant in the lungs and enter into the parasitic phase of the organism's life cycle by transforming into spherules.

Spherules enlarge and form numerous endospores. As the spherules burst, the endospores are released into the adjacent tissues, and the infection is propagated. The hyphal form, which is found in the environment or in laboratory cultures, is extremely infectious. The spherule form, which occurs in the parasitic phase of the organism, does not spread to other persons. Thus, patients with coccidioidomycosis are not contagious to others.

Systemic Implications and Complications

Coccidioidomycosis is usually limited to the lungs. In more than half of cases, the pulmonary manifestations are subclinical, producing minimal if any respiratory symptoms. Often, however, the infection produces a moderate influenza-like illness for a period of weeks. Occasionally, even in immunocompetent persons, coccidioidomycosis runs a fulminant course with severe pneumonia. Chronic pulmonary infection sometimes occurs and manifests as persistent nodules or cavities within the lungs.

Especially in severe infections, the organisms may disseminate hematogenously to other organs. The skin is the most common extrapulmonary site. Dissemination to the bones may cause severe morbidity. Dissemination to the meninges may produce hydrocephalus and neurologic deficits. Coccidioidomycosis may be fatal, especially in immunosuppressed patients. Death may occur due to respiratory failure or central nervous system (CNS) involvement.

Treatment Options

Treatment options are summarized in Table II and Table III.

Table II.

Antifungal Therapy (Adult doses)
Medical Treatment Surgical Procedures
Fluconazole 400-800mg daily by mouth daily Resection of complicated pulmonary cavities
Itraconazole 200mg two to three times daily by mouth Debridement of disseminated bony abscesses
Posaconazole 200mg/5mL oral suspension, 400mg daily Excision of disseminated cutaneous lesions
   
Fluconazole 400-800mg daily intravenously  
Itraconazole 200mg two to three times daily intravenously  
Amphotericin B deoxycholate intravenously  
Amphotericin B colloidal dispersion intravenously  
Amphotericin B lipid complex intravenously  
Amphotericin B liposomal intravenously  

Table III.

Therapy for Reactive Cutaneous Manifestations (Adult doses)
Medical Treatment
Triamcinolone acetonide cream 0.1% applied twice daily to affected areas as needed
Hydroxyzine hydrochloride 10-50mg three times daily as needed for pruritus
Acetaminophen 325-650mg every 4 to 6 hours by mouth as needed for pain
Ibuprofen 200-400mg every 4 to 6 hours as needed for pain

Optimal Therapeutic Approach for this Disease

Multiple factors must be considered in deciding upon therapy for coccidioidomycosis. Therapeutic decisions are usually based upon the severity of the pulmonary infection, the risk factors of the host, and the possible presence of dissemination. Accordingly, therapy is usually directed by infectious disease specialists, pulmonologists, or (in endemic areas) by primary care physicians, while the dermatologist serves an important adjunctive role in the identification of cutaneous manifestations. One of the most helpful contributions of the dermatologist is to distinguish reactive manifestations from disseminated infection. This distinction has significant implications for therapy.

Treatment of uncomplicated coccidioidal pneumonia is controversial. In many cases, patients are simply followed without antifungal treatment, and the infection usually resolves spontaneously over a period of weeks or months. It is not known whether antifungal treatment accelerates the resolution of reactive cutaneous manifestations. The patient's pulmonary infection is monitored clinically and radiographically on a periodic basis to assure resolution of the infection. However, this observational approach is controversial. Some authorities advocate early treatment with antifungal therapy for all symptomatic patients.

Complicated or persistent pneumonia and all disseminated infections do require therapeutic intervention in all cases. Patients with risk factors for severe infection also require therapy. Recommended dosing regimens are variable and depend upon the severity of infection, site of dissemination (if applicable), and underlying risk factors of the host.

For most patients with disseminated cutaneous lesions, fluconazole is considered the treatment of choice. Fluconazole has good bioavailability and penetrates cutaneous adnexa in high concentrations. Itraconazole is also a first-line azole for coccidioidomycosis; however, variable absorption may be problematic.

If itraconazole is selected, serum levels should be measured to document adequate absorption. For uncomplicated pulmonary infections, treatment is typically continued for 3 to 6 months. Disseminated infections involving the skin are treated for at least 6 to 12 months. Duration of therapy is dependent upon clinical response and serologic titers.

As the infection wanes, the complement fixation titers are expected to decrease and may be become undetectable. However, relapsed infections are common when antifungal therapy is discontinued. Lifelong azole therapy is needed in some cases. In cases with meningeal involvement, lifelong azole therapy is generally indicated.

Posaconazole and voriconazole are newer azoles with potential utility in the treatment of coccidioidomycosis. Posaconazole has recently been reported to be effective in some coccidioidal infections that are refractory to other azoles. Voriconazole has also been demonstrated to have activity against Coccidioides species. Additional studies are needed to examine the efficacy of the newer azoles with comparison to fluconazole and itraconazole.

Amphotericin B deoxycholate is less commonly used for the treatment of coccidioidomycosis, given its higher rate of adverse effects. The medication is administered intravenously. Infusion is often associated acutely with fever, chills, rigors, headache, nausea, and vomiting. Hypertension, hypotension, and hypoxia may occur. Premedication with acetaminophen 650-1000mg and diphenhydramine 50mg are typically given. Metaclopramide may be needed to control vomiting.

Amphotericin B deoxycholate is also nephrotoxic and may induce anemia and cardiomyopathy. Newer lipid formulations of amphotericin B (amphotericin B colloidal dispersion, amphotericin B lipid complex, and amphotericin B liposomal) offer the substantial benefit of reduced nephrotoxicity.

The azoles have largely supplanted amphotericin B for the treatment of coccidioidomycosis. Amphotericin derivatives are still considered in specific circumstances of severe pulmonary involvement, rapidly progressive infection, or failed azole therapy. Amphotericin also is given to pregnant patients with coccidioidomycosis, since azoles are contraindicated during pregnancy.

In addition to antifungal therapy, some patients may benefit from symptomatic treatment of cutaneous manifestations. The acute exanthem may be severely pruritic in some cases. Hydroxyzine 10-50mg three times daily may be used as needed for control of pruritus. Triamcinolone cream 0.1% applied twice daily may also provide symptomatic relief.

For painful lesions of erythema nodosum or Sweet's syndrome, over-the counter acetaminophen or ibuprofen may be used as directed. Oral corticosteroids are best avoided in cases of Sweet's syndrome induced by coccidioidomycosis, since corticosteroids may dampen the host's immunologic response to the organism. In most cases, the reactive manifestations of coccidioidomycosis subside spontaneously over a period of weeks. Interstitial granulomatous dermatitis may persist up to several months or more, but is not usually associated with significant pain or pruritus.

Patient Management

Patients with coccidioidomycosis are typically monitored by infectious disease specialists, pulmonologists or primary care physicians, regardless of whether systemic antifungal therapy is initiated. For patients not receiving specific therapy, follow-up is important to ensure appropriate resolution of the infection. For patients receiving antifungal therapy, patients are followed to assess the response to therapy and to monitor for side effects of medications. Dermatologic follow-up is also indicated in some cases to determine whether cutaneous symptoms are adequately controlled.

In patients with dissemination to the skin, follow-up on a monthly basis may be helpful in monitoring the response to systemic antifungal therapy. Dermatologists may assist in distinguishing disseminated lesions from other unrelated cutaneous lesions.

Unusual Clinical Scenarios to Consider in Patient Management

In disseminated coccidioidomycosis, the skin occasionally serves as a sanctuary site for disseminated organisms. Even after the pulmonary infection has resolved, localized cutaneous plaques and nodules containing coccidioidal spherules, may persist for months or many years. In such cases, excisional cutaneous surgery may be helpful in removing the persistent nidus of infection. Concurrent treatment with systemic antifungal medications is recommended.

What is the Evidence?

Carpenter, JB, Feldman, JS, Leyva, WH, DiCaudo, DJ. "Clinical and pathologic characteristics of disseminated cutaneous coccidioidomycosis". J Am Acad Dermatol. vol. 62. 2010. pp. 831-7.

(Retrospective case series of more than 100 patients with disseminated lesions of coccidioidomycosis involving the skin. The inflammatory infiltrates in disseminated lesions showed a wide spectrum of findings. Suppurative and granulomatous infiltrates were most common; however, other patterns included neutrophil-predominant, plasmacytic, and eosinophil-predominant infiltrates.)

DiCaudo, DJ. "Coccidioidomycosis: a review and update". J Am Acad Dermatol. vol. 55. 2006. pp. 929-42.

(Clinical and pathologic review of cutaneous manifestations of coccidioidomycosis. The broad range of reactive cutaneous manifestations and disseminated lesions are discussed in detail.)

DiCaudo, DJ, Yiannias, JA, Lama, SD, Warschaw, KE. "The exanthem of acute pulmonary coccidioidomycosis: Clinical and histopathologic features of 3 cases and review of the literature". Arch Dermatol. vol. 142. 2006. pp. 744-6.

(Case series of three patients with a florid acute exanthem associated with pulmonary coccidioidomycosis The exanthem clinically resembled erythema multiforme, but differed histopathologically. In two of the three patients, the eruption began before the presence of detectable antibodies in the serum. Hence, repeat serologic testing in 2 or 3 weeks may be helpful in suspected cases.)

DiCaudo, DJ, Ortiz, KJ, Mengden, SJ, Lim, KK. "Sweet syndrome (acute febrile neutrophilic dermatosis) associated with pulmonary coccidioidomycosis". Arch Dermatol. vol. 141. 2005. pp. 881-4.

(Description of two patients with Sweet's syndrome occurring during the onset of pulmonary coccidioidomycosis. Recognition of underlying coccidioidomycosis is important so that systemic corticosteroids are not given for treatment the Sweet's syndrome.)

DiCaudo, DJ, Connolly, SM. "Interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis". J Am Acad Dermatol. vol. 45. 2001. pp. 840-5.

(Description of five patients with interstitial granulomatous dermatitis occurring as a reactive manifestation of pulmonary coccidioidomycosis. Cultures and stains revealed no fungi within the skin. Distinction from disseminated coccidioidomycosis is important in order to determine appropriate therapy.)

DiCaudo, DJ. "Coccidioidomycosis". Semin Cutan Med Surg. vol. 33. 2014. pp. 140-5.

(A review of diverse cutaneous manifestations of coccidioidomycosis, including clinical photos of reactive manifestations and disseminated infection.)

Quimby, SR, Connolly, SM, Winkelmann, RK, Smilack, JD. "Clinicopathologic spectrum of specific cutaneous lesions of disseminated coccidioidomycosis". J Am Acad Dermatol. vol. 26. 1992. pp. 79-85.

(Case series of six patients with disseminated coccidioidomycosis involving the skin.)

Galgiani, JN, Ampel, NM, Blair, JE, Catanzaro, A, Johnson, RH, Stevens, DA. "Coccidioidomycosis". Clin Infect Dis. vol. 41. 2005. pp. 1217-23.

(Detailed therapeutic guidelines for coccidioidomycosis, currently available online at the Infectious Diseases Society of America web site (www.IDSociety.org) under the tab for Practice Guidelines.)

Blair, JE. "State-of-the-art treatment of coccidioidomycosis: Skin and soft tissue infection". Ann NY Acad Sci. vol. 1111. 2007. pp. 411-421.

(Review of treatment for coccidioidomycosis disseminated to the skin or soft tissues. Fluconazole or itraconazole is the preferred approach and sometimes must be accompanied by surgical intervention for successful treatment.)

Johnson, RH, Einstein, HS. "Amphotericin B and coccidioidomycosis". Ann NY Acad Sci. vol. 1111. 2007. pp. 434-41.

(Detailed description of amphotericin B as a therapy for coccidioidomycosis. Discussion includes both amphotericin B deoxycholate and the newer lipid preparations.)

Stevens, DA, Clemons, KV. "Azole therapy of clinical and experimental coccidioidomycosis". Ann NY Acad Sci. vol. 111. 2007. pp. 442-54.

(Review of azole therapy for coccidioidomycosis. Standard regimens of fluconazole and itraconazole are described in detail. The newer azole, posaconazole, is also discussed.)

Mease, L. "Pulmonary and extrapulmonary coccidioidomycosis, active component, U.S. Armed Forces 1999-2011". MSMR. vol. 19. 2012. pp. 2-4.

(This report describes the incidence and demographic features of coccidioidomycosis in Armed Services personnel over a 12-year period. Service members of Asian/Pacific Islander ethnicity had markedly higher incidence rates of pulmonary and disseminated coccidioidomycosis compared to service members from other ethnic/racial groups.)

Welsh, O, Vera-Cabrera, L, Rendon, A, Gonzalez, G, Bonifaz, A. Clin Dermatol. vol. 30. 2012. pp. 573-591.

(Review of history, pathogenesis, clinical manifestations, and treatment of coccidioidomycosis.)

Cole, GT, Hurtgen, BJ, Hung, C-Y. "Progress toward a human vaccine against coccidioidomycosis". Curr Fungal Infect Rep. vol. 6. 2012. pp. 235-244.

(This review describes strategies that are currently being explored to develop a vaccine for coccidioidomycosis.)

Wack, EE, Ampel, NM, Sunenshine, RH, Galgiani, JN. "The return of delayed-type hypersensitivity skin testing for coccidioidomycosis". Clin Infect Dis. vol. 61. 2015. pp. 787-91.

(This review of delayed hypersensitivity testing for coccidioidomycosis includes detailed explanations of the clinical and epidemiologic uses for skin testing in coccidioidomycosis.)

Stockamp, NW, Thompson, GR. "Coccidioidomycosis". Infect Dis Clin North Am. vol. 30. 2016. pp. 229-46.

(Review article from 2016 with expanded focus on pulmonary manifestations, coccidioidal meningitis, and approach to treatment.)
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