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Coccidioidomycosis Treatment & Management

  • Author: Duane R Hospenthal, MD, PhD, FACP, FIDSA, FASTMH; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Aug 18, 2015
 

Approach Considerations

Most patients infected with Coccidioides are asymptomatic or have self-limited symptoms and require only supportive care. Symptomatic patients usually come to medical attention because of respiratory tract or systemic manifestations. Management in symptomatic patients varies with the clinical syndrome.

Because most Coccidioides infections resolve without specific therapy, few clinical trials have assessed outcomes in less-severe disease. Most treatment recommendations represent consensus guidelines based on the Mycosis Study Group trials and the experience of many investigators.

Even physicians in endemic regions disagree on who should be treated, the length of treatment, and what agent should be used.[64, 3] However, the Infectious Diseases Society of America has published Practice Guidelines for the Treatment of Coccidioidomycosis.[3]

Three questions should be asked before a case of coccidioidomycosis is treated.

  1. Is intervention necessary?
  2. If antifungal therapy would be beneficial, which agents are appropriate?
  3. Is a surgical procedure necessary for debridement and reconstruction of destructive lesions?

In the decision-making process, significant weight is given to the severity of infection, risk factors for dissemination (eg, race and ethnicity, extremes of age, immunologic status), any severe comorbidity (eg, diabetes, pregnancy, significant preexisting vital organ dysfunction, negative skin test results), and a serum complement-fixation IgG titer of at least 1:32.[14, 6, 2, 3, 7, 4, 8, 9, 59, 65, 60, 40, 45]

Commonly used indicators to judge the severity of illness include the following:

  • Continuous fever for longer than 1 month
  • Body-weight loss of more than 10%
  • Intense night sweats that persist for more than 3 weeks
  • Infiltrates that involve more than half of one lung or portions of both lungs
  • Prominent or persistent hilar adenopathy
  • Anticoccidioidal complement fixation (CF) IgG titers of 1:16 or higher
  • Absence of dermal hypersensitivity to coccidioidal antigens
  • Inability to work
  • Symptoms that persist for more than 2 months

Risk factors for dissemination for which treatment should be initiated include the following:

  • Primary infection during infancy
  • Primary infection during pregnancy, especially in the third trimester or immediately postpartum
  • Immunosuppression (eg, patients with HIV/AIDS, transplant recipients, patients receiving high-dose corticosteroids, those receiving anti–tumor necrosis factor [TNF] medications)
  • Chronic debilitation or underlying disease, including diabetes mellitus or preexisting cardiopulmonary disease
  • High inoculum exposures
  • Certain ethnicities, such as Filipino, black, or Hispanic
  • Age greater than 55 years

The objectives of treatment are resolution of infection, decrease of antibody titers, return of function of involved organs, and prevention of relapse.

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Antifungal Medications

If the option to treat is chosen, several medications are available for management. Amphotericin B, introduced in 1957, remains the treatment of choice for severe infections. It is usually reserved for worsening disease or lesions located in vital organs such as the spine. It can be administered either in the classic amphotericin B deoxycholate formulation or as a lipid formulation.

Azoles

The introduction of azoles revolutionized therapy for coccidioidomycosis, and these agents are usually the first line of therapy. However, none of the azoles is safe to use in pregnancy and lactation because they have shown teratogenicity in animal studies.

Of the azoles, ketoconazole is the only one that is approved by the US Food and Drug Administration (FDA) for treatment of coccidioidomycosis. Nevertheless, although it was initially used in the long-term treatment of nonmeningeal extrapulmonary disease, more-potent, less-toxic triazoles (fluconazole and itraconazole) have replaced it.

Itraconazole (400 mg/day) appears to have efficacy equal to that of fluconazole in the treatment of nonmeningeal infection and have the same relapse rate after therapy is discontinued. However, itraconazole seems to perform better in skeletal lesions,[66] whereas fluconazole performs better in pulmonary and soft tissue infection. Serum levels of itraconazole are commonly obtained at the onset of long-term therapy because its absorption is sometimes erratic and unpredictable.

Dosages vary but usually are as follows:

  • Amphotericin B deoxycholate - 0.5-1.5 mg/kg/day IV
  • Lipid formulations of amphotericin B - 2-5 mg/kg/day IV
  • Ketoconazole - 400 mg/day orally
  • Itraconazole - 200 mg 2-3 times/day orally
  • Fluconazole - 400-800 mg/day orally or IV

For patients who are unresponsive to fluconazole, options are limited. Several case reports have studied the efficacy of 3 newer antifungal agents in the treatment of disease that is refractory to first-line therapy: posaconazole and voriconazole (triazole compounds similar in structure to fluconazole) and caspofungin (glucan synthesis inhibitor of the echinocandin structural class).[67, 68, 69] However, these drugs have not been FDA approved, and clinical trials are lacking. Susceptibility testing of Coccidioides species in one report revealed uniform susceptibility to most antifungal agents, including these newer drugs.[70]

In very severe cases, combination therapy with amphotericin and an azole have been postulated, although no trials have been conducted. Caspofungin in combination with fluconazole has been cited as beneficial in a case report of a 31-year-old Korean man with coccidioidal pneumonia.[71] In a case report of a 23-year-old black male with HIV and coccidioidal meningitis, combination therapy of amphotericin B and posaconazole led to clinical improvement.[72]

Posaconazole has been approved by the European Commission as salvage therapy for refractory coccidioidomycosis.[73] Clinical trials are now ongoing for further evaluation.[74, 75, 67]

Anecdotal reports show that 800 mg/day of posaconazole (a derivative of itraconazole) in divided doses was successful and caused relatively few side effects in patients in whom conventional therapy had failed. Long-term therapy (1-2 years) was well-tolerated. In one case series, 2 patients treated with posaconazole experienced symptomatic and laboratory improvement.[72] In another study, 17 of 20 patients with pulmonary and nondisseminated disease responded well to posaconazole 400 mg/day, and no adverse events were noted.[76]

Voriconazole is also being studied in salvage therapy for refractory cases. A case report indicated that voriconazole in combination with amphotericin B as salvage therapy for disseminated coccidioidomycosis was successful.[77]

Several case reports have studied caspofungin, with differing results. Caspofungin 50 mg/day following administration of amphotericin B in a patient with acute pulmonary coccidioidomycosis who had undergone transplantation showed promising results.[78, 79] In a patient with disseminated coccidioidomycosis, first-line therapy with amphotericin B and caspofungin alone failed to elicit a response, but the patient was then given caspofungin combined with fluconazole, with good results.[71]

A third published report described a patient with disseminated and meningeal coccidioidomycosis in whom conventional therapy with fluconazole, voriconazole, and amphotericin B failed; caspofungin 50 mg/day after a loading dose of 70 mg IV was also unsuccessful.[80]

No studies have directly compared amphotericin B with azole therapy.

Duration of therapy and complications

The duration of therapy is dictated by the clinical course of the illness, but it should be at least 6 months in all patients and often a year or longer in others. Therapy is tailored based on a combination of resolution of symptoms, regression of radiographic abnormalities, and changes in CF IgG titers. Immunocompromised patients and patients with a history of meningeal involvement require lifelong treatment.

Complications related to antifungal medication are as follows:

  • Amphotericin - Renal toxicity, bone marrow toxicity, local systemic effects (fever, rigors)
  • Azoles - Hepatic dysfunction

The cost of antifungal therapy is high, from $5,000 to $20,000 per year. These costs increase for critical patients in need of intensive care. Arizona spent an average of $33,762 per patient with coccidioidomycosis between 1998 and 2001.[81]

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Investigational Agents

Suggestions have been made for the use of interferon-gamma in the treatment of fungal infections, given their association with cell-mediated immunity, although coccidioidomycosis was not specifically mentioned among them.[75]  The description of a case of disseminated severe coccidioidomycosis in a patient with autosomal dominant interferon-gamma receptor 1 deficiency certainly suggests more research in the area.[82] Clinical trials are necessary to evaluate promising in vitro findings against Coccidioides and other dimorphic fungal infections.

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Treatment of Coccidioidomycosis by Disease Stage

Treatment of coccidioidomycosis can be divided as follows:

  • Uncomplicated acute pneumonia
  • Asymptomatic pulmonary nodule
  • Diffuse pneumonia
  • Pulmonary cavity
  • Chronic progressive pneumonia
  • Disseminated extrapulmonary infection other than meningitis
  • Bone and joint disease
  • Meningitis

Uncomplicated acute pneumonia

Antifungal therapy is not usually necessary for uncomplicated acute primary coccidioidal pneumonia. Because coccidioidal pneumonia resolves spontaneously in 95% of cases without any treatment, most uncomplicated cases can be managed with follow-up visits every 3-6 months for as long as 2 years to confirm resolution of symptoms and radiographic abnormalities.

Although no studies demonstrate that therapy hastens resolution or stops dissemination, some experts propose treatment of all symptomatic patients, especially if risk factors are present. Patients with a higher clinical severity score and symptom score are more likely to be treated. Outcomes are not significantly different, although more complications have been seen in those with cessation of treatment.[9, 83]

Treatment should definitely be offered to patients with the following risk factors:

  • HIV/AIDS
  • Organ transplants
  • Immunosuppressive therapy (eg, high-dose corticosteroids)
  • Tumor necrosis factor inhibitor therapy
  • Diabetes mellitus
  • Cardiopulmonary disease
  • Pregnancy, especially peripartum

Elevated CF IgG titers and higher-risk ethnicity (eg, Filipino, black, Hispanic) may sway the decision to treat patients.

Typical antifungal therapy of acute primary pulmonary coccidioidomycosis in these high-risk groups consists mainly of oral azoles at the recommended adult doses (see Medication). During pregnancy, amphotericin B is the treatment of choice because the azoles may be teratogenic.

No consensus has been reached on the duration of therapy, but 6 months of treatment is most common, and CF IgG titers are used to monitor response to therapy. Periodic follow-up is recommended for up to 1 year or longer.

Asymptomatic pulmonary nodule

Antifungal therapy for asymptomatic pulmonary nodules is not typically recommended in immunocompetent patients. Most lesions do not require any further investigation, especially if they are unchanged on serial imaging for 2 or more years. If the nodule starts enlarging, measure coccidial serum antibodies to determine whether disease has become active, which warrants therapy. Resection is indicated if no diagnosis is established and malignancy is a concern.

Diffuse pneumonia

Initially, treat patients with diffuse pulmonary disease (ie, miliary or reticulonodular infiltrates) with amphotericin B or high-dose fluconazole for several weeks until definite signs of improvement are observed. If there is rapid deterioration or significant hypoxia, amphotericin B is used more frequently.

After clear evidence of improvement emerges, therapy may be changed to an oral azole to complete a prolonged course of antifungal therapy. Because these patients are often immunocompromised, the total duration of therapy should be at least 1 year, with secondary prophylaxis continuing indefinitely for subgroups of patients who are severely immunodeficient.

In a retrospective study of oral azole therapy in 224 patients with moderately severe pulmonary disease who received treatment within 30 days of onset of symptoms versus 30 days after the onset of symptoms, the incidence of dissemination and the need for antifungal therapy longer than 1 year were significantly reduced in the group who received early treatment with azoles, but the mortality reduction was insignificant.[37]

In the same study, only 27% of patients developed a complement-fixation titer greater than 1:32 (vs 45% in the group who received late treatment with azoles). These results suggest that in patients with moderately severe pulmonary disease, institution of early or azole therapy should be considered. Further study is needed to confirm this finding.[37]

Pulmonary cavity

Asymptomatic cavities should be monitored because many resolve on their own. Serial imaging can be performed to confirm stability. Cavities should be resected if they are still detectable within 2 years, if they enlarge, or if they are adjacent to the pleura.

Individuals with symptomatic (eg, hemoptysis, or pain) or enlarging cavities may respond to oral azole therapy or to oral antibacterial therapy if bacterial superinfection of the cavity is present. However, symptoms may recur upon cessation of therapy, and the cavities usually do not resolve with antifungal therapy.

Resection should be considered, depending on the risks. Large (>5 cm) or enlarging cavities were previously treated with surgical resection after amphotericin treatment, but in current practice a trial of oral azole therapy is warranted. Surgical resection is reserved for cavities refractory to therapy or for patients with persistent complications such as hemoptysis.

Ruptured cavities (a complication of necrotizing coccidioidal pneumonia) often present as a hydropneumothorax or empyema. Chest tube drainage (if indicated) and antifungal therapy (azoles or amphotericin) are recommended in anticipation of eventual surgical resection. Surgical reduction of cavities is usually performed after 4 weeks of amphotericin treatment. Ruptured nodules may require lobectomy with decortication.

Chronic progressive pneumonia

Individuals with chronic progressive fibrocavitary pneumonia should immediately start antifungal treatment with an oral azole and continue therapy for at least 1 year. Fluconazole at 400 mg/day and itraconazole at 200 mg twice daily appear to be equivalent in efficacy, but more patients demonstrate a response with itraconazole, which becomes evident at 12 months of therapy.

Doses should be increased or a different azole tried, if necessary, to obtain maximal responses. Amphotericin B is an alternative treatment if there is no response. Surgical resection is an option reserved for patients with refractory disease. Surgery in patients with chronic pulmonary coccidioidal infection is not uniformly curative and may result in serious complications. The potential complications of surgery include the development of postoperative bronchopleural fistula and postoperative cavity formation.

Surgical indications include the following:

  • Persistent or massive hemoptysis
  • Enlarging pulmonary cavities (>5 cm) adjacent to the visceral pleural with high risk of rupture
  • Spontaneous pneumothorax with persistent lung collapse
  • Empyema drainage not amenable to chest tube drainage
  • Bronchopleural fistula closure
  • Expansion of lungs restricted by residual pleural disease
  • Symptomatic fungus ball

Limitations to surgical treatment include the following:

  • High complication rate with closure of bronchopleural fistula (30%)
  • Recurrent disease (cavitation) in 18%
  • Reduced postoperative risk seen with preoperative amphotericin B therapy, but experience with azole therapy is unknown

Disseminated extrapulmonary infection other than meningitis

All patients with disseminated coccidioidomycosis warrant prolonged antifungal treatment. Therapy for nonmeningeal extrapulmonary disease can be initiated with oral azoles unless the disease is rapidly progressive or in a critical location (such as the vertebral column); in such situations, the alternative therapy is amphotericin B.

Some authors suggest initial therapy with amphotericin B until significant clinical, radiographic, and laboratory test (in particular, CF IgG titers) improvements are documented, followed by completion of the antifungal regimen with an oral azole. Fluconazole and itraconazole are the most commonly used azoles, at doses from 400-2000 mg/day for fluconazole and up to 800 mg/day for itraconazole.

In patients who warrant amphotericin B therapy but have drug-related toxicities, lipid amphotericin B formulations can be considered and have been effective in animal models, although no human clinical trials have assessed their efficacy. Combination therapy with amphotericin B and an azole has been reported, but no clinical trials have demonstrated its superiority to single-agent treatment, and antagonism with combination therapy has been reported for other fungal infections.

Bone and joint involvement

Vertebral involvement may also require surgical debridement and stabilization. Surgical intervention may also be indicated for debridement or draining of effusions or abscesses.

Bone and joint disease is treated as disseminated coccidioidomycosis, although itraconazole is thought to perform better than fluconazole in bone disease. In patients with chronic osteomyelitis, drainage of sequestrum in bones and debridement of adjacent purulent soft tissues often is necessary. Joint involvement can be managed by incision and drainage, although occasionally synovectomy and arthrodesis are needed. Immobilization of limbs affected by the disease may be necessary.

The benefit of irrigation and local instillation of amphotericin B to joints, cavities, or abscesses affected by coccidioidomycosis is controversial, and no clear data supporting this practice are available.

Septic shock

The treatment of septic shock associated with coccidioidomycosis relies on the use of antifungal therapy and appropriate resuscitative and supportive measures. However, this entity carries a poor prognosis.

Two patients with coccidioidomycosis and septic shock treated with drotrecogin alfa (activated protein C) were the first survivors reported. Drotrecogin alfa was withdrawn from the worldwide market October 25, 2011. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial, drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.

Coccidioidal meningitis

While patients with suspected coccidioidal meningitis can be treated adequately in an outpatient setting, hospitalization helps facilitate confirmation of diagnosis and initiation of therapy.

Fluconazole can be used in the treatment of mild to moderate meningitis and, occasionally, life-threatening meningitis in patients who opt against amphotericin B or who have contraindications to its use. Because of its excellent penetration into the cerebrospinal fluid (CSF), fluconazole has become the drug of choice for long-term therapy of meningeal infection. The 2005 guidelines of the Infectious Diseases Society of America recommend fluconazole as initial therapy.[3]

The usual dosage of fluconazole is 400 mg/day, but many physicians start with 800 or 1000 mg/day. Itraconazole 400-600 mg/day offers comparable efficacy. If the azole therapy elicits a response, treatment is continued indefinitely, because treatment is suppressive rather than curative and relapse rates are high.[45]

Some physicians initiate intrathecal amphotericin B along with the azole, whereas others reserve amphotericin B for cases in which azoles fail.[45, 84] The optimal dose and duration of intrathecal amphotericin is unknown. The IV dose ranges from 0.5-1.5 mg/kg/day, given in 5% glucose over 2-6 hours; the intrathecal dose, administered via cisternal injection, is 0.01-1.5 mg/dose administered at intervals that range from daily to every 48 hours to once per week. Headache, nausea, and fever begin about 30 minutes following the injection and may last for hours.

These injections continue until signs of intolerance appear, including vomiting, prostration, and dose-related mental-status changes. Corticosteroids (eg, 25 mg cortisone succinate) are added to the amphotericin injection to reduce these drug-related inflammation symptoms.

An alternative is continuous infusion of amphotericin B given via a programmable pump implanted into the abdominal wall and connected to the cisternal subarachnoid space. Liposomal amphotericin is lipid-based and has less nephrotoxicity than the deoxycholate formulation

Ventricular peritoneal shunts may be required to treat complications of meningitis (eg, hydrocephalus). In the absence of a CSF block, lumbar peritoneal shunting may be required.

CNS vasculitis is a life-threatening complication of coccidioidal meningitis. Short-term treatment with high-dose IV corticosteroids has been reported with varying results in regards to benefit; however, this information is anecdotal.

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Coccidioidomycosis in High-Risk Patients

Coccidioidal infection in immunocompromised individuals and specific groups of immunocompetent individuals follows a more aggressive course than in other groups. These include pregnant women, organ transplant recipients, and patients with HIV disease. Patients receiving immunosuppressive agents for cancer chemotherapy or autoimmune diseases or patients taking long-term corticosteroids are also at increased risk.[85] Progressive pulmonary disease occurs in 40% of immunocompromised individuals.

Although skin reactivity to coccidioidal antigens may be impaired, serologic response in all patients, except those with the most profound immunocompromise, remains intact.

Pregnant women

Pregnancy can pose a clinical challenge. Pregnancy is a risk factor for disseminated coccidioidomycosis because of shifts in T-cell immunity, cytokine production, and hormone changes. Rates of dissemination and mortality are increased late in pregnancy, particularly in the third trimester.

Pregnant women who develop coccidioidomycosis and present with erythema nodosum are extremely unlikely to have a negative outcome, however. In addition, women who have a history of resolved infection prior to pregnancy do not have a significant rate of recrudescence.

Some of the older literature recommended that abortion be considered in pregnant women because of the virulent nature of coccidioidomycosis in these patients. More recent reviews of coccidioidomycosis in pregnancy, however, concluded that although the disease can complicate pregnancy, appropriate management has led to satisfactory outcomes for the mother and child, suggesting that abortion need not be recommended.[86, 87]

Transplant recipients

The immunosuppressive regimen that transplant recipients require places them at increased risk for coccidioidomycosis. A review of coccidioidomycosis in solid organ transplant recipients in an endemic area showed an incidence of 5.7%.

Patients with a history of the disease may experience reactivation or contract primary infection from the donated organ or the environment.[88] Clinical manifestations are similar to those in normal hosts, but dissemination is more frequent (25%) and more rapid. Previously resolved infections reactivate at a rate of approximately 10% per year. Prior coccidioidomycosis does not contraindicate transplantation.

No clear consensus on prophylaxis has been reached. Many programs advocate lifelong prophylaxis, in which case the risks of emergence of resistance and side effects of azole therapy should be considered. The Mayo Clinic Hospital in Arizona advocates a targeted approach to prophylaxis and treatment.[88, 89] Fluconazole is the most commonly used azole.

Pretransplant period

Special attention should be given to patients with end-stage liver disease or alcoholic liver disease and patients on prednisone therapy, because their risk is higher and diagnosis is difficult, as it mimics the underlying disease. All patients should provide a detailed history (including residence in and travel to endemic areas) and undergo serologic testing, immunodiffusion, complement fixation, and chest radiography. These tests should be repeated the day of the transplant and should be repeated annually. All patients should be cleared by an infectious disease specialist.

If the diagnosis of coccidioidomycosis is made during the pre-evaluation testing, treatment is recommended for a year or more, and transplant surgery should be postponed until coccidioidomycosis is cleared. Follow with lifelong antifungal therapy thereafter.

Posttransplant period

Most commonly, coccidioidomycosis is due to reactivation of previous disease. Primary disease can also occur, however, usually within 6-12 months after transplantation, which is the period of more intense rejection therapy. Treat for 1 year or more, and continue for the duration of immunosuppression.

Infections from the donor organ

The history of the donor is as important as that of the recipient, but is not always available. Several case reports have highlighted the possibility of coccidioidomycosis transmitted from donated kidneys, livers, and especially lungs. Receiving an organ from a previously infected donor does not always result in active infection, however.[90] Nevertheless, coccidioidemia has occurred, and autopsy findings revealed microabscesses in several organs. Lifelong prophylaxis is recommended.

HIV-infected patients

In the appropriate geographical setting, coccidioidomycosis is the most common opportunistic infection in patients with HIV. Presentation with coccidioidomycosis may lead to the diagnosis of HIV, or the disease can manifest if CD4+ counts fall to low levels.[91] Co-infection with coccidioidomycosis and tuberculosis have been described.

The introduction of antiretroviral (ARV) therapy has led to a decline in the rates of coccidioidomycosis morbidity. Patients on ARV therapy who have higher CD4+ counts and undetectable HIV RNA levels tend to have less severe disease.

Primary prophylaxis for patients with HIV in endemic areas is not recommended routinely. Treatment of active disease is the same as in other patients; however, if the CD4+ cell count is less than 250/μL, antifungal therapy should continue until the count recovers to above 250 cells/μL. Indefinitely continue suppressive therapy after active disease (ie, secondary prophylaxis) with oral itraconazole (200 mg twice a day) or fluconazole (400 mg each day), regardless of the CD4+ cell count.

Patients on antitumor necrosis factor therapy

Although biologic agents used to treat rheumatoid arthritis and other autoimmune diseases are usually linked to reactivation of tuberculosis and histoplasmosis, a study found that out of 13 patients with rheumatologic disease in an endemic area, all 12 treated with infliximab developed coccidioidomycosis while on therapy. Of these, one third developed disseminated disease. Given the high risk of developing coccidioidomycosis, empiric therapy should be considered before starting infliximab therapy, if serology findings for Coccidioides are positive.[36]

Elderly patients

Older patients are at an increased risk for disseminated disease and diffuse progressive pulmonary disease, but not because of age itself. The mortality rate in patients older than 65 years is increased, with one report describing a mortality rate of 15%. However, more than age, the state of the immune system seems to be the most important factor for dissemination of coccidioidomycosis.

Hospital Admission

The need for hospitalization in patients with coccidioidomycosis is dictated by symptoms and the severity of disease and does not differ from patients with any other respiratory condition. Oral azole therapy is effective; therefore, most coccidioidal infections can be managed in an outpatient setting.

Indications for admission include the following:

  • Immunocompromise
  • Dissemination
  • Any need for symptomatic support or intravenous therapy

Sepsis syndrome, respiratory distress, severe hypoxemia, or severe or unresolving pneumonia as manifestations of acute or disseminated coccidioidal infection are indications for inpatient management. Coccidioidal disease that requires surgical intervention is best managed in an inpatient setting. Refractory cases requiring intravenous amphotericin also require hospitalization; however, once the patient is stable, he or she can be treated in an infusion center environment.

While patients with suspected coccidioidal meningitis can be treated adequately in an outpatient setting, hospitalization helps facilitate confirmation of diagnosis and initiation of therapy.

In a retrospective assessment 158 of 536 patients identified during the first 4 months of a coccidioidal epidemic required hospitalization.[33] The most important factors associated with hospitalization was shortness of breath, followed by age greater than 50 years; African descent; chills, fever, and cough; a negative skin test result; and an initial complement-fixation titer greater than 1:32. Patients who developed erythema nodosum were approximately one third as likely as the others to require hospitalization.

Isolation precautions are not necessary with hospitalized patients because person-to-person transmission of the disease does not occur; however, draining wounds may pose an infectious risk from aerosolization of organisms growing in the dressing or cast material. Enforce proper disposal of contaminated materials.[2]

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Deterrence and Prevention

Individuals who live or travel to endemic areas should be aware that the risk of infection is related to exposure to disrupted soil and dust, as may occur around construction sites or during dust storms. Occupational risk and exposure are highest among persons in close proximity to soil and dust, such as gardeners, farm workers, construction workers, and persons involved in archaeological digs.

Laboratory personnel in microbiology laboratories should take proper precautions when handling cultures with possible growth of Coccidioides immitis.

Some protection may be afforded with a well-fitted dust face mask, but these are not always practical or available.

For patients with organ transplants and a history of coccidioidomycosis, antifungal treatment at the time of engraftment has been proposed, although no formal recommendations exist.

Vaccines

No vaccines to prevent coccidioidomycosis currently are used in humans.[92] A killed spherule-derived vaccine was found to be efficacious in animals but not protective in humans.

Multiple Coccidioides species cell-surface antigens have been investigated for their ability to stimulate protective T-cell-mediated immune responses.[81] Currently, recombinant DNA techniques to develop vaccines using the proline-rich[93] and other antigens from the Coccidioides spherule appear promising.

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Consultations

Consultation with infectious disease and pulmonary specialists should be requested. Consultation with a neurosurgeon, neurologist, orthopedic surgeon, and/or wound surgeon may be needed to manage complications.

Report cases to the infectious disease and local health departments. Coccidioidomycosis is a reportable disease in states where the disease is endemic, such as California, New Mexico, Arizona, and Nevada.

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Long-Term Monitoring

Regular follow-up visits with a primary physician are necessary to document resolution or development of complications. Monitoring visits should be scheduled every 1-3 months and should include a patient interview, physical examination, serologic testing, radiographic examinations, and procedures, as necessary. Patients receiving antifungal therapy require continued monitoring for adverse effects of these agents by history and laboratory testing.

Expert consultations should be considered if needed. Continue follow-up care for at least 1-2 years or until resolution of all coccidioidal disease occurs.

Patients with complications such as chronic pulmonary and all extrapulmonary infections should receive routine follow-up for several years after diagnosis. Follow-up care of patients with disseminated coccidioidomycosis includes periodic monitoring of the complement fixation (CF) titer. Initially, monitor CF titers monthly until a consistent decrease has been documented; continue to measure titers periodically until the level is less than 1:8. Also monitor other abnormal laboratory or radiographic studies at regular intervals.

Relapses of coccidioidomycosis can be predicted by recurrence of symptoms, physical findings, and increases in the CF titer. Development of hydrocephalus in a patient with coccidioidal meningitis who is otherwise stable and improving does not imply failure of antifungal therapy.

Monitor routine health maintenance as well as reviews of all medications for potential drug interactions with the prescribed antifungal therapy.

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Contributor Information and Disclosures
Author

Duane R Hospenthal, MD, PhD, FACP, FIDSA, FASTMH Adjunct Professor of Medicine, Department of Medicine, University of Texas Health Science Center at San Antonio

Duane R Hospenthal, MD, PhD, FACP, FIDSA, FASTMH is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, International Society for Infectious Diseases, International Society of Travel Medicine, Medical Mycological Society of the Americas, Armed Forces Infectious Diseases Society, International Society for Human and Animal Mycology, American College of Physicians, American Society for Microbiology, Society for Healthcare Epidemiology of America

Disclosure: Nothing to disclose.

Coauthor(s)

Edward L Arsura, MD Chair, Department of Medicine, Chief Medical Officer, Richmond University Medical Center

Edward L Arsura, MD is a member of the following medical societies: American Association for Physician Leadership, American College of Physicians, American Federation for Medical Research, American Heart Association, American Medical Association, California Medical Association, Society of General Internal Medicine, Southern Medical Association

Disclosure: Nothing to disclose.

Ana Paula Oppenheimer, MD, MPH Fellow, Section of Infectious Diseases, Wake Forest University Baptist Medical Center

Disclosure: Nothing to disclose.

George R Thompson III, MD Assistant Professor of Medicine, Assistant Director, Coccidioidomycosis Serology Laboratory, Department of Medical Microbiology and Immunology, Department of Medicine, Division of Infectious Diseases, University of California, Davis, School of Medicine

George R Thompson III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, International Society for Infectious Diseases, Texas Medical Association, Medical Mycological Society of the Americas, International Society for Human and Animal Mycology, HIV Medicine Association

Disclosure: Received research grant from: Astellas<br/>Received grant/research funds from Pfizer for other.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Itzhak Brook, MD, MSc Professor, Department of Pediatrics, Georgetown University School of Medicine

Itzhak Brook, MD, MSc is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Immunocompromised Host Society, International Society for Infectious Diseases,Medical Society of the District of Columbia, New York Academy of Sciences, Pediatric Infectious Diseases Society, Society for Ear, Nose and Throat Advances in Children, Society for Experimental Biology and Medicine, Society for Pediatric Research, Southern Medical Association, and Surgical Infection Society

Disclosure: Nothing to disclose.

David FM Brown, MD Associate Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital

David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Archana Chatterjee, MD, PhD Professor of Pediatrics, Medical Microbiology and Immunology, and Pharmacy, Division of Pediatric Infectious Diseases, Chief of Division of Pediatric Infectious Diseases, Creighton University School of Medicine; Hospital Epidemiologist and Medical Director of Infection Control, Children's Hospital

Archana Chatterjee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, International Society for Infectious Diseases, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Michele M Cheung, MD Consulting Staff, Department of Pediatrics, Division of Pediatric Infectious Diseases, University of California, San Francisco, School of Medicine

Michele M Cheung, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

John E Cho, MD Staff Physician, Providence Tarzana Medical Center

John E Cho, MD is a member of the following medical societies: American College of Chest Physicians, California Medical Association, and Phi Beta Kappa

Disclosure: Nothing to disclose.

James de la Torre, MD Resident Physician, Department of Emergency Medicine, LAC+USC Medical Center

Disclosure: Nothing to disclose.

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious Diseases Society of America, and Infectious Diseases Society of Ohio

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Joseph Kim, MD Chairman, Department of Emergency Medicine, Western Medical Center; Clinical Instructor, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Catherine O'Keefe, DNP, APRN Assistant Professor of Nursing and Pediatric Nurse Practitioner, Pediatric Infectious Diseases, Creighton University Medical Center

Catherine O'Keefe, DNP, APRN is a member of the following medical societies: American Academy of Nurse Practitioners, National Association of Pediatric Nurse Practitioners, and Nebraska Nurse Practitioners

Disclosure: Nothing to disclose.

Michael Peterson, MD Chief of Medicine, Vice-Chair of Medicine, University of California, San Francisco, School of Medicine; Endowed Professor of Medicine, University of California, San Francisco-Fresno, School of Medicine

Michael Peterson, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Allison J Richard, MD Assistant Professor of Emergency Medicine, Keck School of Medicine of the University of Southern California; Associate Director, Division of International Medicine, Attending Physician, Department of Emergency Medicine, LAC+USC Medical Center

Disclosure: Nothing to disclose.

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Barry J Sheridan, DO Chief Warrior in Transition Services, Brooke Army Medical Center

Barry J Sheridan, DO is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: Nothing to disclose.

Guy W Soo Hoo, MD, MPH Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Medical Intensive Care Unit, Pulmonary and Critical Care Section, West Los Angeles Healthcare Center, Veteran Affairs Greater Los Angeles Healthcare System

Guy W Soo Hoo, MD, MPH is a member of the following medical societies: American Association for Respiratory Care, American College of Chest Physicians, American College of Physicians, American Thoracic Society, California Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Kelley Struble, DO Fellow, Department of Infectious Diseases, University of Oklahoma College of Medicine

Kelley Struble, DO is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Peggy Weintrub, MD Chief, Division of Pediatric Infectious Diseases, Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine

Peggy Weintrub, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

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Soft tissue abscess due to cocci.
Pulmonary cocci spherule (Hematoxylin-eosin stain).
Pulmonary cocci spherule, periodic acid-Schiff stain.
Erythema nodosum can be observed in coccidioidomycosis, tuberculosis, histoplasmosis, drug reactions, and streptococcal infections.
A Coccidioides immitis spherule containing endospores. Courtesy of Thomas Matthew.
Arthroconidia become airborne and infect the human host to begin the parasitic phase of its life cycle. The arthroconidia develop into spherules containing endospores, which propagate infection in human tissues. Courtesy of Thomas Matthew.
A granuloma with coccidioides immitis spherule (pretracheal lymph node biopsy).
A ruptured Coccidioides immitis spherule (pretracheal lymph node biopsy).
Gomori methenamine silver stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
Periodic acid-Schiff stain of Coccidioides immitis spherule (pretracheal lymph node biopsy).
Coccidioidal spherules rupturing and releasing endospores. Gomori methenamine silver (GMS) stain. Photograph by Joseph Rabban, MD.
 
 
 
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