Primary pulmonary coccidioidal infection

INTRODUCTION — Coccidioidomycosis is the infection caused by the dimorphic fungi of the genus Coccidioides. Primary pulmonary infection is caused by inhalation of airborne mycelial arthroconidia located in soil. While most infections are asymptomatic, clinical illness ranges from acute pneumonia (Valley Fever) to extrathoracic disseminated infection (table 1). Most cases of coccidioidomycosis in the United States are acquired in the southwestern part of the country, particularly in Arizona and the San Joaquin Valley of California.

The clinical manifestations, diagnostic approach, and management of primary pulmonary infection will be reviewed here. Extrathoracic coccidioidomycosis and complications and prevention of infection are discussed elsewhere. (See "Management of pulmonary sequelae and complications of coccidioidomycosis" and "Coccidioidal meningitis" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)

MICROBIOLOGY — Coccidioidomycosis is caused by the dimorphic fungi of the genus Coccidioides [1]. It is now recognized as consisting of two species, Coccidioides immitis and Coccidioides posadasii [2,3]. However, there is no clinical distinction between these two species, and henceforth the organism will be referred to as Coccidioides.

Coccidioides grows as a mold no more than a few inches below the surface of the soil. Its precise ecologic niche is unclear. The mycelia consist of chains of cells that are approximately 3 to 5 microns in size. Alternating cells degenerate, releasing single cells, called arthroconidia; these cells can remain suspended for prolonged periods of time in the air and penetrate deep into the host airway. (See 'Pathogenesis' below.)

EPIDEMIOLOGY

Geographic distribution — While it has been estimated that there are approximately 150,000 coccidioidal infections each year in the United States [4], more recent calculations suggest that the number is far higher than this [5]. Coccidioidomycosis is endemic to certain regions of the Western Hemisphere; these include specific areas of the United States as well as northern Mexico and areas of Central and South America.

In the United States, most cases of coccidioidomycosis are reported from the San Joaquin Valley of California or from the south-central region of Arizona, including Maricopa and Pima counties, which contain the metropolitan areas of Phoenix and Tucson [6,7]. However, other regions of California, including areas of San Luis Obispo, Ventura, Los Angeles, Riverside, and San Diego counties, have regularly reported cases. In addition, southern Nevada, southwestern Utah, and southern New Mexico have endemic regions. Although not a reportable disease in Texas, the Permian Basin region, including the cities of Midland and Odessa, and the Rio Grande Valley, appear to be endemic for coccidioidomycosis.

Distinct pockets of coccidioidomycosis outside the generally recognized endemic regions have been identified by focal outbreaks of cases. These include an area in eastern Washington state [8-10], a Native American site in Dinosaur National Monument in northeast Utah [11], and an area in the Sierra foothills east of Red Bluff in northern California [12].

There has been a substantial increase in the incidence of coccidioidomycosis in the United States. For example, the incidence of coccidioidomycosis has increased from 5.2 cases per 100,000 in 1990 to 160.6 cases per 100,000 in 2020 in Arizona [13] and from 4.3 cases per 100,000 in 2001 to 18.1 cases per 100,000 in 2020 in California [14]. Several factors that may account for much of this increase have been identified in Arizona. These include a shift to more sensitive serologic test results to define cases, climate change causing prolonged drought, and continued migration of older and presumably uninfected persons into the endemic areas [7,15].

A number of notable outbreaks of coccidioidomycosis have occurred. In California, inmates of two state prisons in the highly endemic San Joaquin Valley were disproportionately affected by coccidioidomycosis compared with the general population, with 180 cases recognized in 2005 [16]. In another instance, a cluster of seven cases occurred among a highway construction crew in Kern County, California [17]. Between 2016 and 2017, there was an outbreak of coccidioidomycosis among workers constructing a solar power farm in Monterey County, California where the worksite-specific incidence rate was substantially higher than background county rates [18], and there was an outbreak among firefighters battling California wildfires [19].

Risk of infection — The risk of infection by Coccidioides spp within known endemic areas is approximately 3 percent per year [20]. Thus, even those who have lived in endemic regions for many years may still be susceptible to new infection. In a telephone survey of patients diagnosed with Valley Fever conducted by the Arizona Department of Health Services, the average time of residence was 16 years [21].

The risk of exposure within endemic regions is seasonal, typically being highest in dry periods following a rainy season. Periods of high incidence in Arizona range from May into July and then between October and early December [22]. By contrast, the Central Valley in California, which rarely receives significant summer rain, has a single peak from late spring to late fall.

Patients with impaired cellular immunity are at higher risk of severe and/or disseminated infection. As an example, in patients with rheumatologic diseases, the increased use of immunosuppressive regimens (eg, tumor necrosis factor alpha inhibitors) increased the risk of more extensive coccidioidal infection [23].

Previously acquired quiescent and clinically inapparent coccidioidal infection can reactivate in the setting of immunosuppression. This is because immunologic control of coccidioidomycosis occurs without eradicating Coccidioides spp from the body. Stable, asymptomatic, solitary pulmonary nodules may yield viable Coccidioides spp many years after infection [24]. In one report, a patient with HIV developed active coccidioidal disease in Spain approximately 12 years after leaving the endemic Southwestern United States [25]. The risk of reactivation appears to depend upon the level of immunosuppression. The extent of underlying Hodgkin lymphoma has been correlated with severity of coccidioidal infection and death [26], and in patients with HIV, loss of in vitro T-cell responsiveness to coccidioidal antigen exposure has been associated with more symptomatic coccidioidomycosis [27]. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)

PATHOGENESIS — Infection is usually acquired by inhalation of arthroconidia. In most cases, no specific environmental exposure is identified and it is presumed that infection has occurred from inhalation of arthroconidia that are airborne. Evidence in the Phoenix metropolitan region indicates that airborne arthroconidia are common and may persist for prolonged periods of time [28]. Once within the lung, barrel-shaped arthroconidia change into spherical structures that then greatly enlarge, sometimes becoming as many as 200 microns in diameter. Enlarging spherules produce internal septations, and within each of the resulting subcompartments, individual cells called endospores develop.

After several days, mature spherules rupture, releasing endospores into the infected tissue; each endospore is potentially capable of producing another spherule [1]. Coccidioides spp exist in the spherule stage within the host, but revert to the mycelial form in the environment, including when plated onto artificial media in the laboratory [29,30]. These cultures represent a significant laboratory hazard [31].

The cellular immune response appears to be the controlling factor in coccidioidomycosis. Patients with resolving acute coccidioidal pneumonia express delayed-type hypersensitivity [32], and bronchoalveolar leukocytes from patients with pulmonary coccidioidomycosis release interferon gamma and other inflammatory cytokines in response to in vitro antigen stimulation [33]. Although there may be an initial polymorphonuclear cell response, once controlled, the pulmonary lesions are characterized by caseating granulomata with an active T-cell response [34]. In immunocompromised patients, the diminished cellular immune response results in less well-formed granulomas that contain a greater number of organisms than those seen in immunocompetent patients [35].

CLINICAL MANIFESTATIONS

Signs and symptoms — Patients who develop primary pulmonary infection can present with a range of pulmonary symptoms as well as extrapulmonary manifestations that are immunological in nature (table 1).

●Asymptomatic/minimally symptomatic disease – At least 60 percent of all coccidioidal infections do not come to medical attention because primary infection is either asymptomatic or minimally symptomatic [36,37]. The proportion of infections that become clinically apparent increases in outbreaks with more intensive exposure to arthroconidia, such as might occur during archaeologic excavations or desert military maneuvers [38,39].

●Focal pneumonia – Symptomatic infection due to Coccidioides spp most frequently presents in a manner similar to bacterial community-acquired pneumonia (CAP) in both immunocompetent and immunocompromised individuals [40-42]. Symptoms occur approximately 7 to 21 days after an exposure, which may or may not be apparent. The most common presenting symptoms are chest pain, cough, and fever (table 2). In a study from Pima County, Arizona, 29 percent of patients diagnosed with CAP were serologically positive for coccidioidal infection at the time of presentation. A subsequent study from Phoenix, Arizona found a rate of 17 percent [12,43-51].

●Diffuse reticulonodular pneumonia – Diffuse reticulonodular pneumonia is a less common presentation that results from hematogenous seeding of the lungs [52]. This presentation is seen most commonly in immunosuppressed patients but can also occur in immunocompetent patients who are exposed to a high inoculum of arthroconidia [40-42,52]. Some patients with diffuse pulmonary disease may be clinically stable without respiratory compromise while others are markedly dyspneic at rest or with minimal exertion and develop symptoms such as fever and night sweats. Such patients frequently progress to respiratory failure requiring mechanical ventilation and often will develop fungemia [48]. Severe diffuse pulmonary disease can be associated with a high mortality [49].

●Systemic symptoms – Night sweats, headache, rash, weight loss, and fatigue are systemic symptoms that are associated with coccidioidomycosis. Any of these findings should alert the practitioner to the possibility of coccidioidomycosis.

●Immunologic manifestations – Immunologic manifestations are frequent in primary pulmonary coccidioidomycosis and are usually expressed as cutaneous or rheumatologic symptoms.

•Cutaneous manifestations – The cutaneous manifestations of primary pulmonary coccidioidal infection include erythema nodosum (usually manifesting as painful, erythematous nodules on the lower extremities), as well as erythema multiforme, which is often seen in a necklace distribution. A toxic erythema consisting of a diffuse, sandpaper-like rash has also been observed. In one report, a patient with acute pulmonary coccidioidomycosis had a rash that was histopathologically consistent with Sweet syndrome [53]. Cutaneous manifestations are more common in females than in males.

•Rheumatologic symptoms – Patients less frequently present with symmetric arthralgias, particularly of the ankles, knees, and wrists. Their symmetricity and lack of local erythema and joint effusions distinguish these from disseminated disease and have been termed "desert rheumatism".

These immunologic extrapulmonary manifestations associated with primary pulmonary infection do not represent disseminated disease (table 1). Discussions of disseminated infection are presented elsewhere. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Coccidioidal meningitis".)

Laboratory findings — Routine laboratory findings are generally unremarkable [54]. The peripheral blood leukocyte count is usually normal or only slightly elevated; however, peripheral blood eosinophilia (>5 percent) may be found in approximately one-quarter of patients [1]. The erythrocyte sedimentation rate is often one- or twofold above the upper limit of normal. Hypercalcemia is sometimes observed [55]. Serum procalcitonin levels are usually below 0.25 ng/mL [56,57], and levels of beta-(1,3)-D-glucan are variably elevated [58,59] and should not be relied upon for diagnosis.

Imaging — Although initial infections usually demonstrate a pulmonary infiltrate, occasionally standard posteroanterior and lateral chest radiographs may be unremarkable.

When present, a common radiographic abnormality is a unilateral dense infiltrate with ipsilateral hilar adenopathy (image 1). Mediastinal adenopathy may also be present. Hilar and mediastinal adenopathy do not occur in bacterial pneumonia and should alert the practitioner to the possibility of coccidioidomycosis. In addition, the pulmonary infiltrate in coccidioidomycosis is often in the upper lobes, distinctly different from bacterial processes. Occasionally, ipsilateral parapneumonic effusions can occur [60]. Nodules or thin-walled pulmonary cavities are detected in 4 to 8 percent of all patients (image 2) [61]. In some cases, empyema may occur due to rupture of a coccidioidal cavity into the pleural space [62]. (See "Management of pulmonary sequelae and complications of coccidioidomycosis", section on 'Coccidioidal cavities'.)

DIAGNOSIS

When to suspect infection — We consider the diagnosis of coccidioidomycosis in patients living in or who have traveled to an endemic area who present with any of the following:

●A respiratory illness of one week or more with an infiltrate on chest radiograph, especially if there is upper lobe involvement or hilar or mediastinal adenopathy. (See 'Imaging' above.)

●Presumed community-acquired pneumonia (CAP) with continued pulmonary symptoms despite appropriate empiric antibacterial therapy. (See 'Signs and symptoms' above.)

●Development of rash, particularly if consistent with erythema nodosum or erythema multiforme, or the onset of diffuse, symmetrical arthralgias. (See 'Signs and symptoms' above.)

●Other findings suggestive of coccidioidomycosis, including night sweats, marked fatigue, weight loss, or unexplained peripheral blood eosinophilia. (See 'Signs and symptoms' above and 'Laboratory findings' above.)

Because exposure usually occurs within an endemic region, it is critical to obtain an accurate travel history [11,63-66], especially in those residing outside the typical endemic region. It is important to consider the diagnosis of primary pulmonary coccidioidal infection in persons who develop CAP within the one- to three-week incubation period after visiting an endemic area [63,67]. Even brief exposures in the endemic region have been sufficient to cause infection. As an example, eight cases of primary pulmonary coccidioidomycosis were reported in four states (Kansas, Maryland, Michigan, and New York) in persons who traveled to Baja California, Mexico to construct houses [67].

Identifying coccidioidal infections as early as possible has many benefits, including: allaying patient anxiety by arriving at a specific diagnosis, often simultaneously dispelling the fear of cancer; reducing the need for additional diagnostic testing, which can involve invasive or costly procedures; eliminating empiric or protracted use of antibacterial treatments; and reducing the morbidity of less frequent but progressively destructive extrapulmonary complications, most of which develop within the first several months following the initial infection [68]. (See "Management of pulmonary sequelae and complications of coccidioidomycosis".)

However, many coccidioidal infections are not identified because the symptoms, signs, and routine laboratory findings are nonspecific, and clinicians do not consider the diagnosis. Low rates of disease recognition have occurred in both nonendemic and endemic areas [22,63,67,69,70]. In a study that evaluated data from two medical centers in metropolitan Phoenix, Arizona, the number of patients with CAP tested for Valley Fever was only 2 and 13 percent, respectively [70].

Diagnostic testing — In most patients, the diagnosis of primary coccidioidal infection relies upon serologic testing (table 1). Serologic tests using enzyme-linked immunoassays (EIAs) for IgM and IgG should be ordered first, if possible [71]. Immunodiffusion tests are generally performed to support the diagnosis when an initial EIA is positive. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Detection of anticoccidioidal antibodies'.)

However, in some patients with early disease, antibody response may be delayed. In one report, serologic evidence of infection was negative in as many as one-third of patients [41]. In such patients, repeating the coccidioidal serologic tests weekly can be helpful.

For those with severe/extensive disease (eg, diffuse reticulonodular pneumonia), more aggressive diagnostic measures, such as a bronchoalveolar lavage, are often performed. In this setting, cytologic examination may reveal spherules. Although fungal cultures of bronchoalveolar lavage fluid are more sensitive than of sputum, it may take several days before growth is evident [72]. If coccidioidal polymerase chain reaction testing is available, this is as sensitive as culture but can be faster for establishing the diagnosis [73]. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Recovery of Coccidioides from clinical specimens'.)

When cultures to detect Coccidioides spp are obtained, the clinician caring for the patient should alert the microbiology laboratory that coccidioidomycosis is a likely possibility, because appropriate biocontainment procedures are needed [31]. Exposure to Coccidioides spp in the laboratory setting can lead to infection of laboratory staff. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Recovery of Coccidioides from clinical specimens'.)

MANAGEMENT

Determining disease severity and risk factors — The approach to treatment of primary pulmonary coccidioidal infection depends upon the severity of disease and the patient's risk of developing severe or disseminated complicated disease. Although many patients with primary pulmonary coccidioidal infection do not require antifungal therapy, treatment should be administered to those with moderate and severe disease and those at high risk for developing more serious/complicated disease (table 3).

Commonly used indicators for moderate disease include:

●Infiltrates involving more than half of one lung or portions of both lungs, regardless of symptoms (see 'Signs and symptoms' above and 'Imaging' above)

●Persistent symptoms of infection, particularly cough, fever, and night sweats, for longer than three weeks (see 'Signs and symptoms' above)

●Greater than 10 percent loss of body weight (see 'Signs and symptoms' above)

●Anticoccidioidal complement-fixing antibody concentrations ≥1:32 (see 'Diagnostic testing' above)

Severe disease is defined by the presence of respiratory compromise. (See 'Severe disease' below.)

High risk factors for developing severe and/or complicated disease include:

●Major suppression of cellular immunity, which can be seen in patients with HIV and CD4 cell count <250 cells/microL [41,42], those undergoing solid organ or hematopoietic cell transplantation [74-76], and those receiving immune-suppressing agents, such as high-dose glucocorticoids (eg, 20 mg or more per day of prednisone or its equivalent) [77]. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Immunocompromised patients'.)

●Hematologic malignancies.

●Cancer chemotherapy associated with cytopenia.

●Pregnancy when disease develops during the second or third trimester or immediately postpartum. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Pregnant patients'.)

Other individuals who may be at increased risk of complications include: those of African or Filipino descent, because these populations are at increased risk of extrapulmonary complications [49,78,79]; those with diabetes, given their higher risk of pulmonary complications, including cavitation [80]; frail older adults [81,82]; and those on anticytokine therapy for rheumatologic, gastrointestinal, or dermatologic diseases [83]. For these patients, we make the decision to provide antifungal therapy on a case-by-case basis.

Approach to antifungal therapy

Immunocompetent nonpregnant patients — The initial approach to treatment in immunocompetent nonpregnant patients depends upon the severity of disease and the presence of risk factors for developing complications (table 3). Our approach is consistent with guideline recommendations from the Infectious Diseases Society of America [4].

Mild disease — In general, antifungal therapy is not needed for healthy patients without evidence of extensive coccidioidal infection or risk factors for developing more serious infection [4]. Those with risk factors for severe disease (eg, African or Filipino descent, diabetes, frailty, presence of immunocompromising conditions) should be considered for treatment with triazole therapy, similarly to those with moderate disease (table 3). (See 'Determining disease severity and risk factors' above and 'Moderate disease' below.)

Observational data indicate that antifungal therapy offers little benefit to those with mild disease [84,85]. As an example, in an observational study that evaluated 36 immunocompetent patients with primary pulmonary coccidioidomycosis followed for 24 weeks, the median time from diagnosis to a 50 percent reduction of symptoms was no different between those treated with an antifungal agent and those who were not treated [85]. Similarly, in an earlier study of 105 patients with primary pulmonary coccidioidomycosis, in which 54 patients were treated and 51 were not, there was no difference between the groups with respect to overall rates of improvement [84]. In this report, none of the untreated patients were found to have complications over a median of 286 days of follow-up. In both of these studies, patients who received treatment had more severe illness, since treatment was initiated based upon severity of disease as assessed by the attending staff.

However, all patients with primary coccidioidal infection, regardless of whether they were treated, should be followed for at least one year to monitor for the development of complications. (See 'Patient monitoring' below.)

Moderate disease — Antifungal therapy is indicated for immunocompetent patients with moderate disease. For most patients, we suggest fluconazole (400 mg daily) for initial therapy; itraconazole (200 mg twice daily) is a good alternative (table 3) [4]. There is no consensus regarding the duration of therapy. We generally treat patients for approximately 12 weeks, although shorter courses (eg, six weeks) may be reasonable for certain immunocompetent patients, such as those who have rapid clinical improvement over days to weeks.

Although fluconazole and itraconazole appeared to have similar efficacy for the treatment of pulmonary disease in a randomized controlled trial of 70 patients (54 versus 57 percent) [86], we usually prefer fluconazole for initial treatment because it is well absorbed and does not require therapeutic drug monitoring, has fewer drug interactions, and has a lower risk of hypokalemia, hypertension, and congestive heart failure. However, fluconazole causes predictable skin and mucous membrane dryness and occasional alopecia [87]. In addition, in the randomized trial mentioned above, fluconazole was associated with a nonsignificant increase in the risk of relapse compared with itraconazole (28 versus 18 percent) [86].

Although ketoconazole was approved for the treatment of coccidioidomycosis by the US Food and Drug Administration (FDA), this agent is no longer recommended because it has more toxicity than either fluconazole or itraconazole. There is little information available about the value of other azoles, such as voriconazole, posaconazole, or isavuconazole, for treating primary coccidioidal pneumonia. However, clinical experience indicates that these triazole antifungals are at least as effective as fluconazole and itraconazole and may be appropriate in situations of toxicity or lack of response [88-90].

Discussions of patient monitoring and the management of those with refractory disease are found below. (See 'Patient monitoring' below and 'Refractory disease' below.)

Severe disease — For those meeting the criteria of moderate disease who also have respiratory compromise, we suggest initiating intravenous amphotericin B in combination with fluconazole 400 to 800 mg daily (itraconazole 200 mg twice daily is a good alternative) (see 'Moderate disease' above). To reduce toxicity, we prefer a lipid formulation of amphotericin B at a dose of 3 to 5 mg/kg daily. If the deoxycholate formulation is used instead, we administer a dosage of 0.5 mg/kg daily. (See "Pharmacology of amphotericin B".)

Once clinically stable, the patient can transition to oral fluconazole or itraconazole monotherapy. In patients with severe disease, triazole therapy is generally given for at least 12 to 24 weeks.

Immunocompromised patients — Immunocompromised patients are at risk for developing severe or disseminated disease, and therefore require treatment even if they present with mild symptoms.

Immunocompromised patients include:

•Patients with HIV and CD4 cell counts <250 cells/microL.

•Transplant recipients who are on immunosuppression.

•Patients receiving tumor necrosis factor alpha inhibitors, high-dose glucocorticoids, and certain other immunomodulators.

•Patients with solid tumor malignancies who are receiving lymphodepleting chemotherapy [91].

•Patients with active hematologic malignancies, as well as those in remission; severe illness has been reported in such patients even after completion of chemotherapy and radiation therapy [92].

•Chimeric antigen receptor (CAR)-T cell therapy recipients [93].

•Patients with specific gene mutations (gamma-interferon receptor [IFN-gammaR1], IL-12 receptor [IL-12Rbeta1] [94], STAT1 [95], and STAT3 [96]).

The general principles of management of coccidioidomycosis in the immunocompromised host (table 3) are the same as those for the normal host, but there are a few major differences:

●All immunocompromised patients with clinically active coccidioidomycosis at any anatomic site should receive antifungal therapy because of their high risk for both severe disease and extrathoracic dissemination.

●Antifungal therapy is generally prolonged and often lifelong in those who remain immunocompromised.

●Minimizing immunosuppression and improving cellular immunity in an immunocompromised patient is a key part of coccidioidomycosis therapy. In patients with HIV, this means initiation of ART as soon as safely possible and monitoring the patient closely for adherence and complications. In patients on immunosuppressive drugs (eg, transplant recipients), this means reduction in dose or complete discontinuation of immunosuppressants, when possible. Patients with specific gene mutations generally require prolonged antifungal therapy and, if possible, immune modulation therapy to overcome the genetic defect.

All such cases should be managed in conjunction with an infectious diseases expert who is experienced in the treatment of coccidioidomycosis.

Antifungal selection in immunocompromised patients is the same as in immunocompetent patients (see 'Immunocompetent nonpregnant patients' above). Aspects of management specific to certain groups of immunocompromised patients are discussed elsewhere. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Immunocompromised patients'.)

Screening and prevention of coccidioidomycosis in immunocompromised patients are discussed separately. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients".)

Pregnant patients — Approach to antifungal therapy in pregnant patients is discussed elsewhere. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Pregnant patients'.)

Patient monitoring — All patients should be monitored for complications and/or relapse at regular intervals, regardless of whether they receive antifungal therapy. In addition, monitoring can help assess for toxicity and guide duration of therapy. (See 'Moderate disease' above and 'Severe disease' above.)

What to monitor — Patients should be monitored for clinical, serologic, and radiographic improvement.

●Clinical – Patients should be monitored for improvement in both respiratory and systemic signs and symptoms. Patients with primary pulmonary coccidioidal infection should be monitored approximately every 6 to 12 weeks for improvement. During the weeks to months following presentation, respiratory symptoms (eg, cough and pleurisy) and systemic signs (eg, weight loss, night sweats, and fever) typically diminish or resolve. Once such improvement has occurred, intervals between clinic visits may be extended to every six months.

●Serology – Serologic testing for complement-fixing-type anticoccidioidal antibodies should be repeated about every 12 weeks. (See "Coccidioidomycosis: Laboratory diagnosis and screening", section on 'Detection of anticoccidioidal antibodies'.)

•With clinical improvement, complement-fixing antibody titers should decline and eventually become undetectable. However, the decline in complement-fixing antibody titer can be slow and unpredictable [97], and the complement-fixing antibody titer should not be the sole test used to determine when to discontinue antifungal therapy.

•Elevated titers, such as those ≥1:32, suggest continued fungal growth. This could be associated with progressive disease and, in some cases, suggests that extrathoracic dissemination may be occurring [98]. In such instances, careful correlation with clinical examination and imaging is required. (See 'Refractory disease' below.)

●Imaging – When radiographic abnormalities are initially noted, they should be rechecked within the first 12 weeks following diagnosis and then again, several months later to determine if there is a residual nodule or cavity. Determining whether pulmonary lesions evolve into residual nodules is also useful because it obviates the need to investigate the etiology of this radiographic finding in the future. (See "Management of pulmonary sequelae and complications of coccidioidomycosis".)

●Adverse effects of therapy – Patients receiving antifungal therapy should be monitored for toxicity. This includes monitoring aminotransaminases in all patients and reviewing concurrent medications to avoid severe drug interactions [89].

•For patients receiving amphotericin B, renal function and electrolytes should be monitored daily. (See "Pharmacology of amphotericin B", section on 'Adverse effects' and "Pharmacology of amphotericin B", section on 'Drug interactions'.)

•For patients receiving fluconazole, patients should be monitored for the development of severe xerosis and alopecia. (See "Pharmacology of azoles", section on 'Drug-specific adverse effects' and "Pharmacology of azoles", section on 'Drug interactions'.)

•For those receiving itraconazole, patients should undergo therapeutic drug monitoring and measurement of serum potassium. Serial assessment for the development of peripheral edema and hypertension are also important. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring' and "Pharmacology of azoles", section on 'Drug-specific adverse effects' and "Pharmacology of azoles", section on 'Drug interactions'.)

Duration of monitoring — For patients not treated with antifungal drugs, follow-up is usually complete by one year. However, those who receive antifungal therapy should be followed annually for at least two years after the completion of treatment, because later recurrences have been noted occasionally in such patients [4]. In the observational study of 105 patients with primary pulmonary coccidioidomycosis described above, 38 treated patients were followed after discontinuation of therapy, and eight had relapse or progression of their coccidioidal infection [84], emphasizing the importance of close and prolonged follow-up for patients who were treated.

Immunocompromised patients are generally treated longer than immunocompetent patients due to slower resolution of illness and risk of relapse. In addition, some patients may require suppressive therapy. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Secondary prevention' and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Duration of therapy'.)

Refractory disease — If the patient has not experienced clinical improvement and/or the patient has additional symptoms or signs, and complement-fixing antibody titers remain elevated, we typically search for evidence of pulmonary complications and for disseminated disease. In the latter cases, clinicians should ask about a persistent headache, new joint effusions, or new skin lesions. The clinical manifestations of these complications are discussed in detail elsewhere. (See "Management of pulmonary sequelae and complications of coccidioidomycosis" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis".)

If there is evidence of persistent disease, it is reasonable to switch from fluconazole to itraconazole. Although the randomized trial comparing these agents did not demonstrate that either agent was superior to the other, there was a trend towards greater efficacy with itraconazole in patients with persistent infection for more than three months [86]. Thus, in this setting, the potential improved efficacy may be worth the increased risk of drug interactions and the need to monitor drug levels. Such patients should be managed in conjunction with an infectious diseases expert experienced in the management of coccidioidomycosis. In some cases, using other mold-active triazole antifungals, such as voriconazole, posaconazole, or isavuconazole, may be required either because of lack of response or toxicity to fluconazole and itraconazole.

SEQUELAE OF PRIMARY PULMONARY INFECTION

Prolonged fatigue — Fatigue and lethargy associated with coccidioidal pneumonia may persist for months, far beyond the resolution of all other symptoms and laboratory abnormalities [99]. Antifungal therapy is not helpful for these symptoms. However, reassurance and education about the protracted nature of fatigue are very important. Some patients may benefit from physical therapy.

Pulmonary complications — Some patients develop pulmonary consequences of coccidioidomycosis, such as residual pulmonary nodules, coccidioidal cavities, chronic and progressive fibrocavitary pneumonia, and diffuse reticulonodular pneumonia. The management of these conditions is discussed elsewhere. (See "Management of pulmonary sequelae and complications of coccidioidomycosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Coccidioidomycosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Valley Fever (coccidioidomycosis) (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Coccidioidomycosis is caused by the dimorphic fungi of the genus Coccidioides. Infection is caused by inhalation of arthroconidia (table 1). (See 'Introduction' above and 'Pathogenesis' above.)

●Epidemiology – Coccidioidomycosis is endemic to certain arid regions of the Western Hemisphere, including the San Joaquin Valley of California, south-central Arizona, as well as other parts of the United States. It is also found in parts of Mexico and Central and South America. (See 'Epidemiology' above.)

●Clinical manifestations – It is estimated that fewer than one-half of all infections come to medical attention, because illness is often subclinical. However, when illness is clinically significant, primary infection frequently manifests as community-acquired pneumonia approximately 7 to 21 days after exposure. Patients can also develop systemic complaints (eg, night sweats, weight loss, fatigue), as well as rheumatologic or cutaneous manifestations that are immunologic in nature. (See 'Clinical manifestations' above.)

●When to suspect infection – We consider the diagnosis of coccidioidomycosis in patients living in or who have traveled to an endemic area who present with any of the following:

•A respiratory illness of more than one week's duration with an infiltrate on chest radiograph, especially if there is upper lobe involvement or hilar or mediastinal adenopathy. (See 'Imaging' above.)

•Presumed community-acquired pneumonia with continued symptoms despite appropriate empiric antibacterial therapy. (See 'Signs and symptoms' above.)

•New onset of diffuse symmetrical arthralgias and/or the rash of either erythema nodosum or erythema multiforme. (See 'Signs and symptoms' above.)

•Persistent night sweats, weight loss, and fatigue; respiratory symptoms may occasionally be minimal in such patients. (See 'When to suspect infection' above.)

●Diagnostic testing – Diagnosis usually relies upon serologic testing. However, in patients with early disease, especially those with severe infection, repeated serologic testing or isolation of Coccidioides spp in culture may be needed to establish the diagnosis. (See "Coccidioidomycosis: Laboratory diagnosis and screening".)

●Antifungal therapy

•Mild disease – Healthy patients without evidence of extensive coccidioidal infection or risk factors for more serious infection usually do not need antifungal therapy. Those with risk factors for severe disease (eg, African or Filipino descent, diabetes, frailty, immunocompromising condition) should be considered for treatment with triazole therapy, similarly to those with moderate disease (table 3). (See 'Determining disease severity and risk factors' above and 'Approach to antifungal therapy' above.)

•Moderate disease – For patients with moderate pulmonary illness, we suggest antifungal therapy with either fluconazole or itraconazole (table 3) (Grade 2C).

•Severe disease – For patients with respiratory compromise due to coccidioidomycosis, we suggest initiating lipid-formulated amphotericin B plus fluconazole (itraconazole is a good alternative) and then transitioning to triazole monotherapy when the patient is clinically stable (table 3) (Grade 2C). (See 'Determining disease severity and risk factors' above and 'Mild disease' above and 'Moderate disease' above.)

●Duration of therapy – We generally treat patients without respiratory compromise for approximately 12 weeks, although shorter courses (eg, six weeks) may be reasonable for certain patients, such as those who have rapid clinical improvement over days to weeks. Patients with severe disease warrant 12 to 24 weeks of therapy. (See 'Approach to antifungal therapy' above.)

●Patient monitoring – It is important that patients with coccidioidal infection, regardless of treatment, be followed for a year or longer to monitor for the development of complications. Patients should be monitored for clinical, serologic, and radiographic improvement. (See 'Patient monitoring' above and 'Sequelae of primary pulmonary infection' above.)

●Sequalae of infection – Some patients may develop fatigue and lethargy associated with coccidioidal pneumonia without evidence of complications, and this may persist for many weeks or months. Antifungal therapy is not helpful in this setting. (See 'Prolonged fatigue' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Galgiani, MD, who contributed to an earlier version of this topic review.