Coccidioides Species in Transplant Recipients

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INTRODUCTION

Coccidioidomycosis is a fungal infection caused by either of two species, Coccidioides immitis or C. posadasii; (25, 45) it is acquired in geographically restricted endemic areas of the Western Hemisphere, including the desert southwestern United States, northern Mexico, and Central and Southern America. C. immitis is the predominant species in California, whereas C. posadasii is found in the remainder of the endemic areas (25, 31). The manifestations of infection caused by either species appear to be identical. This chapter will summarize current knowledge regarding this infection in the transplant recipient.

MYCOLOGY

Coccidioides species are dimorphic, with a saprophytic phase that is perpetuated in the environment, and a parasitic phase in humans and animals. These organisms thrive in the sandy soils of the arid to semi arid endemic regions which are characterized by long hot summers, mild winters, and low rainfall (30). Infection is acquired by inhalation of arthroconidia that settle in the terminal bronchioles, where they undergo morphologic transformation into spherules. Rupture of mature spherules releases hundreds to thousands of endospores, which can settle nearby, or spread by a hematogenous route to other locations. Endospores enlarge to form spherules and continue the life cycle (45).

PATHOGENESIS

Once the arthroconidia is in the lung, the early innate immune response is followed by the activation of cell mediated responses, primarily comprised of CD4+ T and B lymphocytes, and the development of delayed type hypersensitivity and cellular immunity (1, 27, 42). Once a host has developed cellular immunity, protection is complete and long-lived; no subsequent infection occurs, despite ongoing exposure, unless a profound change develops in their immune system, such as with the receipt of immunosuppressing medications, organ transplantation or infection with human immunodeficiency virus (1).

Persons with defects in any aspect of the immune response, but especially of cellular immunity, as is seen in transplant recipients, may be subject to severe or disseminated coccidioidomycosis. Once Coccidioides escapes an immune response in the lungs or hilar lymph nodes, extrathoracic dissemination can be accomplished by a hematogenous route. Skin, lymph nodes, bones and joints, and central nervous system are common locations of extrapulmonary spread in transplant recipients as in otherwise healthy hosts, and it is common to find multiple concurrent sites of infection involving multiple organ systems in transplant recipients. The transplanted allograft is a frequent site of dissemination (13).

EPIDEMIOLOGY

An estimated 150,000 coccidioidomycosis infections occur annually in the United States (35), the majority of which occur in the highly endemic areas of southern Arizona and central California. Because only a few states in the endemic area mandate coccidioidomycosis reporting, there is an unknown disease burden of persons who were infected within but diagnosed outside the endemic area (46). The incidence of coccidioidomycosis has been rising for several years. In the decade between 1997 and 2006, the incidence rose from 21 to 91 cases per 100,000 population in Arizona (64). Similar increases have been seen in California (68). The reasons for this explosive rise in infections is not completely understood, but may in part be due to local environmental and climatic changes (52), new construction in previously undisturbed desert (64), immigration of previously unexposed persons (35) or a growing population of immunosuppressed persons (32, 68). In addition, increased awareness of the general public and medical providers (34), better compliance with reporting (64), and (perhaps) better diagnostic tools (40) may contribute toward the increase in reported cases.

Infections usually occur during dry seasons, and exposure to dust is an established risk factor for acquisition of infection (46). Outdoor occupations (such as military maneuvers or construction work) and recreational activities associated with dust exposure can increase the risk of exposure to arthroconidia. Severe coccidioidomycosis requiring hospitalization is increased among African Americans (32) or those who smoke tobacco (57), have diabetes mellitus (57), are elderly (32), HIV infected or pregnant (32, 57).

Similar risk factors are noted for extrapulmonary dissemination: race (especially Filipinos and African Americans), male sex, pregnancy (especially in the 3rd trimester), and cell mediated immunodeficiency (46).

Owing to their cellular immunodeficiency, transplant recipients are at increased risk of complicated coccidioidomycosis. 1.5 – 8.7% of transplant recipients in the endemic area had a post transplant course complicated by coccidioidomycosis (8, 13); the lower rates of infection were observed in programs where antifungal prophylaxis was used (8, 59). Among transplant recipients in the endemic area, risk factors for infection include the receipt of at least 2 episodes of allograft rejection (8, 13), positive serology at the time of transplantation, history of coccidioidal infection (13). The latter risks imply that coccidioidomycosis following transplantation may be due to reactivation of previous infection. The risk factors for dissemination noted in the general population do not portend additional risk in the transplant recipient (13). Cases of donor derived coccidioidomycosis have been described (48, 65, 70), but the contribution of this phenomenon within the endemic area is unknown.

Having acquired coccidioidomycosis, transplant recipients have increased risk of disseminated infection. Whereas 1 - 5% of unselected patients with coccidioidomycosis experience extrapulmonary infection, transplant recipients may have up to 75% dissemination (59, 71). Mortality can be high: early reports of outcomes in transplant recipients revealed 63% mortality in pulmonary infection and up to 72% in recipients with dissemination (22). More recent studies have shown that mortality is variable, ranging 0 - 50% (8, 16, 38, 41, 67).

Several case reports have described transplant recipients who travelled briefly to the Coccidioides endemic area and came back with coccidioidomycosis, some with dramatic or disseminated infection with poor outcomes (19, 47, 66). Observing this situation led one author to discourage transplant recipients to travel to the endemic area (22). However, the individual risk of acquiring such infections in not known, but likely depends on a number of variables, including the amount of exposure to the organism, and the net state of the patient’s immunosuppression. The only study thus far to address this situation was an evaluation of liver transplant recipients who were transplanted outside the endemic area then relocated residence within the endemic area and received no fungal prophylaxis. In 37 patients with at least 1 year of follow-up, 1 (2.7%) acquired active coccidioidomycosis (11).

CLINICAL MANIFESTATIONS

In the general population, 60% of patients experience no symptoms and the only manifestation of coccidioidal infection is the conversion of a negative to positive skin test, indicating the presence of delayed type hypersensitivity. The majority of the remaining patients experience a febrile respiratory syndrome of varying severity, and typically symptoms include some or all of the following: fever, chills, sweats, headache, myalgias and arthralgias, rash, cough dyspnea, and hemoptysis.

Among transplant recipients, the proportion of patients with asymptomatic coccidioidomycosis is not known, but has been observed, either as asymptomatic seroconversion (8), or by the identification of asymptomatic cavitary coccidioidal lung lesions, discovered while undergoing radiographic imaging for other purposes (13, 41). Most transplant recipients with recognized episodes of coccidioidomycosis experience a febrile illness of varying severity, with cough or dyspnea with or without altered sensorium, while others have a fulminant respiratory failure and septic shock (13, 19). Still other recipients may manifest their coccidioidal illness as an insidious onset of fatigue, anorexia or weight loss with or without fever, and with or without respiratory symptoms (13). Symptoms of disseminated infection are variable and depend on the severity and extent of infection in the various locations of involvement.

Historically, coccidioidal infections were more likely to occur in the first year following transplantation; among 47 transplant recipients whose course was complicated by coccidioidomycosis, 24 (51%) occurred in the first 3 months and 33 (70%) occurred in the first year post transplantation (13). This observation led investigators to hypothesize that much of the coccidioidal infection following transplantation was due to reactivation of a previous infection (13). However, when targeted prophylaxis was administered to transplant recipients at high risk for reactivated coccidioidomycosis, (i.e., the administration of fungal prophylaxis given to persons with a history of or serology positive for coccidioidomycosis), the incidence of coccidioidomycosis in the first year following transplantation was improved, though it did not disappear (12), demonstrating that transplant recipients are at risk for de novo coccidioidal infection at a time of heavy immunosuppression (7). A recent study of liver recipients within the endemic area identified 15 patients with post-transplantation coccidioidomycosis, among 391 recipients, most of whom received targeted anticoccidioidal prophylaxis. Twelve of these 15 were determined to be de novo infections, 2 were reactivated infections despite antifungal prophylaxis, and 1 was an active infection in a recipient with indeterminate serology. Because 9 of these 15 cases occurred in the first 6 post-transplantation months, the authors recommended that all recipients residing in the endemic area receive fluconazole for 6-12 months following transplantation (67)

Donor-Derived Coccidioidomycosis

Donor-derived coccidioidomycosis was first recognized in organ transplant recipients who had never lived in or travelled to the endemic area. To date, 6 cases of donor transmission have been published (15, 17, 48, 65, 70), of whom 4 resulted in the death of the organ recipient (17, 48, 70). A few episodes of donor-derived coccidioidal infections have been identified within the endemic area (65, 67). There may be more unrecognized cases of such episodes within the endemic area, since, in the absence of evidence of pre-transplantation coccidioidomycosis, coccidioidal infections following transplantation may be presumed by medical practitioners to be a newly-acquired infection.

The clinical features of donor-derived coccidioidomycosis appear to be similar to any coccidioidal infection in an immunosuppressed transplant recipient, and characterized by a febrile respiratory illness that may be complicated by multi-organ dissemination or sepsis; one clue to its donor derivation may be the onset of symptoms soon (6-21 days) after transplantation in patients not receiving systemic antifungal prophylaxis (48, 65, 70), or soon after the discontinuation of such prophylaxis (15).

Donor transmission may occur as a result of active infection in the donor; however, live organisms in an old and quiescent coccidioidal granuloma of a seronegative donor has also been the source of such transmission (65). Donors with quiescent or active infection have transmitted coccidioidomycosis via lungs (15, 48, 65), kidney (17, 70) and liver (70).

How to optimally identify donors who are at risk for transmitting infection via organ donation is an unsettled issue. Donors who had a history of travel to or residence in the endemic area may be potentially at risk, but the risk is undefined. While most of the reported donors of coccidioidomycosis transmission certainly had this history, within the endemic area, the donors have a nearly universal history of either such travel or residence. Seropositivity may not be an adequate screen either, since, following the resolution of coccidioidal illness, antibody titers wane and often disappear altogether, even in the presence of a quiescent granuloma. A seroprevalence study of live donors within the endemic area indicated that 12 of 568 (2.1%) potential live donors were seropositive (14); yet among the 4 who went on to donate an organ, 2 recipients of 2 seropositive donors did not receive antifungal prophylaxis, and did not develop coccidioidomycosis (14).

Further study may clarify some of these questions. In the absence of data, it may be prudent to identify any history of residence in or travel to the endemic area among potential organ donors; donors with such a history should undergo serological evaluation for coccidioidal infection. Any non-lung organ recipient of a seropositive donor may benefit from 6 months of fluconazole 200-400 milligrams daily, and undergo serial serological assessment following the discontinuation of such prophylaxis. Since the likelihood of quiescent granuloma is highest in the lung tissue, lung recipients of a donor with a history of travel to or residence in an endemic area, or who is seropositive may require long term antifungal prophylaxis.

DIAGNOSIS

Summary of Diagnostic Tests

Initial serologic testing includes an enzyme immunoassay (EIA) and complement fixation (CF) or immunodiffusion (IDCF). Subsequent serologic tests should repeat the positive quantitative assay, CF or IDCF. Cultures should be performed on sputum, bronchoalveolar lavage fluid and any tissue specimen; cytology or histopathology should be done on all available specimens.

Once the diagnosis of coccidioidomycosis is made, a search for the extent of infection should be conducted (35). History and physical examination are paramount in this effort. Depending on the findings of the history and physical exam, studies such as computed tomography, bone scans or cerebral spinal fluid examinations should be considered.

Culture and Histopathology

Any sterile or nonsterile specimen can be cultured for Coccidioides, and a positive result is diagnostic, since there is no natural state of colonization. Coccidioides species grow easily on most bacterial and fungal media within 2 - 7 (and up to 16) days incubation at 35 degrees Celsius; incubation on fungal media is recommended to assure adequate incubation time. Coccidioides colonies are generally white or gray, and the presence of septate hyphae with barrel-shaped arthroconidia give a presumptive identification and confirmed using a nucleic acid chemiluminescent probe (58). A major disadvantage to the use of culture is the risk of accidental exposures and subsequent infection among laboratory personnel handling such specimens. Microbiology personnel should be advised of any clinical suspicion of coccidioidomycosis illness, and suspected and established cultures of Coccidioides should be handled using Biosafety Level 3 precautions (58).

Histopathological specimens, either tissue or cytology, typically show a granulomatous background and the presence of spherules is diagnostic. Fresh specimens can be examined using KOH, Papanicolaou or calcifluor, although the yield on such specimens is relatively low. Histological examination of fixed specimens using Gomori-methenamene silver is sensitive, though the internal structures of the spherule are better demonstrated by the less sensitive periodic acid Schiff (70) or hematoxlyn and eosin (H & E) stains (58).

Chest radiographic imaging can be nonspecific in patients with coccidioidomycosis, and include a variety of abnormalities such as focal or multifocal consolidation, nodular or alveolar infiltrates, diffuse military pattern, nodules, or cavities or a combination thereof (13, 71).

Serology is an important and useful diagnostic tool for the establishment of a diagnosis of coccidioidomycosis. A number of modalities are available, each with advantages and disadvantages.

The measurement of tube precipitin antibodies (TP) and complement fixing antibodies (CF) has been performed for years. In general TP antibodies appear earlier and correspond to an IgM response, and CF antibodies appear after a few weeks into the course of infection, corresponding to an IgG response. Quantification of the CF antibodies allows for a serial measurement that correlates to the response to the infection (51). Some labs employ a variant of the test, using immunodiffusion in agar reported as IDTP and IDCF (2).

The enzyme immunoassay (EIA) has been widely employed within the endemic area due to its ease of use, and ability to be used as a point of care test. The EIA measures both IgM and IgG responses, and appears to be very sensitive in early disease (10). It is a qualitative test and not used for subsequent follow-up. The EIA test had demonstrated false positive results when tested against serum from patients with pulmonary infections due to other etiologies.

Among transplant recipients with established coccidioidomycosis, serologic tests have lower sensitivity when compared with healthy hosts with coccidioidomycosis. In a small cohort of transplant recipients with known coccidioidomycosis, EIA was positive in 71%, whereas CF was positive in 33% and ID did not show any positive result. By comparison, among healthy hosts with known coccidioidal infection, EIA was positive in 87%, CF and ID positive in 75% and 73% respectively (10). Therefore, negative serology should not exclude the diagnosis (58).

In transplant recipients, initial serology could include both EIA and CF or ID/IDCF testing to maximize the sensitivity of the serologic query. When following a patient with known coccidioidomycosis, periodic evaluation of the quantitative tests (i.e., CF or IDCF) every 3-4 months can be helpful to follow response to therapy, whereas there is little demonstrated utility in repeating the qualitative tests over time.

Detection of Antigen

In the past, assays to detect circulating coccidioidal antigen were developed but did not have adequate sensitivity for clinical use. Recently a test to detect coccidioidal antigen in urine and blood has been developed and preliminary studies indicate that the antigen detection has a sensitivity of 73% (28). Further study is needed to evaluate the use of this assay in transplant recipients who might not be able to mount a serological response.

ANTIFUNGAL THERAPY

Guidelines for the treatment of coccidioidomycosis have been published (35). Once the diagnosis has been established, an evaluation must be conducted to establish the extent of the infection to establish the baseline for future assessments (35). The treatment of coccidioidomycosis in transplant recipients is similar to that of non-transplant recipients, with a few exceptions: 1.) Whereas many healthy patients do not require treatment for mild, asymptomatic or self-limited coccidioidomycosis, transplant recipients, with ongoing deficiencies in the cellular immune system, are advised to receive treatment (35). On occasion, if treatment is declined or withheld (such as in asymptomatic mild seroconversion in a transplant recipient on low level immunosuppression) very close monitoring and follow-up is recommended. 2.) Secondary prophylaxis, following successful treatment, is recommended (8).

Drugs of Choice

Fluconazole or itraconazole are effective treatment for most types of coccidioidomycosis; an amphotericin B formulation is recommended for severe and rapidly progressing infection (35).

Fluconazole: Fluconazole has been a mainstay of antifungal treatment for years, and for most situations, will be adequate for the treatment of coccidioidomycosis (35). Doses of 400-800 (occasionally higher) milligrams given singly or divided are given. Fluconazole has good oral bioavailability (60), and routine therapeutic levels are not generally drawn. Like all other azoles, fluconazole interferes with the metabolism of calcineurin inhibitors (5) such as cyclosporine or tacrolimus, so that doses of calcineurin inhibitors will need to be adjusted downward to avoid toxicity. Fluconazole is fungistatic for Coccidioides, and transplant recipients require secondary prophylaxis with fluconazole once the infection is controlled, to avoid relapse.

Itraconazole: Itraconazole is very active against Coccidioides species in vitro and in vivo. For the treatment of coccidioidomycosis, the dose is 200 mg twice or thrice daily. It is available only in oral formulation (capsules or solution) and bioavailability (55% using solution under fed conditions) is lower than fluconazole. Bioavailability of the capsule formulation is best achieved in the fasted state. In contrast, better serum levels are achieved in less time using the solution formulation with concurrent administration of food. Itraconazole is highly protein bound and has excellent tissue penetration. Itraconazole was superior to fluconazole in the treatment of skeletal coccidioidomycosis (36).

Amphotericin B: Amphotericin B deoxycholate (AMB) has been the drug of choice for decades, but with the advent of orally administered and better tolerated azoles, has been relegated to situations where the coccidioidal infection is severe, or rapidly progressing (35). The dose of amphotericin is 0.5 to 1.5 milligrams per kilogram daily or every other day by slow intravenous infusion (35). AMB treatment is often complicated by symptoms during infusion (vomiting, fever, rigors, hypo- or hypertension, and others) and cumulative doses are complicated by renal insufficiency and renal losses of potassium and magnesium (43).

The newer lipid formulations of amphotericin (LAMBs) consist of amphotericin B colloidal dispersion, amphotericin lipid complex, and liposomal amphotericin B. Notably, LAMBs have much less renal toxicity than the original deoxycholate formulation (43), though varying amounts of infusional toxicity accompany the various LAMBs. In animal models, the higher tolerable doses of LAMBs allow better results when compared to the older AMB, but no clear advantage of one liposomal preparation over another (20, 21). For the treatment of coccidioidomycosis, the dose is 5 milligram per kilogram by intravenous infusion daily (43).

Other Agents

Caspofungin: In vitro studies of caspofungin as a single agent have been performed, showing more activity than placebo (23, 56); however, in vivo studies indicate that caspofungin is inferior as a single agent compared with amphotericin B (37). In a single report of a transplant recipient with disseminated coccidioidomycosis, caspofungin was successfully used in a combination antifungal regimen, within in a series of antifungal agents (3). In the absence of controlled clinical trials, there is no recommendation for the use of this agent.

Nikkomycin Z: Nikkomycin Z interrupts the formation of chitin, an essential component of the fungal cell wall. In vitro studies have shown greater fungicidal activity when compared with fluconazole and amphotericin B. This agent is currently under development as an orphan drug for the treatment of coccidioidomycosis (49). Its role in the treatment or prophylaxis of coccidioidomycosis in transplant recipients remains to be delineated.

Combination Therapy

The role of combination antifungal agents for coccidioidomycosis has not been formally studied, although a single case report is noted in transplant recipients. A patient with a failed kidney transplant and coccidioidal meningitis was treated initially with itraconazole and LAMB with progressive illness; the patient appeared to improve only after his antifungal regimen was switched to a combination of voriconazole and LAMB (4). What role the combination of medications played is unclear.

Special Situations

Meningeal Infection: The treatment of choice for coccidioidal meningitis is fluconazole 400-800 mg daily; the lower dose was used in treatment trials, and the higher dose is preferred by some experienced practitioners in the endemic area (35). Itraconazole in doses of 400-600 mg daily has also been used (35). Intrathecal AMB is an alternative treatment (63). Since discontinuation of azole treatment was associated with 78% relapsed infection (26), lifelong treatment is recommended for all patients (26), transplant recipients or otherwise.

Nonmeningeal Extrapulmonary Infection: If the coccidioidal infection is rapidly progressive or in critical locations, antifungal treatment can be initiated with AMB or the LAMBs at doses noted above (35). Many extrapulmonary infections can be treated with an oral azole, generally fluconazole or itraconazole in doses noted above (35). When single drug treatment is failing, combination treatment with azole and an amphotericin preparation has been used (35), although no studies have been performed to assess the efficacy of this approach. The duration of treatment is not protocolized, but may take months to years, depending on the response to treatment; duration should take into account clinical, radiological and serological responses. Transplant recipients have a high risk of relapsed coccidioidomycosis when azoles are discontinued, and are advised to remain on secondary prophylaxis to avoid such relapse.

Alternative Therapies

Voriconazole: Voriconazole has better in vitro activity versus Coccidioides than itraconazole, and is available in oral and intravenous formulations (60). Variable absorption is noted, and serum levels are recommended. Animal models have been hindered by metabolism issues. Retrospective case series and single case reports document the efficacy of voriconazole in recalcitrant coccidioidomycosis (24, 33, 53, 54). The only report of the use of voriconazole in a transplant recipient with cerebral abscess was unsuccessful (17); another case of voriconazole as a component of combination antifungal therapy is noted below (3).

Posaconazole: Posaconazole is more than 200 fold more potent versus Coccidioides species than fluconazole (60). It has been shown to be fungicidal in vivo, and has proven to be useful as salvage treatment for recalcitrant pulmonary and nonmeningeal extrapulmonary coccidioidomycosis (18, 62). It is available only in oral formulation, and bioavailability is improved with a fatty meal (55). Because variations in body weight, comorbidities, age and sex lead to variable serum concentrations, serum levels are suggested to document absorption (55). No formal studies of posaconazole have been conducted in transplant recipients with coccidioidomycosis.

ADJUNCTIVE THERAPY

In addition to antifungal therapy, adjunctive measures for coccidioidomycosis may be warranted. When at all possible, reduction of immunosuppression is recommended during the efforts to control the infection (44).

Occasionally, surgical debridement of a coccidioidal abscess or phlegmon is required to quickly reduce the burden of disease. Situations to consider such a maneuver would include (but not be limited to) the presence of a large abscess or destructive lesions, continued enlargement of an inflammatory mass despite medical therapy, impingement on a critical structure such as an epidural abscess on a spinal cord, or pericardial effusion or phlegmon with impending tamponade (35). Other situations where surgery should be considered are the presence of a boney sequestration, unstable spine, or recurrence of a lesion following successful medical therapy (35). Hemoptysis recalcitrant to medical therapy and stemming from a coccidioidal cavity might also warrant surgery.

ENDPOINTS FOR MONITORING THERAPY

Initially, patients with active coccidioidomycosis should be followed frequently, but as the infection becomes controlled, can be followed every 3-6 months.

Patients with active coccidioidomycosis prior to transplantation will be treated with antifungal agents and monitored clinically, radiographically and serologically (Table 1). If the patient was able to mount a positive CF antibody response, this serology should be repeated every 3-4 months at the time of clinical re-evaluation. The CF titer should get to 1:2 or less (ideally) prior to transplantation. In addition to serological resolution, transplantation should not proceed until clinical symptoms have resolved and radiographic abnormalities have resolved or stabilized.

When the coccidioidal infection occurs after transplantation, the patient should be treated for life, assuming there will be lifelong immunosuppression. Several authors have reported relapsed and disseminated coccidioidomycosis after discontinuation of treatment or secondary prophylaxis following an initial treatment (6, 41, 59, 69). If the quantitative serology is positive, it should be repeated every 3-4 months to assess the titer as one marker of response to treatment. Often times, however, the quantitative serology is negative, and follow-up is purely clinical and radiographic. Abnormalities identified radiographically can be followed serially until resolved. Follow-up with careful clinical evaluation is warranted with close attention to areas that previously had inflammatory changes; in addition, attention should be given to lymph nodes, skin, musculoskeletal and CNS to exclude extrapulmonary infection.

If coccidioidal meningitis is diagnosed, in addition to the above, the patient will need careful clinical evaluations to detect evidence of elevated pressure of the central nervous system (CNS) (9). Periodic repeat CSF examination to assess inflammatory markers will be needed until resolution is confirmed, but once resolved on stable lifelong antifungal therapy and stable immunosuppression, need not be repeated in the absence of new clinical signs or symptoms.

When pulmonary coccidioidomycosis is quiescent (symptomatically, serologically, and radiographically) for at least 1 year, patients with stable and low dose immunosuppression can be assessed for a possible reduction in the azole dose if they are intolerant of the current dose. No data exists to guide this reduction, but dosages should not be less than 200 milligrams daily, and more frequent clinical, serological and radiographic monitoring will be required. Such a reduction in medication should not routinely occur with extrapulmonary coccidioidomycosis.

VACCINES

A vaccine for the prevention or attenuation of coccidioidomycosis has long been sought. However, no vaccine is currently commercially available for the prevention of coccidioidomycosis.

A formalin-killed spherule (FKS) vaccine was effective in animal models, but failed in human trials, proving to elicit too strong an inflammatory reaction (50). Current vaccine efforts are primarily associated with the academic consortium of the Valley Fever Vaccine Project, and are focused on antigen discovery, characterization and production, and evaluation of efficacy of potential candidates in vivo (39).

ANTIFUNGAL PROPHYLAXIS

Among transplant programs within the endemic area, there is no consensus regarding the optimal approach to coccidioidomycosis prophylaxis (8). Some programs institute a program of lifelong azole prophylaxis, but have not published their results. One program utilizes a program of targeted prophylaxis, whereby patients with risk factors for reactivated coccidioidomycosis receive azole prophylaxis for a variable period of time, depending on the level of risk (Table 2). This approach to prophylaxis resulted in 4 (0.4%) asymptomatic seroconversions and 11 (1.2%) active infections in 929 solid organ recipients. Recent data indicates that the more than half of the cases of coccidioidomycosis occur in the first 6 months post transplantation despite targeted prophylaxis; therefore it may be prudent for all transplant recipients residing in the endemic area to receive 6-12 months of fluconazole in addition to the more extended targeted prophylaxis outlined in Table 2 (67).

INFECTION CONTROL MEASURES

Within the endemic region, Coccidioides is potentially ubiquitous in the environment, and there is no action or maneuver to completely avoid exposure to the organism, short of relocation outside the endemic area. However, given that persons exposed to dust or dirt may have an increased risk of contact with the organism, it seems reasonable (but unproven) to advise persons at risk for severe infections (such as transplant recipients) to avoid such situations, and if unavoidable, consider wearing a mask, such as during a dust storm.

Since the predominant form of Coccidioides within the host (i.e. the spherule) is not infectious to others (i.e., no person to person spread), no special Infection Control Measures are necessary. However, there have been rare occasions described when drainage of a coccidioidal lesion has dried on the skin, and organisms reverted back to the mycelial phase, causing aerosolization of arthrospores and transmission of infection upon removal of the dressing (29). Therefore, care should be taken when changing dressings from coccidioidal lesions.

There is significant risk to personnel in the microbiology laboratory, since even small amounts of fungal growth on specimen plates can be aerosolized and easily inhaled, precipitating an acute episode of coccidioidomycosis. A recent publication emphasizes safety within the laboratory, and recommends that handling of any unknown mold should be conducted in a biological safety cabinet appropriate for Coccidioides (61). When an exposure occurs, an artificially large exposure to arthroconidia can result and may require laboratory evacuation, containment and decontamination (61). Exposed personnel should be considered for postexposure azole prophylaxis and followed closely (61).

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Table 1. Antifungal Therapies for the Treatment of Coccidioidomycosis in Transplant Recipients

Medication	Indication	Dose	Duration	Other
First Line Treatments
Amphotericin Liposomal preparations	Life-threatening or rapidly progressing infection	5 mg/kg/day	Until the rapid progression of infection is controlled, then transition to an azole alone	Consider adding concurrent azole in severe life-threatening infection. Monitor serum creatinine and K, Mg
Fluconazole*	Most non-life-threatening infections	400 – 800 mg daily	Full treatment dose until clinically resolved, then lifelong secondary prophylaxis 200-400 mg
	Meningitis (fluconazole preferred)	400 – 800 mg daily	Lifelong	Higher doses preferred by experts
Itraconazole*	Most non-life- threatening infections	200 mg BID - TID	Indefinite duration; full treatment dose until completely resolved, then change to the lower dose or fluconazole as secondary lifelong prophylaxis	Monitor serum itraconazole and hydroxyitraconazole
	Skeletal infections (itraconazole preferred)	200 mg BID – TID	Indefinite duration; full treatment dose until infection resolved, then continued secondary prophylaxis.
Second Line Antibiotics
Posaconazole*	Most non-life-threatening infections, when first line therapies fail or not tolerated	400 mg BID orally	Indefinite duration; full treatment dose until completely resolved, then consider a lower dose as secondary lifelong prophylaxis.
Voriconazole*	Most non-life-threatening infections, when first line therapies fail or are not tolerated	6 mg/kg BID x 2 doses, then 4mg/kg BID, or 200-300 mg BID	Indefinite duration, full treatment dose until completely resolved, then consider the lower dose as secondary lifelong prophylaxis.

*All azoles have drug interactions with calcineurin inhibitors

Table 2. Targeted Prophylaxis for Coccidioidomycosis in Solid Organ Transplant Recipients at Mayo Clinic Arizona (8)

1. For recipients with a prior history of coccidioidomycosis

A physician’s diagnosis is required for patient to qualify for this prophylaxis schedule. The patient is usually able to describe a compatible clinical illness. Corroborating medical records are helpful but not required.
Patients do not receive this prophylaxis if they think they may have had coccidioidomycosis because of time spent in the endemic area, self diagnosis, or granuloma on chest radiograph.
Chest radiograph, serology must be negative for this prophylaxis schedule.
Following transplantation, oral fluconazole 200 mg daily for 6 months.

2. For recipients with positive serology at transplantation evaluation or surgery.

Any positive serology by enzyme immunoassay, complement fixation or immunodiffusion.
Fluconazole 400 mg daily by oral route for the first year, then 200-400 mg daily thereafter for the duration of immunosuppression.

3. For recipients with active coccidioidomycosis within 1-2 years of transplantation

Patients with a compatible clinical illness with positive serology, chest radiograph, or asymptomatic seroconversion (documented negative serology followed by positive serology).
Infection must have resolved clinically, serologically, and radiographically. Patient must be cleared for transplantation by Infectious Diseases in consultation with the transplant team.
Fluconazole 400 mg* daily for the first year following transplantation, then 200-400 mg daily thereafter.

4. Active infection at pre-transplantation evaluation or transplantation surgery.

Defer from transplantation until patient meets criteria 3A above.
If infection discovered after transplantation, treat initial infection, then give prophylaxis with lifelong fluconazole 400 mg* daily for first year, then 200-400 mg daily thereafter, in conjunction with Infectious Disease consultation.

5. Active Coccidioidomycosis or positive serology in donor.