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Coccidioidal Meningitis

Clinical Presentation and Management in the Fluconazole Era

Mathisen, Glenn MD; Shelub, Aaron MD; Truong, Jonathan MD; Wigen, Christine MD, MPH

doi: 10.1097/MD.0b013e3181f378a8
Article
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Despite the advent of new antifungal agents, coccidioidal meningitis (CM) remains a difficult-to-treat condition with significant morbidity and mortality. In this study we directly compare the clinical presentation and management of patients with Coccidioides immitis meningitis in the azole era (after 1980) to that of a cohort of patients from the pre-azole era. We reviewed 30 CM cases seen at 3 Los Angeles hospitals between the years 1993 to 2008 ("2008 cohort") and compared them to 31 patients ("1980 cohort") described by Bouza et al in a previous study. The demographics and clinical presentation of patients in the 2008 cohort were similar to those of the 1980 cohort except for a higher incidence of Hispanic patients (2008: 53% vs. 1980: 6%) and a greater percentage of patients with underlying, predisposing clinical conditions (2008: 66% vs. 1980: 32%). Ten patients in the 2008 cohort had human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), a condition not reported in the earlier study. Laboratory findings were similar between the 2 groups except for a lower incidence of peripheral leukocytosis and eosinophilia in the 2008 group.

There were marked differences in drug treatment between the 2 eras. In the 2008 cohort, 29 patients received fluconazole therapy: 13 were treated with fluconazole monotherapy, and 16 received a combination of fluconazole and intravenous amphotericin B. Although almost all patients (29/31) in the 1980 cohort received intrathecal amphotericin B, only 3 patients in the 2008 study received amphotericin B via this route. With respect to complications of CM, a similar percentage of patients in each cohort developed complications such as stroke and hydrocephalus. The 2008 cohort (40%) had similar mortality compared to patients in the 1980 study (39%); survivors in both groups experienced significant impairment of activities of daily living. Although recommended as first-line therapy for CM, azole-based therapies are not curative and do not necessarily prevent complications associated with the disease.

CM remains a serious illness with a high rate of morbidity and mortality. Immunocompromised individuals, especially those with HIV/AIDS, are at special risk for CM and represent a greater share of the overall population with this condition. Despite the clear advantages of azole treatment in CM, new therapeutic approaches are needed to provide definitive cure and to reduce the need for long-term suppressive therapy.

Abbreviations: AIDS = acquired immunodeficiency syndrome, AmB D = amphotericin B desoxycholate, CF = complement fixation, CM = coccidioidal meningitis, CSF = cerebrospinal fluid, CT = computerized tomography, ELISA = enzyme-linked immunoserologic assay, HAART = highly active antiretroviral therapy, HIV = human immunodeficiency virus, IRB = institutional review board, LAmB = liposomal amphotericin B, MRI = magnetic resonance imaging, po = orally, VP = ventriculoperitoneal.

From Cedars Sinai-UCLA Affilialted Multicampus Infectious Disease Program (GM, AS, JT, CW), Los Angeles; Cedars Sinai Medical Center, Los Angeles; Olive View-UCLA Medical Center (GM, JT, CW), Sylmar; VA West Los Angeles Medical Center, Los Angeles; Los Angeles County Department of Public Health (CW), Los Angeles; and Southern California Kaiser Permanente Medical Group (JT), Los Angeles, California.

This work was supported by an unrestricted educational grant from Pfizer Pharmaceuticals.

Reprints: Glenn Mathisen, MD, Chief, Infectious Disease Service, Olive View-UCLA Medical Center, Department of Medicine, Rm 2B182, 14445 Olive View Drive, Sylmar, CA 91342 (e-mail: gmathisen@ladhs.org).

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INTRODUCTION

Despite the advent of new antifungal agents, coccidioidal meningitis (CM) remains a difficult-to-treat condition with significant morbidity and mortality. Up until the 1980s, intrathecal amphotericin B was the mainstay of treatment for this condition.32 Although the drug offered the first effective therapy for the condition, administration of amphotericin B via the intrathecal route is difficult and is associated with significant toxicity.30 The advent of azole agents in the early 1980s offered the hope that a new class of antifungal drugs would prove more effective and less toxic than previous drug regimens. Subsequent studies established the utility of fluconazole in the management of CM,25 and the drug has now become the accepted first-line agent in the treatment of the condition.24,30,67 In addition to fluconazole, other azoles such as itraconazole and voriconazole appear to have activity in CM and have been used to treat this condition.17,49,63 Unfortunately, a major drawback of azole therapy is the need to continue treatment indefinitely-in patients with clinically proven CM, suspension of therapy is usually associated with relapse of the condition, sometimes with serious complications.21

We conducted the current study to compare the present management of CM with management of the condition in the pre-fluconazole era (before 1990). Our study is a retrospective analysis of a recent cohort of 30 patients in Los Angeles compared to a similar cohort of patients from the pre-azole era, described by Bouza and colleagues in 1981.8

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History

Coccidioidomycosis was first described by the Argentinian physician Alejandro Posadas in 1892.47 The initial case was a soldier who presented with progressive, destructive verrucous lesions of the face. A skin biopsy demonstrated a spherical, nonmotile organism with a highly refractile double wall. Despite the presence of the "parasite" on biopsy, Posadas (and his mentor Wernicke) did not believe this was the cause of the condition, and thought the patient actually had mycoses fungoides. Four years later, Rixford and Gilchrist described a similar condition in 2 patients residing in the San Joaquin Valley of central California.52 Again, an organism was present on skin biopsy; however, these investigators believed the condition was caused by an underlying parasitic infection. The parasite resembled protozoa from the genus Coccidia and, upon the suggestion of the noted parasitologist G. W. Stiles, they named the organism Coccidioides immitis. The appellation "immitis" means "severe" and refers to the severe, progressive clinical course observed in the affected patients.

The next major advance in understanding the disease occurred in 1900 when William Ophüls, a professor of pathology at Cooper Medical College (which became Stanford Medical School in 1921), identified the fungal nature of the organism and succeeded in transmitting it to mice.20 He later described the clinical spectrum of the disease in a case series that documents CM in a patient who died from disseminated coccidioidomycosis.43 This is presumably the first described case of CM. Over the next several decades, clinicians and researchers delineated the clinical presentation and course of CM in a series of papers. In 1924 Morris reported the first case of CM as the sole site of extrapulmonary dissemination.40 In 1936, Abbott and Cutler1 reviewed 14 cases and described the typical cerebrospinal fluid (CSF) findings in the condition. A subsequent pathological report demonstrated the prime role of meningeal involvement with coccidioidal central nervous system infection.18

Early therapies for CM were ineffective, and patients almost always died within a few years of diagnosis. The Veterans Affairs (VA)-Armed Forces Cooperative Study of Coccidioidomycosis tracked over 700 patients with coccidioidomycosis during a period (1955-1958) before the advent of effective antifungal therapies. Vincent et al65 reviewed these data and identified 21 patients who developed CM while under observation; 17 of these individuals died within 31 months of symptom onset. There were a few patients with more prolonged survival (55-146 mo); however, lacking effective antifungal therapy, CM was almost always a serious illness with a high mortality-there was significant neurologic disability, and most patients died within 2 years of diagnosis.

The outlook for coccidioidomycosis began to change with the introduction of amphotericin B in 1957. This drug is a lipophilic molecule that exerts its action by binding to ergosterols in the fungal cell; the subsequent altered membrane permeability and intracellular potassium loss leads to decreased cell viability. Parenteral amphotericin B was the first effective drug treatment for coccidioidomycosis, and quickly became the treatment of choice for severe and disseminated coccidioidomycosis. Unfortunately, parenteral amphotericin B had poor CSF penetration and was largely ineffective in treatment of CM. In the early 1960s, William Winn (and other investigators) pioneered the use of intrathecal amphotericin B for management of CM.22,69 Although there was still a significant morbidity and mortality associated with the condition, intrathecal amphotericin B became the mainstay of management for CM until the advent of the azole therapies in the 1980s.8

Miconazole, a substituted imidazole, was the first azole used to treat coccidioidomycosis.61 Imidazoles and related agents (triazoles) bind to fungal cytochrome P-450 enzymes and inhibit C-14α demethylation of lanosterol, a key step in production of ergosterol, an important component of the fungal cell membrane. Miconazole is fungistatic against C immitis and requires parenteral administration. Although the drug had some degree of CSF penetration, patients with CM often required intrathecal therapy for a clinical response. Early studies of miconazole (often in patients who had failed or had difficulty tolerating amphotericin B) provided mixed results. The high rates of relapse, due to its lack of fungicidal activity and the necessity for parenteral administration, made it an impractical agent for long-term therapy. Ketoconazole, a close relative of miconazole, was introduced in 1976 and was subsequently used to treat CM.16 While ketoconazole had activity against C immitis, its poor CSF penetration and high rate of nausea/vomiting (associated with higher dosing) made it an ineffective agent for long-term therapy.

In 1990, Tucker et al63 reported the first use of a triazole-itraconazole in the treatment of CM. Compared to the imidazoles, triazoles generally have more favorable pharmacokinetics including improved absorption, greater tissue penetration, and less inhibition of the human cytochrome P450 system. Although itraconazole had some demonstrable clinical benefit, its variable oral absorption and poor CSF penetration limited its use as a first-line agent for CM. In 1990, the triazole fluconazole was introduced in the United States. Compared to previous agents it has almost complete oral absorption, good CSF penetration, and excellent in vitro activity against C immitis. Similar to other members of the azole family, it is fungistatic to C immitis at clinically achievable concentrations. Animal studies in the late 1980s demonstrated potential efficacy of fluconazole in murine CM.27,57 Subsequent case reports and studies outlined the use of fluconazole in humans with CM.14,64 A report of 18 patients by Tucker et al64 delineated the pharmacokinetics of fluconazole and reported a clinical response in 15 of the patients treated with the drug. The drug was well tolerated when given in doses ranging from 50 to 400 mg/day. The investigators commented on relapse of CM (when the drug was discontinued) and suggested that the higher doses might be useful in nonresponding patients. In 1993, the results of a National Institute of Allergy and Infectious Diseases (NIAID)-Mycoses Study Group trial further supported the use of fluconazole in the treatment of CM.25 In this study, 50 patients with CM were treated with fluconazole at a dose of 400 mg per day for up to 4 years; 37 of 47 patients who could be evaluated (79%) responded to therapy, regardless of previous treatment with other antifungal agents (amphotericin B). Although discontinuance of fluconazole was associated with clinical relapse, this study further established the prominent role of fluconazole in the modern era of CM management. Published reports34 of excellent in vitro activity of voriconazole against C immitis led to subsequent use of the drug in patients with CM.17

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PATIENTS AND METHODS

Patient Selection

We retrospectively reviewed the medical records of all patients with a diagnosis of CM at 3 Los Angeles-area hospitals (VA West Los Angeles Hospital, Olive View Medical Center, and Cedars Sinai Medical Center) from the years 1993 to 2008. Institutional review board approval for chart review was obtained. CM was defined by a) positive CSF cultures or detection of complement-fixing antibody to Coccidioides antigen in the CSF in the presence of other CSF abnormalities typical of CM, or b) illness plus CSF abnormalities compatible with chronic meningitis and either detection of serum complement-fixing type antibodies or isolation of Coccidioides species from an extraneural site.24 CSF abnormalities compatible with meningitis included CSF pleocytosis (CSF cell count >4 cells/mm3), elevated total protein, and/or decreased CSF glucose (hypoglycorrhachia) according to laboratory standards at each facility. Lumbar arachnoiditis was defined as nerve root/back pain with evidence of lumbar nerve root enhancement on gadolinium-enhanced lumbosacral magnetic resonance imaging (MRI).

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Conduct of Study

We obtained baseline information for patients at time of initial presentation with CM at the aforementioned hospitals. We reviewed patient admission data, hospital course, treatment, and follow-up. The majority of patients were followed for over 2 years. We compiled data regarding patient age, predisposing risk factors, initial presentation symptoms and signs, evidence of neurologic deficits, general serum and CSF laboratory parameters, serum and CSF serologies, imaging procedures, evidence of dissemination, dissemination interval, therapy received, neurosurgical interventions, and response to therapy including the ability to perform activities of daily living. Response to therapy was determined by clinical improvement including improved function/symptoms, CSF parameters, and decrease in CSF coccidioidal titer. We compared the data for this group ("2008 cohort") to data for a group of 31 patients with CM treated between 1964 and 1976 in the pre-fluconazole era described in a retrospective study by Bouza et al ("1980 cohort").8

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Data Analysis

Patient clinical presentation and predisposing conditions in the present cohort (2008 cohort) were compared with those in the 1980 cohort. We compared the diagnostic modalities (for example, serology, CSF analysis, radiographic procedures) between the 2 groups when appropriate. Patient response to therapy in the 2008 cohort and subgroups was compared with that in the 1980 cohort. Special attention was placed on whether patients received azole alone or azole therapy in some combination with amphotericin. In addition, the need for VP shunt or Ommaya reservoir was contrasted with the need in the 1980 cohort. We also compared CM morbidity (for example, activities of daily living; employment status) and mortality among cases in the 2 cohorts.

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RESULTS

We compared 30 patients with CM from 1993 to 2008 (2008 cohort) to 31 cases from the pre-1980 period (1980 cohort) (Tables 1-4). More extensive information on the current cohort (2008), including clinical presentation, laboratory studies, radiologic procedures, therapy and outcome is presented in Tables 5-12. Instructive cases from the current study are presented in the Appendix at the end of the paper. Similar data from the 1980 cohort can be obtained from the original paper by Bouza et al.8

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

TABLE 6

TABLE 6

TABLE 7

TABLE 7

TABLE 8

TABLE 8

TABLE 9

TABLE 9

TABLE 10

TABLE 10

TABLE 11

TABLE 11

TABLE 12

TABLE 12

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Background Information

The age of our patients varied from 27 to 72 years (mean age, 42.9 yr). Men outnumbered women (24 male patients [80%]; 6 females [20%]). Sixteen (53%) patients were Hispanic, 8 (27%) were white, 4 (13%) were black, and 2 (7%) were Asian. All patients had lived in California for at least 2 months, and many came from endemic areas within the state. In the 1980 cohort, 19 (61%) patients were white, 10 (32%) were black, and only 2 (6%) patients were Hispanic.

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Predisposing Factors and Underlying Disease

Of the 30 patients in the present cohort, 20 (66%) had predisposing conditions, including human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (10 patients; 33%), diabetes mellitus (4 patients; 13%), alcohol abuse (3 patients; 10%) and pregnancy (1 patient; 3%). If Asian/black/Hispanic race were also considered as risk factors, then 97% (29/30) of the patients in the 2008 cohort would be considered to have at least 1 predisposing factor. In the 1980 cohort, 32% of patients (10/31) had predisposing factors; of these individuals, 8 (26%) had a recent history of alcohol abuse and 3 (10%) had underlying diabetes mellitus.

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History of Non-Meningeal Coccidioidomycosis

Background information on both patient cohorts is summarized in Table 1. Meningitis was part of the initial manifestation of disease in 60% (18/30) of patients in the current cohort and in 65% of patients in the 1980 cohort. Diagnosis of extra-CNS coccidioidomycosis before the clinical presentation of meningitis was similar in both groups (2008: 40%; 1980: 35%). With regard to extra-CNS disease, rates of lung involvement (2008: 57%; 1980: 48%) were similar in both groups; however, the 2008 cohort had lower rates of both skin disease (10% vs. 42%) and bone involvement (7% vs. 27%) compared to the 1980 cohort, respectively. For the 2008 cohort, pathological evidence of involvement outside the central nervous system is tabulated in Table 8 and discussed in the pathology section.

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Interval Between First Symptom (or Exposure) and Meningitis

In the current study, the interval between the first symptom suggestive of any form of coccidioidomycosis and the first clinical sign of meningeal involvement could be estimated in 12 patients. The mean interval was 6.9 months with a maximum of 19 months (Patient 21). This compares with the 1980 cohort where the interval was less than 3 months in 17 of 24 patients.

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Clinical Data

Headache

Headache is a common presenting clinical symptom of CM and is often described as "bilateral, intense and throbbing."8 In the 2008 cohort, 77% (23/30) of patients had an initial presentation with headache; this was similar to the 1980 cohort, where the symptom was recorded in 74% (23/31) of patients. With respect to other signs of intracranial hypertension, 55% (15/27) of patients in the 2008 cohort presented with nausea and vomiting on admission, a figure that was comparable to the 1980 cohort (48%: 15/31 patients). Only 1 patient (Patient 19) in the current study had documentation of the triad of intracranial hypertension (headache, vomiting, and papilledema). Meningismus was equally common on physical examination in both groups (2008: 39%; 1980: 32%).

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Neurologic Complications

In the 2008 cohort, 73% (22/30) of patients presented with mental status changes (for example, lethargy, obtundation/confusion, dizziness, bizarre behavior, and disorientation) compared to 45% (14/31) in the 1980 cohort (see Table 1). Neurologic signs and symptoms were common in our patient cohort; 24 of 30 (80%) patients presented with focal (7/30) or nonfocal (17/30) neurologic findings; these abnormalities included generalized weakness, ataxia, diplopia, focal weakness, and confusion (see Table 5). Patients 8 (facial weakness), 13 (pupillary dilatation) and 27 (diplopia) had evidence of cranial nerve dysfunction. Focal findings in the 1980 study were seen in 16% of patients (5/31). Hydrocephalus (based on computerized tomography [CT] scan or MRI) was seen in 12 of 30 (40%) patients in the 2008 cohort; only 6 cases underwent CT scanning in the 1980 study, and 5 patients (5/31; 16%) had documented hydrocephalus. Lumbar arachnoiditis ultimately developed in 10% of patients (3/30) in the 2008 cohort compared to 35% (11/31) of individuals in the 1980 study.

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Constitutional Signs and Symptoms

Constitutional symptoms such as fever (2008: 66%; 1980: 77%) and weight loss (2008: 56%; 1980: 53%) were similar in both groups.

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Other Physical Findings

At clinical presentation, coccidioidal skin lesions were noted in 3 patients (10%) in the 2008 cohort compared to 13 patients (42%) in the 1980 cohort.

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Laboratory Data

A comparison of admission laboratory data between the 2008 and 1980 cohort is presented in Table 2, and detailed laboratory data (serum and CSF) from the 2008 cohort are outlined in Table 6. In the present cohort, the peripheral white cell count (leukocyte count ≥10,000 cells/mm3) was elevated in only 1 of 30 patients (3%) compared to 10 of 27 cases (37%) from the 1980 cohort. Peripheral eosinophilia (for example, eosinophil count ≥350 cells/mm3) was less common in the current patient population (5/28; 18%) compared to the 1980 cohort (13/27; 48%). Significant anemia (hemoglobin <12.0 g/dL) was equally common in both studies (2008: 40%; 1980: 38%).

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Serum Serology

The serum enzyme-linked immunoserologic assay (ELISA) test was not available in the 1970s at the time of the initial study, but was used for patients in the current protocol. In the present study, ELISA IgG was positive in 93% of patients (25/27) at some time during their clinical illness, and the ELISA IgM was positive in 56% (15/27). In 1 patient (Patient 30) both titers were negative early in the disease but subsequently turned positive. In the present cohort, the serum coccidioidal complement fixation (CF) test was elevated in 22 of 28 patients (range, 1:4 to 1:512); most of these patients (20/23; 87%) had titers of 1:16 or greater.

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Cerebrospinal Fluid

More detailed data on CSF findings at clinical presentation from the 2008 study are presented in Table 6. In patients where an opening pressure was recorded, 9 of 11 cases (82%) had an opening pressure that was ≥250 mm H2O. In the current study, other CSF parameters associated with CM include elevated CSF leukocyte count (25/28; 89%), lymphocyte predominance (18/27; 67%), hypoglycorrhachia (19/27; 70%), and increased total protein (23/27; 85%). These parameters were similar to those seen in the 1980 cohort (see Table 2). In a subset analysis of the current cohort, there was a slight trend toward polymorphonuclear predominance in patients with HIV (4/10; 40%) compared with non-HIV patients (4/17; 24%). Approximately one-third of patients in both studies (2008: 32%; 1980: 28%) had a positive CSF culture for C immitis sometime during their clinical course.

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CSF Serology

In the 2008 study, the CSF ELISA IgG was positive in 11 of 21 cases (52%); the CSF ELISA IgM was positive in 8 of 22 cases (36%). In the present cohort, the CSF coccidioidal CF test was positive in 10 of 17 patients (58%) compared to 25 of 30 patients (83%) in the 1980 study.

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Other Laboratory and Clinical Studies

Although not recorded in the 1980 study, a significant percentage of patients in the current cohort had hyponatremia at the time of clinical presentation (18/30; 60%). This tended to be a poor prognostic sign: 11 of these patients ultimately died. Liver chemistries were not reported in the 1980 cohort; however, approximately a third of the cases in the current study (30%) had abnormal liver function tests at clinical presentation. Unlike the 1980 cohort, the Coccidioidin skin test (1:100) was not performed in the 2008 study.

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Radiologic Studies

Radiologic findings within the 2 cohorts are compared in Table 3, and data from the 2008 cohort are detailed in Table 7.

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Chest Radiograph

In the 2008 cohort, chest radiographs were abnormal in 19 of 28 patients (68%), demonstrating findings that included diffuse bilateral infiltrates (30%), mediastinal adenopathy (27%), miliary nodules (37%), and focal pneumonitis (23%). In the 1980 cohort, 22 of 30 patients (73%) had abnormal chest radiographs, with a spectrum similar to the current study. Four patients in the 1980 cohort (compared to 2 patients in the 2008 cohort) had evidence of pulmonary cavities; 2 of these individuals had concurrent pulmonary tuberculosis, a finding not seen in the 2008 study.

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Bone Involvement

Bone surveys were not routinely performed in the 2008 cohort; however, at least 1 patient (Patient 21) had a lytic lesion seen on a routine radiograph (see Table 7). In the 2008 cohort, bone scans were performed in 13 of 30 patients (43%); at least 2 patients (Patients 22, 25) showed areas of multiple uptake consistent with osteomyelitis, however, the remainder (11 patients) demonstrated nonspecific uptake that did not appear clinically significant. In the 1980 cohort, bone surveys were more commonly done, with 8 of 17 patients (47%) having signs of "osteomyelitis" including focal lytic lesions and vertebral involvement (4 patients).

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Neuroradiology

CT brain scans have become an important tool in the diagnosis and management of CM. In the 2008 cohort, 21 of 29 patients (72%) had an abnormal CT brain scan that included findings of basilar meningitis (17%), cerebral infarct (31%), and hydrocephalus (34%). CT was an emerging technology at the time of the 1980 study, and only 6 patients underwent a CT brain scan; 1 of these patients had an intraventricular hemorrhage, and all 6 eventually were found to have hydrocephalus. Other radiologic studies performed in the 1980 cohort, including cerebral angiogram, pneumoencephalography, radionuclide brain scan, were not performed in any of the patients from the 2008 cohort.

MRI scanning was not available for the 1980 cohort but was used extensively (20/30 patients; 66%) in the 2008 cohort. Of patients who underwent an MRI brain scan, only 1 of 20 had a "normal" MRI; abnormal findings in the remainder of individuals included basilar meningitis (31%), hydrocephalus (30%), and cerebral infarct (20%). MRI of the lumbar spine was helpful in delineating the presence of spinal coccidioidomycosis; 3 patients (Patients 18, 21, 28) in the current study developed persistent back pain and were found to have cauda equina arachnoiditis on lumbosacral MRI.

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Meningeal Biopsy

In the 1980 cohort it was noted that 2 patients had meningeal biopsies done at time of exploratory craniotomy to rule out tumor. Although meningeal involvement was discovered postmortem in 2 patients (Patients 20, 23), none of the patients in the 2008 cohort had a diagnosis of CM made by premorbid meningeal biopsy.

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Pathology

We compared extra-CNS coccidioidal involvement in the 2008 cohort with that in the 1980 cohort (Table 8). In both groups, the respiratory tract was the most common site for involvement (2008: 17 patients; 1980: 15 patients). Skin involvement was the next most frequent extra-CNS site, although it was more common in the 1980 cohort (13 patients) than in the 2008 cohort (5 patients). In the current study, 7 patients had either biopsy or zautopsy specimens sent for pathological examination, including lung biopsy (2 patients), skin (3 patients), lymph node (2 patients), and prostate (1 patient). Autopsies were performed in 3 patients in the 2008 cohort, and all demonstrated multiple organ involvement. All autopsy patients (Patients 4, 20, 23) had meningeal involvement; Patient 23 had parenchymal involvement of the lumbar spinal cord in addition to meningeal findings.

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Treatment

Antifungal therapy in the 2008 cohort is compared to that in the 1980 cohort in Table 4; more detailed information about the 2008 cohort is outlined in Table 9. In the 2008 cohort, a total of 29 patients received fluconazole therapy; 10 of these patients were treated with fluconazole monotherapy, and 16 patients received a combination of fluconazole and intravenous amphotericin B. Of the patients receiving combination azole/amphotericin B therapy, 8 patients (Patients 5, 7, 10, 11, 13, 15, 20, 21) had polyene and azole therapy started concurrently or within several days of each other. In this group, various forms of amphotericin B were used, including 6 patients (Patients 2, 8, 10, 11, 13, 15) who received amphotericin B desoxycholate (AmB D) alone, 4 patients (Patients 5, 18, 20, 21) who received liposomal amphotericin B (LAmB), and 1 patient (Patient 7) who received either drug (AmB D or LAmB) at separate times. One patient (Patient 2) received parenteral AmB D therapy alone without any additional azole or intrathecal amphotericin B. A comparison of the maximum dose of fluconazole with patient mortality is outlined in Table 10.

In those receiving intravenous amphotericin B, the number of cycles varied from 1 to 3 with a mean of 1.36 cycles per patient. The total dosage of amphotericin product administered was able to be calculated in 10 patients; the range was 345 mg to 6000 mg, with 4 patients receiving ≥4 g of intravenous polyene therapy (note: these high dosages were associated with lipid forms of amphotericin). With regard to drug toxicities, the average drop in hematocrit per cycle in patients receiving polyene therapy was 9.52 percentage points. Some patients actually had an increase in hematocrit while on polyene therapy, but this may have been due to concurrent transfusions and/or overall improvement in clinical status with treatment. The average serum creatinine increase per cycle was 1.35, although only 1 patient developed serious nephrotoxicity (Patient 20: creatinine increase of 4.1 mg/dL).

In the 1980 cohort, almost all patients (29/31; 94%) received a combination of intrathecal and intravenous amphotericin B. The total dosage of intravenous amphotericin ranged from 131 mg to 8658 mg (mean, 3595 mg); 11 patients received ≥4 g of intravenous amphotericin B. Although patients did experience a creatinine increase per drug cycle (mean, 0.9 mg/dL), only 1 patient suffered serious nephrotoxicity requiring removal of a renal allogeneic homograft. Fluconazole was unavailable during this period; however, 3 patients who failed amphotericin B therapy received intravenous miconazole but had no clinical improvement.

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Intrathecal Amphotericin B and Methods of Administration

Three patients in the 2008 cohort (Patients 8, 28, 30) received intrathecal therapy; however, only Patient 28 survived. Patient 8 received a cumulative dose of approximately 0.13 mg via the lumbar route for 8 days, but continued to do poorly and died following hospital discharge. Patient 28 received a total of 12.5 mg of amphotericin B via an Ommaya reservoir over a course of 6 months; this appeared to "stabilize" the patient, who was subsequently switched back to an azole regimen. Patient 30 had a ventricular catheter with external drainage and received intrathecal amphotericin B for approximately 19 days; she did poorly and ultimately died from presumed cerebral herniation. In the 1980 cohort, almost all patients (29/31; 94%) received intrathecal amphotericin B at some point during their treatment regimen (see Table 4). These injections occurred via a number of routes including cisternal (11 patients), lumbar (17 patients), and CSF reservoir (21 patients). In the 1980 study, 10 of the individuals who received the intralumbar injections subsequently developed lumbar arachnoiditis.

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Use of Intracranial Devices (Reservoirs)

Only 2 of 30 patients in the 2008 cohort (Patients 23, 28) had an Ommaya reservoir placed for intrathecal chemotherapy; Patient 28 had a bacterial infection of the reservoir and required shunt replacement (Table 10). Patient 23 had placement of an Ommaya reservoir for intrathecal chemotherapy but did not receive amphotericin B via this route; he subsequently developed hydrocephalus and required a ventriculoperitoneal (VP) shunt. These findings contrast with the 1980 cohort, in which 15 of 31 patients (48%) had a total of 27 intraventricular reservoirs implanted for administration of intrathecal amphotericin B. Many of these patients suffered significant complications associated with this procedure including intraventricular hemorrhage (1 patient), bacterial infection (9/15; 60%), and obstruction requiring shunt removal or surgical revision (6/15; 40%).

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Shunting Procedures

The results and subsequent course of CSF shunting procedures performed in 9 patients from the 2008 cohort are summarized in Table 11. The need for shunt placement in the 2008 study (9/30 patients; 33%) was similar to that in the 1980 cohort (9/31 patients; 31%). Five of the 9 patients in the current study had documented shunt complications including shunt infection (Patients 13, 25) and obstruction (Patients 13, 15, 30), and 1 patient who suffered an inguinal hernia believed secondary to VP shunt placement (Patient 9). As in the 1980 cohort, there was no evidence of intraperitoneal dissemination of coccidioidomycosis associated with the use of VP or ventriculo-jugular shunts. Three of the 8 HIV/AIDS patients (Patients 3, 15, 28) required a shunt or Ommaya reservoir.

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Survival and Follow-Up Data

Follow-up data for the 2008 cohort are presented in Table 4 and Table 12; 12 of the 30 patients died, for an overall mortality of 40%. Follow-up time varied from less than 1 week to 9 years and 7 months. Almost all of the patients who died from complications suffered from a rapidly progressive course-initial survival time following diagnosis of CM varied from 2 days (postadmission) to 6 weeks. Of the 12 individuals who died, 1 patient (Patient 1) died from a seemingly unrelated cause (perforated duodenal ulcer), and another patient with HIV/AIDS (Patient 11) died from unclear causes. Four of the 12 patients who died had underlying HIV/AIDS. In the 1980 cohort, 12 of 31 patients (39%) died during the course of the study. Among living patients in the 1980 cohort, follow-up varied from 3 years to 16 years.

With respect to the 2008 study, 14 of the 17 survivors (82%) were able to perform activities of daily living. Although 2 of these individuals subsequently found work, the remaining patients did not appear to be employed. Three patients who had initially responded to treatment died from unrelated causes. As of their last follow-up visit, all survivors continued to receive therapy, except for 1 individual (Patient 10) who self-discontinued therapy after 1 year. In the 1980 cohort, specific follow-up is less certain; however, 11 patients appeared to be able to do activities of daily living and 10 patients were able to return to some type of employment.

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DISCUSSION

In the current study we reviewed the clinical and therapeutic features of 30 patients with CM seen from November 1993 to April 2008 (the 2008 cohort) and compared this information with similar data from the pre-fluconazole era as represented by the 1981 study8 in the journal Medicine (referred to here as the 1980 cohort). Review of the similarities and differences between these 2 cohorts demonstrates the changes in clinical presentation and management of this condition over the past 30 years.

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Demographics and Risk Factors

In comparison to the 1980 cohort (see Table 1), a larger percentage of patients in the 2008 cohort had an underlying, predisposing medical condition. The presence of HIV/AIDS is a well-known risk factor for disseminated coccidioidomycosis-this was not present in the pre-1980 era but was found in 10 of 30 patients in the current study. Another difference was the much larger percentage of Hispanic patients (53%) in the 2008 cohort compared with the 1980 cohort (6%). Although there may be an increased risk of disseminated disease in this group, the larger percentage of cases in our series more likely reflects changing population demographics in Southern California-a large Hispanic influx has added to the labor pool, especially in outdoor trades (such as construction, landscaping) that place a patient at greater risk for acquiring coccidioidomycosis. CM is more common in male patients-in the current cohort, there was a 5:1 male to female ratio, a finding comparable to the 6:1 ratio seen in the 1980 cohort. As with the 1980 cohort, two-thirds of patients presented with meningitis as an initial or primary manifestation of disseminated coccidioidomycosis; in both groups, extra-CNS coccidioidomycosis was diagnosed before CM in approximately one-third of patients.

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Clinical Presentation

The clinical presentation of the 2 groups was quite similar (see Table 1). Headache remained the most common presenting symptom (approximately 80% of patients) and signs of increased intracranial pressure (for example, nausea/vomiting) were seen in about 50% of patients. In our experience, headache is almost a universal complaint in CM; failure to report this may be seen when other symptoms (for example, altered mental status, confusion, stupor) alter the reliability of the patient history. Bedside findings consistent with meningitis (for example, meningeal irritation) were found in about a third of patients in both cohorts; however, the diagnosis remains heavily dependent on CSF examination, and absence of meningeal signs does not exclude underlying CM. In the 1980 cohort, there was chart documentation of funduscopic examination in all 31 patients, and approximately 16% of patients had papilledema. In the 2008 cohort, only 9 patients had a recorded funduscopic examination (1 patient with papilledema), a practice that likely reflects a greater reliance on CT scanning (rather than physical examination) for evaluation of the complications associated with CM.

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Complications

Stroke remains an important complication of CM and may develop in apparently stable patients who appear to be improving clinically.66 Evidence from pathological studies suggests that extensive meningeal involvement, especially at the base of the brain, results in localized vasculitis, endarteritis obliterans, and vascular obstruction.39,66 These processes lead to brain parenchymal infarction with attendant neurologic findings such as hemiparesis, cranial nerve abnormalities, and altered consciousness. Coccidioidomycosis-induced vasculitis may be present in up to 40% of cases and, when present, is associated with a high mortality. Approximately one-third of patients in the 2008 cohort developed a stroke or had evidence of infarct on CT or MRI scanning (see Tables 2 and 3). As in the 1980 cohort, these patients had a myriad of focal neurologic signs including cranial nerve palsies, extremity weakness, and abnormal neurologic signs (for example, positive Babinski sign). Although the numbers were small, the presence of a focal stroke did not portend excess mortality when compared to other patients in the cohort. Optimal management of stroke or vasculitis in CM remains unclear-in addition to antifungal therapy, some authorities recommend a trial of corticosteroids (oral dexamethasone 20 mg po daily × 7 d with subsequent taper) in those with new-onset stroke or severe meningeal inflammation.30

Hydrocephalus is a serious complication of CM and remains responsible for significant morbidity and mortality in the condition. In the initial study of fluconazole, 25% of the 50 patients with CM developed hydrocephalus.25 As with stroke, hydrocephalus appears related to the extensive arachnoidal fibrosis associated with meningeal inflammation. Patients may present with communicating or noncommunicating hydrocephalus depending on the level of obstruction.53 Despite widespread use of azole therapy, hydrocephalus was seen in almost a third of the patients in the current study. Although CT documentation was less common in the 1980 study, the equivalent need for VP shunting (9 patients in each cohort) suggests that the incidence of hydrocephalus was similar between the 2 groups. Hydrocephalus may develop rather suddenly in patients with CM and should be considered in any patient who experiences worsening headache or sudden neurologic deterioration. In this situation, the clinician should arrange for immediate CT scanning and should obtain neurosurgical consultation if hydrocephalus is present.

There was a clear difference in the incidence of lumbar arachnoiditis between the 2 cohorts (2008: 10%; 1980: 35%) (see Table 1). The increased incidence in the 1980 cohort may be due to the more common use of intralumbar amphotericin B during that period8-in that study, the majority of patients received intrathecal amphotericin via the lumbar route (see Table 4). Nevertheless, even without a history of intralumbar therapy, lumbosacral myelopathy/arachnoiditis may appear as a complication of CM-although they had not received intralumbar amphotericin B, 3 patients in the current study developed this problem (documented via clinical history and MRI scan). Optimal management of this complication remains unclear. In an earlier report, a case of coccidioidal spinal arachnoiditis was managed with a combination of VP shunting (the patient had concomitant hydrocephalus) and a course of intensive antifungal therapy (intravenous amphotericin B and oral ketoconazole).70 Similarly, 2 of our patients appeared to improve after a repeat course of intravenous LAmB (1 wk) followed by azole therapy. Aside from the decreased incidence of lumbar arachnoiditis, the current widespread use of azole therapy has not altered the incidence of serious complications, such as stroke and hydrocephalus, in patients with CM.

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Laboratory Findings

Table 2 outlines some of the differences and similarities in laboratory studies between the 2 groups. In the 2008 cohort, leukocytosis was actually uncommon compared to the 1980 cohort (2008: 3%; 1980: 37%). The cause of this difference is unclear; however, impaired leukocyte response is recognized in HIV/AIDS patients, and patients in this subset had a lower leukocyte count compared to non-HIV patients (2008 HIV patients: mean, 6480 cells/mm3; 2008 non-HIV patients: mean, 8710 cells/mm3). In endemic regions, the presence of eosinophilia is a clinical clue to active infection with C immitis. Although eosinophilia was seen in the 2008 cohort, there was a lower incidence compared to the 1980 cohort (eosinophil count ≥350 cells/mm3; 2008: 18%; 1980: 48%). Upon further analysis, the presence of HIV/AIDS did not appear to have a significant effect on this parameter-absolute eosinophil counts were slightly higher in HIV patients compared to non-HIV patients (mean eosinophil counts: HIV patients, 224 cells/mm3 vs. non-HIV patients, 197 cells/mm3). A notable finding in the 2008 cohort, not reported in the 1980 cohort, is the incidence of hyponatremia (serum Na <135 mEq/L) at the time of clinical presentation. This was seen in 60% of patients and was often a poor prognostic factor: 11 of the 18 patients with this finding subsequently died.

CSF findings were generally similar between the 2 studies and reflected the typical presentation for fungal meningitis-over half of the patients in each group had a lymphocyte predominance or evidence of low CSF glucose. While almost all patients with CM have CSF pleocytosis, a "normal" CSF does not exclude the diagnosis-in the 1980 cohort, up to 5 patients had initially normal studies yet eventually developed CM or had concurrent positive cultures. Overall, about one-third of patients in each group eventually had a CSF culture positive for C immitis. This finding demonstrates the difficulty in culturing the organism from CSF and reemphasizes the importance of not excluding the diagnosis based on a "negative" spinal fluid culture. Although we were unable to assess the amount of spinal fluid collected, culture yields are likely to be higher when a large volume (for example, 8-10 cc of CSF) is sent to the laboratory.

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Serology

A major difference between the current study and the 1980 protocol is the present availability of the ELISA IgG/IgM test for both serum and CSF. In the current study (see Table 2), the serum ELISA IgG was positive in almost all patients (25/27; 93%) at some time during their illness and was positive in the CSF in 75% of cases (15/21 patients). ELISA IgM, a marker of acute infection, was found to be less reliable; at clinical presentation, the serum ELISA IgM was positive in only 55% (15/27) of patients and was present in only 35% (8/22) CSF samples. An important caveat for serologic diagnostics is the timing of the studies. In a patient with "early" disease (<4-6 wk), serologic testing may well be negative, a finding that could lead to premature exclusion of the diagnosis. In the current study, this was seen in Patient 30: despite a compatible clinical presentation, this individual had a significant delay in receiving effective therapy, in part related to the initial negative serologies and fungal cultures. Effective therapy was not started until almost 2 months after the onset of symptoms, when a repeat CSF fungal culture (obtained 1 month after initial presentation) turned positive. While Coccidioides serology can be quite helpful in confirming a suspected diagnosis of CM, a negative serology does not exclude the diagnosis and should not dissuade the clinician from initiating empiric therapy in the appropriate clinical setting.

Our experience with the serum CF test in the 2008 cohort demonstrated a relatively high sensitivity-titers were positive in 95% of patients (22/23) at some time during their clinical course, and almost all positive patients (20/23; 87%) had titers ≥1:16, a traditional marker of disseminated disease. In the current study, the CSF CF was not as sensitive-only 10 of 17 patients (59%) were positive in comparison to the 1980 cohort (83%). Again, serology can be helpful in confirming a diagnosis of CM, provided that enough time has elapsed for seroconversion to occur. Several studies have demonstrated impaired serologic response in immunocompromised patients, and clinicians must avoid being misled by negative serologic studies.6,7

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Radiology

As noted in Table 3, the initial chest radiographic findings were similar between the 2 cohorts. An abnormal chest radiograph was found in about two-thirds of patients in each group (2008: 68%; 1980: 73%) with a myriad of findings including bilateral infiltrates, focal pneumonitis, pulmonary cavities, and mediastinal/hilar adenopathy. Findings suggestive of dissemination- diffuse bilateral infiltrates and miliary nodules-were more common in the current cohort, probably reflecting the high incidence of clinically apparent "disseminated" disease in patients with HIV/AIDS.

A major difference between the 2 studies is the ready availability of CT and MRI scanning in the current era, which have become indispensable tools in the diagnosis and management of CM-related complications. In the current study, 21 of 29 patients (72%) had an abnormal CT scan. Most patients in the 1980 cohort did not undergo CT scanning; however, scans were ultimately abnormal in all 6 patients who underwent the procedure. MRI scanning was not available for the 1980 cohort but was extensively used in the 2008 cohort. Although the numbers are relatively small, MRI scanning appeared to be more sensitive in detection of basilar meningitis compared to CT scanning (MRI: 9/20 [45%] vs. CT: 5/29 [17%]).

Previous investigators have attempted to use neuroimaging to predict patient outcome in CM.4 In that study, the presence of basilar meningitis did not appear to influence outcome; however, development of hydrocephalus predicted a higher mortality, especially in HIV/AIDS patients. Our study had smaller numbers of patients but generally similar trends-mortality with basilar meningitis was 18% (2/11 patients) compared to 50% in those who developed hydrocephalus.

Patients with suspected CM should initially undergo a brain CT scan to rule out hydrocephalus or cerebral edema. If the initial scans are negative, most experts recommend obtaining an MRI scan (with gadolinium contrast reagent) to look for the presence of basilar meningitis, a finding suggestive of underlying mycobacterial or fungal meningitis. In patients with an established diagnosis of CM, a repeat head CT scan is generally adequate to screen for complications such as hydrocephalus or cerebral edema. Although a head CT scan (with contrast) may also detect stroke, our experience suggests that an MRI might be more sensitive in selected cases. Radiographic scanning is invaluable in the management of CM; a head CT scan should always be obtained in patients with suspected complications or significant signs of clinical deterioration.

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Therapy

Antifungal Therapy: Azoles

The almost complete change to azole therapy from the previous standard of intrathecal amphotericin B (see Table 4) is the most obvious difference between the 1980 and 2008 cohorts. In the 2008 group, only 3 patients received intrathecal amphotericin (usually with concomitant azole therapy), and then only for relatively short periods of time. Approximately half (13 cases) of the patients in the 2008 cohort received an azole alone, while 16 patients received some combination of fluconazole plus parenteral amphotericin B. Since about 5 patients died in each of these 2 groups, it is difficult to say if there were any differences between the 2 approaches to therapy. The optimal starting dose of fluconazole for CM patients is unclear, with some data suggesting that a lower starting dose (400 mg) might be successful in some cases.24,25,30 In the current study, about two-thirds of patients ultimately received high-dose (≥800 mg) fluconazole in accord with Infectious Diseases Society of America guidelines for treatment of CM24 (see Table 10). While overall numbers are small, mortality was high (5/8 patients) in those receiving lower-dose (<800 mg) fluconazole, suggesting that early, high-dose (≥800 mg) fluconazole therapy is likely to have better outcomes in patients with CM. Following successful initial therapy with parenteral fluconazole, patients were converted to equivalent doses of oral azole and maintained under clinical control for considerable periods of time (Patient 16 has been on fluconazole for over 10 years). Azoles are not curative for CM, and almost all patients who stopped therapy suffered a clinical relapse that required re-treatment. The only exception was Patient 10, where the diagnosis of CM must remain clinically suspect. Although he met study criteria for CM (for example, symptoms and minimally elevated CSF leukocyte count), other parameters (CSF glucose, total protein, CSF serology, and CSF cultures) were normal, raising questions about the true presence of CM in this case.

Six patients in the 2008 cohort received voriconazole, an agent with reported efficacy in patients with fluconazole failure.17,49 This was clearly the situation in 1 of our cases (Patient 26; see Appendix) who responded to oral voriconazole (200 mg po twice daily) after experiencing 2 clinical relapses while receiving high-dose fluconazole (800 mg daily). Although voriconazole is an attractive agent for CM, there is less experience with it than with fluconazole, and its use is hampered by selected side effects such as photosensitivity and visual disturbances. Despite these concerns, a trial of voriconazole could be helpful in patients who appear to be failing high-dose fluconazole.

Drug interactions between voriconazole and antiretroviral agents are complex, which makes using voriconazole difficult in HIV/AIDS patients with CM.71 Concomitant use of ritonavir both increases (early) and decreases (later) concentrations of voriconazole as the drug induces changes in P450 CYP-dependent levels.35 Because of these interactions, voriconazole is generally contraindicated in patients receiving concomitant ritonavir or efavirenz.13 Nevertheless, recent studies suggest that voriconazole can be given in patients receiving low-dose ritonavir (100 mg twice daily) provided that serum voriconazole levels are available to help guide voriconazole dosing.41

Posaconazole has excellent in vitro activity against C immitis; however, it has poor CSF penetration and it is not currently recommended for treatment of CM. Nevertheless, the drug has been successful in some patients with poorly controlled, non-meningeal coccidioidomycosis3,59 and has been used in other types of CNS fungal infection.46 We used posaconazole in combination with fluconazole to help manage 1 case of lumbosacral coccidioidal arachnoiditis (Patient 21). Although this patient experienced some clinical improvement, the role of posaconazole is unclear, and we do not routinely recommend posaconazole for management of CM.

The occurrence of azole "failure" raises the question of preexisting or acquired fungal resistance to azole agents, similar to that seen with Candida species. There are few data supporting this in the coccidioidomycosis literature; however, a recent case raises the possibility of fluconazole resistance as a cause of treatment failure.33 The patient had a history of chronic pulmonary disease and CM and was receiving long-term fluconazole (sometimes on an intermittent basis). He experienced a relapse of pulmonary symptoms with C immitis recovered again from pulmonary specimens. The patient clinically responded to intravenous LAmB and was subsequently maintained on weekly treatments with the drug. The C immitis isolate demonstrated decreased susceptibility to several azoles including fluconazole. This was an unusual case and its significance for management of CM remains unclear-although a "resistant" C immitis isolate was isolated from pleural fluid, the CSF examination (after LAmB) was within normal limits. Previous studies suggest that almost all isolates of C immitis are susceptible to fluconazole; most patients have a clinical response to treatment, and routine susceptibility testing is not necessary. Nevertheless, if C immitis is re-isolated in patients failing therapy, consider obtaining fungal susceptibilities to rule out the possibility of azole resistance.

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Antifungal Therapy: Azole Toxicity

Previous studies of high-dose fluconazole demonstrate variable degrees of hepatotoxicity depending on the dose and clinical situation. In a study of high-dose fluconazole (800 mg daily) in patients with disseminated candidiasis,51 9% of individuals required discontinuation of fluconazole due to hepatitis. In addition, other studies suggest that fluconazole toxicity may be more common in patients in the intensive care unit,26 or in patients with AIDS.9 In the first major study of fluconazole in CM (dose of 400 mg daily), abnormal liver function abnormalities were seen in only 3 patients (out of 47), and there were no documented cases of serious hepatotoxicity.25 Despite the high doses of fluconazole used, we found relatively little azole toxicity in the current study. Some patients had difficulty tolerating higher doses (for example, nausea/vomiting); however, none of our cases appeared to experience clinically significant hepatotoxicity. Despite these observations, hepatotoxicity remains a potentially serious side effect of azoles. When prescribing these agents, it is important to warn patients about relevant symptoms, and it is reasonable to check liver tests periodically to exclude subclinical hepatitis. Clinicians should exercise special caution when using high-dose azole therapy in patients with underlying hepatitis or in those receiving other hepatotoxic drugs.

In addition to hepatotoxicity, other serious side effects associated with high-dose fluconazole include ventricular arrhythmias and adrenal insufficiency. Ventricular tachycardia, especially torsades de pointes, is a rare but recognized complication of azole therapy.38,62 One of the cases (Patient 18) in the 2008 cohort developed ventricular tachycardia (torsades de pointes) while receiving high-dose fluconazole (800 mg po daily). This episode occurred several weeks after the patient had received a course of intravenous amphotericin B; this treatment was associated with hypokalemia, and the patient had persistent hypomagnesemia at the time of the event. Following correction of the electrolyte disorder, the patient was able to tolerate azoles without evidence of subsequent arrhythmia. When prescribing high-dose fluconazole, be cautious in patients with preexisting QT prolongation, with underlying electrolyte abnormalities (for example, hypokalemia, hypomagnesemia), or in those receiving drugs known to be associated with QT prolongation.

Adrenal insufficiency is an uncommon, but well-described, side effect of high-dose azole therapy.54 Since fluconazole does not appear to impair mineralocorticoid production, traditional electrolyte abnormalities associated with adrenal insufficiency (for example, hyperkalemia, hyponatremia) are generally not present. We did not see evidence of overt cortisol deficiency in any of the patients in the current study; however, another of our coccidioidomycosis cases-a patient receiving treatment for vertebral coccidioidomycosis-developed adrenal insufficiency while receiving high-dose (800 mg/d) fluconazole. Consider the possibility of adrenal insufficiency in fluconazole-treated patients who develop unexplained fatigue, malaise, or hypotension. In this situation, order additional studies to rule out adrenal insufficiency (for example, cortisol levels; ACTH stimulation test) and consider administering empiric cortisol therapy until test results are available.

Photosensitivity drug eruption due to sun exposure is a significant side effect of voriconazole.36 This condition is likely to be more common in desert regions where CM is endemic, and was seen in at least 3 of the 6 individuals treated with voriconazole in our study. Although individuals with severe photosensitivity may need to discontinue the drug, most patients have milder reactions and can minimize the condition by limiting sun exposure or using protective measures such as clothing and sunblock.

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Antifungal Therapy: Intrathecal Amphotericin B

In the pre-azole era, intrathecal amphotericin B was the mainstay of therapy for CM. The relative convenience and tolerability of azole therapy has relegated intrathecal amphotericin to a more subsidiary role in the management of CM. In the current study, only 3 patients (10%) received intrathecal amphotericin B, compared to 94% of patients from the 1980 study. Despite these changes, there may still be benefits to intrathecal amphotericin B, especially in patients with a poor response to azoles. Shirvani et al55 retrospectively reviewed 23 patients who were "nonresponders" to fluconazole and found that a majority responded to a relatively brief course (<3 mo) of intrathecal amphotericin B. One potential advantage of intrathecal amphotericin B is the fact that some patients appear "cured" (or have long-term control) of CM following aggressive intrathecal therapy. In the 1980 study, 15 of the survivors were no longer receiving drug therapy at the time of follow-up. While a future relapse requiring additional therapy could not be ruled out, some individuals appeared to have prolonged periods of drug-free survival. Aside from 1 patient where the diagnosis of CM remains in doubt (Patient 10), none of the patients in the 2008 cohort was cured of their condition, and all required long-term azole therapy.

While our experience was limited, there are clearly situations where intrathecal amphotericin B might be appropriate, especially in patients who appear to be doing poorly on azole therapy. In the 2008 study, Patient 28 (HIV with CM) appeared to be failing azole/intravenous amphotericin B and seemed to benefit from a 6-month course of intrathecal amphotericin B (cumulative dose of 12.8 mg). There is some debate about the best route of administration-some investigators recommend intralumbar administration,60 while others prefer the intracisternal approach.30 Amphotericin B may also be administered directly into the cerebral ventricle via Ommaya reservoir or ventricular catheter. Some patients benefit from this approach; however, it may be less effective because the drug is not being delivered directly to the basilar cisterns where most disease resides. A recent paper described successful management of CM following continuous infusion amphotericin B therapy via a programmable implanted pump into the cisternal subarachnoid space.5 Although intrathecal amphotericin B may be necessary in selected cases, it is not without toxicities-there are often significant side effects (such as nausea/vomiting, headache) as well as serious neurotoxicity (for example, arachnoiditis, paraparesis) associated with chemical meningitis. In the 1980 cohort, a far larger percentage of patients developed lumbar myelopathy/arachnoiditis, probably related to prolonged intralumbar administration of amphotericin B.

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Antifungal Therapy: Parenteral Amphotericin

Intravenous AmB D has poor CSF penetration and, by itself, has a limited role in CM management. Nevertheless, many patients with CM often receive concomitant parenteral amphotericin B as supplemental therapy, especially in those with severe, disseminated extrameningeal disease. This was true in the 1980 study-almost all patients who received intrathecal amphotericin B received a concomitant course of intravenous AmB D. In general, serious long-term nephrotoxicity was rare in this group-the average creatinine increase per cycle was 0.9 mg/dL, and only 1 patient (Patient 30) developed serious nephrotoxicity resulting in failure of a renal allogeneic homograft. In the 2008 study, the presence of serious nephrotoxicity was equally rare-the average increase in creatinine per cycle of parenteral amphotericin B was 0.85 mg/dL, and in almost all patients, the creatinine returned to normal following completion of the amphotericin B. The 1 patient who experienced significant renal failure on parenteral amphotericin B (2008 study: Patient 20; creatinine increase 4.1 mg/dL) died from overwhelming disseminated coccidioidomycosis; in this case, the renal failure was likely multifactorial and related to the hypotension associated with sepsis syndrome. The availability of less-nephrotoxic lipid preparations is likely to reduce further the risk of long-term nephrotoxicity: in the 2008 cohort there was a definite trend toward use of these products in patients that had any evidence of rising creatinine while receiving standard AmB D. An important point to remember is that lipid-based amphotericin B products, while less nephrotoxic, still have electrolyte loss associated with renal tubular toxicity. As described above, this became especially important in 1 patient (Patient 18) who developed fluconazole-induced ventricular tachycardia associated with electrolyte disorders (for example, hypokalemia, hypomagnesemia) related to a previous course of LAmB.

Recent studies examining lipid preparations of amphotericin B, such as LAmB, suggest that these preparations have better penetration of brain parenchyma and meningeal tissue, a feature that would predict improved outcomes in CM.15 Indeed, in an experimental rabbit model of CM, LAmB alone was sometimes curative when used at higher than normal doses (7.5 mg/kg).11 These results need to be interpreted with caution, because the animal model of CM may not completely mimic human CM. Such outcomes have not been duplicated in humans, and this therapy approach (high-dose LAmB alone) awaits further clinical trials. Nevertheless, many investigators see a benefit in combined therapy, and some form of amphotericin B is often given in combination with azole therapy, especially in patients with severe disease or clinical relapse. In the current study, about half of the patients received concomitant amphotericin B, either the standard agent (9 patients) or the less toxic lipid formulations (9 patients). Although outcomes in these cases were similar to those seen with azole-alone therapy, the numbers are too small to make any definitive conclusions.

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Neurosurgical Procedures

Not surprisingly, the number of patients who underwent placement of an intraventricular reservoir for intrathecal amphotericin B was far less in the present study (2 patients; 7%) compared to the 1980 cohort (15/31 patients; 48%). In the 1980 group, this procedure was often problematic-13 of the 15 cases had complications requiring removal of the device, such as catheter obstruction or bacterial meningitis. While the need for intraventricular reservoirs has decreased, the widespread use of azole agents has not necessarily reduced the need for placement of VP shunts-almost a third of patients in the 2008 cohort required a VP shunt, a percentage similar to that reported in the 1980 cohort. Hydrocephalus remains a common complication of CM, and patients with severe recurrent headache should have a repeat CT scan to rule out the condition. Those with significant hydrocephalus may require a ventriculostomy or VP shunt and should be evaluated by a neurosurgeon.53

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Outcomes

Despite the switch to more convenient azole therapies, CM remains a serious disease with a relatively high mortality. The mortality in the 2008 cohort (40%) was almost identical to that in the 1980 cohort (38%). Morbidity in both groups was also significant-only about 40% of individuals in each cohort were able to carry out activities of daily living. It is noteworthy that fewer patients in the present cohort (2008: 2 patients vs. 1980: 10 patients) were able to return to some type of employment. The presence of HIV/AIDS in the present cohort may also have influenced this observation-mortality was similar in this group (compared to other patients); however, none of these individuals was able to return to gainful employment. Although this may reflect other factors (for example, presence of underlying disease, availability of disability insurance), it raises questions about the durability of the azole response and reemphasizes the morbidity associated with this condition.

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HIV/AIDS

A major difference between the 1980 cohort and the 2008 cohort is the advent of HIV/AIDS during the post-1980 period-almost a third of patients in the 2008 group had underlying HIV infection. In HIV patients, coccidioidomycosis is often a manifestation of significant immunosuppression-many patients have low CD4 T-cell counts (<250 cells/mm3) with signs of associated disseminated, extrameningeal disease. Reported mortality of CM in HIV is high: of the 32 cases of CM reported in 3 studies of coccidioidomycosis-infected HIV patients, over two-thirds of the patients died.23,25,56 Although some of these deaths were due to underlying HIV-associated conditions, complications of CM accounted for mortality in many of the individuals.25

The clinical presentation in the HIV/AIDS patients in the current study was varied and was similar to that seen in the non-HIV cohort (Table 13). Most individuals presented with findings of "typical" chronic meningitis-a several-week history of headache, often accompanied by fever and mental status changes. Some individuals (Patients 2, 3, 4) had a rapidly progressive downhill course leading to stupor/coma and death from suspected cerebral herniation. Other cases survived their initial hospitalization and were successfully started on antiretroviral therapy in addition to continued treatment for CM. When compared to the non-HIV patients, HIV-infected patients were more likely to have evidence of widespread disseminated coccidioidomycosis. Although 1 of our patients (Patient 28) presented with isolated CM, 9 of 10 patients had disseminated extrameningeal disease as evidenced by diffuse pulmonary infiltrates or miliary nodules. As with previous studies, CM was associated with more advanced HIV infection-at the time of clinical presentation, all our patients had CD4 T-lymphocyte counts less than 250 cells/mm3. Compared to non-HIV patients, HIV-infected patients had a lower incidence of peripheral leukocytosis and a decreased percentage of CSF lymphocytosis. These findings likely reflect the impaired marrow response and T-cell lymphocytopenia seen in HIV. The CSF findings may have clinical import: in at least 1 of the cases in the 2008 cohort (Patient 3), the CSF polymorphonuclear leukocyte predominance led to an initial suspicion of bacterial meningitis. In coccidioidomycosis-endemic regions, consider the possibility of C immitis infection in HIV patients with suspected pyogenic meningitis.

TABLE 13

TABLE 13

Because the numbers in our study are relatively small, and previous studies were from the era before highly active antiretroviral therapy (HAART), it is difficult to compare the effects of antiretroviral therapy on clinical presentation and progression of CM. Recent studies suggest that the advent of HAART is likely to have a salutary effect on control of coccidioidomycosis-researchers from Arizona found a correlation between successful control of HIV infection (secondary to HAART) and decreased severity of coccidioidomycosis in HIV-infected individuals.37 Although most HIV patients in the 2008 cohort had not received prior antiretroviral therapy, 2 individuals (Patients 3, 4) developed CM while receiving HAART. Both patients developed obtundation and died within a relatively short time. Patients diagnosed later in the study period seemed to have improved survival, perhaps as a consequence of earlier recognition of CM and more aggressive antiretroviral therapy. More recent cases (Patients 5, 15, 27, 28) were still alive several years after their diagnosis. Despite the apparent improved outcomes in our cohort, the morbidity of CM remained impressive. One individual (Patient 15) developed hydrocephalus and had several procedures including placement of bilateral VP shunts with subsequent revision; at 1 point he was hospitalized for almost a year because of complications related to CM and HIV/AIDS. Although at last follow-up he was clinically stable and able to perform activities of daily living, he had definite cognitive impairment and a possible seizure disorder, and was unable to work. Another patient (Patient 28) was stable on HAART and fluconazole but had recurrent seizures and cognitive impairment. A third patient (Patient 27) had a history of substance abuse (with sometimes poor medication compliance) and required significant family assistance. All 3 of these patients had several hospital admissions requiring re-treatment with intravenous amphotericin B and high-dose azoles. Reports from other AIDS clinicians mirror these observations-management of CM in HIV/AIDS remains difficult with a high incidence of treatment failure and relapse.13

In 2009, the federal government released updated guidelines on the prevention and management of opportunistic infections in HIV/AIDS patients, including those individuals at risk for coccidioidomycosis.31 In coccidioidomycosis-endemic regions, the guidelines recommend primary antifungal prophylaxis (fluconazole or itraconazole) in individuals with a positive serologic test for C immitis (either IgG or IgM) and a CD4 count <250 cells/μL. HIV-infected patients with CM should have initial therapy with fluconazole at a standard dose of 400-800 mg per day. Considering the severity of the cases in the 2008 cohort, our experience suggests that a higher starting dose of fluconazole (for example, 800 mg daily) may be more appropriate. Because of the high incidence of extrameningeal dissemination, concomitant amphotericin B may well be appropriate, especially in moderately to severely ill individuals. Because of the potential for drug interactions, experts generally recommend against voriconazole use in patients receiving HIV protease inhibitor drugs and/or efavirenz.13 Despite this warning, a 2009 paper suggested that dual administration of voriconazole and antiretroviral drugs (for example, efavirenz) may be successful if therapeutic drug monitoring is available.12 Likewise, determination of drug levels permitted successful treatment of cryptococcal meningitis with voriconazole in an HIV patient receiving lopinavir/ritonavir.41 For HIV patients, voriconazole therapy for fluconazole failures is a definite option; however, monitoring of voriconazole levels should be done in patients receiving selected antiretroviral agents. Although only minimal data are available, voriconazole does not appear to have significant interactions with nucleoside reverse transcriptase inhibitors or the integrase-inhibitor raltegravir.71 Despite optimal azole dosing, treatment failure with azoles may occur, and some patients may require intrathecal amphotericin B. Our experience with intrathecal amphotericin B in HIV-CM co-infection (only 1 patient) suggests that a limited course (3-6 mo) of intrathecal amphotericin B may help stabilize a failing patient and permit subsequent control with an oral azole. Nevertheless, complications of CM (hydrocephalus, stroke) are common in HIV/AIDS patients, and the morbidity can be quite considerable. As with non-HIV patients, lifelong azole therapy is likely to be necessary for HIV patients with CM.

Based on these observations, a clinical picture of CM in patients with HIV/AIDS can be outlined. The presentation of CM in HIV/AIDS patients is similar to that seen in non-HIV infection. There is a spectrum from cases with a relatively acute presentation (with a relatively sudden onset with rapid progression to obtundation/coma) to cases resembling a more subacute, chronic meningitis. In HIV/AIDS, CM is usually seen in patients with more advanced immunologic impairment (CD4 T-cell counts <250 cells/mm3), often reflected in a high incidence of extrameningeal dissemination as demonstrated by diffuse pulmonary infiltrates. Although serology may be negative in early disease, patients who survive usually develop positive confirmatory serology (for example, positive ELISA IgG/IgM, CF) or grow C immitis from 1 or more sites. Therapy of CM in HIV-infected patients is similar to that of non-HIV cases. In those with mild to moderately severe disease, high-dose fluconazole (≥800 mg/d) is the appropriate initial therapy, with dose-escalation in those who do not respond to the initial regimen. In patients with more severe disease, especially those with evidence of extrameningeal dissemination, a course of parenteral amphotericin B may be appropriate. Voriconazole remains an option for individuals who fail fluconazole; however, because of drug interactions (CYP450), the use of long-term voriconazole may require therapeutic drug monitoring in those on selected HIV antiretroviral agents (for example, protease inhibitors, efavirenz). As with non-HIV cases, some patients fail high-dose azole therapy and require a course of intrathecal amphotericin B to stabilize the disease. Serious complications of CM are equally common in HIV patients, and some individuals will require a VP shunt to manage hydrocephalus. The morbidity and mortality of CM remains high in HIV-infected individuals, and their course is complicated by drug adherence difficulties in those requiring treatment for 2 serious medical conditions.

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Study Limitations

Although the outcomes between the 2008 and 1980 cohorts seemed similar, these groups are not strictly comparable and there may be referral bias in the current group (2008 cohort). In the current study, there was a higher incidence of preexisting clinical disorders, a factor that could have skewed our cohort to more adverse outcomes. The study is also hampered by the varied treatment experiences at different sites-these patients were cared for by a large number of individuals with varying levels of experience with CM. Although treatment might not be as consistent as at a single referral center, our experience more likely represents the level of treatment available in the community setting. Widespread availability of oral azoles may also have influenced our referral patterns-we may have received more difficult, complicated cases while patients with "milder" disease remained in community settings. We cannot exclude this possibility; however, the experience in 1 of our hospitals (Olive View Medical Center), a community-based facility, suggests otherwise-our patient mix seems similar to that seen by other colleagues in our community. No matter what the venue of care, our experience confirms that CM remains a difficult-to-treat illness with a high rate of relapse and complications.

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Therapy Recommendations

The treatment in the 2008 cohort generally followed recommendations outlined by the Infectious Diseases Society of America and experts in the field.24,30 In patients with suspected CM, empiric therapy with fluconazole is appropriate pending the initial diagnostic studies. Although there is some disagreement about the optimal starting dose, we prefer a higher initial dose (800-1000 mg/d) when CM is suspected. Whatever the starting dose of fluconazole, dose escalation to higher levels (>1000 mg/d) is appropriate in those who appear to be failing initial therapy. Patients receiving high-dose fluconazole should be monitored for serious side effects such as hepatotoxicity and (rarely) ventricular arrhythmia and adrenal insufficiency. If patients continue to do poorly with a fluconazole regimen, some patients may benefit from a switch to voriconazole. Our experience emphasizes the importance of medication compliance-those who discontinued azole therapy almost always suffered from relapses with the attendant complications.

While the utility of concomitant parenteral amphotericin B therapy is uncertain, we often add this drug in critically ill patients or those who have evidence of widespread extrameningeal dissemination. Although the best amphotericin B formulation in this situation remains unclear, we generally prefer high-dose LAmB (5 mg/kg) because of a more favorable toxicity profile and the potential benefits of CNS penetration. For critically ill patients, or those who fail to respond to azole therapy, a trial of intrathecal amphotericin B may be indicated. While the best approach is unclear, treatment via the intracisternal or intralumbar route can be used as described in previously published protocols.30,59 Intraventricular amphotericin B therapy (via an Ommaya reservoir) also appears beneficial; however, it may be less likely to deliver drug to the site of the infection (for example, basilar cisterns) and is hampered by complications associated with long-term catheter placement (such as bacterial meningitis, obstruction). When using intrathecal amphotericin, it is important to use AmB D, because lipid-associated products have not been approved for intrathecal administration. In general, except for the reservations concerning voriconazole in patients receiving selected antiretroviral agents, recommendations for therapy in HIV/AIDS patients are similar to those in non-HIV patients.

In addition to antifungal therapy, proper management of CM-associated complications remains critical. Individuals who develop worsening headache or altered mental status should have a repeat CT scan to rule out hydrocephalus. Patients with this complication may require a VP shunt and should be seen by a neurosurgeon as soon as possible. The management of complications associated with vasculitis such as stroke remains unclear. Although the long-term benefit is unclear, many practitioners recommend treatment with corticosteroids to ameliorate basilar and perivascular inflammation. An empiric trial of corticosteroids is especially appropriate in patients who suffer severe clinical deterioration or have evidence of life-threatening cerebral herniation.

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Summary

To our knowledge, this is the first study comparing management of Coccidioides meningitis in the azole era (1993-2008) with a well-defined patient population from the pre-azole era (pre-1980). The clinical presentation of the 2 cohorts was quite similar except for a higher prevalence of Hispanic patients in the current group and the emergence of HIV/AIDS (30% of patients in the current study) as a significant underlying predisposing factor. The laboratory findings were also quite similar except for a lower incidence of peripheral leukocytosis and eosinophilia in the 2008 cohort. Since the advent of azoles, fluconazole and related agents have almost completely supplanted intrathecal amphotericin B in the management of CM. Although azoles have become the first-line therapy of CM, concomitant parenteral amphotericin B is often administered, especially in patients with severe clinical illness and widely disseminated disease. Because intrathecal amphotericin B was rarely used in the 2008 cohort, very few patients had placement of an Ommaya reservoir for intrathecal therapy. Despite the differences in therapy, there did not seem to be major changes in the complications associated with the condition: approximately one-third of patients in the 2008 cohort experienced a stroke or developed hydrocephalus requiring a VP shunt. Morbidity and mortality remain high-over a third of patients in the current cohort died as a consequence of CM, a mortality rate similar to that seen in the pre-azole era. Despite the convenience associated with fluconazole use, these agents are not curative and do not necessarily prevent the more serious complications associated with CM. New therapeutic approaches are required to provide definitive cure of CM without the need for long-term azole suppressive therapy.

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ACKNOWLEDGMENTS

The authors deeply appreciate the efforts of the authors of the 1981 study (Drs. Bouza, Dreyer, Hewitt, and Meyer). We also wish to thank the many physicians and health care personnel at our respective institutions who participated in the care of the patients in this study.

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APPENDIX

ILLUSTRATIVE CASES

Case 4: CM in a Patient With AIDS

A 32-year-old white man with a history of AIDS (on HAART: abacavir/lamivudine/efavirenz; CD4 = 171 cells/mm3) presented to the emergency room on May 19, 2002, with a 2-week complaint of "migraine headache" and fever, accompanied by recent (5 d) history of nausea/vomiting, photophobia, and stiff neck. Following initial evaluation, the patient refused a lumbar puncture and signed out against medical advice. He returned 1 day later with "altered mental status" and underwent a repeat head CT scan-this now showed a focal hypodensity in left posterior temporal lobe without evidence of midline shift. A lumbar puncture demonstrated an opening pressure of 50 cm H2O, a leukocyte count of 793 cells/mm3 (79% polymorphonuclear leukocytes), total protein of 94 mg/dL, and glucose of 31 mg/dL. A chest radiograph showed bilateral interstitial infiltrates. The patient was started on ceftriaxone, ampicillin, vancomycin, and fluconazole (400 mg IV daily). On the second day of hospitalization, the patient rapidly decompensated, requiring intubation and pressor support. Considering the severity of the illness, the family decided "do not resuscitate" (DNR), and he died 3 days after admission with progressive hypothermia and an episode of ventricular arrhythmia.

All Coccidioides serology was negative; however, CSF, sputum, and lung cultures subsequently grew C immitis. The autopsy demonstrated a large inflammatory mass (6 cm) in the left lower lobe of the lung containing confluent necrotizing granulomas and spherules consistent with C immitis. The central nervous system showed granulomatous meningitis secondary to coccidioidomycosis, with associated cerebral edema and tonsillar herniation. The cause of death was determined to be disseminated coccidioidomycosis secondary to AIDS.

Comment: This case demonstrates several features of CM in HIV-infected individuals. In HIV patients with meningitis from coccidioidomycosis-endemic areas, the presence of diffuse pulmonary infiltrates or a miliary pattern on chest radiograph might be clues to the diagnosis of CM. The CSF results may mimic bacterial meningitis with an elevated leukocyte count with polymorphonuclear predominance. Coccidioides serologies may be negative, reflecting recent onset of symptoms (seroconversion may take 6-12 wk) or the failure to develop a serologic response in HIV/AIDS patients (up to 20% of patients). The role of HAART in preventing disseminated coccidioidomycosis is unclear-this patient developed CM despite excellent control of the HIV infection. Although he received antifungal therapy on the second emergency room visit (intravenous fluconazole), the poor outcome is not surprising considering the rapid progression of symptoms and the onset of severe brain edema. Although intrathecal or parenteral amphotericin may be helpful in seriously ill patients, it is unlikely that amphotericin would have changed the clinical course in this case. With the increasing number of HIV-infected patients in the American Southwest, disseminated coccidioidomycosis with CM is likely to be a continuing problem in this population.

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Case 21: Disseminated Coccidioidomycosis in Pregnancy With Subsequent CM

A 30-year-old white woman with a past medical history of asthma presented during her 26th week of pregnancy with fever, hip pain, and diffuse pulmonary infiltrates. She became progressively hypoxic and developed respiratory failure, requiring intubation and mechanical ventilation. Biopsy of a lytic hip lesion demonstrated C immitis; a serum Coccidioides CF titer was 1:32. Given her pregnant status, she was initially treated with intravenous amphotericin B rather than fluconazole. Her hospital course was complicated with multiorgan failure, fetal demise (requiring a dilatation and curettage) and renal failure (secondary to amphotericin B); however, she gradually recovered and was ultimately discharged from the hospital on voriconazole therapy. Her first lumbar puncture (after having already received several weeks of voriconazole) was negative and showed no evidence of CM. The patient's compliance with the voriconazole was poor, and 1 year later she was readmitted to the hospital with headache and CSF pleocytosis. CM was diagnosed, and she was re-treated with intravenous amphotericin B and fluconazole. After a second attempt to reintroduce voriconazole failed, the patient was eventually transitioned to oral fluconazole (800 mg po daily). More recently, she developed persistent back pain and was found to have lower lumbar arachnoiditis (L2, L4-L5 on MRI scan) with a normal neurologic examination. She received a brief (1 wk) course of LAmB and was discharged on a combination of oral fluconazole (400 mg po daily) and posaconazole (200 mg po twice daily). At last follow-up the patient was stable on this regimen with minimal back pain, and had no evidence of neurologic deterioration.

Comment: This case was originally reported in 2007 with an emphasis on the initial clinical presentation and associated fetal loss.28 Our report outlines her subsequent course, including the development of CM approximately 1 year later. As predicted in the original report, her later course was marked by periodic relapses, often related to medication intolerance or poor compliance with an azole regimen. Although pregnancy does not appear to be a risk factor for primary coccidioidomycosis, pregnant patients with coccidioidomycosis have a higher rate of dissemination compared to "normal" hosts (10% vs. 1%).10 In this situation, CM is the most common site of extrapulmonary dissemination and is especially likely during the third trimester. The increased risk for dissemination during the latter stages of pregnancy is probably related to the hormonal changes and increased immunosuppression (due to lower CD4 T-lymphocyte counts) seen during this period.58 In a literature review of over 80 published cases of coccidioidomycosis in pregnancy, fetal or maternal demise was seen in up to 70% of patients; these figures are considerably better in the modern era, probably related to earlier diagnosis and more effective antifungal therapy.19 CM treatment during pregnancy is problematic because of the known association of azole agents with teratogenicity. Although short course (<10 d), low-dose (<700 mg daily) fluconazole appears relatively safe in pregnant women,42 prolonged use of high-dose fluconazole during pregnancy has been associated with Antley-Bixler syndrome, a cluster of fetal craniofacial and skeletal abnormalities linked to azoles.50 The risk of azole therapy is especially high during the first trimester of pregnancy when the fetus has the greatest risk of developing the characteristic skeletal abnormalities. Although data are limited, some experts believe that azole therapy may be safe in late stages of pregnancy, when fetal skeletal development is less likely to be affected.58 Several decades of experience with amphotericin B suggest that this drug is safe during pregnancy and can be given without concern for teratogenicity. During the first trimester, every effort should be made to avoid azole therapy and to use intrathecal or parenteral amphotericin B.45

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Case 23: CM Masquerading as Carcinomatous Meningitis

The patient was a 42-year-old African American man without significant past medical history who presented to Olive View Medical Center with bizarre behavior and acute mental status changes. On brain MRI the patient had bilateral enhancement of the basal ganglia and sylvian fissures. A CT of the chest demonstrated "right middle lobe linear air space opacity with nodularity and possible cavity"; however, no biopsy was performed, and the cause of the lung lesion was unclear. CSF cytology revealed what appeared to be malignant cells, compatible with carcinomatous meningitis. Flow cytometry of CSF sent to an outside laboratory demonstrated LCA (leukocyte common antigen) positive/CD20 positive cells, a finding believed to be highly suggestive of B-cell lymphoma. Because of this finding, carcinomatous meningitis from unknown primary (most likely B-cell lymphoma) was diagnosed, and the patient was started on intrathecal methotrexate and corticosteroids. On this regimen, the patient failed to show improvement, and he was transferred to another hospital for placement of an Ommaya reservoir and chemotherapy infusion. His mental status continued to worsen, and he developed hydrocephalus requiring placement of a VP shunt. The patient died 2 days after surgery secondary to brainstem herniation. At autopsy, the patient was found to have disseminated coccidioidomycosis with CM; there was no evidence of CNS lymphoma.

Comment: This patient's clinical presentation demonstrates how CM can mimic other disease processes, including carcinomatous meningitis. The initial misdiagnosis was related to the negative CSF cultures and the failure to obtain serologies for C immitis. This was compounded by the abnormal CSF cytology and flow cytometry results suggesting the diagnosis of CNS lymphoma. The patient's clinical status was likely made worse by the subsequent chemotherapy (with corticosteroids) and failure to start empiric antifungal treatment. Only at postmortem was a there a clear diagnosis of CM leading to withdrawal of the CNS lymphoma diagnosis. Another patient (Patient 30) presented with a somewhat similar issue. Initial studies (bronchoalveolar lavage with sputum fungal culture, CSF fungal culture, CSF/blood serologies) were negative for coccidioidomycosis; however, a subsequent CSF cytology suggested the possibility of CNS lymphoma. There was a delay in antifungal therapy, and consideration was given to starting antineoplastic chemotherapy. The diagnosis of CM became apparent when an earlier CSF sample (taken 1 mo after the initial presentation) began to grow C immitis. Following the return of these culture results, the interpretation of the CSF cytology was revised to "benign, most likely inflammatory." In a patient with possible CM, great care must be exercised in CSF analysis: over-reliance on CSF cytology may lead to a false diagnosis of carcinomatous meningitis.

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Case 26: CM Failing Fluconazole With Subsequent Response to Voriconazole Therapy

A 25-year-old previously healthy Hispanic woman presented to Olive View Medical Center with a several-week history of headache, nausea/vomiting, and fever. On examination she was confused and had nuchal rigidity. Chest radiograph and head CT were normal. Examination of the CSF showed an opening pressure of 200 mm H20 with 700 leukocytes (92% lymphocytes), glucose of <32 mg/dL, and a total protein of 242 mg/dL. CSF cultures were negative but CM was confirmed by serology (serum/CSF ELISA +; serum CF 1:16; CSF CF 1:8). She improved on intravenous fluconazole and was discharged on oral fluconazole, 800 mg po daily. Despite stated adherence to this regimen, she returned with an episode of recurrent meningitis in October 2004, and was treated in-hospital with intravenous LAmB and oral voriconazole (200 mg po twice daily). She did well on oral voriconazole as an outpatient; however, she developed a possible photosensitivity reaction and was switched back to fluconazole (800 mg po daily). Despite adherence to this regimen, she returned 3 months later with recurrent meningitis. The patient again responded to intravenous amphotericin B and voriconazole and was discharged on oral voriconazole. At last follow-up she remained clinically stable on voriconazole (200 mg po twice daily) with normalization of her CSF parameters, except for a positive CSF ELISA (+IgG/+IgM).

Comment: This case is similar to several other reports in the literature and represents the potential benefit of voriconazole in patients who have failed or are intolerant of fluconazole therapy.17,48,49 As alluded to earlier, the optimal dose of fluconazole in CM is unclear and is likely to vary from patient to patient. In addition to intolerance of the agent, failure of the drug may be secondary to subtherapeutic levels due to inadequate absorption or poor patient compliance. Although not assessed in this patient, serum fluconazole levels may be helpful if there is a question about drug absorption or medication adherence. Voriconazole is not approved for treatment of endemic mycoses; however, it has good in vitro activity against C immitis, and its pharmacokinetic profile (95% oral availability; low protein binding; good CSF/tissue penetration) suggests it would be a reasonable choice for treatment of this condition.29 Voriconazole can be given initially via an intravenous route (6 m/kg for 2 doses, then 4 mg/kg IV Q12 hr) followed by oral therapy (200 mg po twice daily). Higher oral doses (300 mg po twice daily) can be used, but these may have a higher rate of side effects. Recent studies in patients with invasive mycoses suggest a wide range of voriconazole blood levels following standard dosing.44 In selected cases, therapeutic drug monitoring (serum levels) may be helpful in documenting adequate serum levels (>1 μg/mL) or explaining side effects secondary to toxic levels (>5 μg/mL). In our experience, the photosensitivity reaction may be serious; however, in most cases symptoms can be ameliorated by using sunblock or protective clothing to reduce light exposure.

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REFERENCES

1. Abbott KH, Cutler OI. Chronic coccidioidal meningitis: review of the literature and report of seven cases. Arch Pathol. 1936;21:320-330.
2. Ampel NM. Delayed-type hypersensitivity, in vitro T-cell responsiveness and risk of active coccidioidomycosis among HIV-infected patients living in the coccidioidal endemic area. Med Mycol. 1999;37:245-250.
    3. Anstead GM, Corcoran G, Lewis J, Berg D, Graybill JR. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis. 2005;40:1770-1776. [Epub 2005 May 13].
    4. Arsura EL, Johnson R, Penrose J, Stewart K, Kilgore W, Reddy CM, Bobba RK. Neuroimaging as a guide to predict outcomes for patients with coccidioidal meningitis. Clin Infect Dis. 2005;40:624-627.
    5. Berry CD, Stevens DA, Hassid EI, Pappagianis D, Happs EL, Sahrakar K. A new method for the treatment of chronic fungal meningitis: continuous infusion into the cerebrospinal fluid for coccidioidal meningitis. Am J Med Sci. 2009;338:79-82.
    6. Blair JE, Coakley B, Santelli AC, Hentz JG, Wengenack NL. Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts. Mycopathologia. 2006;162:317-324.
    7. Blair JE. Coccidioidomycosis in liver transplantation. Liver Transpl. 2006;12:31-39.
    8. Bouza E, Dreyer JS, Hewitt WL, Meyer RD. Coccidioidal meningitis. An analysis of thirty-one cases and review of the literature. Medicine (Baltimore). 1981;60:139-172.
    9. Brockmeyer NH, Tillmann I, Mertins L, Barthel B, Goos M. Pharmacokinetic interaction of fluconazole and zidovudine in HIV-positive patients. Eur J Med Res. 1997;2:377-383.
    10. Caldwell JW, Arsura EL, Kilgore WB, Garcia AL, Reddy V, Johnson RH. Coccidioidomycosis in pregnancy during an epidemic in California. Obstet Gynecol. 2000;95:236-239.
    11. Capilla J, Clemons KV, Sobel RA, Stevens DA. Efficacy of amphotericin B lipid complex in a rabbit model of coccidioidal meningitis. J Antimicrob Chemother. 2007;60:673-676. [Epub 2007 Jul 23].
    12. Carbonara S, Regazzi M, Ciraci E, Villani P, Stano F, Cusato M, Heichen M, Monno L. Long-term efficacy and safety of TDM-assisted combination of voriconazole plus efavirenz in an AIDS patient with cryptococcosis and liver cirrhosis. Ann Pharmacother. 2009;43:978-984. [Epub 2009 Apr 21].
    13. Carmichael JK. Coccidioidomycosis in HIV-infected persons. Clin Infect Dis. 2006;42:1059.
    14. Classen DC, Burke JP, Smith CB. Treatment of coccidioidal meningitis with fluconazole. J Infect Dis. 1988;158:903-904.
    15. Clemons KV, Sobel RA, Williams PL, Pappagianis D, Stevens DA. Efficacy of intravenous liposomal amphotericin B (AmBisome) against coccidioidal meningitis in rabbits. Antimicrob Agents Chemother. 2002;46:2420-2426.
    16. Cloud G, Dismukes WE. Ketoconazole treatment of coccidioidal meningitis. Ann N Y Acad Sci. 1988;544:488-496.
    17. Cortez KJ, Walsh TJ, Bennett JE. Successful treatment of coccidioidal meningitis with voriconazole. Clin Infect Dis. 2003;36:1619-1622.
    18. Courville CB, Abbott KH. Pathology of coccidioidal granuloma of the central nervous system and its envelopes. Bull Los Angeles Neurol Soc. 1938;3:27-e41.
    19. Crum NF, Ballon-Landa G. Coccidioidomycosis in pregnancy: case report and review of the literature. Am J Med. 2006;119:993.e11-e17.
    20. Derensinski S, Hector R. The History of Coccidioidomycosis I. The Early History of the Disease in North America. II. Biographies of Four Coccidioidomycologists. In: Proceedings of the 5th International Conference of Coccidioidomycosis; Stanford University, 24-27 August, 1994. Washington, DC: National Foundation for Infectious Diseases; 1996.
    21. Dewsnup DH, Galgiani JN, Graybill JR, Diaz M, Rendon A, Cloud GA, Stevens DA. Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med. 1996;124:305-310.
    22. Einstein HE, Holeman CW, Sandidge LL, Holden DH. Coccidioidal meningitis. The use of amphotericin B in treatment. Calif Med. 1961;94:339-343.
    23. Fish DG, Ampel NM, Galgiani JN, Dols CL, Kelly PC, Johnson CH, Pappagianis D, Edwards JE, Wasserman RB, Clark RJ, Antoniskis D, Larsen RA, Englender SJ, Petersen EA. Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients. Medicine (Baltimore). 1990;69:384-391.
    24. Galgiani JN, Ampel NM, Blair J, Catanzaro A, Johnson RH, Stevens DA, Williams PL. Coccidioidomycosis IDSA guidelines. Clin Infect Dis. 2005;41:1217-1223. [Epub 2005 Sep 20].
    25. Galgiani JN, Catanzaro A, Cloud GA, Levine BE, Williams PL, Johnson RH, Rendon A, Mirels LF, Lutz JE, Holloway M, Galgiani JN. Fluconazole therapy for coccidioidal meningitis. The NIAID-Mycoses Study Group. Ann Intern Med. 1993;119:28-35.
    26. Garbino J, Lew DP, Romand JA, Hugonnet S, Auckenthaler R, Pittet D. Prevention of severe Candida infections in nonneutropenic, high-risk, critically ill patients: a randomized, double-blind, placebo-controlled trial in patients treated by selective digestive decontamination. Intensive Care Med. 2002;28:1708-1717. [Epub 2002 Nov 1].
    27. Graybill JR, Sun SH, Ahrens J. Treatment of murine coccidioidal meningitis with fluconazole (UK 49,858). J Med Vet Mycol. 1986;24:113-119.
    28. Hooper JE, Lu Q, Pepkowitz SH. Disseminated coccidioidomycosis in pregnancy. Arch Pathol Lab Med. 2007;131:652-655.
    29. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis. 2003;36:630-637.
    30. Johnson RH, Einstein HE. Coccidioidal meningitis. Clin Infect Dis. 2006;42:103-107.
    31. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.
    32. Kelly PC. Coccidioidal meningitis. In: Stevens DA, ed. Coccidioidomycosis. A Text. New York: Plenum Medical Book Company; 1980:163-193.
    33. Kriesel JD, Sutton DA, Schulman S, Fothergill AW, Rinaldi MG. Persistent pulmonary infection with an azole-resistant Coccidioides species. Med Mycol. 2008;46:607-610.
    34. Li RK, Ciblak MA, Nordoff N, Pasarell L, Warnock DW, McGinnis MR. In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum. Antimicrob Agents Chemother. 2000;44:1734-1736.
    35. Liu P, Foster G, Gandelman K, LaBadie RR, Allison MJ, Gutierrez MJ, Sharma A. Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects. Antimicrob Agents Chemother. 2007;51:3617-3626. [Epub 2007 Jul 23].
    36. Malani AN, Aronoff DM. Voriconazole-induced photosensitivity. Clin Med Res. 2008;6:83-85. [Epub 2008 Sep 18].
    37. Masannat FY, Ampel NM. Coccidioidomycosis in patients with HIV-1 infection in the era of potent antiretroviral therapy. Clin Infect Dis. 2010;50:1-7.
    38. McMahon JH, Grayson ML. Torsades de pointes in a patient receiving fluconazole for cerebral cryptococcosis. Am J Health Syst Pharm. 2008;65:619-623.
    39. Mischel PS, Vinters HV. Coccidioidomycosis of the central nervous system: neuropathological and vasculopathic manifestations and clinical correlates. Clin Infect Dis. 1995;20:400-405.
    40. Morris M. Coccidioides of the central nervous system. Cal West Med. 1924;22:483-485.
    41. Nierenberg NE, Thompson GR, Lewis JS, Hogan BK, Patterson TF. Voriconazole use and pharmacokinetics in combination with interferon-gamma for refractory cryptococcal meningitis in a patient receiving low-dose ritonavir. Med Mycol. 2010;48:532-536. [Epub 2009 Oct 19].
    42. Norgaard M, Pedersen L, Gislum M, Erichsen R, Søgaard KK, Schønheyder HC, Sørensen HT. Maternal use of fluconazole and risk of congential malformations: a Danish population-based cohort study. J Antimicrob Chemother. 2008;62:172-176. [Epub 2008 Apr 9].
    43. Ophuls W. Coccidioidal granulomas. J Am Med Assoc. 1905;14:1291.
    44. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46:201-211.
    45. Peterson CM, Johnson SL, Kelly JV, Kelly PC. Coccidioidal meningitis and pregnancy: a case report. Obstet Gynecol. 1989;73:835-836.
    46. Pitisuttithum P, Negroni R, Graybill JR, Bustamante B, Pappas P, Chapman S, Hare RS, Hardalo CJ. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother. 2005;56:745-755. [Epub 2005 Aug 31].
    47. Posadas A. Un nuevo caso de micosis fungoide con psorospermias. Circulo Medico Argentino. 1892;5:585-597.
    48. Prabhu RM, Bonnell M, Currier BL, Orenstein R. Successful treatment of disseminated nonmeningeal coccidioidomycosis with voriconazole. Clin Infect Dis. 2004;39:e74-e77.
    49. Proia LA, Tenorio AR. Successful use of voriconazole for treatment of Coccidioides meningitis. Antimicrob Agents Chemother. 2004;48:2341.
    50. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22:336-340.
    51. Rex J, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, Brass C, Vazquez JA, Chapman SW, Horowitz HW, Zervos M, McKinsey D, Lee J, Babinchak T, Bradsher RW, Cleary JD, Cohen DM, Danziger L, Goldman M, Goodman J, Hilton E, Hyslop NE, Kett DH, Lutz J, Rubin RH, Scheld WM, Schuster M, Simmons B, Stein DK, Washburn RG, Mautner L, Chu TC, Panzer H, Rosenstein RB, Booth J; National Institute of Allergy and Infectious Diseases Mycoses Study Group. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis. 2003;36:1221-1228. [Epub 2003 May 8].
    52. Rixford E, Gilchrist TC. Two cases of protozoan (coccidioidal) infection of the skin and other organs. Johns Hopkins Hosp Rep. 1896;1:209-269.
    53. Romeo JH, Rice LB, McQuarrie IG. Hydrocephalus in coccidioidal meningitis: case report and review of the literature. Neurosurgery. 2000;47:773-777.
    54. Santhana Krishnan SG, Cobbs RK. Reversible acute adrenal insufficiency caused by fluconazole in a critically ill patient. Postgrad Med J. 2006;82:e23.
    55. Shirvani VN, Gaucher DJ, Johnson RH, et al. Coccidioidal Meningitis: Evaluation of Intrathecal Amphotericin B after Non-Response to Fluconazole. 45th Coccidioidomycosis Study Group. Tucson, Arizona. March 31, 2001.
    56. Singh VR, Smith DK, Lawrence J, Kelly PC, Thomas AR, Spitz B, Sarosi GA. Coccidioidomycosis in patients infected with human immunodeficiency virus: review of 91 cases at a single institution. Clin Infect Dis. 1996;23:563-568.
    57. Sorensen KN, Sobel RA, Clemons KV, Pappagianis D, Stevens DA, Williams PL. Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis. Antimicrob Agents Chemother. 2000;44:1512-1517.
    58. Spinello IM, Johnson RH, Baqi S. Coccidioidomycosis and pregnancy-a review. Ann N Y Acad Sci. 2007;1111:358-364.
    59. Stevens DA, Rendon A, Gaona-Flores V, Catanzaro A, Anstead GM, Pedicone L, Graybill JR. Posaconazole therapy for chronic refractory coccidioidomycosis. Chest. 2007;132:952-958. [Epub 2007 Jun 15].
    60. Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect. 2001;16:263-269.
    61. Sung JP, Grendahl JG, Levine HB. Intravenous and intrathecal miconazole therapy for systemic mycoses. West J Med. 1977;126:5-13.
    62. Tholakanahalli VN, Potti A, Hanley JF, Merliss AD. Fluconazole-induced torsade de pointes. Ann Pharmacother. 2001;35:432-434.
    63. Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med. 1990;112:108-112.
    64. Tucker RM, Galgiani JN, Denning DW, Hanson LH, Graybill JR, Sharkey K, Eckman MR, Salemi C, Libke R, Klein RA, et al. Treatment of coccidioidal meningitis with fluconazole. Rev Infect Dis. 1990;12(Suppl 3):S380-S389.
    65. Vincent T, Galgiani JN, Huppert M, Salkin D. The natural history of coccidioidal meningitis: VA-Armed Forces cooperative studies, 1955-1958. Clin Infect Dis.. 1993;16:247-254.
    66. Williams PL, Johnson R, Pappagianis D, Einstein H, Slager U, Koster FT, Eron JJ, Morrison J, Aguet J, River ME. Vasculitic and encephalitic complications associated with Coccidioides immitis infection of the central nervous system in humans: report of 10 cases and review. Clin Infect Dis. 1992;14:673-682.
    67. Williams PL. Coccidioidal meningitis. Ann N Y Acad Sci. 2007;1111:377-384. [Epub 2007 Mar 15].
    68. Williams PL. Vasculitic complications associated with coccidioidal meningitis. Sem Resp Infect. 2001;16:270-279.
      69. Winn WA. The use of amphotericin B in the treatment of coccidioidal disease. Am J Med. 1959;27:617.
      70. Winston DJ, Kurtz TO, Fleischmann J, Morgan D, Batzdorf U, Stern WE. Successful treatment of spinal arachnoiditis due to coccidioidomycosis. Case report. J Neurosurg. 1983;59:328-331.
      71. Yakiwchuk EM, Foisy MM, Hughes CA. Complexity of interactions between voriconazole and antiretroviral agents. Ann Pharmacother. 2008;42:698-703. [Epub 2008 Apr 15].
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