Residents of the area now occupied by the southwestern United States and northwestern Mexico have had to deal with coccidioidomycosis and complicating meningitis for >1500 years. The hundredth anniversary of the reporting of disseminated coccidioidomycosis has just passed. This year has the dubious distinction of being the hundredth anniversary of the first description of coccidioidal meningitis. Although intrathecal amphotericin B began to be used for therapy 50 years ago, and although we have benefited from azole therapy for >10 years, the morbidity and mortality associated with this all-too-common disease remain unacceptably high. This review will endeavor to discuss the pathogenic, pathophysiologic, clinical, laboratory, radiologic, and therapeutic features of meningitis secondary to Coccidioides infection.

An unprecedented epidemic of coccidioidomycosis began in 1991 in the Southern San Joaquin Valley of California. Data from medical records and patient interviews of 536 cases with laboratory-confirmed diagnosis from the Kern County Health Department were analyzed for hospital days, return clinic visits, drug usage, and employment status. Estimates of work days missed were made from historical and current data from the military. Usual costs for hospital days and return clinic visits, and average wholesale acquisition prices for antifungal medications were utilized for medical costs. Lost wages were estimated from the employment rate in the epidemic population and salary estimates according to race from the 1990 census in Kern County.A total yearly cost per case of $8,096 was calculated from this analysis, with 63 percent attributed to hospitalization, 18 percent to clinic visits, 12 percent to lost wages, and 7 percent to the cost of drug treatment. Nondisseminated cases averaged $5,400 as compared to $48,000 for those with dissemination. Twenty-three percent of total cost was due to disseminated disease, which was present in only 4 percent of the infected population.The total estimated cost for 7,130 cases occurring from 1991 to 1993, utilizing these methods, is more than $56 million. This does not include the cumulative costs of continuing care, beyond 1 year, for those with chronic disease and disability.

Fluconazole, a significant advance in treating disseminated coccidioidomycoses (DC), is frequently required in doses > 400 mg. We retrospectively evaluated 70 consecutive patients receiving fluconazole (F) for adverse effects (AE's). All patients had DC. The mean age of the 47 males and 23 females was 33 years. Fifty-five (percent) had meningitis and fifteen (19 percent) had other sites of dissemination. All patients received F in doses ranging hom 400 mg to 1200 mg/day. Twenty three (32 percent) received 400 mg only, while 47 (68 percent) required higher doses. Adverse events were more common with higher doses. Fifty percent of 57 patients receiving daily F 400 mg had at least one AE, as compared to 60 percent of 47 on greater than or equal to 800 mg. Multiple AE's occurred in 16 percent when receiving 400 mg as compared to 34 percent when doses were greater than or equal to 800 mg (p = 0.05). AE's in order of frequency were: nausea/vomiting (27 percent), weightless (23 percent), arthralgias (16 percent), alopecia (14 percent), skin reactions (14 percent), increased alkaline phosphatase (11 percent), abdominal pain (5.7 percent), and increased transaminases (5 percent). Mean serum levels ranged from 18mcg/ml for skin reactions to 26mcg/ml for alkaline phosphatase elevations. Dose limiting reactions (7 nausea/vomiting, 3 increased transaminases, 5 other) occurred in 15 patients (21 percent). Seventy-five percent of the time, patients had stable or improving disease symptoms at the time AE's were noted. One patient with fatty liver was removed from therapy.Adverse reactions to F are dose related and significantly higher when doses equal or exceed 800 mg in DC. Nausea and vomiting, weight loss, alopecia, and arthralgias are more common than previously appreciated. Nausea/vomiting and liver-function abnormalities can be temporarily dose limiting. Tolerance to AE's improves over time.

Recently published data demonstrating the efficacy of Fluconazole (F) for coccidioidal meningitis (CM) by the NIAID Mycosis Study Group (MSG) prompted a retrospective evaluation of our experience with patients initially treated with (F) since 1991. Fifty patients from the coccidioidomycosis clinic at Kern Medical Center and the private practices of two investigators were identified for review.Two evaluable groups were identified for comparison who received greater than 3 months treatment at a stable dose. Group I (F-400) consisted of 16 patients treated initially with 400 mg/day for a mean duration of 219 days. Group II (F-800) consisted of 18 patients initially treated with 800 to 1600 mg for a mean duration of 276 days. A third non-evaluable group included 16 patients that did not receive stable dosing or a minimum duration of 3 months. There were no differences in the two patient groups in age, sex, race, or skin test. The unevaluable group had a greater co-morbidity of diabetes.The F-400 and F-800 groups were compared using the MSG-scoring system. Initial baseline scores were 7.81 for the F-400 group and 7.00 for the F-800 group. The F-800 group responded with a mean score of 3.6 (mean duration of 276 days). However, the F 400 group only dropped to 6.5 (mean duration 219 days). A mean score of 3.8 in the F-800 group at 180 days was nearly identical to the 276 day score, suggesting that dose was more important than duration of treatment. Patients with a 40 percent decrease from baseline score were considered responders. Five of 16 (31 percent) in the F 400 group responded, compared to 12 of 18 (67 percent) in the F-800 group (p = 0.04 chi-square). There was one death in each evaluable treatment group. Of the 16 patients in the unevaluable group, there were 3 responders, 7 early deaths, and 6 non-responders. Eleven patients were started on 400 mg and five on 800 mg or greater.Compared with 400 mg, initial doses equal to or greater than 800 mg of fluconazole in coccidioidal meningitis are associated with an improved early response. Evaluation at 1 and 2 years of treatment are necessary to assess the long-term efficacy.

The decision to treat patients with primary coccidioidomycosis sis (CM) is fraught with uncertainty. An ongoing epidemic in Kern County California provided opportunity to evaluate treatment in a community based retrospective analysis. Forty eight percent of patients received drug treatment. Response analysis of treated cases revealed a worse outcome compared to nontreated cases. To evaluate a treatment effect in a comparable population, the following patients were excluded: those cases with early death, given amphotericin B in < 30 days, or with dissemination < 30 days from symptom onset. Fifty-four such cases were removed from study. Determination of dissemination and disease onset were made by two physician-authors blinded to treatment and out come.Two groups were created from the remaining cases based on treatment timing. The ''EarlyRx'' group included those receiving azole treatment in less than 30 days from symptom onset. The ''LateRx'' group included those receiving any antifungal treatment after 30 days.The EarlyRx group had 124 cases and the LateRx group 80. There were no significant differences between patient groups in age, sex, race, or treatment with azoles or amphotericin. The EarlyRx group had a higher rate of skin test negativity (64 percent vs. 47 percent p = 0.08). Patients were evaluated up to 1 year or until recovered. There were five with unknown outcomes in the EarlyRx group and one in the LateRx group. The EarlyRx group had a significantly decreased incidence of peak complement fixation (CF) titer greater than or equal to 1:32 (27 percent vs. 45 percent, p = 0.009), dissemination (2 percent vs. 9 percent, p = 0.05), and chronic disease requiring treatment at 1 year (1.6 percent vs. 10 percent, p = 0.015), Comparing serious disease outcome (dissemination + death + chronic disease) revealed a 6 percent rate for the EarlyRX group and a 16 percent rate for the LateRx group. (p = 0.01).Conclusion: Treatment of moderate eases of CM with azoles initiated less than 30 days from symptom onset appears associated with a significant reduction in peak CF titer > 1:32, dissemination, and chronic disease. Combined serious disease endpoints were reduced by 68 percent.

The incidence of coccidioidomycosis has increased dramatically in the Southern San Joaquin Valley of California. Between September 1991 and January 1994 there have been over 7,000 seropositive cases. An average of the 10 years preceding 1991 would have predicted only 1,000 cases during this interval. Cases from September 1, 1991 to January 1, 1992, were selected for review, from which extensive data with 1 year of followup were obtained on 536 patients.Presenting symptoms included fever (76 percent), cough (73 percent), chest pain (44 percent), fatigue (38 percent), chills (28 percent), erythema nodosum (26 percent), shortness of breath (22 percent), and headache (18 percent). Pulmonary disease was most frequently lower lobe in distribution but found in all lobes. Among those with abnormal chest x-rays, infiltrate occurred only in 68 percent, infiltrate with effusion in 10 percent, and infiltrate plus adenopathy in 9.8 percent. Twenty-five cases (4.7 percent) developed disseminated disease, 44 percent of which were meningitis.Disease outcome was evaluated after 1 year of follow-up. Sixty-three percent recovered, 11 percent probably recovered, and 8.2 percent developed serious disease (continued treatment at 1 year, disease dissemination, or death) In 17 percent the outcome was unknown. There were 17 deaths (3.2 percent), thirteen of which were without evidence of dissemination and four where disseminated disease was confirmed.Evaluation of outcome compared individuals with serious disease to those who recovered and those who probably recovered. Stepwise multivariate regression analysis revealed significant associations to serious disease with age, African-American race, negative skin test, and maximum complement fixation titer.

Journal Article Coccidioidomycosis: New Aspects of Epidemiology and Therapy Get access Hans E. Einstein, Hans E. Einstein From the Departments of Medicine, Bakersfield Memorial Hospital and Kern Medical Center, Bakersfield; and the USC and UCLA Schools of Medicine, Los Angeles, California Reprints or correspondence: Dr. Hans E. Einstein, Medical Staff Office, Bakersfield Memorial Hospital, 430 34th Street, Bakersfield, California 93301. Search for other works by this author on: Oxford Academic PubMed Google Scholar Royce H. Johnson Royce H. Johnson From the Departments of Medicine, Bakersfield Memorial Hospital and Kern Medical Center, Bakersfield; and the USC and UCLA Schools of Medicine, Los Angeles, California Search for other works by this author on: Oxford Academic PubMed Google Scholar Clinical Infectious Diseases, Volume 16, Issue 3, March 1993, Pages 349–356, https://doi.org/10.1093/clind/16.3.349 Published: 01 March 1993 Article history Received: 24 November 1992 Published: 01 March 1993