Demosthenes Pappagianis

Epidemiology of Coccidioidomycosis

Coccidioides immitis naturally occurs in the soil and air of certain areas of the New World. These are generally arid to semiarid areas that have relatively modest rainfall, mild winters, and prolonged hot seasons. Coccidioidomycosis is usually a disease of human and nonhuman residents of these areas; but visitors may develop the disease after entering these areas and returning home long distances from the endemic areas. Inhalation (rarely percutaneous introduction) of arthroconidia of C. immitis leads to usually benign but occasionally severe and even fatal infection. Recovery from or asymptomatic infection leads to resistance to reinfection. Exposure to soil (dust) means that certain occupations are more likely to be exposed to C. immitis. Persistence of the organism in the soil means that infections will be encountered in the future, particularly as long as susceptible newcomers continue to enter endemic areas. Those who have been infected and recovered generally will be resistant to later infection, although exacerbation may occur as a result of superimposed immunosuppression.

Serology of coccidioidomycosis.

Serologic tests have assisted in the diagnosis and prognosis of coccidioidomycosis for a half-century. The causative agent, Coccidioides immitis, is a dimorphic fungus existing in a hyphal form with arthroconidia in nature and in the usual culture. The arthroconidia represent the inhaled infective forms which in vivo and under special laboratory conditions form spherules which endosporulate. The culture filtrate/autolysate (coccidioidin) from the hyphal phase has provided antigens of suitable reliability for currently used serologic tests. These tests are primarily to determine the two major antibody responses: the early immunoglobulin M (IgM) response is useful in the diagnosis of acute primary coccidioidomycosis. Later, IgG is produced and usually outlasts the IgM, persisting in chronic coccidioidomycosis. The IgM is detectable by tube precipitin, a corresponding immunodiffusion, or latex particle agglutination tests. The pertinent antigen(s) is heat stable and pronase resistant and appears to be largely carbohydrate, mainly mannose with some 3-O-methyl mannose. The IgG detectable in the serum and other body fluids by complement fixation and a corresponding immuno-diffusion is useful in diagnosis, and its quantitation provides an indicator of progression of disease (increasing titer) or regression (decreasing titer). The pertinent antigen appears to be a heat-labile, pronase-sensitive protein which in an unreduced form has a molecular weight of 110,000. A third very useful serologic procedure is the exoantigen test for identification of putative cultures of C. immitis. Images

Coccidioidomycosis during human immunodeficiency virus infection: A review of 77 patients

Through a retrospective review, we identified 77 previously unreported cases of coccidioidomycosis during HIV infection. Patients were classified into 1 of 6 categories based on their primary clinical presentation: 20 had focal pulmonary disease (Group 1), 31 had diffuse pulmonary disease (Group 2), 4 had cutaneous coccidioidomycosis (Group 3), 9 had meningitis (Group 4), 7 had extrathoracic lymph node or liver involvement (Group 5), and 6 has positive coccidioidal serology without a clinical focus of infection (Group 6). Coccidioidal serologies were positive on initial testing in 83% of the patients in whom such serologic testing was performed. Sera from 39% of patients were positive for TP antibodies while 74% had CF antibodies. Eleven of 12 seronegative patients had pulmonary disease (Group 1 or 2). Serologic results of other patients sent to a single reference laboratory were similar, with 26% positive for immunodiffusion TP antibodies and 79% positive for immunodiffusion CF antibodies. For the 77 patients in this study, the CD4-lymphocyte count was below 0.250 X 10(9) cells/L in 46 of the 55 patients who had this test performed, and a low CD4 count was significantly associated with mortality (p less than 0.01). At the time of follow-up, 32 of the 77 patients (42%) had died. There were significantly more deaths in those with diffuse pulmonary disease (Group 2) than in other groups (p less than 0.001). Amphotericin B, ketoconazole, fluconazole, and itraconazole were all used as antifungal therapies. Outcome could not be related to the therapy used. Of note, 3 patients developed coccidioidomycosis while receiving ketoconazole for other conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of Resistance to Amphotericin B in Candida lusitaniae Infecting a Human

Candida lusitaniae associated with infection in a patient with acute myelogenous leukemia developed resistance to amphotericin B during systemic treatment of the patient. The organism, when isolated initially, was inhibited by 0.31 μg of amphotericin B per ml in yeast nitrogen base agar, but when isolated (20 days later) just antemortem and postmortem, required 100 and 50 μg/ml, respectively, for complete inhibition at 48 h.

Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis.

Nikkomycins X and Z, competitive inhibitors of fungal chitin synthase, were evaluated as therapeutic agents in vitro and in mouse models of coccidioidomycosis, histoplasmosis, and blastomycosis. In vitro, the nikkomycins were found to be most effective against the highly chitinous, dimorphic fungi Coccidioides immitis and Blastomyces dermatitidis, were less effective against yeasts, and were virtually without effect on the filamentous fungus Aspergillus fumigatus. Additionally, by transmission electron microscopy, nikkomycin Z was highly disruptive to the cell wall and internal structure of the spherule-endospore phase of C. immitis in vitro. In vivo, nikkomycin Z was more effective than nikkomycin X, was also found to be superior on a milligram per milligram basis to the majority of azoles tested in the models of coccidioidomycosis and blastomycosis, and was moderately effective in histoplasmosis. A study of the pharmacokinetics in mice showed that nikkomycin Z was rapidly eliminated after intravenous infusion but that absorption after oral administration was sufficiently slow to allow inhibitory levels to persist for more than 2 h. Results of limited toxicology tests suggest that nikkomycin Z was well tolerated at the dosages employed. Images

Donor-Related Coccidioidomycosis in Organ Transplant Recipients

Most cases of coccidioidomycosis in organ transplant recipients arise from either primary infection with Coccidioides immitis after environmental exposure or from reactivation of latent infection. Herein, we report 2 cases of rapidly fatal, disseminated coccidioidomycosis that occurred in organ transplant recipients who had never lived in or visited an area where C. immitis is endemic. Both subjects had received a transplanted organ from the same donor, an individual with unrecognized active coccidioidomycosis at the time of his death.

Outbreak of coccidioidomycosis in Washington state residents returning from Mexico.

In July 1996 the Washington State Department of Health (Seattle) was notified of a cluster of a flulike, rash-associated illness in a 126-member church group, many of whom were adolescents. The group had recently returned from Tecate, Mexico, where members had assisted with construction projects at an orphanage. After 1 member was diagnosed with coccidioidomycosis, we initiated a study to identify further cases. We identified 21 serologically confirmed cases of coccidioidomycosis (minimum attack rate, 17%). Twenty cases (95%) occurred in adolescents, and 13 patients (62%) had rash. Sixteen symptomatic patients saw 19 health care providers; 1 health care provider correctly diagnosed coccidioidomycosis. Coccidioides immitis was isolated from soil samples from Tecate by use of the intraperitoneal mouse inoculation method. Trip organizers were unaware of the potential for C. immitis infection. Travelers visiting regions where C. immitis is endemic should be made aware of the risk of acquiring coccidioidomycosis, and health care providers should be familiar with coccidioidomycosis and its diagnosis.

Efficacy of Intravenous Liposomal Amphotericin B (AmBisome) against Coccidioidal Meningitis in Rabbits

ABSTRACT The efficacy of intravenously administered liposomal amphotericin B (AmBisome [AmBi]) for the treatment of experimental coccidioidal meningitis was compared with those of oral fluconazole (FLC) and intravenously administered conventional amphotericin B (AMB). Male New Zealand White rabbits were infected by intracisternal inoculation of arthroconidia of Coccidioides immitis. Starting 5 days postinfection, animals received one of the following: 5% dextrose water diluent; AMB given at 1 mg/kg of body weight; AmBi given at 7.5, 15, or 22.5 mg/kg intravenously three times per week for 3 weeks; or oral FLC given at 80 mg/kg for 19 days. One week after the cessation of therapy, all survivors were euthanatized, the numbers of CFU remaining in the spinal cord and brain were determined, and histological analyses were performed. All AmBi-, FLC-, or AMB-treated animals survived and had prolonged lengths of survival compared with those for the controls (P < 0.0001). Treated groups had significantly lower numbers of white blood cells and significantly lower protein concentrations in the cerebrospinal fluid compared with those for the controls (P < 0.01 to 0.0005) and had fewer clinical signs of infection (e.g., weight loss, elevated temperature, and neurological abnormalities including motor abnormalities). The mean histological scores for AmBi-treated rabbits were lower than those for FLC-treated and control rabbits (P < 0.016 and 0.0005, respectively); the scores for AMB-treated animals were lower than those for the controls (P < 0.0005) but were similar to those for FLC-treated rabbits. All regimens reduced the numbers of CFU in the brain and spinal cord compared with those for the controls (P ≤0.0005). AmBi-treated animals had 3- to 11-fold lower numbers of CFU than FLC-treated rabbits and 6- to 35-fold lower numbers of CFU than AmB-treated rabbits. Three of eight animals given 15 mg of AmBi per kg had no detectable infection in either tissue, whereas other doses of AmBi or FLC cleared either the brain or the spinal cord of infection in fewer rabbits. In addition, clearance of the infection from both tissues was achieved in none of the rabbits, and neither tissue was cleared of infection in AMB-treated animals. Overall, these data indicate that intravenously administered AmBi is superior to oral FLC or intravenous AMB and that FLC is better than AMB against experimental coccidioidal meningitis. These data indicate that AmBi may offer an improvement in the treatment of coccidioidal meningitis. Additional studies are warranted.

Coccidioides Niches and Habitat Parameters in the Southwestern United States A Matter of Scale

Abstract:  To determine habitat attributes and processes suitable for the growth of Coccidioides, soils were collected from sites in Arizona, California, and Utah where Coccidioides is known to have been present. Humans or animals or both have been infected by Coccidioides at all of the sites. Soil variables considered in the upper 20 cm of the soil profile included pH, electrical conductivity, salinity, selected anions, texture, mineralogy, vegetation types and density, and the overall geomorphologic and ecological settings. Thermometers were buried to determine the temperature range in the upper part of the soil where Coccidioides is often found. With the exception of temperature regimes and soil textures, it is striking that none of the other variables or group of variables that might be definitive are indicative of the presence of Coccidioides. Vegetation ranges from sparse to relatively thick cover in lower Sonoran deserts, Chaparral‐upper Sonoran brush and grasslands, and Mediterranean savannas and forested foothills. No particular grass, shrub, or forb is definitive. Material classified as very fine sand and silt is abundant in all of the Coccidioides‐bearing soils and may be their most common shared feature. Clays are not abundant (less than 10%). All of the examined soil locations are noteworthy as generally 50% of the individuals who were exposed to the dust or were excavating dirt at the sites were infected. Coccidioides has persisted in the soil at a site in Dinosaur National Monument, Utah for 37 years and at a Tucson, Arizona site for 41 years.

Coccidioidomycosis and pregnancy

Pregnant women with respiratory symptoms of pleuritic pain and productive cough should undergo evaluation for coccidioidomycosis. This should include a history of travel or residency in endemic areas and careful assessment for toxic erythema, erythema nodosum, or erythema multiforme. To confirm a diagnosis of this disease, a sputum culture, wet mount, and serological tests should be performed. The risk of dissemination, which is highest in the second and third trimesters, can be estimated by a complement-fixation titer. In disseminated cases aggressive treatment with amphotericin B has improved the previously reported high maternal and neonatal mortality rate. Fortunately, case reports do not indicate that transplacental spread occurs. Reactivation or exacerbation of a chronic low-grade infection during pregnancy may occur in patients treated for prior disseminated disease (32, 34). Interestingly, both of the reported cases of reactivation or exacerbation occurred in insulin-dependent diabetics.