Forms Of Coccidioidomycosis Research Articles

Comparative Study of Newer and Established Methods of Diagnosing Coccidioidal Meningitis.

Meningitis is the most devastating form of coccidioidomycosis. A convenient, rapid diagnostic method could result in early treatment and avoid many meningitis complications. We studied cerebrospinal fluid (CSF) samples in patients with documented coccidioidal meningitis, and controls, with complement fixation (CF), immunodiffusion (ID) (the “classical” assays), lateral flow assays (LFA; one-strip and two-strip), and two enzyme immunoassays (EIA). The two-strip LFA and EIAs not only enabled separate testing for IgG and IgM antibodies separately, but also could aggregate results for each method. CF with ID or the aggregate use of IgG and IgM tests were considered optimal test uses. LFAs and EIAs were evaluated at 1:21 and 1:441 dilutions of specimens. All assays were compared to true patient status. With 49 patient specimens and 40 controls, this is the largest comparative study of CSF coccidioidal diagnostics. Sensitivity of these tests ranged from 71–95% and specificity 90–100%. IgM assays were less sensitive. Assays at 1:441 were similarly specific but less sensitive, suggesting that serial dilutions of samples could result in assays yielding titers. Agreement of positive results on cases was 87–100%. When kits are available, hospital laboratories in endemic areas can perform testing. LFA assays do not require a laboratory, are simple to use, and give rapid results, potentially even at the bedside.

Cutaneous effects associated with fluconazole in patients treated for coccidioidomycosis.

Fluconazole is the most commonly used antifungal treatment for various forms of coccidioidomycosis. Although we had anecdotally observed a high proportion of patients reporting cutaneous adverse effects associated with fluconazole treatment, this observation was not well described in the medical literature, and we were unsure of the additional effect of the arid desert environment of Arizona. We performed a one-time, voluntary survey of patients with coccidioidomycosis and compared the responses of patients treated with fluconazole with those of untreated patients. From January 1, 2015, to August 22, 2017, 62 fluconazole-treated and 35 untreated patients with coccidioidomycosis provided consent and were enrolled in the study; demographics were similar between the two groups. Among the 62 fluconazole-treated patients, daily dosages ranged from 200 mg to 800 mg. However, most (44/62, 71%) took 400 mg daily, the typical dose for the treatment of coccidioidomycosis. The median fluconazole treatment duration at the time of study participation was 6 months. When compared with untreated patients, those taking fluconazole had more moderate to severe dry lips (74.2% [46/62] vs. 23.5% [8/34]; P < 0.001), dry skin (45.8% [27/59] vs. 22.9% [8/35]; P = 0.03), and alopecia (31.1% [19/61] vs. 11.4% [4/35]; P = 0.004). For the treatment of coccidioidomycosis, patients receiving fluconazole reported significantly more severe cutaneous effects, including dry lips, dry skin, and alopecia, than untreated patients. Our findings identify an association but do not prove causality.

Approach to Management of Coccidioidomycosis in Patients Receiving Inhibitors of Tumor Necrosis Factor-α

Abstract Inhibitors of tumor necrosis factor-α (TNFIs) have revolutionized the treatment for patients with a variety of inflammatory illnesses, including rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, and other inflammatory diseases, and have improved the outcomes and quality of life for such patients. Endemic fungal infections, such as coccidioidomycosis, are observed to occur in persons who are treated with these agents and who live in the Coccidioides-endemic area with similar frequency as persons in the general, healthy public but with an increased likelihood of symptomatic infection and extrapulmonary dissemination. Because the control of coccidioidal infections requires the formation and maintenance of granuloma, it is not unexpected that TNFIs, which inhibit granuloma formation, seem to increase the risk of clinical disease. No guidelines exist to address the prevention and management of disease in patients whose treatment course with TNFIs is complicated by subclinical or clinical coccidioidal infection. Therefore, we reviewed the available medical literature and offer suggestions to the approach and treatment of patients with various forms of coccidioidomycosis before and during therapy with TNFIs.

THE TREATMENT OF COCCIDIOIDOMYCOSIS

SUMMARYTherapy of coccidioidomycosis continues to evolve. For primary pulmonary disease, antifungal therapy is frequently not required while prolonged courses of antifungals are generally needed for those in whom extrathoracic disseminated has occurred. Intravenous amphotericin B should be reserved for those with severe disease. Oral triazole antifungals have had a great impact on the management of coccidioidomycosis. Both fluconazole and itraconazole at 400 mg daily have been effective for various forms of coccidioidomycosis, including meningitis, although relapse after therapy is discontinued is a problem. Individuals with suppressed cellular immunity are at increased risk for symptomatic coccidioidomycosis and they include those with HIV infection, those on immunosuppressive medications, and those who have received a solid organ transplant. Pregnant women and African-American men have been identified as two other groups who are at an increased risk for symptomatic and severe infection.

Revision and Return of a Coccidioidal Skin Test Reagent

The revival of a skin test reagent reported by Johnsonet al. [1] provides the potential for renewal of amodality that is useful for evaluation of the immuno-logic response of patients with coccidioidomycosis.Ampel and Hector [2] in a prior commentary pointedout the value of skin testing and in vitro measurementof cellular immunity in coccidioidomycosis.Even before the differing geographic distribution ofthe presumed two species of Coccidioides immitis andCoccidioides posadasii was demonstrated, the reac-tivity to coccidioidin (mycelial) or spherulin derivedfrom the spherule-endospore (S/E) phase was demon-strated across broad geographic areas that were hometo Coccidioides species.While various coccidioidins had been prepared frommycelialphasecultures(reviewedbySmithetal.[ 3]),themost extensive evaluation and practical application wereculture filtrates of Coccidioides grown in the synthetic(non-antigenic) modified asparagine-containing Bureauof Animal Industry medium previously used for tuber-culin. Smith et al. [3] responding to the possible thoughunlikely antigenic differences among strains of Coccid-ioides,culturedmultiplestrainsfromCalifornia,Arizona,Texas and elsewhere. Grown s tatic, the culture-yieldedfiltrates are harvested severa l weeks later, filter sterilizedand preserved with thimerosal 1:10,000 final concentra-tion.Fromexaminationofthecultures,itwasevidentthatautolysis of mycelium had taken place. Later, deliberateautolysisofmyceliaresulted inreleaseofpotentserologicandskintestantigens[4]. HB Levine et al. [5]hadsuccessfully adapted the method and synthetic mediumof John Converse for cultivation of the S/E phase ofCoccidioides. They deliberately allowed the S/E phasecellstoautolyzeinsterilewatertoyieldspherule-derivedcoccidioidin which they termed ‘‘spherulins’’. WhileSmith’scoccidioidinwasderivedfrommultiplestrainsofCoccidioides, Levine et al. [5] prepared spherulin from asingle strain, either strain Silveira, later categorized asC. posadasii,orstrain46,aC. immitis. As laterrecognized for serologic reactivity [6], antigens preparedfrom either species suffice for skin testing regardless ofthe geographic provenance of patients. Moreover, withinthe coccidioidin and spherulinweremorethan20antigenic components, some of which were not commonto both preparations [7]. Coccidioidal skin test antigensdo not affect serologic reactivity as may accompanyhistoplasmin skin tests [8]. Levine et al. [9, 10]inanumber of papers provided evidence that spherulindetected a higher proportion of reactors (was more‘‘sensitive’’) than coccidioidin among various groups ofhumansinendemicareas.However,adissentingreportofGifford and Cantanzaro [11] suggested that there was nosignificant difference in se nsitivity of the two reagentsamong patients with various forms of coccidioidomyco-sis. Anergy tococcidioidalskintestshadbeenconsideredan unfavorable response in patients with coccidioidal

Mannose-Binding Lectin Serum Levels are Low in Persons with Clinically Active Coccidioidomycosis

Mannose-binding lectin (MBL) is a circulating collectin that is part of the innate immune response. We explored the serum levels of MBL in persons with different forms of coccidioidomycosis. Serum MBL was measured by ELISA from samples obtained from healthy donors with immunity to Coccidioides, and those with various forms of active coccidioidomycosis. Blood cell specimens from a subgroup of subjects with active coccidioidomycosis were examined for single nucleotide polymorphisms of the MBL gene and promoter regions. The control group comprised 29 healthy immune subjects. Patient groups with active coccidioidomycosis consisted of 20 patients with symptomatic primary pulmonary coccidioidomycosis, 26 with non-meningeal disseminated coccidioidomycosis, and nine with coccidioidal meningitis. The group with active coccidioidomycosis was significantly older and more likely to be male than the control group (for both, P < 0.001). The mean +/- SEM level of serum MBL in the healthy controls was 169.4 +/- 28.6 ng/ml, significantly higher than the 79.2 +/- 10.9 ng/ml for all active groups (P < 0.001). Moreover, the active coccidioidomycosis group was significantly more likely to have serum MBL level <or=70 ng/ml compared to the control group (P = 0.001). Genetic analysis in 27 subjects with active coccidioidomycosis revealed marked variation based on race and ethnicity. Among a subgroup of 10 white, non-hispanic men with active coccidioidomycosis, there was a significant association between the H and P haplotypes and MBL levels <or=70 ng/ml (P < 0.036 and P < 0.035, respectively). These data suggest that there is an association between low serum MBL levels and symptomatic coccidioidomycosis.

In vitro modulation of proliferation and cytokine production by human peripheral blood mononuclear cells from subjects with various forms of coccidioidomycosis.

Using peripheral blood mononuclear cells (PBMC) from individuals with or without coccidioidal delayed-type hypersensitivity (DTH), we examined and attempted to modulate the in vitro responses of PBMC from various donors to the coccidioidal antigen toluene spherule lysate (TSL). Among healthy DTH-positive donors, 100 ng of human recombinant interleukin-10 (IL-10) per ml suppressed both PBMC proliferation (P = 0.01) and gamma interferon (IFN-gamma) and IL-12 production (for both, P < 0.05). In vitro proliferation and production of IFN-gamma and IL-12 by PBMC were significantly higher in DTH-positive donors with active coccidioidomycosis than in healthy, nonimmune controls (P < 0.05) but not in active DTH-negative donors with or without human immunodeficiency virus infection (for both, P > 0.05). Human recombinant IL-12 increased IFN-gamma production by PBMC from active, DTH-positive donors (P = 0.01) but not by PBMC from DTH-negative groups. For healthy DTH-positive donors, the median antigen-reactive cell frequency per 10(5) PBMC was 3.7, compared to 1.7 in DTH-negative donors with active coccidioidomycosis (P = 0.03). These data indicate that the in vitro TSL response is highly dependent on coccidioidal DTH. Not only do PBMC from individuals with DTH appear to respond to TSL, but their response can be modulated in vitro with either IL-10 or IL-12. On the other hand, PBMC from DTH-negative individuals do not respond in vitro to TSL and their response is not modulable, suggesting a lack of antigen response.

Acute Disseminated Coccidioidomycosis: Two Cases Treated with Amphotericin B

Amphotericin B* has been shown to have marked fungistatic action in vitro against a number of nonpathogenic and pathogenic fungi, including Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatiditis, and Coccidioides immitis. 1-3 Some fungi, such as nocardia and aspergillus, are relatively more resistant to the antibiotic. In vivo, amphotericin has been protective in experimental animals infected with C. albicans, C. neoformans, H. capsulatum, and C. immitis. 2,4-6 In patients with disseminated fungus diseases, amphotericin has been effective in the therapy of histoplasmosis and blastomycosis, 7,8 and patients with cryptococcal meningitis have usually responded to treatment. 8-11 However, the number of patients with the disseminated form of coccidioidomycosis so far treated with amphotericin is relatively small, and the results of therapy have been inconclusive. Aside from difficulties in evaluation due to the variable course of the disease, an apparent lack of response may have been due in some instances to inadequate dosage of amphotericin.