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Coccidioides immitis (and Coccidioides posadasii) are endemic fungi of the southwestern United States and northern Mexico. Uncomplicated, symptomatic Coccidioides infection most commonly causes a self-limited pneumonia; however, immunocompromised patients can manifest severe pneumonia with an additional risk of dissemination to bone, joints, soft tissues, and in the most severe cases, the central nervous system. In 2020, clinicians were challenged with a previously unseen volume of acute respiratory complaints as a result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. We present a patient with respiratory failure secondary to SARS-CoV-2 who experienced prolonged hypoxia and neurologic deterioration, eventually leading to a diagnosis of occult disseminated coccidiomycosis involving meningitis, miliary-pattern pneumonia, and cutaneous lesions.

Background Coccidioides are endemic, dimorphic fungi found in soils of southwestern United States, Mexico and Central America. Infection occurs via inhalation of arthroconidia which swell, differentiate into spherules and rupture releasing endospores. While the majority of infected individuals will never report illness, roughly 1/3 seek medical attention for fungal pneumonia and ~1% of those present with disseminated coccidioidomycosis (DCM). IL12-IFNγ pathway mutations have been reported in DCM but are exceedingly rare and cannot account for the ~500–600 cases of DCM/year. Methods We performed whole exome sequencing on 66 individuals with DCM, retaining variants predicted damaging (CADD >15) with a population frequency < 10%. Results Homozygous CLEC7A c.714T >G; p.Y238* causing a truncated Dectin-1 receptor was overrepresented (OR=9.8449, 95% CI 3.0841 to 31.4260, P=0.0001). Dectin-1 signaling pathway variants included 3 homozygous and 11 heterozygous CLEC7A p.Y238* individuals, one each CLEC7A p.I223S and MALT1 p.R149Q and five PLCG2 p.R268W. Since Dectin-1 is the receptor for b-glucan, a major Coccidioides cell-wall component, we hypothesized that Dectin-1 pathway variants could affect fungal recognition and cellular response. Healthy control PBMCs stimulated with purified β-glucan or heat-killed Candida albicans induced 6-fold more TNFα than patients with homozygous or heterozygous CLEC7A, PLCG2 or MALT1 variants (P=0.0022, Ordinary one-way ANOVA). Additionally, one patient with a family history of DCM but lacking a defined mutation also failed to up-regulate TNFα after stimulation. Normalized TNF production from healthy control and DCM patient’s peripheral blood mononuclear cells Conclusion These data are consonant with increased dissemination in Clec7a-/- mice as well as in patients receiving anti-TNF biologics. These gene variants accounted for 31% of our DCM cohort (21/66 patients). This is the first demonstration of variants outside the IL12-IFNg pathway impairing fungal recognition and cellular response in coccidioidomycosis. Common heterozygous variants may be sufficient for disease susceptibility to highly pathogenic organisms. Disclosures Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)

Background Reported coccidioidomycosis has increased with case rates of 198/100,000 in Arizona (2012). In California alone, 2000–2011 hospitalizations were $2.2B. Dissemination occurs in 8% of reports with significant morbidity and occasional deaths. DCM was found in 3 generations: grandmother (skin), mother (skin), and son (bone). Whole exome sequencing identified a heterozygous (het) STAT4 mutation (p.E626G) in all three. This mutation alters the phosphotyrosine binding pocket and is predicted to impair STAT4 function, interfering with (i) receptor binding and phosphorylation, (ii) nuclear localization, and/or (iii) transcription. Expression profiling of antigen-stimulated peripheral blood mononuclear cells from one patient showed dampening of known STAT4 targets compared with controls. Methods STAT4 p.E626G was generated and confirmed in C57BL/6NJ (WT) mice using CRISPR-Cas9. With continued breeding, neither homozygous (hom) nor het mice had gross abnormalities. There were normal spleen and lung lymphoid cell numbers. Thymus and bone marrow had normal development of lymphoid subsets. We performed intranasal infection with reduced virulence C. posadasii strain 1038 or with F. tularensis live vaccine- strain (LVS). Naïve or Δcps1-vaccinated mice were tested for resistance to C. posadasii strain Silveira. Results At day 21 post Cp 1038 infection, hom, het, and WT mice had similar lung fungal burdens (~104.7 cfu). All p.E626G mice died between days 31 and 39 with lung burden significantly higher (~9 × 106 cfu) than WT sacrificed on day 44 (7 × 105 cfu, P = 0.015). After LVS infection, p.E626G mice had increased lung bacterial cfu and all had dissemination to the spleen compared with WT lung bacterial burden and no splenic dissemination. Immunized het and WT mice all had significantly reduced lung cfu 14 days following C. posadasii infection compared with unvaccinated WT mice. Conclusion The STAT4 p.E626G mutated mouse recapitulated patients’ increased susceptibility to coccidioidal infection. The decreased fungal burdens seen in Δcps1-vaccinated mice suggest that vaccination may be effective in those persons genetically susceptible to DCM. Given the increasing frequency and economic burdens of coccidioidomycosis, pursuit of vaccination strategies should continue. Disclosures All Authors: No reported Disclosures.

Background Sarcoidosis is a granulomatous disease of unknown etiology and coccidioidomycosis is a granulomatous fungal infection endemic to the southwestern United States. Clinical observations on patients with sarcoidosis and coccidioidomycosis simultaneously led to the hypothesis that sarcoidosis can be caused by the fungus Coccidioides. Methods Two patients with sarcoidosis and coccidioidomycosis were studied, one prospectively (ie, a patient with sarcoidosis was predicted to develop coccidioidomycosis) and the other retrospectively (ie, a patient with coccidioidomycosis develops sarcoidosis). In addition, a literature review found 5 patients with these 2 diseases, and they were analyzed to establish an archived relationship between the 2 entities. In addition, polymerase chain reaction (PCR) testing for Coccidioides deoxyribonucleic acid (DNA) was performed on tissue from 15 Arizona patients diagnosed with sarcoidosis. Results Patient 1 was diagnosed with sarcoid in Arizona and followed prospectively. There was no evidence for coccidioidomycosis at diagnosis. This patient was observed for 8 years before he was documented to have disseminated coccidioidomycosis. Patient 2 was retrospectively studied. He was diagnosed with disseminated coccidioidomycosis, but after 3 years, while on antifungal therapy, he developed respiratory failure. A lung biopsy was consistent with sarcoidosis with no evidence of Coccidioides; cultures, histopathology, and serology were all negative. Paradoxically, PCR testing for Coccidioides DNA on tissue taken at the time of the sarcoidosis diagnosis were all negative, including Patient 2 who had proven coccidioidomycosis. Conclusions The 2 study patients and 5 case reports from the literature support the hypothesis that Coccidioides can cause sarcoidosis in Arizona. There are similar reports in the literature that Histoplasma can be associated with sarcoidosis. Based on these observations, we propose that sarcoidosis can be caused by endemic fungi in different areas of the United States, coccidioidomycosis in the Southwest and histoplasmosis in the Midwest.

Background While it has been previously well described that central nervous system (CNS) coccidioidomycosis (CM) is nearly always fatal without treatment, the natural history of non-CNS disseminated coccidioidomycosis (DCM) infections is not well characterized. The historical VA-Armed forces CM patient group provides a unique cohort of patients not treated with standard antifungals to characterize the natural history of non-CNS DCM. Methods We conducted a retrospective study of 595 VA-Armed forces CM patients diagnosed between 1955 and 1958 and followed to 1966. Cohorts were identified as non-disseminated disease (487 patients), non-CNS DCM (72 patients), and CNS DCM (36). A combination of statistical analyses were used to compare demographic information, laboratory data including serologies and complete blood count data, symptom severity, fate of primary infection, and mortality. Results There were significant differences in the ethnicity between the cohorts with trends toward increased Black and Filipino patients in the disseminated cohorts (P < 0.001). There was a trend showing increased frequency of leukocytosis regardless of eosinophilia in the disseminated cohorts (P = 0.009). Patients with disseminated disease presented with more severe symptoms (P = 0.006). Primary fate of infection demonstrated decreased rates of residual pulmonary nodule in DCMs: 38.19% in non-DCM, 13.89% in non-CNS DCM, and 19.44% in CNS DCM (P < 0.001). In addition, there were decreased rates of residual cavities in DCM: 33.26% in non-DCM, 8.33% in non-CNS DCM, and 8.33% in CNS DCM (P < 0.001). Forty-five percent and 53% of patients in the non-CNS DCM and CNS DCM cohorts, respectively, developed dissemination with initial infection. Mortality at last known follow-up due to CM was significantly different across the cohorts: 1.03% in non-DCM, 15.28% in non-CNS DCM, and 77.78% in CNS DCM (P < 0.001). Conclusion This large retrospective cohort study helps further characterize the natural history of non-CNS DCM in comparison to CNS DCM in a population that was not treated with conventional antifungal therapy. While not as fatal as CNS DCM, non-CNS DCM shares many characteristics and has a high associated morbidity. Disclosures All authors: No reported disclosures.

Background Disseminated coccidioidomycosis occurs in Methods A549 cells transfected with MIF promoter/luciferase plasmids of 0 or 8 CATT repeats were stimulated with 50 µg/mL of inactivated C. posadasii spherule lysate, and luciferase expression was measured as relative units (RU) of luminescence. Genomic DNA from patients with disseminated coccidioidomycosis (n = 37) and healthy controls (n = 371) was analyzed for the 794 CATT5-8 microsatellite and the -173 G/C SNP. Cohorts were divided into self-identified African Americans and Caucasians, and allele frequencies were compared using Fisher exact test. Plasma MIF levels were analyzed by enzyme-linked immunosorbant assay using specific antibodies, and levels were compared by T-test. Results Human lung epithelial cells exposed to Coccidioides spherules had significantly higher MIF expression than unexposed cells (3.94 ± 0.44 vs. 3.02 ± 0.24 RU, P = 0.0162). Among Caucasians (n = 26), the high MIF expression −173C containing genotype was present in 50% of the coccidioidomycosis patients vs. 40% of healthy controls (P = 0.396). The -794 CATT7 containing genotype was present in 40% of patients vs. 27% of controls (p = 0.240). Plasma MIF levels were higher in coccidoidomycosis patients with high- vs. low-expression alleles (P = 0.008), but lower in patients vs. controls (P < 0.0001). Conclusion Coccoidioides spherules stimulated MIF expression in human lung epithelial cells supporting the hypothesis that MIF is involved in immunity against this pathogen. In Caucasian subjects, the higher MIF expression genotypes were more common in patients with disseminated coccidioidomycosis when compared with healthy controls, although significance was limited by sample size. This is consistent with high expression MIF alleles associated with other granulomatous diseases, and may reflect destruction of the granuloma with pathogen dissemination. Disclosures All authors: No reported disclosures.

Background Antibody detection is the main method for diagnosis of coccidioidomycosis but has limitations including sensitivity and turnaround time. The MVISTA Coccidioides antigen enzyme immunoassay (EIA) is recommended for testing CSF in suspected Coccidioides meningitis. The early reports on urine and serum antigen testing evaluated small numbers of patients who were mostly immunocompromised with advanced disease. Methods A retrospective study, including all patients in whom Coccidioides antigen testing was performed between January 2013 and May 2017, was conducted at Maricopa Integrated Health System (MIHS). Sensitivity and specificity of antigen testing at MiraVista Diagnostics and antibody testing at MIHS or commercial laboratories were evaluated in 164 cases and 508 controls. Results The sensitivity of antigen testing was 51% and specificity was 99%. The sensitivity of antigen detection was highest if both urine and serum were tested (57%) than if only urine was tested (38%). The sensitivity of antibody testing was 84% and the specificity was 94% by immunodiffusion (ID). The sensitivity and specificity of antigen or ID antibody testing both were 94%. Sensitivity of antigen testing was 57% in proven and 58% in probable cases, ID antibody in 85% of proven and 75% of probable and antigen or ID antibody in 93% of proven and 95% of probable cases. Antigen was detected more often in disseminated (79%) than pulmonary cases (42%) as was ID antibody, 91% and 79%, respectively. Antigen testing was more sensitive in immunocompromised (76%) than non-immunocompromised patients (41%) while ID antibody was less sensitive in immunocompromised (74%) than in non-immunocompromised patients (93%). Combined antigen and ID antibody testing provided the highest sensitivity, 94% in all cases, 94% in immunocompromised and 95% in non-immunocompromised patients. Conclusion These findings support testing urine and serum for Coccidioides antigen and serum for ID antibodies for diagnosis of progressive pulmonary or disseminated coccidioidomycosis. Disclosures All authors: No reported disclosures.

Background There are limited prospective data available to guide the management of severe coccidioidomycosis. In particular, the treatment of disseminated coccidioidomycosis often requires extended courses of antifungal therapy, for which there are often intolerable side-effects, toxicities, and failures. In recent years, newer oral triazole antifungals with in vitro activity against Coccidioides have become available, but data are lacking on their efficacy in coccidioidomycosis. Isavuconazole lacks many of the toxicities of older triazole antifungals, such as QT prolongation and certain key drug interactions, making it an appealing option in selected patients. Methods Based on pharmacy prescription history at two federal facilities in southern California, we identified adult patients with coccidioidomycosis who received isavuconazole from 2017 to 2019. Patient records were reviewed to identify age, sex, ethnicity, sites of infection, prior antifungal therapy, indication for switch to isavuconazole, duration of follow-up, and outcomes. Results 12 patients were identified between the ages of 36 and 86 years; 3 were women. 6 were of Pacific Islander descent, 4 were African American, 1 European-American, and 1 Latino. 6 (50%) had significant pre-infection comorbidities. 8 (67%) had evidence of extrapulmonary dissemination, including 1 patient with meningitis. All but one had received prior treatment with other azoles; two had previously been treated with amphotericin B. Six (50%) were switched to isavuconazole due failure or progression of disease on prior therapy; 3 (25%) due to drug toxicity; and 2 (17%) due to drug interactions. Seven (58%) patients improved on isavuconazole; 4/12 (33%) were stable; one developed hepatotoxicity but improved on posaconazole, and one patient deteriorated. Conclusion Isavuconazole appears to be a promising agent for the treatment of coccidioidomycosis. Long-term follow-up will be required to assess the risks of toxicity, disease progression, or relapse. For patients who are clinically stable but with an extensive disease burden or toxicity from older agents, isavuconazole may present an amphotericin-sparing option. Disclosures All authors: No reported disclosures.

We present a case of donor-derived coccidioidomycosis in a cardiac transplant patient and review previous cases of donor-derived coccidioidomycosis in solid organ transplant. Donor-derived coccidioidomycosis is rare, can be difficult to diagnose and has significant mortality., Background. Endocarditis is a rare manifestation of infection with Coccidioides. This is the first reported case of donor-derived Coccidioides endocarditis obtained from a heart transplant. Methods. We present a unique case of donor-derived Coccidioides immitis endocarditis and disseminated infection in a heart transplant patient. We also conducted a review of the literature to identify other cases of donor-derived coccidioidomycosis in solid organ transplant recipients and reviewed their clinical characteristics. Results. Fifteen prior cases of donor-derived coccidioidomycosis were identified. A majority of these cases were diagnosed by positive culture (83%). Mortality was high at 58%. Conclusions. Clinicians should maintain a high index of suspicion for disseminated coccidioidomycosis in patients who received transplants with organs from donors with a history of residing in endemic regions.

Background The number of patients with coccidioidomycosis continues to increase yearly. Patients with CNS disease require lifelong antifungal therapy due to the high morbidity and mortality of this disease. However, the morbidity and mortality in non-CNS disseminated disease has not been well characterized. Methods We conducted a retrospective study of 373 VA-armed forces coccidioidomycosis patients diagnosed between 1955 and 1958 and followed to 1966. Groups were identified as non-disseminated disease, non-CNS disseminated disease with and without multisite dissemination, and disseminated disease to the CNS with and without multisite dissemination. Clinical variables including demographic information, duration and severity of symptoms, coccidioidal serologies, type of infection and complications, time to disseminated disease, and mortality were abstracted from patient charts. Results Mortality attributed to coccidioidomycosis in the non-disseminated group was 0.3% (1/297) compared with the non-CNS disseminated group of 8.5% (4/47, median survival 12 months, range 12–24 months, P = 0.0002). Mortality in the CNS disseminated group was 86% (19/22, median survival of 12 months, range 12–156 months, P < 0.0001 compared with non-CNS disseminated). The single site non-CNS disseminated group had a mortality of 4.1% (1/24, survival of 12months) compared with the multiple site non-CNS disseminated group of 13% (3/23, median survival of 18 months, range of 12–24 months, P = 0.57). Conclusion This retrospective cohort study demonstrates significant mortality differences between different forms of disseminated coccidioidomycosis. CNS dissemination exhibited the highest mortality rate; however, non-CNS dissemination also exhibited an unacceptably high mortality rate. There was no significant difference in mortality between single site non-CNS disseminated disease and multiple site non-CNS disseminated disease. Disclosures All authors: No reported disclosures.

Background The burden of coccidioidomycosis in central California is significant among children. Yet, the literature on such infection is limited, particularly on disseminated coccidioidomycosis (DC) in children. Objectives Review the natural history, treatment and outcomes of DC in a tertiary children’s hospital. Methods Retrospective review of patients ≤21 years old with DC seen at our facility during 1/1/07–12/31/16. Results Eighty cases were identified. Median age was 8.5 years (IQR 4.3–14.6); majority was hispanic (66%) and without comorbid conditions (85%). Pulmonary disease with other organ involvement occurred in 69%; 19% had meningitis. Overall, 82% had resolved and/or stable disease (RS), whereas 14% experienced relapse and/or progressive disease (RP). Meningitis more commonly seen in older age group (14.3 vs. 6.9 years, P = 0.04) and had low eosinophil’s (0.8 vs. 2.1%, P < 0.01). More organ involvement (64% vs. 35%, P = 0.03) and RP disease (22% vs. 5%, P = 0.04) commonly seen in children 10 years or older. Non-Hispanics also found to be older than Hispanics (12.2 vs. 7.4 years, P < .01); received multiple drug therapy (48% vs. 18%, P = 0.02). Although not significant, Non-Hispanics were more likely to have meningitis (30% vs. 13%, P = 0.07), coccidioidal complement fixation (CF) titers ≥ 32 (92% vs. 73%, P = 0.07), and RP disease (24% vs. 7%, P = 0.06) than Hispanics. No significant association was found between gender and age, CF titers, and/or outcomes. Higher CF titers were seen with >1 organ involvement (1:256 vs. 1;64, P < 0.01) and more antifungal therapy (1:256 vs. 1:32, P < 0.01). Coccidioides EIA antibody was positive in 50% of cases and 48% with negative/indeterminate results were positive by Immunodiffusion. On multivariate analysis, age remained independently associated with RP (OR = 1.2, 95% CI 1.0–1.5, P = 0.02); age (OR = 1.1, 95% CI 1.0–1.3, P = 0.01) and more antifungal therapy (OR = 3.7, 95% CI 1.4–9.5, P < 0.01) with non-Hispanics. Conclusion To our knowledge this is the largest series for pediatric DC. We identify older age group, non-Hispanics and higher CF titers as potential risk factors for DC, which require early intervention. Prospective studies are needed to identify predictors for adverse outcomes in pediatric DC. Disclosures All authors: No reported disclosures.