Coccidioides Immitis Research Articles

Donor Derived Coccidioides in a Lung Transplant Recipient

<h3>Introduction</h3> There are no universal guidelines on screening donors for coccidioides. We describe a fatal case of coccidioides empyema from a donor previously residing in an endemic region. <h3>Case Report</h3> This is a 72 year old male, status post right single lung transplantation 3 weeks prior for chronic hypersensitivity pneumonitis, who presents to clinic with a productive cough. The donor was a 31 year old male with no medical history from the southern inland region of California. A chest X-ray in clinic demonstrated a right pleural effusion. He underwent thoracentesis and bronchoscopy on post-operative day (POD) 22. Pleural fluid was lymphocytic and exudative with negative cultures, and transbronchial biopsies showed mild acute cellular rejection. He was treated with pulse dose steroids. His symptoms worsened one week later when he was seen in the emergency department. Chest CT showed a large right loculated pleural effusion. The patient was started on broad spectrum antibiotics, and a thoracostomy tube was placed, demonstrating a neutrophil predominant exudate. Repeat chest CT showed the effusion extending through the chest wall, and an additional thoracostomy tube was placed. The patient became more hypoxemic requiring mechanical ventilation and VV-ECMO. Pleural cultures taken two-days prior demonstrated mold and the patient underwent irrigation with amphotericin in the operating room, along with intravenous amphotericin. Ultimately, the patient had multi-organ failure and cardiac arrest. Following his passing, pleural fluid cultures confirmed growth of Coccidioides immitis. <h3>Summary</h3> This case describes a patient with initial negative serologies to coccidioides and a donor from the southern inland region of California, where the incidence of coccidioides is increasing. Transmission of donor-derived coccidioides has been shown to be 43% within 30 days post-transplant, with a 29% mortality. Given the high mortality and treatment availability, screening donors in endemic areas with serologies may prevent post-transplant complications.

Skeletal Infections Caused by Coccidioides Species.

Background: Coccidioidomycosis represents an endemic and challenging disease, with rare extrapulmonary manifestations. The present review of all published cases of core and extremities osseous coccidioidomycosis aims to describe epidemiology, patients’ characteristics, symptoms as well as medical and surgical treatment options and their effectiveness. Methods: A thorough review of all published skeletal core and extremity infections due to Coccidioides species was conducted. Information regarding demographics, causative fungus, antifungal treatment (AFT), surgical management as well as the infection outcome was recorded. Results: A total of 92 cases of Coccidioides spp. skeletal infections were recorded in 87 patients. The patients’ mean age was 35.3 years. The most common site of infection was the spine (82.6%), followed by the foot (6.5%), while the predominant symptom upon presentation was pain (29.9%). Immunosuppressive conditions and/or medications were observed in 21 patients (24.1%). Regarding imaging methods, indicating diagnosis, plain X-rays or CT scans were performed in most patients (50.6%), followed by magnetic resonance imaging (MRI) (47.1%). Most cases were diagnosed through histopathology (62; 71.3%), followed by serology testing (36; 42.4%) and by cultures (35; 40.2%). In 32 cases (36.8%), Coccidioides immitis was cultured, while in the remaining 55 cases (63.2%) the fungus was not further characterized. Regarding AFT, amphotericin B was the preferred agent (52.9%), followed by fluconazole (43.3%). In most cases (78.2%) surgical treatment was also performed. Treatment was successful in 80.5% of cases. Conclusions: Skeletal core and extremity infections due to Coccidioides spp. represent a severe disease. With the available data, the combination of prolonged proper AFT with surgical intervention seems to be the optimal current therapeutic approach.

A chromosomal-level reference genome of the widely utilized Coccidioides posadasii laboratory strain "Silveira".

Coccidioidomycosis is a common fungal disease that is endemic to arid and semi-arid regions of both American continents. Coccidioides immitis and Coccidioides posadasii are the etiological agents of the disease, also known as Valley Fever. For several decades, the C. posadasii strain Silveira has been used widely in vaccine studies, is the source strain for production of diagnostic antigens, and is a widely used experimental strain for functional studies. In 2009, the genome was sequenced using Sanger sequencing technology, and a draft assembly and annotation were made available. In this study, the genome of the Silveira strain was sequenced using single molecule real-time sequencing PacBio technology, assembled into chromosomal-level contigs, genotyped, and the genome was reannotated using sophisticated and curated in silico tools. This high-quality genome sequencing effort has improved our understanding of chromosomal structure, gene set annotation, and lays the groundwork for identification of structural variants (e.g. transversions, translocations, and copy number variants), assessment of gene gain and loss, and comparison of transposable elements in future phylogenetic and population genomics studies.

Disseminated Coccidioidomycosis: Cutaneous, Soft Tissue, Osseous, and "Shotgun Intraparenchymal" Brain Disease.

Coccidioidomycosis is a disease found in the southwestern United States and caused by inhalation of arthroconidia of Coccidioides immitis and posadasii. Although the disease is most commonly asymptomatic or respiratory, it has a propensity to disseminate to any tissue in the body with the most common being skin, bone, joints, and central nervous system. This case demonstrates the dissemination of coccidioidomycosis to several foci along with a rare form of parenchymal dissemination with an unusual neuroradiological finding.

263. Antibody Spill-Over vs. True Coccidioidal Meningitis in a Patient with HIV/AIDS and Disseminated Coccidioidomycosis

Abstract Background The diagnosis of coccidioidal meningitis merits life-long antifungal therapy given high rates of disease recurrence. Accurate diagnosis is important. Antibody spill-over into cerebrospinal fluid (CSF) can happen when serum titers are high. We present a case of antibody spill-over vs. true fluconazole-resistant coccidioidal meningitis. Methods A 49-year-old man presented with 6 months of intermittent fever, myalgias, decreased appetite, vomiting, diarrhea, unsteadiness and 60-pound weight loss. He was recently diagnosed with HIV and a prior lymph node biopsy had grown Coccidioides immitis (C. i) for which he was given fluconazole 100 mg twice daily. Figure 1. Timeline of Coccidioides immitis lab results in relation to treatment regimen. CF: Complement fixation, EIA: Enzyme immunoassay for Coccidioides antigen, CSF: Cerebrospinal fluid, c/mL: copies/mL, R: resistant, S: susceptible. Results Vitals revealed a temperature of 102°F. He was cachectic and a 0.5 cm right supraclavicular lymph node was palpable. No meningeal signs were appreciated. CD4 count was 50/µL (18%), HIV-1 viral load 2,969,945 copies/mL. Computed tomography (CT) of the abdomen/pelvis suggested lung and spleen involvement. Serum C. i enzyme immunoassay (EIA) was 1.38 ng/mL, immunodiffusion (ID) was positive and complement fixation (CF) titer was 1:256. C. i was isolated from expectorated sputum. CSF cell count was normal, but ID was positive and CF titer was 1:2 however, lab reported concern for spill-over due to high serum IgG titers. He left against medical advice with fluconazole 400 mg daily. He was hospitalized a month later for failure to thrive. MRI head revealed enlarged lateral and third ventricles with increased periventricular hyperintensity concerning for coccidioidal meningitis. Repeat serum studies were stable. CSF revealed CF 1:4 and C. i antigen by EIA 1.31ng/mL, distinguishing between spill-over and meningitis. Susceptibility results showed resistance to fluconazole and amphotericin B with minimum inhibitory concentrations (MICs) of 50 and 4 respectively, posaconazole susceptibility (MIC &amp;lt; 1) and itraconazole borderline (MIC 3.7). Despite amphotericin B resistance, it was used for bridge to posaconazole. ART was initiated after concern for immune reconstitution had resolved. Conclusion This case highlights the difficulty in making an accurate diagnosis of coccidioidal meningitis. It also describes a fluconazole-resistant C. i isolate in the setting of prolonged low-dose fluconazole therapy. Disclosures All Authors: No reported disclosures

DELAYED DIAGNOSIS OF COCCIDIODES IMMITIS INFECTION WITH PULMONARY ABSCESS AND ARDS DIAGNOSED IN CHICAGO

TOPIC: Chest Infections TYPE: Fellow Case Reports INTRODUCTION: Coccidiodes immitis is a highly pathogenic fungus that is found in western and southern California's desert's regions. It frequently presents as a pneumonia that does not get better after anti-biotic therapy. With less than 5% of immunocompetent patient's progressing to have disseminated or severe infections (1). A disseminated Coccididiodes infection can be treated with liposomal amphotericin B, fluconazole, and steroids when there is Acute Respiratory Distress Syndrome (ARDS) (1,2). CASE PRESENTATION: In this case, a relatively healthy 80-year-old male with a past medical history of gastroesophageal reflux disease, hypertension, and hyperlipidemia who comes in shortness of breath, cough, and congestion. He had completed a course of azithromycin without resolution of symptoms. His initial chest x-ray showed a right upper lobe consolidation (Figure 1a). Bronchoscopy with transbronchial biopsies was performed which showed an acute organizing pneumonia (Figure 2). Despite antibiotic therapy and steroids, the patient did not have significant clinical improvement. So liposomal amphotericin B was started. An open lung biopsy was performed on day 14 as his chest X-ray was significantly worse with significant hypoxia (Figure 1b). Open lung biopsy showed a large abscess. A chest tube was placed. The abscess was irrigated with saline containing antibiotics. Pathology reported numerous coccidiodes spores (Figure 3). Antibiotics were discontinued. The patient's hospital course was complicated by a persistent air leak post lung biopsy and ARDS. Adjunctive steroids were added with improvement of his hypoxia. The patient was transitioned to a lower dose of steroids and to high dose fluconazole for long term treatment of his Coccidiodes infection. He was stable for placement of a tracheostomy and discharged to a long term acute care hospital (LTACH) for further care. His chest x-ray showed significant fibrosis (Figure 1c). DISCUSSION: When we re-examined the patient's history, he had a short trip to the southwestern United states for a total of 10 days with his family. This is the source of the patient's exposure. A thorough history may have helped, but urine Coccidiodes antigen testing was negative even after the open lung biopsy was performed. Despite clinical improvement, the patient passed 6 weeks after discharge to long term acute care hospital. CONCLUSIONS: Severe Coccoidiodes pulmonary infections can progress to ARDS. While, it is responsive to liposomal amphotericin B and steroids, it is still associated with a high morbidity and mortality (2). A high index of suspicion for a fungal infection should be maintained in patient's who have pneumonia refractory to antibiotic therapy. Speaking directly with the pathologist will also aide in the diagnosis of fungal infections non-endemic to the area especially like in this case (3). REFERENCE #1: Kirkland TN, Fierer J. Coccidioides immitis and posadasii; A review of their biology, genomics, pathogenesis, and host immunity. Virulence. 2018;9(1):1426-1435. doi:10.1080/21505594.2018.1509667 REFERENCE #2: Shibli M, Ghassibi J, Hajal R, O'Sullivan M. Adjunctive corticosteroids therapy in acute respiratory distress syndrome owing to disseminated coccidioidomycosis. Crit Care Med. 2002 Aug;30(8):1896-8. doi: 10.1097/00003246-200208000-00037. PMID: 12163812. REFERENCE #3: Pitcher JH, Zuckerman JB. Coccidioides Immitis Infection with Involvement of the Airway. Conn Med. 2016 Oct;80(9):539-541. PMID: 29772139 DISCLOSURES: No relevant relationships by Justin Ching, source=Web Response

REACTIVATION OF PULMONARY COCCIDIOIDES IN THE SETTING OF COVID-19 INFECTION

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Clinical course and management of severe acute respiratory syndrome COVID-2 (Covid-19) infection has been full of uncertainties. As a viral respiratory illness, its presentation can be very similar to other respiratory diseases. Therefore, it is essential to have a high degree of suspicion for superimposed bacterial and fungal infections. CASE PRESENTATION: A 65-year-old male with insulin-dependent diabetes mellitus presented to the emergency department with fever, sudden shortness of breath, cough, and diffuse chest discomfort. Upon arrival his blood pressure was 155/76 mmhg, heart rate 91 bpm, respiratory rate of 22, with temperature of 101.9 F. The patient's Covid-19 PCR nasopharyngeal swab resulted positive. Imaging showed moderate to severe bilateral lung ground-glass infiltrates and consolidation pattern and a 1.9 cm, left upper lobe cavitary lesion. No prior imaging was available for review. Patient was treated with supplemental oxygen, antibiotic therapy for community acquired pneumonia, Remdicivir, and convalescent plasma therapy. Given low suspicion for active TB, steroid therapy was continued. Patient's QuantiFERON gold resulted positive, and he was found to have positive coccidioides IgG, but the complement fixation titer was negative on the day of admission. Three AFB samples, serum (1-3)-beta-D-Glucan assay and Aspergillus assay resulted negative. Bronchoalveolar lavage was performed. Serum coccidioides antibody complement fixation and immunodiffusion results were made available after the patient's passing, which showed positive for IgG and IgM with titers 1:256. Bronchoalveolar lavage cultures revealed Coccidioides Posadasii and Immitis. DISCUSSION: Coccidioidomycosis, commonly known as valley fever, is caused by dimorphic fungi of the Coccidioides family, which is endemic to California, south-central Washington, and northern Mexico. Pulmonary Coccidioides has a similar clinical presentation to Covid-19 infection and seldom, associated with cavitary lesions. Fever, cough, and shortness of breath are the most common presenting symptoms. Radiographic findings vary with COVID -19 showing bilateral peripheral ground glass opacifications with or without consolidations. Among the bacterial co-infections, streptococcus pneumoniae is the most common followed by Klebsiella pneumoniae and Haemophilus influenzae. Due to lengthy wait periods for many laboratory studies to be resulted, it is challenging to distinguish co-infection cases. Reactivation of coccidiodes has been seen in patients with HIV, and patients on chemo and immunotherapy despite antifungal prophylaxes. CONCLUSIONS: Given nonspecific radiological findings of Covid-19 infection that are seen with other causes of pneumonia and its uncertain and similar clinical course to other respiratory infections, it is crucial to have a high degree of suspicion for superimposed bacterial and fungal infections. REFERENCE #1: Freedman M, Jackson BR, McCotter O, Benedict K. Coccidioidomycosis Outbreaks, United States and Worldwide, 1940-2015. Emerg Infect Dis. 2018;24(3):417-423. doi:10.3201/eid2403.170623 REFERENCE #2: Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin Infect Dis. 2016;63(6):e112-e146. doi:10.1093/cid/ciw360 REFERENCE #3: Zhu X, Ge Y, Wu T, et al. Co-infection with respiratory pathogens among COVID-2019 cases. Virus Res. 2020;285:198005. doi:10.1016/j.virusres.2020.198005 DISCLOSURES: No relevant relationships by Nami Moradi, source=Web Response No relevant relationships by Paloma Rivero-Moragrega, source=Web Response

Multifocal Coccidioides immitis in a donkey (Equus asinus)

SummaryThis case report discusses the clinical signs, diagnostic findings, treatment and outcome for a donkey (Equus asinus) diagnosed with coccidioidomycosis. At presentation, the donkey was lame, was in poor body condition, had a draining tract over the left femur and was hyporexic. Further investigation of the draining tract via radiography and ultrasonography showed a focal lesion of extensive bony proliferation and lysis on the mid‐shaft of the left femur. There was also a soft tissue swelling over the fifth left rib. AGID titres were positive for Coccidioides immitis. Recommended treatment for C. immitis consists of two antifungal classes, the azoles and amphotericin B, with this donkey being prescribed daily fluconazole. A recheck 3 months from initial diagnosis showed marked improvement of clinical signs, but the C. immitis titre remained unchanged. The 18‐month recheck showed improvement radiographically and significantly decreased titres. After 3 years of daily treatment of fluconazole, the C. immitis titre was decreased, but radiographs of the femur still showed persistent bony proliferation.

A REVIEW OF FUNGAL INFECTIONS OF ORAL CAVITY AND ITS EMERGING TRENDS

Oral commensal ora consists of a wide range of micro-organisms that include eubacteria, archaea, fungi, mycoplasmas and protozoa. From oral commensals, fungi are classied as eukaryotes. Fungal species that are present as commensal inhabitants in the oral cavity but can lead to a very serious infection with broadcast to various parts of body in patients with immune-suppressed state and therefore are referred to as opportunistic pathogenic fungi . Mucor and Cryptococcus too are etiological agents of signicant number of oral infections. Clinical presentations of the fungal infections vary from pseudo-membranes, purulent swellings, erosive lesions, pustules to widespread destruction due to necrosis that may extend upto bone.(1,2) Despite advances in treatment modalities, the frequency of deaths associated with invasive candidiasis remains high and is about one-third to one-half of affected patients. (3) The candida species, adhere utilizing both specic and nonspecic mechanisms including dimorphism with direct tissue invasion &amp; extra-cellular enzymes. (7) Oral supercial candidiasis may occur in various clinical forms. Also, besides candida, the fungi that can cause deep-seated fungal infections in humans are : Aspergillus fumigatus, Cryptococcus neoformans, Histosplasma capsulatum, Blastomyces dermatitidis, Zygomycetes class, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei, Sporotrix schenckii and Geotrichum candidum. Detection of invasive fungal disease cannot be done from isolation and identication of fungal DNA alone. At present, treatment of candidiasis, of any type, relies only on a limited arsenal of antifungal agents. (2, 7)

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing.

Coccidioides immitis and C. posadasii are dimorphic fungi that transform from mycelia with internal arthroconidia in the soil to a tissue form known as a spherule in mammals. This process can be recapitulated in vitro by increasing the temperature, CO2 and changing other culture conditions. In this study, we have analyzed changes in gene expression in mycelia and young and mature spherules. Genes that were highly upregulated in young spherules include a spherule surface protein and iron and copper membrane transporters. Genes that are unique to Coccidioides spp. are also overrepresented in this group, suggesting that they may be important for spherule differentiation. Enriched GO terms in young spherule upregulated genes include oxidation-reduction, response to stress and membrane proteins. Downregulated genes are enriched for transcription factors, especially helix–loop–helix and C2H2 type zinc finger domain-containing proteins, which is consistent with the dramatic change in transcriptional profile. Almost all genes that are upregulated in young spherules remain upregulated in mature spherules, but a small number of genes are differentially expressed in those two stages of spherule development. Mature spherules express more Hsp31 and amylase and less tyrosinase than young spherules. Some expression of transposons was detected and most of the differentially expressed transposons were upregulated in spherules.

Hypercalcemia in Disseminated Coccidioidomycosis

Abstract Introduction: Hypercalcemia is associated with various granulomatous diseases, most commonly sarcoidosis and tuberculosis, less frequently fungal disease. We present a rare case of hypercalcemia associated with disseminated coccidioidomycosis. Clinical Case: A 44-year-old man with ESRD s/p DDRT on immunosuppression presented with fever and cough. His physical exam was significant for tender scattered cutaneous nodules. His labs revealed non-PTH mediated hypercalcemia: calcium 12 mg/dL (normal 8.5–10.1 mg/dL), albumin 2.2 g/dL (normal 3.6–5.1 g/dL) and PTH 41 pg/mL (normal 14–72 pg/mL). Further hypercalcemia work-up was unremarkable: PTHrP 16 pg/mL (normal 14–27 pg/mL); 25-hydroxyvitamin D 33 ng/mL (normal 30–100 ng/mL); 1,25-hydroxyvitamin D 62 pg/mL (normal 20–79 pg/mL); serum electrophoresis was indeterminate; and immunofixation did not detect monoclonal proteins. His highest calcium level was 12.8 mg/dL with albumin 1.9 g/dL. He underwent additional tests that explained his presentation: sputum culture grew Coccidioides immitis; CT scan showed miliary pulmonary nodules, and bilateral deep cervical and mediastinal lymph node enlargement; lumbar puncture revealed elevated protein and cell counts; and a biopsy of a nodule on his thigh revealed Coccidioides immitis. He was treated with amphotericin for disseminated coccidioidomycosis with pulmonary, cutaneous and possible CSF involvement. He received IV fluids, furosemide and pamidronate for treatment of hypercalcemia. Based on his presentation, evaluation and complete resolution without recurrence of hypercalcemia after treatment of disseminated coccidioidomycosis, the most likely cause of hypercalcemia was disseminated coccidioidomycosis. Hypercalcemia is associated with various granulomatous diseases. It is a rare complication of disseminated coccidioidomycosis that is important to recognize as Coccidioides is endemic in the United States. The pathology of the disease is pyogenic granuloma. In contrast to sarcoidosis, our case and previous case studies of hypercalcemia in coccidioidomycosis did not show an elevation of 1,25 dihydroxyvitamin D. Various potential inducers have been implicated including PTHrP, lipopolysaccharide, prostaglandin E, interleukin 1 and transforming growth factor β. It has been demonstrated that granulomas produce PTHrP; however, not all patients with granulomas develop hypercalcemia. One theory is that hypercalcemia may be a sequelae in cases with a greater number and extent of lesions making PTHrP as seen in disseminated disease. Conclusion: Hypercalcemia is a rare complication of disseminated coccidioidomycosis that is important to recognize as coccidioidomycosis is endemic in the United States. The mechanism of hypercalcemia is poorly understood; in contrast to other granulomatous disease, it appears to be unrelated to 1,25-hydroxyvitamin D.

Lung microbiome influences Coccidioides colonization and invasiveness

Abstract It has long been thought that the lung is a sterile environment; however, recent studies revealed that healthy lungs are colonized by bacteria, fungi, and viruses. Coccidioidomycosis, also known as Valley fever, is a lung infection caused by the fungal species Coccidioides. Because of poor testing strategies 60–80% of patients are treated with antibiotics prior to accurate diagnosis of coccidioidomycosis. This potentially depletes bacteria with symbiotic relationships within the lung microenvironment and promotes susceptibility to invasion by Coccidioides. Coccidioides immitis is a dimorphic fungal pathogens whose fungal life cycle alternates between the saprophytic phase (soil mycelia) and parasitic phase (tissue infecting spherules). Natural microbial antagonists that inhibit soil Coccidioides immitis have been identified; Bacillus subtilis displays antifungal activity against Coccidioides growth through a clear zone of inhibition between fungi and bacteria. Whether these findings hold true in the host phase of the Coccidioides life cycle is unknown but have major implications for patient treatment. Our preliminary data suggest that host microbiome inhibits Coccidioides growth, and antibiotic treatment shifts or depletes the lung microbiome allowing a niche for Coccidioides growth. We are also exploring how this interface between the lung, Coccidioides, and the microbiome influences host innate and adaptive immune responses. Furthermore, these findings could shape the way physicians assess prescription of antibiotics prior to fungal diagnosis.

Mitochondrial genomes of the human pathogens Coccidioides immitis and Coccidioides posadasii.

Fungal mitochondrial genomes encode genes involved in crucial cellular processes, such as oxidative phosphorylation and mitochondrial translation, and the molecule has been used as a molecular marker for population genetics studies. Coccidioides immitis and C. posadasii are endemic fungal pathogens that cause coccidioidomycosis in arid regions across both American continents. To date, approximately 150 Coccidioides isolates have been sequenced to infer patterns of variation in nuclear genomes. However, less attention has been given to the mitochondrial genomes of Coccidioides. In this report, we describe the assembly and annotation of mitochondrial reference genomes for two representative strains of C. posadasii and C. immitis, as well as assess population variation among 77 selected genomes. The sizes of the circular-mapping molecules are 68.2 Kb in C. immitis and 75.1 Kb in C. posadasii. We identify 14 mitochondrial protein-coding genes common to most fungal mitochondria, which are largely syntenic across different populations and species of Coccidioides. Both Coccidioides species are characterized by a large number of group I and II introns, harboring twice the number of elements as compared to closely related Onygenales. The introns contain complete or truncated ORFs with high similarity to homing endonucleases of the LAGLIDADG and GIY-YIG families. Phylogenetic comparisons of mitochondrial and nuclear genomes show extensive phylogenetic discordance suggesting that the evolution of the two types of genetic material is not identical. This work represents the first assessment of mitochondrial genomes among isolates of both species of Coccidioides, and provides a foundation for future functional work.

Activity and substrate specificity of Candida, Aspergillus, and Coccidioides Tpt1: essential tRNA splicing enzymes and potential anti-fungal targets.

The enzyme Tpt1 is an essential agent of fungal tRNA splicing that removes an internal RNA 2′-PO4 generated by fungal tRNA ligase. Tpt1 performs a two-step reaction in which: (i) the 2′-PO4 attacks NAD+ to form an RNA-2′-phospho-(ADP-ribose) intermediate; and (ii) transesterification of the ADP-ribose O2″ to the RNA 2′-phosphodiester yields 2′-OH RNA and ADP-ribose-1″,2″-cyclic phosphate. Because Tpt1 does not participate in metazoan tRNA splicing, and Tpt1 knockout has no apparent impact on mammalian physiology, Tpt1 is considered a potential antifungal drug target. Here we characterize Tpt1 enzymes from four human fungal pathogens: Coccidioides immitis, the agent of Valley Fever; Aspergillus fumigatus and Candida albicans, which cause invasive, often fatal, infections in immunocompromised hosts; and Candida auris, an emerging pathogen that is resistant to current therapies. All four pathogen Tpt1s were active in vivo in complementing a lethal Saccharomyces cerevisiae tpt1Δ mutation and in vitro in NAD+-dependent conversion of a 2′-PO4 to a 2′-OH. The fungal Tpt1s utilized nicotinamide hypoxanthine dinucleotide as a substrate in lieu of NAD+, albeit with much lower affinity, whereas nicotinic acid adenine dinucleotide was ineffective. Fungal Tpt1s efficiently removed an internal ribonucleotide 2′-phosphate from an otherwise all-DNA substrate. Replacement of an RNA ribose-2′-PO4 nucleotide with arabinose-2′-PO4 diminished enzyme specific activity by ≥2000-fold and selectively slowed step 2 of the reaction pathway, resulting in transient accumulation of an ara-2′-phospho-ADP-ribosylated intermediate. Our results implicate the 2′-PO4 ribonucleotide as the principal determinant of fungal Tpt1 nucleic acid substrate specificity.

Actual problems of mycoses caused by dimorphic pathogens

The literature review focuses on actual problems of the particularly dangerous mycoses – coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis. The review presents modern data on the global spread of these fungal infections. Planetary climate changes widen the endemic areas of particularly dangerous mycoses by increase of the inhalational exposure of soil after dust storms, earthquakes and floodings. The prevaling view on the life cycle of agents of coccidioidomycosis (Coccidioides immitis, C.posadasii) is that these fungi dwell in soil (are saprobes) and so for them human and small-mammal fauna are only accidental hosts. The new alternative hypothesis implies that tissue form (spherule) of Coccidioides spp. lives in host granulomas of small mammals and transforms into spore producing hyphae when the animal host dies. It is demonstrated that Histoplasma capsulatum contains at least four different cryptic species, that differ genetically and express different virulence. Recently, discoveries of novel dimorphic systemic fungal pathogens have challenged the current taxonomy of family Ajellomycetacae. The new genus Emergomyces including five species is described. Another dimorphic pathogen is discovered and named Blastomyces percursus. These fungi cause disseminated mycoses globally, primarily in HIVinfected patients.

14329 Primary cutaneous coccidioidomycosis mimicking foliculitis: Case report

Coccidioidomycosis is the oldest of the major systemic mycoses disease, itś caused by the dimorphic fungus Coccidioides immitis and Coccidioides posadasii, ocurring mainly in semi desert areas. Up to 98% of all clinical presentations correspods to the primary pulmonary coccidioidomycosis, the remaining 2% corresponds to the primary cutaneous form. Clinically causes nodules sometimes with ulceration and in some other cases presenting verrucosum injuries, occurring 15-20 days after traumatic inoculation.

Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections.

Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant Candida and azole-resistant Aspergillus. Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as Scedosporium, Lomentospora prolificans, and Fusarium with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to C. albicans, C. glabrata, C. auris, C. tropicalis, Coccidioides immitis, and F. solani as well as pulmonary infection models of A. fumigatus, A. flavus, S. prolificans, S. apiospermum and Rhizopus arrhizus. Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix.

Anticipatory Stress Responses and Immune Evasion in Fungal Pathogens.

In certain niches, microbes encounter environmental challenges that are temporally linked. In such cases, microbial fitness is enhanced by the evolution of anticipatory responses where the initial challenge simultaneously activates pre-emptive protection against the second impending challenge. The accumulation of anticipatory responses in domesticated yeasts, which have been termed 'adaptive prediction', has led to the emergence of 'core stress responses' that provide stress cross-protection. Protective anticipatory responses also seem to be common in fungal pathogens of humans. These responses reflect the selective pressures that these fungi have faced relatively recently in their evolutionary history. Consequently, some pathogens have evolved 'core environmental responses' which exploit host signals to trigger immune evasion strategies that protect them against imminent immune attack.

TRAVEL-ASSOCIATED COCCIDIOIDOMYCOSIS WITH ENDOTRACHEAL INVOLVEMENT: A CASE REPORT

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Coccidioidomycosis is a fungal infection caused by dimorphic fungi which is endemic to the Southwestern parts of America. However, it can be imported to non-endemic areas due to travel for business or pleasure. Involvement of airways including endotracheal and endobronchial lesion is rare and can present with a wide array of symptoms ranging from cough to airway obstruction1. We present a case of non-endemic coccidioidomycosis with rare endotracheal involvement. CASE PRESENTATION: Our patient is a 53-year-old male who presented with complaints of having productive cough, fever, and shortness of breath for past few weeks. Patient was recently treated with azithromycin and oral steroids in outpatient settings with no improvement in symptoms. Chest x-ray (CXR) on presentation was suggestive of consolidation in the right middle lobe. Patient was started on ceftriaxone, azithromycin, and prednisone. As patient continued to spike high-grade fever despite being on antibiotics, computerized tomography (CT) scan of the chest was done which was suggestive consolidation in right middle lobe with central areas of necrosis. Antibiotics were escalated to vancomycin, cefepime, and metronidazole. Blood culture, urinary legionella, and streptococcous antigen were negative. Fungitell-B-D glucan level was elevated to 73 pg/ml and coccidioides antibody and histoplasma galactomannan antigen were negative. Sputum culture was remarkable for coccidioides immitis. Upon a detailed review of history, patient reported that he recently went to vacation in California and was golfing there quite often. Since then he has been having fever with night sweats and cough. Patient was diagnosed with travel-related coccidioidomycosis and was discharged on diflucan. Patient continued to have a persistent cough with hoarseness and low-grade fever. Bronchoscopy was done which was suggestive of tracheal mass above carina in a concentric fashion. Considering disseminated coccidioidomycosis and fluconazole induced transaminitis, patient was started on amphotericin B with improvement in symptoms. DISCUSSION: Coccidioidomycosis is being increasingly reported in non-endemic areas as a result of travel to endemic areas. There is a need to increase awareness to help in early diagnosis and treatment and prevent progression and dissemination. Dissemination to airway can cause mass lesions, nodules, and papillary growths. These can be particularly life-threatening as they can cause airway obstruction, especially in children. CONCLUSIONS: Further research is required to establish a better understanding of disease so that travel medicine guidelines are updated and appropriate changes can be made in pre-travel consultation before travel to endemic areas. The need of the hour is development of vaccine for primary prevention of this disease to prevent morbidity and improve cost effectiveness. Reference #1: Polesky A, Kirsch CM, Snyder LS, et al. Airway coccidioidomycosis--report of cases and review. Clin Infect Dis. 1999;28(6):1273-1280. doi:10.1086/514778 DISCLOSURES: No relevant relationships by michael centore, source=Web Response No relevant relationships by Haris Zia, source=Web Response

COCCIDIOIDES KILLS: A CASE REPORT

SESSION TITLE: Fellows Lung Pathology Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Coccidioidomycosis immitis is a dimorphic fungus that infects the host via inhalation of spores found in the soil of endemic areas such as the southwestern United States. In immunocompetent patients it usually presents as a flu like illness. In patients that are immunocompromised it can lead to disseminated disease affecting numerous organs. CASE PRESENTATION: A 32-year-old male with a history of asthma presented to the ED with fevers, back pain, shaking chills, shortness of breath, and a nonproductive cough for two weeks. A CT chest was performed that revealed diffuse bilateral ground glass opacities (Figure 1). His respiratory status worsened despite treatment for pneumonia and he was subsequently intubated. MRI of the thoracic spine was performed given his back pain, which showed T8-T12 paravertebral abscess (Figure 2). It was also noted while gathering history that he played football in Arizona and lived in that area for some time. Aspiration of the paraspinal abscess was performed. Patient was placed on empiric amphotericin B as he developed worsening acute respiratory distress syndrome (ARDS). Despite being on lung protective strategies, he was difficult to oxygenate and placed on ECMO. Infectious workup for other organisms was also performed including bacterial and viral co-infection in the blood, cerebrospinal fluid (CSF), and bronchial fluids. His spinal cultures and CSF grew Coccidioides immitis along with spherules noted in his bronchial washings. He was also found to have cutaneous disseminated lesions on his upper extremity (Figure 3). Despite best efforts, patient continued to decompensate. Palliative care was consulted and withdrawal of support was performed after patient was noted to have multiple cardiac arrests. DISCUSSION: Symptomatic patients with coccidioidomycosis typically present with community acquired pneumonia. Uncommonly, in about 1% of infections, hematogenous, extra pulmonary dissemination can occur to the spine, meninges, joints, and skin. Coccidioidomycosis is commonly diagnosed in disease-endemic areas but frequently overlooked in disease-nonendemic areas because of a low index of suspicion among physicians. Individuals at risk of dissemination have suppressed cellular immunity, including those with advanced HIV infection, transplantation recipients, and those receiving chronic immunosuppressive medications such as glucocorticoids. Interestingly, this patient had no such risk factors, but the key in his case was obtaining travel/living history as it increased suspicion of coccidioidomycosis infection earlier. Unfortunately, in his case, this did not change his outcome. CONCLUSIONS: Although coccidioidomycosis is rare in non-endemic areas, physicians must keep it in mind when evaluating patients who have traveled or lived in endemic areas even without immunosuppression. Reference #1: Ramanathan D, Sahasrabudhe N, Kim E. Disseminated Coccidioidomycosis to the Spine-Case Series and Review of Literature. Brain Sci. 2019 Jul 7;9(7). doi: 10.3390/brainsci9070160. PubMed PMID: 31284663; PubMed Central PMCID: PMC6680672. DISCLOSURES: No relevant relationships by Alireza Nathani, source=Web Response No relevant relationships by Sean OConnor, source=Web Response No relevant relationships by Chhaya Patel, source=Web Response No relevant relationships by Jorge Velazco, source=Web Response