Mucocutaneous Candidiasis Research Articles

IL-17 Producing T cells as Predictors of Primary Immunodeficiencies in Patients with Candida Infections

Background: IL-17 producing T cells are a distinct subset of CD4+ T cells, which are recognized to have an essential role in protection against certain fungi and extracellular pathogens. Objectives: This study aims to evaluate the number of IL-17 producing T cells as a predictor of primary immunodeficiency disorders in patients with Candida infections and low numbers of IL-17 producing T cells. Methods: Seven newly diagnosed patients with documented Candida infections aged between 4 and 35 years were included in this study. Before establishing the diagnosis of chronic mucocutaneous candidiasis, a thorough immunodeficiency workup, including complete blood count, serum Ig levels and antibody responses, flow-cytometry evaluation, and LTT, was completed for all the patients, and other immunodeficiency disorders, including combined and phagocytic deficiencies, were ruled out. Then, IL-17 producing T cells were detected using antiCD3 and anti-IL-17 antibodies through flow-cytometry evaluation. Results: The IL-17 producing T cells significantly decreased in the peripheral blood of patients with PID and candida infections. A P-value of less than 0.05 was considered statistically significant. Conclusions: To conclude, in cases of recurrent candida infections, initial assessment of IL-17 producing T cells may act as a predictor of an underlying primary immunodeficiency. In patients with low counts of IL-17 producing T cells, selecting a targeted panel of genetic tests may become more helpful in the detection of certain immunodeficiency disorders than performing whole-exome sequence analysis.

Generation and Characterization of iPS Cells Derived from APECED Patients for Gene Correction.

APECED (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy) is a severe and incurable multiorgan autoimmune disease caused by mutations in the AIRE (autoimmune regulator) gene. Without functional AIRE, the development of central and peripheral immune tolerance is severely impaired allowing the accumulation of autoreactive immune cells in the periphery. This leads to multiple endocrine and non-endocrine autoimmune disorders and mucocutaneous candidiasis in APECED patients. Recent studies have suggested that AIRE also has novel functions in stem cells and contributes to the regulatory network of pluripotency. In preparation of therapeutic gene correction, we generated and assessed patient blood cell-derived iPSCs, potentially suitable for cell therapy in APECED. Here, we describe APECED-patient derived iPSCs’s properties, expression of AIRE as well as classical stem cell markers by qPCR and immunocytochemistry. We further generated self-aggregated EBs of the iPSCs. We show that APECED patient-derived iPSCs and EBs do not have any major proliferative or apoptotic defects and that they express all the classical pluripotency markers similarly to healthy person iPSCs. The results suggest that the common AIRE R257X truncation mutation does not affect stem cell properties and that APECED iPSCs can be propagated in vitro and used for subsequent gene-correction. This first study on APECED patient-derived iPSCs validates their pluripotency and confirms their ability for differentiation and potential therapeutic use.

Human autoantibodies underlying infectious diseases.

The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.

Progressive, refractory macrophage activation syndrome as the initial presentation of anti-MDA5 antibody positive juvenile dermatomyositis: a case report and literature review

BackgroundMacrophage activation syndrome (MAS) is a severe and under-recognized complication of rheumatologic diseases. We describe a patient who presented with rapidly progressive, refractory MAS found to have anti-MDA5 antibody Juvenile Dermatomyositis (JDM) as her underlying rheumatologic diagnosis.Case presentationWe describe a 14-year-old female who at the time of admission had a history of daily fevers for 6 weeks and an unintentional sixteen-pound weight loss. Review of systems was significant for cough, shortness of breath, chest pain, headaches, sore throat, muscle aches, rash, nausea, and loss of appetite. An extensive initial workup revealed findings consistent with an autoimmune process. While awaiting results of her workup she had clinical decompensation with multi-organ system involvement including pancytopenias, interstitial lung disease, hepatitis, cardiac involvement, gastrointestinal distension and pain, feeding intolerance, extensive mucocutaneous candidiasis, and neuropsychiatric decline. Due to her decompensation, significant interstitial lung disease, and likely underlying rheumatologic condition she was started on high dose pulse steroids and mycophenolate. An MRI was performed due to her transaminitis and shoulder pain revealing significant myositis. Intravenous immunoglobulin was then initiated. The myositis antibody panel sent early in her workup was significant for anti-MDA5 and anti-SSA-52 antibodies. Despite high dose pulse steroids, mycophenolate, and IVIG, her disease progressed requiring escalating therapies. Ultimately, she responded with resolution of her MAS as well as significant and steady improvement in her feeding intolerance, interstitial lung disease, cardiac dysfunction, myositis, arthritis, and cutaneous findings.ConclusionsJDM in the pediatric patient is rare, as is MAS. In patients with complex rheumatologic conditions and lack of response to treatment, it is important to continually assess the patient’s clinical status with MAS in mind, as this may change the treatment approach. Without proper recognition of this complication, patients can have a significant delay in diagnosis leading to life-threatening consequences.

Rheumatologic diseases in patients with inborn errors of immunity in the USIDNET registry.

There is a gap in clinical knowledge regarding associations between specific inborn errors of immunity (IEIs) and rheumatologic diseases. This study reports the frequency of rheumatologic conditions in a large cohort of patients with IEI using the USIDNET (United States Immunodeficiency Network) registry. We used the USIDNET registry to conduct the analysis. We included all IEI patients within the registry for whom a diagnosed rheumatologic disease was reported. The total number of patients with IEI in our query was 5058. Among those, 278 (5.49%) patients had a diagnosis of rheumatologic disease. This cohort included 172 (61.8%) female and 106 (38.2%) male patients. Rheumatologic complications were highest in the interferonopathies (66.6%), autoimmune lymphoproliferative syndrome (ALPS) (13.7%), and immunoglobulin G subclass deficiency (IgGSD) (11.11%). Additionally, disease patterns were noted to be different in various IEI disease groups. Inflammatory myopathies were the most common rheumatologic condition in patients with X-linked agammaglobulinemia (1.65%), Sjogren's syndrome was the most common rheumatologic disease reported in ALPS patients (6.85%), and systemic lupus erythematosus was the most common rheumatologic disease in patients with chronic mucocutaneous candidiasis (CMC) (7.41%). Rheumatoid arthritis (RA) report rate was highest in patients with IgGSD (3.70%), specific antibody deficiency (SAD) (3.66%), and ALPS (2.74%). This study reports that rheumatologic diseases are frequently observed in patients with IEI. The frequency of different rheumatologic conditions was variable based on the underlying diagnosis. Clinicians caring for patients with IEI should be vigilant to monitor for rheumatologic complications. Key Points • The rates of reported rheumatologic diseases in the USIDNET registry are different in individual IEIs. • Further studies are needed to guide clinicians for detecting rheumatologic conditions earlier in patients with IEI.

Treatment of STAT3-deficient hyper–immunoglobulin E syndrome with monoclonal antibodies targeting allergic inflammation

Single transducer and activator of transcription 3 (STAT3) dominant negative (DN) is a primary immunodeficiency (PID) manifested by oto-sinopulmonary and skin bacterial infections; eczematoid dermatitis; mucocutaneous candidiasis; elevated serum immunoglobulin E (IgE); and skeletal, vascular, and connective tissue abnormalities. In recent years, monoclonal antibodies have emerged to manage atopic dermatitis (AD) and eosinophilic disease raising interest in whether STAT3 DN patients could have clinical benefit.

IL-17 serum level in patients with chronic mucocutaneous candidiasis disease.

BackgroundChronic mucocutaneous candidiasis (CMC) is defined by recurrent or persistent superficial infections involving nails, skin, and/or oral and genital mucosae. IL‐17 promotes the recruitment, chemotaxis, and expansion of neutrophils and acts directly on keratinocytes and epithelial cells, driving the production of antimicrobial peptides, essential for the immune response against Candida.AimTo evaluate the serum level of IL‐17 in a family affected by CMC restricted to the nails of the hands and feet.MethodsSerum IL‐17 was assayed on 16 patients (aged 21 ± 3.1 years) suffering from persistent onychomycosis caused by Candida and 18 healthy controls (aged 19 ± 2.7 years). Comparisons between groups were performed by Student's unpaired t‐test. The level of significance was set at 0.05.ResultsThe mean serum IL‐17 level in patients was 74 ± 1.42 pg/ml, whereas the control group showed a significantly lower level of 25.6 ± 6.7 pg/ml (p < 0.05).ConclusionsWe showed a potential defect in the IL‐17 signaling pathway in a family affected by CMC restricted to the nails of the hands and feet. Further research is needed to clarify the immunological mechanisms and the genetic etiology at the basis of the unusual clinical presentation in this family.

A Subcutaneous Abscess Caused by Candida Krusei Infection: A rare Manifestation

Candida is considered a normal microbiota of the gastrointestinal and genitourinary systems with a tendency for an invasive disease if the predisposing conditions exist. Mucocutaneous manifestations of Candida infection include the commonly encountered oropharyngeal thrush, vulvovaginitis, balanitis, intertrigo, paronychia, diaper dermatitis, and the rare chronic mucocutaneous candidiasis. Subcutaneous abscess due to Candida (albicans and non-albicans) is rare, with the literature available only in case reports. We report the first case of a subcutaneous perineal abscess due to C. krusie in a patient with poorly controlled diabetes without immune compromised conditions or a hematologic malignancy.

Chronic mucocutaneous candidiasis in an 11-year-old child – A case report from South India

Chronic mucocutaneous candidiasis in an 11-year-old child – A case report from South India

Chronic mucocutaneous candidiasis, pancytopenia, and systemic mycosis in a patient with STAT1 gene mutation ineffectively treated with ruxolitinib

Chronic mucocutaneous candidiasis, pancytopenia, and systemic mycosis in a patient with STAT1 gene mutation ineffectively treated with ruxolitinib

123. Oral Ibrexafungerp Outcomes by Fungal Disease in Patients from an Interim Analysis of a Phase 3 Open-label Study (FURI)

Background Candida species are a major cause of invasive and mucocutaneouls infections. There are limited oral treatment options available for patients with Candida infections who are unresponsive to or who are intolerant of currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. We present an analysis of patient outcomes from the FURI study by fungal disease type. Table 1: FURI Outcomes by Fungal Disease MethodsFURI patients were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis,other fungal diseases and evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy is clinically undesirable or unfeasible. ResultsAn independent Data Review Committee (DRC) provided an assessment of treatment response for 74 patients enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total of 39 (52.7%) patients had invasive candidiasis, 32 (43.2%) had mucocutaneous candidiasis and 3 (4.5%) patients had invasive aspergillosis. The percent of patients who were determined to have a complete response (CR), partial response (PR), clinical improvement (CI) was 63.5%, stable disease (SD) was 23.0%, patients with progression of disease 6.8% and 4 patients were indeterminate. Additionally, there was 1 death in the FURI study that was not related to fungal disease. Table 1 shows outcomes by fungal disease type as determined by the DRC. ConclusionAnalysis of 74 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker's Bureau)Astellas Pharma (Speaker's Bureau)Euopean Confederation of Medical Mycology (Speaker's Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker's Bureau)MSD (Speaker's Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker's Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Consultant) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker's Bureau)Pfizer (Scientific Research Study Investigator, Speaker's Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker's Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, Astellas (Grant/Research Support)Gilead (Grant/Research Support)Pfizer (Grant/Research Support) Martin Hoenigl, MD, Astellas (Individual(s) Involved: Self): Grant/Research Support; F2G (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Pfiyer (Individual(s) Involved: Self): Grant/Research Support; Scýnexis (Individual(s) Involved: Self): Grant/Research Support Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

992. Oral Ibrexafungerp Outcomes in Patients with Oropharyngeal and Esophageal Candidiasis from an Interim Analysis of a Phase 3 Open-label Study (FURI)

Abstract Background Candida albicans is the predominant organism causing esophageal candidiasis (EC) and oropharyngel candidiasis (OPC). These infections may arise from subjects colonized with Candida who are predisposed due to illness, debility or a local reduction in host resistance to an overgrowth of their own indigenous flora. Patients with mucocutaneous Candida infections can be treated in the outpatient setting, yet there are limited oral treatment options available for patients who are unresponsive to or who are intolerant to currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. Table 1. FURI Outcomes in OPC and EC Methods FURI subjects were eligible for enrollment if they had proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases with evidence of treatment failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment or if they were unable to receive an approved oral antifungal option (e.g., susceptibility of the organism) and a continued IV antifungal therapy was clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total 32 subjects (43.2%) had mucocutaneous candidiasis and 24 subjects were diagnosed with OPC or EC. The percent of patients who were determined to have a complete response (CR) or partial response (PR) was 62.5%, stable disease (SD), 20.8%, and progression of disease, 16.7%. Table 1 shows outcomes by EC and OPC as determined by the DRC. Conclusion Analysis of 24 EC and OPC patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging mucocutaneous fungal disease and limited treatment options. Disclosures Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) G. Marshall Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Peter Pappas, MD, Astellas (Grant/Research Support)Cidara (Grant/Research Support, Advisor or Review Panel member)Mayne (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)SCYNEXIS, Inc. (Consultant, Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker’s Bureau)Pfizer (Scientific Research Study Investigator, Speaker’s Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, SCYNEXIS, Inc. (Consultant, Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Oliver Witzke, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

983. Outcomes of Candida Bone and Joint Infections in Eight Patients from a Phase 3 Open-label Study (FURI)

Abstract Background Candida osteoarticular infections are often preceded by candidemia with the intervertebral discs and knee joints the most common area for candidemic seeding. Candida osteomyelitis has significant morbidity and diagnosis is often delayed difficult to treat. Treatment courses are usually long and there are limited oral options available for patients who have an azole-resistant infection. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients with fungal disease refractory or who intolerant of to standard of care antifungal therapy. Table 1. FURI Bone and Joint Infection Outcomes Methods FURI subjects were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis and documented evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) or a continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for a total 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. There were 8 subjects out of the 74 subjects who were diagnosed with various bone and joint infections, 5 subjects with spondylodiscitis, 1 subject with a knee/prosthetic joint infection and 2 subjects with bone infections, one of the tibia and one of the zygomatic arch. Table 1 shows outcomes for this patient group, five (75%) patients had a clinical benefit (complete or partial response and stable response), one (12.5%) had progression of disease and one patient was indeterminate. The median days of therapy for this group was 210.5 days. Conclusion Analysis of 8 subjects from the FURI study indicates that oral ibrexafungerp provides a promising therapeutic response in option for patients with bone and/or joint infections. Disclosures Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Guenter Weiss, MD, MSD (Speaker’s Bureau)Novartis (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Pharmacosmos (Speaker’s Bureau)Scynexis (Scientific Research Study Investigator)Vifor (Speaker’s Bureau) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

Candidiasis in patients with APS-1: low IL-17, high IFN-γ, or both?

Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS-1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene. APS-1 patients suffer from various autoimmune diseases, due to the defective thymic deletion of autoreactive T cells, and the development of a large range of autoantibodies (auto-Abs) against various tissue antigens, and some cytokines. The mechanisms underlying CMC remained elusive for many years, until the description in 2010 of high serum titers of neutralizing auto-Abs against IL-17A, IL-17F, and/or IL-22, which are present in almost all APS-1 patients. Excessively high mucosal concentrations of IFN-γ were recently proposed as an alternative mechanism for CMC in APS-1.

Infections in the monogenic autoimmune syndrome APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune Regulator (AIRE) gene, which impair the thymic negative selection of self-reactive T-cells and underlie the development of autoimmunity that targets multiple endocrine and non-endocrine tissues. Beyond autoimmunity, APECED features heightened susceptibility to certain specific infections, which is mediated by anti-cytokine autoantibodies and/or T-cell driven autoimmune tissue injury. These include the 'signature' APECED infection chronic mucocutaneous candidiasis (CMC), but also life-threatening coronavirus disease 2019 (COVID-19) pneumonia, bronchiectasis-associated bacterial pneumonia, and sepsis by encapsulated bacteria. Here we discuss the expanding understanding of the immunological mechanisms that contribute to infection susceptibility in this prototypic syndrome of impaired central tolerance, which provide the foundation for devising improved diagnostic and therapeutic strategies for affected patients.

Intracranial Calcifications in Autoimmune Polyendocrine Ectodermal Dystrophy Syndrome (APECED): About A Case Report

Autoimmune polyendocrinopathy ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS I), is an uncommon, but debilitating autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE), It is characterized by a broad and diverse clinical spectrum which can lead to severe metabolic alterations and eventually life-threatening events. Hypoparathyroidism is one of the major criteria for clinical diagnosis, in addition to chronic mucocutaneous candidiasis and autoimmune adrenal insufficiency. This component is responsible for the forming of brain calcifications which tend to have a characteristic predilection for the basal ganglia. In this article, we report an additional case to the literature and provide a literature review of the expanding radiological spectrum of this syndrome

Autoimmune hepatitis as the first manifestation of autoimmune polyendocrine syndrome type 1 in a 5-year-old girl

Autoimmune hepatitis is a chronic inflammatory liver disease of unknown etiology; the prevalence of juvenile autoimmune hepatitis is unknown. Autoimmune hepatitis occurs in 10–20% of patients with type 1 autoimmune polyendocrine syndrome, a rare (orphan) disease, which is characterized by a clinical triad in 70–100% of cases: chronic mucocutaneous candidiasis, hypopara thy roidismand adrenal insufficiency, as well as more 25 possible autoimmune endocrine and non-endocrine manifestations.Thisstudy describes a case of a 5-year-old girl with autoimmune hepatitis as the first clinical manifestation of the disease. The symptoms of chronic mucocutaneous candidiasis enabled us to suggest and genetically confirm the diagnosis of autoimmune poly endocrine syndrome type 1 before the lesions of endocrine organs. The girl had nonsense mutations R257 * and p.Q94* of the AIRE gene in a compound heterozygous state. Later, there appeared another autoimmune disorder – common vitiligo.Timelydiagnosisoftype1autoimmunepolyendocrinesyndromeinachildwiththefirstnon-endocrine autoimmune manifestation, initiation of therapy and further medical management made it possible to preventseve recomplications and improve the patient’s quality of life.

Hypoadrenalism as the Single Presentation of Autoimmune Polyglandular Syndrome Type 1

Type 1 autoimmune polyglandular syndrome (APS1) is a rare hereditary disease affecting nearly 600 patients worldwide. The first of its cardinal manifestations, chronic mucocutaneous candidiasis, hypoparathyroidism, or Addison’s disease, presents in childhood. Additional nonclassical landmarks of APS1 continue to develop as late as the fifth decade of life. Two thirds of patients develop the full triad before 25 years of age. Only 20% of patients develop the entire triad simultaneously. Addison’s disease is rarely reported as the first manifestation. According to APS1 classifications, restricted criteria for a single cardinal component, although elements of suspicion are not sufficient to diagnose APS1. This case report is peculiar as hypoadrenalism was the first and only manifestation of APS1 for nearly 3 decades since its diagnosis. Theoretically, exceptions from the protocol of APS1 diagnostic criteria would be recognized as acceptable for diagnosis in the future, when similar case reports of only 1 component of APS1 appear.

Comment on "Aberrant type 1 immunity drives susceptibility to mucosal fungal infections".

Break et al. (Research Articles, 15 January 2021, eaay5731) conclude that T cell overproduction of interferon-γ causes chronic mucocutaneous candidiasis (CMC), a typical early feature of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). This contradicts studies implicating interleukin IL-17 and IL-22 deficiencies as a cause of CMC. We propose that Break et al. have focused on late-arising events rather than more common primary causes of CMC.