Phenotypic and Genomic Evolution in Candida albicans during Long-term Pathologic Interaction in Patients with Chronic Mucocutaneous Candidiasis

Abstract Background Candida albicans causes debilitating mucosal infections in patients with inherited susceptibility to chronic mucocutaneous candidiasis (CMC), often requiring long-term azole-based treatment. Due to increasing azole resistance, alternative treatments are desirable. Acquired resistance to amphotericin B (AMB) is rare but AMB use is limited by parenteral administration and nephrotoxicity. Cochleated AMB (CAMB) is a new oral formulation of AMB and thus an attractive option for oropharyngeal candidiasis (OPC), esophageal candidiasis (EC) and vulvovaginal candidiasis (VVC). We assessed the efficacy of CAMB in mouse models of OPC and VVC and in 4 patients with azole resistant CMC manifesting as OPC, EC or VVC. Methods Act1 -/- mice were infected with C. albicans in models of OPC and VVC and were treated once daily via oral gavage with CAMB or vehicle or intraperitoneal AMB-deoxycholate (AMBd) from day 1 through 4 post-infection (pi). At day 5 pi, the tongue or vaginal tissue was harvested to quantify fungal burden. Patients with azole resistant CMC enrolled in a phase 2A CAMB dose escalation study. The primary endpoint was clinical improvement at 2 weeks based on an efficacy scale, followed by optional extension for long-term suppression of CMC to assess safety and efficacy. Results CAMB-treated mice had significantly reduced tongue and vaginal tissue fungal burden compared to vehicle-treated mice, while they exhibited comparable fungal control relative to AMBd-treated mice. Among 4 CAMB-treated patients, 3 reached clinical efficacy by 2 weeks at a dose of 400 mg twice daily and one reached clinical efficacy at 200 mg twice daily. Three of 4 patients continued on the extension phase past 48 months with sustained clinical improvement of OPC and EC; patient #3 had relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical response was not seen for onychomycosis or VVC. CAMB was safe and well-tolerated without renal toxicity. Conclusion Oral administration of CAMB in IL-17-signaling deficient mice resulted in reduced tongue and vaginal tissue fungal burden during mucosal C. albicans infections. A proof-of-concept clinical trial in humans with inherited CMC showed efficacy in OPC and EC with good tolerability and safety. Disclosures Benjamin Colton, PharmD, Merck (Shareholder)Pfizer (Shareholder) Ruying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Theresa Matkovits, PhD, Matinas BioPharma (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder) Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)

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Laryngeal Candidiasis Presenting as Inspiratory Stridor

PEDIATRICS ◽

10.1542/peds.69.2.234 ◽

1982 ◽

Vol 69 (2) ◽

pp. 234-236

Author(s):

Richard F. Jacobs ◽

Kyle Yasuda ◽

Arnold L. Smith ◽

Denis R. Benjamin

Keyword(s):

Candida Albicans ◽

Vocal Cord Paralysis ◽

Upper Airway ◽

Neonatal Infection ◽

Chronic Mucocutaneous Candidiasis ◽

Inspiratory Stridor ◽

Mucocutaneous Candidiasis ◽

Initial Symptoms ◽

Candida Albicans Infection ◽

Laryngeal Involvement

In 1970, Perrone1 first reported laryngeal obstruction secondary to Candida albicans infection in a newborn. There have been several descriptions of congenital or neonatal infection with C albicans including pustubar dermatitis,2 pneumonia,3 meningitis, and arthritis.4 However, none of these reports noted laryngeal involvement. Recently, laryngitis and esophagitis were described in children with chronic mucocutaneous candidiasis.5 Adult patients predisposed to invasive candidal infections have had laryngeal involvement; on occasion their initial symptoms were those of upper airway obstruction.6 Infants and newborns with inspiratory stridor are usually evaluated for laryngomalacia, congenital subglottic stenosis, or vocal cord paralysis. Candidal laryngitis presenting as inspiratory stridor has not been well documented in the pediatric literature.

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Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines

Journal of Experimental Medicine ◽

10.1084/jem.20091669 ◽

2010 ◽

Vol 207 (2) ◽

pp. 299-308 ◽

Cited By ~ 409

Author(s):

Kai Kisand ◽

Anette S. Bøe Wolff ◽

Katarina Trebušak Podkrajšek ◽

Liina Tserel ◽

Maire Link ◽

...

Keyword(s):

Candida Albicans ◽

Tolerance Induction ◽

Chronic Mucocutaneous Candidiasis ◽

Mucocutaneous Candidiasis ◽

Autoimmune Polyendocrine Syndrome ◽

Self Tolerance ◽

Multicenter Survey ◽

Autoimmune Polyendocrinopathy ◽

Patient Groups ◽

Endocrine Features

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

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Long-term therapy of chronic mucocutaneous candidiasis with ketoconazole: Experience with twenty-one patients

The American Journal of Medicine ◽

10.1016/0002-9343(83)90511-9 ◽

1983 ◽

Vol 74 (1) ◽

pp. 23-29 ◽

Cited By ~ 90

Author(s):

Charles R. Horsburgh ◽

Charles H. Kirkpatrick

Keyword(s):

Term Therapy ◽

Chronic Mucocutaneous Candidiasis ◽

Mucocutaneous Candidiasis ◽

Long Term Therapy

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CHRONIC MUCOCUTANEOUS CANDIDIASIS—ASSOCIATED IMMUNOLOGIC ABNORMALITIES

PEDIATRICS ◽

10.1542/peds.42.2.227 ◽

1968 ◽

Vol 42 (2) ◽

pp. 227-230

Author(s):

Joseph W. Landau

Keyword(s):

Candida Albicans ◽

Host Defense ◽

Defense Mechanisms ◽

Etiologic Agent ◽

Chronic Mucocutaneous Candidiasis ◽

Internal Organs ◽

Predisposing Factor ◽

Mucocutaneous Candidiasis ◽

Mucous Membranes ◽

Systemic Infections

Candidiasis (moniliasis, candidosis) includes a group of fungous diseases varying in severity from commonly encountered local superficial involvement of the oral mucosa to fulminating systemic infections rapidly terminating in death.1 The etiologic agent is Candida albicans or occasionally another species of candida. These fungi are frequently found as saprophytes in the oral cavity, gastrointestinal tract, and vaginal area. Some local or systemic impairment of host defense mechanisms usually appears to be an essential predisposing factor for the development of candidiasis. The term chronic mucocutaneous candidiasis refers to a heterogeneous group of fungous diseases characterized by persistent or recurrent candida infection of mucous membranes, nails, and skin.1-3 Involvement of internal organs seldom, if ever, occurs.

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Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients

PLoS ONE ◽

10.1371/journal.pone.0145888 ◽

2016 ◽

Vol 11 (2) ◽

pp. e0145888 ◽

Cited By ~ 13

Author(s):

Alexander J. Moorhouse ◽

Claire Rennison ◽

Muhammad Raza ◽

Desa Lilic ◽

Neil A. R. Gow

Keyword(s):

Candida Albicans ◽

Chronic Mucocutaneous Candidiasis ◽

Mucocutaneous Candidiasis ◽

Clonal Strain

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Successful Therapy of a Patient with a Novel STAT1 Gain of Function Mutation and Life-Threatening Cytopenias with Janus Kinase Inhibitor Ruxolitinib

Blood ◽

10.1182/blood.v126.23.3434.3434 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3434-3434 ◽

Cited By ~ 2

Author(s):

Katja G. Weinacht ◽

Louis m Charbonnier ◽

Ashley Plant ◽

Troy Torgerson ◽

Sergei Rosenzweig ◽

...

Keyword(s):

T Cells ◽

Opportunistic Infections ◽

Janus Kinase ◽

Chronic Mucocutaneous Candidiasis ◽

Gain Of Function ◽

Mucocutaneous Candidiasis ◽

Life Threatening ◽

Ifn Γ ◽

Tgf Β1

Abstract Monoallelic gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity. The immunodeficiency is caused by impaired IL-17 immunity and typically presents with chronic mucocutaneous candidiasis, variably associated with other opportunistic infections. The autoimmune manifestations due to exaggerated responsiveness to interferon are more diverse and include SLE, thyroiditis, hepatitis, and alopecia areata. The phenotypic spectrum of STAT1 GOF mutations is extremely wide, ranging from intermittent localized disease to chronic systemic illness and fatality. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor, leaving a void for alternate long-term strategies to control the disease and maintain remission. Recently, we diagnosed a patient suffering from chronic mucocutaneous candidiasis and life-threatening autoimmune cytopenias with a novel monoallelic mutation in the linker domain of STAT1 (c.1633G>A; p.E545K). The mutation caused a profound increase in STAT1 phosphorylation in response to type 1 and 2 interferon without affecting dephosphorylation kinetics, which is mechanistically distinct from all reported STAT1 GOF mutations to date. The potential of naïve patient CD4+ T cells to become IFN- γ or IL-17 producing cells was investigated under TH0 (anti-CD3/28), TH1 (anti-CD3/28, IL-12) and TH17 (anti-CD3/28, IL6, IL-23, TGF-β1) conditions and revealed that patient CD4+ T cells are biased to produce IFN-γ irrespective of polarizing conditions, and resistant to TH17 induction upon stimulation with IL6, IL-23 and TGF-β1. In addition, the patient's proportion of T follicular helper cells (TFH) relative to regulatory T cells (Treg) was increased. Treatment with the Janus Kinase (JAK) 1/2 inhibitor Ruxolitinib reduced the hyperresponsiveness to interferon, normalized the TH1 response, enabled naïve T cells to differentiate into TH17 cells and decreased the TFH to Treg ratio. Under therapeutic dose Ruxolitinib the patient maintained clinical remission with respect to both autoimmunity and mucocutaneous candidiasis. Conclusion: Clinical vigilance for an underlying immune dysregulation syndrome due to abnormal JAK-STAT signaling is critical when evaluating patients with autoimmunity combined with opportunistic infections as JAK-inhibitors represents an effective targeted therapy for long-term disease control even in severely affected patients for whom hematopoietic stem cell transplantation is not available. Disclosures Off Label Use: Ruxolitinib use for STAT1 GOF mutation.

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