Atypical Presentation of Severe Fungal Necrotizing Fasciitis in a Patient with X-Linked Agammaglobulinemia

Chear, Chai Teng; Nallusamy, Revathy; Chan, Kwai Cheng; Tap, Ratna Mohd; Baharin, Mohd Farid; Yahya, Sharifah Nurul Husna Syed; Krishnan, Prasobhan Bala; Mohamad, Saharuddin Bin; Ripen, Adiratna Mat

doi:10.1007/s10875-021-01017-3

Cited by 4 publications

(4 citation statements)

References 48 publications

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“…Moreover, BTKi-treated patients not only experience neutrophil defects due to BTK inhibition, but they may also exhibit additional immunological impairments arising from their underlying hematological disorder and/or advanced age (90,91). These additional predisposition factors potentially further enhance the risk of aspergillosis and likely contribute to the higher incidence of aspergillosis in this group (4-10) relative to the rare reports of aspergillosis in XLA patients (22,23). Interestingly, a similar differential susceptibility to fungal infection between acute pharmacological inhibition of an immunological pathway and inherited deficiency of the same pathway has also been observed with C5-targeted monoclonal antibody therapy and inherited C5 deficiency (92)(93)(94).…”

Section: Discussionmentioning

confidence: 99%

“…As with XLA patients, bacterial and viral infections have been reported in BTKi-treated patients (5,17). Surprisingly, patients receiving BTKi have also exhibited a heightened risk for life-threatening invasive fungal infections, primarily aspergillosis (4)(5)(6)(7)(8)(9)(10)21), with such infections being infrequently reported in XLA patients (22,23). These observations suggest a critical, yet unforeseen role for BTK in orchestrating human antifungal immune responses, the mechanistic basis of which remains poorly-defined (24)(25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

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BTK drives neutrophil activation for sterilizing antifungal immunity

Desai,

Zarakas,

Wishart

et al. 2024

Journal of Clinical Investigation

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We describe a previously-unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcgR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40 phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47 phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BTK drives neutrophil activation for sterilizing antifungal immunity

Desai,

Zarakas,

Wishart

et al. 2024

Journal of Clinical Investigation

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“…Most XLA patients in this study exhibited common presentations such as respiratory infections, arthritis, skin infections, meningitis, and encephalitis. A minority of XLA patients exhibited atypical clinical presentations such as necrotizing fasciitis caused by rare fungus (n=1) ( 27 ), and tuberculosis caused by Mycobacterium tuberculosis (n=1). Apart from the manifestation of tuberculosis, some patients with BTK mutation affecting the kinase or SH2 domain exhibited other inflammatory conditions such as abscesses (n=7), cellulitis (n=4), arthritis (n=3), cholecystitis (n=1), and ulcers (n=1).…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, there have been many reports on XLA from East Asia regions (3,(15)(16)(17)(18)(19)(20)(21)(22)(23), while a few XLA reports were from Southeast Asia (15,24). In addition, information on XLA incidence in Malaysia is scarce (25)(26)(27)(28)(29)(30). Hence, the objective of this study was to describe the genotypes and clinical phenotypes of Malaysian patients with XLA.…”

Section: Introductionmentioning

confidence: 99%

Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

Chear,

Ismail,

Chan

et al. 2023

Front. Immunol.

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BackgroundBruton’s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.ResultsTwenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.ConclusionThis report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.

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Atypical Presentation of Severe Fungal Necrotizing Fasciitis in a Patient with X-Linked Agammaglobulinemia

Cited by 4 publications

References 48 publications

BTK drives neutrophil activation for sterilizing antifungal immunity

BTK drives neutrophil activation for sterilizing antifungal immunity

Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia

Multiple drugs

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