Invasive fungal infections in paediatric patients treated with macromolecular immunomodulators other than tumour necrosis alpha inhibitors

Abstract

An expanding list of immunomodulatory or immunosuppressive monoclonal antibodies (mAbs) and biologic therapeutics is currently entering clinical practice, particularly in the areas of oncology, transplantation and autoimmune disorders. These agents are directed against molecules or cells involved in inflammation and immunity and may therefore be associated with serious and opportunistic infections. The purpose of this review was to critically analyse the literature on invasive fungal infections (IFIs) occurring in association with mAbs and fusion proteins other than tumour necrosis alpha (TNF-α) inhibitors, including therapeutics modulating T-cell-mediated pathologies (muromonab, abatacept, belatacept, ipilimumab, basiliximab, daclizumab), inducing lymphopenia (alemtuzumab), depleting CD20+ B cells (rituximab) and interfering with various targets (anakinra, natalizumab, blodalumab, ixekizumab and others) with a focus on children, and to provide a framework of evaluating the risk for IFIs in this population.

Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts

“…Less often, cryptococcosis or PJP occurs. Instead, the IL-1 receptor-targeting anakinra does not increase fungal susceptibility, consistent with absence of fungal disease in patients with inherited MYD88 mutations who have impaired IL-1R signaling (154).…”

“…The IL-6 receptor-targeting tocilizumab is occasionally associated with systemic candidiasis, consistent with impaired neutrophil recruitment and increased Candida susceptibility of Il6 −/− mice (154,155). Less often, cryptococcosis or PJP occurs.…”

Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts

“…Less often, cryptococcosis or PJP occurs. Instead, the IL-1 receptor-targeting anakinra does not increase fungal susceptibility, consistent with absence of fungal disease in patients with inherited MYD88 mutations who have impaired IL-1R signaling (154).…”

“…The IL-6 receptor-targeting tocilizumab is occasionally associated with systemic candidiasis, consistent with impaired neutrophil recruitment and increased Candida susceptibility of Il6 −/− mice (154,155). Less often, cryptococcosis or PJP occurs.…”

Baseline immunoglobulin G and immune function in non-Hodgkin lymphoma: a retrospective analysis

“…The findings in the present study are consistent with existing literature which showed rituximab only increased risk of grade ≥3 infections in advanced-stage Hodgkin lymphoma ( 26 ). The authors hypothesize that although CD20 is expressed in increasing concentration during normal and malignant B-lymphocyte maturation, it is absent on pro-B cells and plasma cells explaining why rituximab does not directly impair immunoglobulin production ( 27 ). Per current guidelines, patients with recurrent bacterial infection or severe bacterial infections with IgG <500 mg/dL may be supplemented with IVIG.…”

Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management

“…Antimicrobial resistance of P. jirovecii appears to be clinically rare, and although in vitro cultivation of the organism for susceptibility testing has been feasible since 2014, it remains unavailable for everyday clinical diagnostics. Finally, the population of children at risk for PJP will likely increase in the future beyond children with hematological malignancies to include pediatric patients with a variety of autoimmune and inflammatory disorders treated with corticosteroids, anti-Tumor Necrosis Factor agents, and calcineurin inhibitors [145][146][147].…”

Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts

“…Less often, cryptococcosis or PJP occurs. Instead, the IL-1 receptor-targeting anakinra does not increase fungal susceptibility, consistent with absence of fungal disease in patients with inherited MYD88 mutations who have impaired IL-1R signaling (154).…”

“…The IL-6 receptor-targeting tocilizumab is occasionally associated with systemic candidiasis, consistent with impaired neutrophil recruitment and increased Candida susceptibility of Il6 −/− mice (154,155). Less often, cryptococcosis or PJP occurs.…”

Baseline immunoglobulin G and immune function in non-Hodgkin lymphoma: a retrospective analysis

“…The findings in the present study are consistent with existing literature which showed rituximab only increased risk of grade ≥3 infections in advanced-stage Hodgkin lymphoma ( 26 ). The authors hypothesize that although CD20 is expressed in increasing concentration during normal and malignant B-lymphocyte maturation, it is absent on pro-B cells and plasma cells explaining why rituximab does not directly impair immunoglobulin production ( 27 ). Per current guidelines, patients with recurrent bacterial infection or severe bacterial infections with IgG <500 mg/dL may be supplemented with IVIG.…”

Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management

“…Antimicrobial resistance of P. jirovecii appears to be clinically rare, and although in vitro cultivation of the organism for susceptibility testing has been feasible since 2014, it remains unavailable for everyday clinical diagnostics. Finally, the population of children at risk for PJP will likely increase in the future beyond children with hematological malignancies to include pediatric patients with a variety of autoimmune and inflammatory disorders treated with corticosteroids, anti-Tumor Necrosis Factor agents, and calcineurin inhibitors [145][146][147].…”

Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts

“…Less often, cryptococcosis or PJP occurs. Instead, the IL-1 receptor-targeting anakinra does not increase fungal susceptibility, consistent with absence of fungal disease in patients with inherited MYD88 mutations who have impaired IL-1R signaling (154).…”

“…The IL-6 receptor-targeting tocilizumab is occasionally associated with systemic candidiasis, consistent with impaired neutrophil recruitment and increased Candida susceptibility of Il6 −/− mice (154,155). Less often, cryptococcosis or PJP occurs.…”

Baseline immunoglobulin G and immune function in non-Hodgkin lymphoma: a retrospective analysis

“…The findings in the present study are consistent with existing literature which showed rituximab only increased risk of grade ≥3 infections in advanced-stage Hodgkin lymphoma ( 26 ). The authors hypothesize that although CD20 is expressed in increasing concentration during normal and malignant B-lymphocyte maturation, it is absent on pro-B cells and plasma cells explaining why rituximab does not directly impair immunoglobulin production ( 27 ). Per current guidelines, patients with recurrent bacterial infection or severe bacterial infections with IgG <500 mg/dL may be supplemented with IVIG.…”

Pneumocystis jirovecii Pneumonia in Children with Hematological Malignancies: Diagnosis and Approaches to Management

“…Antimicrobial resistance of P. jirovecii appears to be clinically rare, and although in vitro cultivation of the organism for susceptibility testing has been feasible since 2014, it remains unavailable for everyday clinical diagnostics. Finally, the population of children at risk for PJP will likely increase in the future beyond children with hematological malignancies to include pediatric patients with a variety of autoimmune and inflammatory disorders treated with corticosteroids, anti-Tumor Necrosis Factor agents, and calcineurin inhibitors [145][146][147].…”