Role of Hypogammaglobulinemia in Invasive Fungal Infections in Children May Be Overlooked

To the Editor,

We attentively read the paper by Sezgin Evim et al. [1] recently published in Turkish Journal of Hematology. They investigated the clinical features and prognosis of invasive fungal infections (IFIs) in children with leukemia and found that IFIs significantly increased mortality and were poor prognostic factors in children with hematologic malignancies [1]. Therefore, physicians must be aware of these rare but potentially lethal infections. Furthermore, Sezgin Evim et al. [1] also revealed that prolonged severe neutropenia was one of the major risk factors for the incidence of IFI, and this conclusion was reached based on data from 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18).

However, in this letter, we highlight another important factor that may be overlooked regarding the prognosis of IFIs in children with leukemia, which is hypogammaglobulinemia. Importantly, patients with ALL have lymphocyte deficits, resulting in hypogammaglobulinemia and impaired cell-mediated immunity predisposing them to bacterial, viral, and fungal infections [2]. Chemotherapy often aggravates those deficits, resulting in prolonged periods of severe neutropenia that further increase the risk of infection [2]. Recently, Jowik et al. [3] found that a majority of ALL patients required immunoglobulin replacement during chemotherapy. Moreover, Lange et al. [4] found that hypogammaglobulinemia is a poorly described complication of chemotherapy in young adults and adolescents with ALL. The majority of treated ALL patients had hypogammaglobulinemia, and infectious events during maintenance and febrile neutropenia episodes during the course of treatment occurred more frequently in patients with hypogammaglobulinemia compared to patients with normal immunoglobulin G (IgG) levels [4].

However, hypogammaglobulinemia (e.g., IgG of <5 g/L) or dynamic polyclonal Ig levels before or during the IFIs were not documented or investigated in the study by Sezgin Evim et al. [1], which may mean that the role of hypogammaglobulinemia in the risk of IFIs was overlooked for these childhood leukemia patients. Hypogammaglobulinemia is the hallmark of secondary immunodeficiency and increased infection risk [2]. Therefore, monitoring the polyclonal Ig levels before or during IFIs and calculating the cutoff Ig values for IFI risk could further enhance the surveillance of IFI risk in childhood leukemia patients. Furthermore, using Ig replacement therapy for these potential cases of hypogammaglobulinemia with IFI risk factors could be a feasible method for the prevention of IFIs, significantly reducing the mortality of these children with leukemia [2]. Such supportive care is critical for the quality of life and longer survival of children with acute leukemia [5,6]. However, these hypotheses should be more broadly discussed and more large studies are warranted to validate the effects of hypogammaglobulinemia or other polyclonal Ig levels on IFIs among childhood leukemia patients.