Etiology and Factors Affecting Severe Complications and Mortality of Febrile Neutropenia in Children with Acute Leukemia

Objective: Febrile neutropenia (FN) is an important complication that causes high rates of morbidity and mortality in patients with malignancies. We aimed to investigate the etiology, epidemiological distribution and its change over the years, clinical courses, and outcomes of FN in children with acute leukemia. Materials and Methods: We retrospectively analyzed the demographic data, clinical characteristics, laboratory results, severe complications, and mortality rates of pediatric patients with FN between January 2010 and December 2020. Results: In 153 patients, a total of 450 FN episodes (FNEs) occurred. Eighty-four (54.9%) of these patients were male, the median age of the patients was 6.5 (range: 3-12.2) years, and 127 patients (83%) were diagnosed with acute lymphoblastic leukemia. Fever with a focus was found in approximately half of the patients, and an etiology was identified for 38.7% of the patients. The most common fever focus was bloodstream infection (n=74, 16.5%). Etiologically, a bacterial infection was identified in 22.7% (n=102), a viral infection in 13.3% (n=60), and a fungal infection in 5.8% (n=26) of the episodes. Twenty-six (23.2%) of a total of 112 bacteria were multidrug resistant (MDR) The rate of severe complications was 7.8% (n=35) and the mortality rate was 2% (n=9). In logistic regression analysis, refractory/relapsed malignancies and high C-reactive protein (CRP) at first admission were found to be the most important independent risk factors for mortality. Prolonged neutropenia after chemotherapy, diagnosis of acute myeloid leukemia, identification of fever focus or etiological agents, invasive fungal infections, polymicrobial infections, and need for intravenous immunoglobulin treatment increased the frequency of severe complications. Conclusion: We found that there was no significant change in the epidemiological distribution or frequency of resistant bacteria in our center in the last 10 years compared to previous years. Prolonged duration of fever, relapsed/refractory malignancies, presence of fever focus, and high CRP level were significant risk factors for poor clinical course and outcome.

The clinical follow-up and management of COVID-19 in children and adolescents with an immunocompromised state or a malignancy.

BACKGROUND: It is still not known how an immunosuppressive state affects the response to coronavirus disease 2019 (COVID-19) in children and adolescents. The aim of this study was to evaluate clinical characteristics, outcomes, and follow-up results of COVID-19 in pediatric patients with a history of immunocompromise or malignancy, retrospectively. METHODS: Patients with a diagnosis of COVID-19 who were under 18 years of age and had a history of immunosuppressive chronic disease or under immunosuppressant treatment were included in the study. Patients were applied to our outpatient clinic or consulted to our department in a tertiary center during the first year of the pandemic. RESULTS: We evaluated 18 patients with a median age of 15.0 (0.6-17.8) years. Twelve patients (66.6%) were tested because of a symptom and the most common symptom was fever (44.4%, n = 8). Ten of the symptomatic patients (55.5% of all cohort) had a mild disease, the remaining two patients (11.1%) with an end-stage malignancy had critical diseases. Twelve patients (66.7%) were managed on an outpatient basis and were followed up at home, while the remaining six (33.3%) required hospitalization. One patient, who had Ewing sarcoma, died during the follow-up in the intensive care unit, and others were recovered without any morbidities. Lymphocyte (LYM) counts were significantly lower, C-reactive protein (CRP), and ferritin levels were higher in the individuals that needed hospitalization (p = 0.039, 0.027, and 0.039, respectively). DISCUSSION: Immunocompromised children and adolescents with COVID-19 should be monitored closely, especially those with an end-stage malignancy, low LYM count, or high CRP and ferritin levels.

Evaluation of paediatric immune thrombocytopenia patients with clinical and laboratory findings: emphasizing the role of monocytosis.

We aimed to investigate the relationship between demographics, clinical features, laboratory findings including monocytosis and clinical course in children with immune thrombocytopenia (ITP). Data of 100 ITP patients were analysed. Complete blood count findings of the patients at certain time points were evaluated to classify the disease as acute, persistent and chronic. An effect of sex on chronicity was not observed ( P  = 0.166). Of the patients enrolled in the study, 38% ( n  = 38) had chronic course. The mean age of patients with the chronic course was 7 ±â€Š4.1 years, which was significantly higher than the other groups ( P  = 0.007). Sixty-five percent ( n  = 13) of the patients presenting with mucosal bleeding and 27.4% ( n  = 20) of the patients presenting with skin bleeding became chronic ( P  = 0.008). MPV was found to be significantly high in chronic ITP patients ( P  = 0.049). Monocytosis was noted in 80% of the patients at diagnosis. Intravenous immunoglobulin was used in 84% of the patients with acute ITP; 33% of them developed chronic ITP. The age at diagnosis, presence of mucosal bleeding and increased MPV on admission were high-risk factors for the development of the chronic course. Monocytosis was detected in 80% of the patients on admission, and it may play a role in the pathogenesis of ITP.

Blended Phenotype of Pelger-Huet Anomaly with Osteochondroma and Autosomal Recessive Deafness with Enlarged Vestibular Aqueduct.

Pelger-Huet anomaly (PHA) is a benign hematological anomaly that is characterized by impaired lobulation of neutrophils with a coarse nuclear chromatin. Skeletal abnormalities may accompany this anomaly. Autosomal recessive deafness-4 (DFNB4) with enlarged vestibular aqueduct (EVA) comprises a phenotypic spectrum of sensorineural hearing loss (SNHL). We report a case with SNHL, multiple skeletal anomalies including osteochondroma, developmental delay, and PHA. Molecular studies revealed a heterozygous pathogenic variant in the LBR gene and a homozygous likely pathogenic variant in the SLC26A4 gene. Due to these 2 variants, he was diagnosed with PHA and DFNB4 with EVA. If goiter develops, DFNB4 with EVA is named Pendred syndrome (PDS), so the patient will be followed up for this condition, and in the current literature, there is no case with PDS and PHA co-existence either. PHA may be accompanied by multiple skeletal abnormalities. In our case, there is also concomitance with osteochondroma. Although these are independent and distinct diagnoses, we present this case due to the concomitance of these situations.

Evaluation of Possible Effects of the COVID-19 Pandemic on Febrile Neutropenia Episodes in Children With Acute Leukemia.

With the rapid spread of coronavirus disease 2019 (COVID-19) around the globe, concerns about the management of patients with malignancy have risen significantly. This study aimed to investigate the possible impact of the COVID-19 pandemic and prevention policies on the incidence and etiology of febrile neutropenia (FN) episodes in children with acute leukemia. Children who had acute leukemia and were diagnosed as FN in a tertiary center from March 2018 to March 2021 were included in the study. FN episodes were grouped as prepandemic and postpandemic based on the date that pandemic was declared. Relevant data were collected retrospectively. We evaluated 113 FN episodes (75.2% were prepandemic) of 46 patients, a median of 4.7 (2.6 to 12.6) years of age. The number of FN episodes per patient did not differ between prepandemic and postpandemic periods ( P =0.476). There was no significant difference among the 2 groups regarding the microbiologic causes, focus of fever, and clinical outcomes in FN episodes. Two of the patients were diagnosed as COVID-19 and recovered without any complications. In conclusion, we showed that the incidence and etiology of FN episodes were similar before and during the COVID-19 pandemic in children with acute leukemia.

Congenital afibrinogenemia in a 4-year-old girl complicated with acute lymphoblastic leukemia.

BACKGROUND: Congenital fibrinogen deficiency is one of the rare inherited coagulation disorders. Congenital fibrinogen deficiency complicated with a hematological malignancy can be life threatening. CASE: We present a four-year-old girl with congenital fibrinogen deficiency complicated with acute lymphoblastic leukemia. CONCLUSION: This case aims to highlight therapeutic approaches for the management of afibrinogenemia patients with acute leukemia.

Different Clinical Presentation of 3 Children With Familial Hemophagocytic Lymphohistiocytosis With 2 Novel Mutations.

Although familial hemophagocytic lymphohistiocytosis (FHL) generally manifest with a combination of unremitting fever, hepatosplenomegaly, and pancytopenia; unusual presentations should also be taken into account. Herein, we present 3 FHL cases with 2 novel mutations with different initial presentations. The first patient bearing a homozygous truncation mutation in UNC13D (c.2650C>T.p.Gln884Ter) presented with central nervous system involvement and skin rash. The patient responded to the HLH-2004 protocol, and allogenic hematopoietic stem cell transplantation was performed from her healthy sister. The second and third patients with homozygous splice site mutation (c.430-1G>A) in STXBP2 were siblings who presented at birth with fevers, elevated aspartate aminotransferase, alanine aminotransferase, and hyperferritinemia but did not fulfill FHL criteria. The last 2 infants died despite intervention. Hematologists should be vigilant about the different presentation of FHL in children.

Genetic Deficiency and Biochemical Inhibition of ITK Affect Human Th17, Treg, and Innate Lymphoid Cells.

PURPOSE: Interleukin-2-inducible T cell kinase (ITK) is an important mediator of T cell receptor signaling. Loss of function mutations in ITK results in hypogammaglobulinemia and CD4+ T cell loss in humans, and the patients often present with EBV-associated B cell lymphoproliferative syndrome. Itk-deficient mice show loss of T cell naivety, impaired cytolytic activity of CD8+ T cells, and defects in CD4+ T cell lineage choice decisions. In mice, Itk mutations were shown to affect Th17-Treg lineage choice in favor of the latter. In this study, we explored whether human ITK reciprocally regulates Th17-Treg balance as its murine ortholog. METHODS: Whole Exome Sequencing was used to identify the mutation. ITK-deficient peripheral blood lymphocytes were characterized by FACSAria III-based flow cytometric assays with respect to proliferation, apoptosis, cytokine production, and innate lymphoid cell (ILC) frequency. Sorted T cells from healthy donors were exposed to ibrutinib, an irreversible ITK inhibitor, to assess ITK's contribution to Th17 and Treg cell generation and functions. RESULTS: In this study, we report a child with a novel ITK mutation who showed impaired CD3/CD28 induced proliferation in T cells. ITK-mutant cells were more apoptotic irrespective of TCR activation. More importantly, T cells produced less Th17-associated cytokines IL-17A, IL-22, and GM-CSF. Conversely, Th1-associated IFN-γ production was increased. An irreversible inhibitor of ITK, ibrutinib, blocked ex vivo Th17 generation and IL-17A production, conversely augmented FOXP3 expression only at low doses in Treg cultures. Finally, we analyzed peripheral ILC populations and observed a relative decrease in ILC2 and ILC3 frequency in our ITK-deficient patient. CONCLUSIONS: To our knowledge, this is the first report showing that both genetic and chemical inhibition of ITK result in reduced Th17 generation and function in humans. We also report, for the first time, a reduction in ILC2 and ILC3 populations in an ITK-deficient human patient.