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.

Timing of Central Venous Line Insertion During Induction in Children With Acute Lymphoblastic Leukemia.

PURPOSE: Central venous lines (CVL) in children with acute lymphoblastic leukemia (ALL) provide comfortable administration of intensive chemotherapy and blood sampling. The optimal time for the insertion of CVL in patients with ALL during induction therapy is controversial. This study aimed to investigate the frequency of CVL-related complications in children with ALL concerning the time of CVL insertion. PATIENTS AND METHODS: We reviewed the records of 52 pediatric ALL patients with CVL. CVL placement before or on treatment day 15 was defined as "early insertion", and after treatment day 15 was defined as "late insertion". Demographics, preoperative blood counts, type of central line, time of CVL placement, CVL-related complications, and blood counts during complications were all noted. All the data were collected from those with the first catheter use. RESULTS: CVL was placed ≤15 days in 26 patients (50%) and after 15 days in 26 patients (50%). Regarding the infection rates, no statistical difference was found between early and late CVL-inserted groups ( P =n.s.). Five patients developed thrombosis, and risk was found to be similar between early and late CVL-inserted groups ( P =n.s.). Catheter-related mechanical complications were recorded in 7 patients (3 in early and 4 in late CVL-inserted group, ( P =n.s.). CONCLUSION: The present study showed no relation between the timing of CVL placement during induction therapy and the occurrence of infection and thrombosis. Our results suggest that CVL can be placed safely at the time of diagnosis or early induction treatment to provide a comfortable administration of chemotherapy and decrease painful blood samplings.

Evaluation of voriconazole related adverse events in pediatric patients with hematological malignancies.

BACKGROUND: Despite therapeutic drug monitoring and pharmacogenetic-guided dose selection are recommended for pediatric patients, safety of voriconazole is mostly monitored by clinical assessment. Having comprehensive knowledge of safety profile and distinguishing incidental events from the reactions that are truly related to voriconazole use are crucial for safer and uninterrupted treatment. OBJECTIVES: This study aimed to address adverse reactions during the first month of voriconazole use by systematically evaluating retrospective records of all adverse events. Patients/Methods: It is a single-center, retrospective analysis of patients who received voriconazole from 1 September 2010 to 1 September 2020. Severity of abnormal findings in medical records were systematically graded. Causality between voriconazole and the events was evaluated by Liverpool Causality Assessment Tool (LCAT), Naranjo Algorithm and World Health Organization Causality Assessment System. The events with possible or probable causal relation to voriconazole are classified as adverse reaction. RESULTS: Records of 45 patients included in the study. The overall frequency of adverse reactions was 51.1%. Hepatobiliary laboratory adverse reactions identified in 48.9% of the patients and led to treatment discontinuation in 20.0%. Amylase and lipase elevation (2.2%), ventricular extra systoles (2.2%), hallucination and nightmares (2.2%) were other adverse reactions. CONCLUSIONS: Hepatobiliary abnormalities were the most common adverse reactions and the most common cause of treatment discontinuation. For safer treatment in critically ill patients, the dose should be personalized. To clearly identify the accurate frequency and the causality of all adverse reactions, prospective studies with much larger sample size are needed.

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.

A novel Mecom gene mutation associated with amegakaryocytic thrombocytopenia in a premature infant.

BACKGROUND: Hereditary bone marrow failure syndromes are a category of biologically different syndromes that can cause cytopenia in at least one hematopoietic cell lineage. CASE: We present a 29-week-old male infant who had a low Apgar Score, advanced delivery room resuscitation, widespread petechial rash, and ecchymoses at birth, without any dysmorphic features. Initial laboratory tests revealed bicytopenia (platelet count 7x10 3 /uL, hemoglobin of 3.9 g/dL, neutrophil 2.0x103 /uL) with findings of disseminated intravasculer coagulation (DIC). Imaging studies demonstrated accompanying left-sided congenital pulmonary airway malformation. On the second postnatal week pancytopenia occurred and the bone marrow findings were consistent with congenital amegakaryocytic thrombocytopenia. Further evaluations for differential diagnosis of pancitopenia were performed and the results of congenital viral infections, metabolic and immunologic tests were negative. While supportive treatments were in progress, haploidentical bone marrow transplantation (BMT) was performed from the father at 84th day due to unavailability of HLA-matched relative or nonrelative donor. Whole exome sequencing revealed a novel heterozygous frameshift variation (c.1242dupT [p. Thr538fs]) in exon 8 of the MECOM gene and validated by Sanger sequencing. No variation was detected in the parents genetic analysis. CONCLUSIONS: In this report, we present a patient with congenital bone marrow failure successfully treated with haploidentic BMT and describe a novel, de novo pathogenic variant in MECOM gene.

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.

Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder.

INTRODUCTION: SLC29A3 spectrum disorder is an autosomal, recessively inherited, autoinflammatory, multisystem disorder characterized by distinctive cutaneous features, including hyperpigmentation or hypertrichosis, hepatosplenomegaly, hearing loss, cardiac anomalies, hypogonadism, short stature, and insulin-dependent diabetes. CASE PRESENTATION: Herein, we report a 6-year-old boy who presented with features resembling type 1 diabetes mellitus, but his clinical course was complicated by IgA nephropathy, pure red cell aplasia, and recurrent febrile episodes. The patient was tested for the presence of pathogenic variants in 53 genes related to monogenic diabetes and found to be compound heterozygous for two SLC29A3 pathogenic variants (p. Arg386Gln and p. Leu298fs). CONCLUSION: This case demonstrated that SLC29A3 spectrum disorder should be included in the differential diagnosis of diabetes with atypical comorbidities, even when the distinctive dermatological hallmarks of SLC29A3 spectrum disorder are entirely absent.

Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey.

Assestment of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) is of utmost importance both for risk classification and tailoring of the therapy. The data of pediatric ALL patients that received treatment with Berlin-Frankfurt-Münster (BFM) protocols were retrospectively collected from 5 university hospitals in Turkey. Of the 1388 patients enrolled in the study 390 were treated according to MRD-based protocols. MRD assestment was with real time quantitative polymerase chain reaction (qPCR) in 283 patients and with multiparametric flow cytometry (MFC)-MRD in 107 patients. MRD monitoring had upstaged a total of 8 patients (2%) from intermediate risk group to high-risk group. Univariate analysis revealed age 10 years or above, prednisone poor response, PCR-MRD ≥10-3 on day 33 and on day 78 as poor prognostic factors affecting event-free survival (EFS). Detection of >10% blasts on day 15 with MFC (MFC-high-risk group) was not shown to affect EFS and/or overall survival (log-rank P=0.339). Multiple logistic regression analysis revealed PCR-MRD ≥10-3 on day 78 as the only poor prognostic factor affecting EFS (odds ratio: 8.03; 95% confidence interval: 2.5-25; P=0.000). It is very important to establish the infrastructure and ensure necessary standardization for both MRD methods for optimal management of children with ALL.

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.

Hepatitis-Associated Aplastic Anemia: Etiology, Clinical Characteristics and Outcome.

Hepatitis-associated aplastic anemia (HAA) is a form of acquired aplastic anemia (AA) in which bone marrow failure develops after an acute attack of hepatitis. Bone marrow failure leading to AA is generally severe in cases of HAA and fatal if left untreated. This retrospective multicenter study investigated clinical and laboratory characteristics, possible causes, treatment, and outcome of HAA in children. Twenty patients from 8 centers were included in the study. Aspartate aminotransferase and alanine aminotransferase were <3 to 5×upper limit of normal (ULN) in 2 patients, <5 to 10×ULN in 2 patients, and >10×ULN in 16 patients. Acute liver failure developed in 5 (29%) patients. Pancytopenia was simultaneously present in 6 of 20 (30%) patients. Eleven of the 20 patients (55%) were alive, in remission and transfusion free. Those who were alive either had undergone hematopoietic stem cell transplantation and/or immunosuppressive treatment, except 1 patient who had received no treatment. Patients with the diagnosis of acute hepatitis should be evaluated and followed up carefully for presence of cytopenia, so that definitive treatment of AA can be initiated in a timely and appropriate manner when needed.

Invasive Fungal Infections in Children with Leukemia: Clinical Features and Prognosis

Objective: The incidence of invasive fungal infections (IFIs) has increased due to intensive chemotherapy in childhood leukemia. The aim of this study was to evaluate the incidence, risk factors, causative pathogens, and impact on survival of IFIs among pediatric leukemia patients. Materials and Methods: The hospital records of 307 children with acute lymphoblastic leukemia (ALL, n=238), acute myeloid leukemia (AML, n=51), and relapsed leukemia (n=18) between January 2010 and December 2015 were retrospectively evaluated. Results: A total of 1213 febrile neutropenia episodes were recorded and 127 (10.4%) of them were related to an IFI. Of 307 children, 121 (39.4%) developed IFIs. The mean age was significantly older in the IFI group compared to children without IFIs (p<0.001). IFIs were defined as possible, probable, and proven in 73.2%, 11.9%, and 14.9% of the attacks, respectively. Invasive aspergillosis (81.9%) was the most frequent infection, followed by invasive candidiasis (13.4%) and rare fungal diseases (4.8%). The majority of IFI attacks in both ALL and AML occurred during the induction phase. In total, the death rate was 24% and the IFI-related mortality rate was 18%. The mortality rate among children with IFIs was found to be significantly higher than that of children without IFIs (p<0.001). Overall and event-free survival rates at 5 years were also found to be significantly lower in the IFI group (p<0.001). Relapse (odds ratio: 8.49) was the most effective risk factor for mortality, followed by developing an IFI episode (odds ratio: 3.2) and AML (odds ratio: 2.33) according to multivariate regression analysis. Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode Conclusion: Our data showed that IFIs were more common in older children. Although proven and probable IFI episodes were more frequently diagnosed in cases of relapse and AML, children with ALL and AML had similar frequencies of experiencing at least one episode

Pediatric trauma: Blood product transfusion characteristics in a pediatric emergency department, a single center experience.

AIM: To investigate clinical and laboratory data, management and outcomes of pediatric trauma patients who initially received blood product transfusions. METHODS: Between January 2011-January 2021, traumatic children who underwent blood product transfusions within 24 h of arrival at the emergency department were included. Demographics, clinical and laboratory data, Injury Severity Score (ISS), volume of transfused blood products and crystalloid boluses in 24 h were recorded. Massive transfusion (MT) was defined as transfusion of ≥40 mL/kg of all blood products in 24 h. RESULTS: Among 32 cases, 8 (25.0 %) patients met the MT threshold criterion. Length of pediatric intensive care unit (PICU) stay and mechanical ventilation (MV) were longer for patients who received MT although there was no difference for age, ISS, volume of crystalloid boluses, length of hospital stay, and 30-day mortality between those who received MT or not. Volume of crystalloid boluses was higher in patients who died than those who survived but the volume of blood products was similar for two groups. An APTT value of >37.5 s was identified as a predictor of 30-day mortality (OR = 48.000, 95 % CI: 3.704-621.998, p: 0.003). CONCLUSION: Children who received MT had longer durations of MV and PICU stay than those who did not receive, but there was no significance for ISS, volume of crystalloid boluses, hospital stay, or mortality between two groups. Volume of crystalloid boluses was higher in patients who died than those who survived. An APTT value of >37.5 s can be used to predict 30-day mortality.

Thrombolysis with Systemic Recombinant Tissue Plasminogen Activator in Children: A Multicenter Retrospective Study

Objective: This study aimed to evaluate systemic thrombolysis experiences with recombinant tissue plasminogen activator (rtPA). Materials and Methods: Retrospective data were collected from 13 Turkish pediatric hematology centers. The dose and duration of rtPA treatment, concomitant anticoagulant treatment, complete clot resolution (CCR), partial clot resolution (PCR), and bleeding complications were evaluated. Low-dose (LD) rtPA treatment was defined as 0.01-0.06 mg/kg/h and high-dose (HD) rtPA as 0.1-0.5 mg/kg/h. Results: Between 2005 and 2019, 55 thrombotic episodes of 54 pediatric patients with a median age of 5 years (range: 1 day to 17.75 years) were evaluated. These patients had intracardiac thrombosis (n=16), deep vein thrombosis (DVT) (n=15), non-stroke arterial thrombosis (n=14), pulmonary thromboembolism (PE) (n=6), and stroke (n=4). The duration from thrombus detection to rtPA initiation was a median of 12 h (range: 2-504 h) and it was significantly longer in cases of DVT and PE compared to stroke, non-stroke arterial thrombosis, and intracardiac thrombosis (p=0.024). In 63.6% of the episodes, heparin was initiated before rtPA treatment. LD and HD rtPA were administered in 22 and 33 of the episodes, respectively. Concomitant anticoagulation was used in 90% and 36% of the episodes with LD and HD rtPA, respectively (p=0.0001). Median total duration of LD and HD rtPA infusions was 30 h (range: 2-120 h) and 18 h (2-120 h), respectively (p=0.044). Non-fatal major and minor bleeding rates were 12.5% and 16.7% for LD and 3.2% and 25.8% for HD rtPA, respectively. At the end of the rtPA infusions, CCR and PCR were achieved in 32.7% and 49.0% of the episodes, respectively. The most successful site for thrombolysis was intracardiac thrombosis. HD versus LD rtPA administration was not correlated with CCR/PCR or bleeding (p>0.05). Conclusion: Systemic thrombolytic therapy may save lives and organs effectively if it is used at the right indications and the right times in children with high-risk thrombosis by experienced hematologists with close monitoring of recanalization and bleeding.

Different Kinetics and Risk Factors for Isolated Extramedullary Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia.

Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most frequent cause of post-transplantation mortality. Isolated extramedullary (EM) relapse (iEMR) after HSCT is relatively rare and not well characterized, particularly in pediatric patients. We retrospectively analyzed 1527 consecutive pediatric patients with acute leukemia after allo-HSCT to study the incidence, risk factors, and outcome of iEMR compared with systemic relapse. The 5-year cumulative incidence of systemic relapse (either bone marrow [BM] only or BM combined with EMR) was 24.8%, and that of iEMR was 5.5%. The onset of relapse after allo-HSCT was significantly longer in EM sites than in BM sites (7.19 and 5.58 months, respectively; P = .013). Complete response (CR) 2+/active disease at transplantation (hazard ratio [HR], 3.1; P < .001) and prior EM disease (HR, 2.3; P = .007) were independent risk factors for iEMR. Chronic graft-versus-host disease reduced the risk of systemic relapse (HR, 0.5; P = .043) but did not protect against iEMR. The prognosis of patients who developed iEMR remained poor but was slightly better than that of patients who developed systemic relapse (3-year overall survival, 16.5% versus 15.3%; P = .089). Patients experiencing their first systemic relapse continued to have further systemic relapse, but only a minority progressed to iEMR, whereas those experiencing their iEMR at first relapse developed further systemic relapse and iEMR at approximately similar frequencies. A second iEMR was more common after a first iEMR than after a first systemic relapse (58.8% versus 13.0%; P = .001) and was associated with poor outcome. iEMR has a poor prognosis, particularly after a second relapse, and effective strategies are needed to improve outcomes.

Investigating the risk factors for antibiotic lock therapy failure in pediatric cancer: a single center retrospective analysis.

BACKGROUND: Catheter-related bloodstream infection (CRBSI) is one of the most common complications of central lines. Data concerning the effectiveness and safety of antibiotic lock therapy (ALT), especially in pediatric hematology and oncology patients, have not yet reached sufficient levels of evidence. We aimed to share our center`s experience on ALT in pediatric cancer and to investigate the causes of ALT failure. METHODS: All cases with CRBSI and treated with ALT administiration in children with cancer between January 2015 and May 2019 were reviewed. Patients characteristics, laboratory and clinical findings, treatments, outcome of ALT, recurrences and reinfections were recorded. Patients with successful and unsuccessful ALT outcomes were compared in order to identify the risk factors for ALT failure. RESULTS: Sixteen eligible CRBSI treated with adjunctive ALT were identified. The most common pathogens were coagulase negative staphylococci (8/16, 50%). Treatment failure was observed in 31.2% (5/16). Younger age alone was an independent risk factor for treatment failure (0.9 vs 6.8 years, p = 0.038). Recurrence and reinfection rates were 23.1% and 16.7%. Mild bleeding occured in two cases (12.5%) and occlusion causing catheter removal was seen in one (6.3%). CONCLUSIONS: ALT was found to be a safe modality with a success rate of 68.8% in children with cancer at our center and younger age was an independent risk factor for treatment failure. Future studies with larger sample sizes are needed to determine the factors affecting the ALT outcome, especially in childhood malignancies.