Therapeutic plasma exchange in critically ill children: A single center experience.

INTRODUCTION: Therapeutic plasma exchange (TPE) is used in a wide spectrum of diseases in critically ill pediatric patients. We aim to review the indications, complications, safety, and outcomes of critically ill children who received TPE. METHODS: All of the TPE procedures performed in a pediatric intensive care unit providing tertiary care during 19 years (January 2013-January 2023) were evaluated retrospectively. A total of 154 patients underwent 486 TPE sessions. RESULTS: Median age was 6 years (2-12.5) and 35 children had a body weight of <10 kg (22.7%). Number of organ failure was 4 (2-6). Liver diseases were the most common indication for TPE (31.2%) followed by sepsis with multiorgan dysfunction syndrome (27.3%). Overall survival rate was 72.7%. The highest mortality was observed in hemophagocytic lymphohistiocytosis group. Non-survivors had significantly higher number of organ failure (p < 0.001), higher PRISM score (p < 0.001), and higher PELOD score on admission (p < 0.001). Adverse events were observed in 68 (13.9%) sessions. Hypotension (7.8%) and hypocalcemia (5.1%) were the most frequent adverse events. CONCLUSION: TPE is safe for critically ill pediatric patients with experienced staff. Survival rate may vary depending on the underlying disease. Survival decreases with the increase in the number of failed organs.

Primary Mold-Active Antifungal Prophylaxis Decreases the Need for Chest Computed Tomography Scans in Patients with Acute Lymphoblastic Leukemia.

Current guidelines recommend computed tomography (cCT) scans of the chest in children with leukemia following 96 h of the onset of idiopathic neutropenia to eliminate pulmonary invasive fungal infections (IFIs). However, cCT exposes some children who are at a very high risk of developing secondary cancers to radiation. We aimed to determine the effect of antifungal prophylaxis (AFP) with voriconazole (VCZ) on the need for cCT scans in children with acute lymphoblastic leukemia (ALL) to eliminate pulmonary IFIs during chemotherapy. We retrospectively screened all patients' data from their electronic charts. Children who were diagnosed as having ALL before February 2013 and did (AFP group) or did not (NoP group) receive AFP were divided into two groups and compared regarding cCT scans and relapse-mortality rates. Ninety-six children were diagnosed before February 2013 and did not receive primary AFP and 146 children were administered VCZ following a diagnosis of ALL. There were no significant demographic differences between the groups. A total of 128 cCTs had been required in 62 children in the NoP group, compared with 64 cCTs in 52 children in the AFP group. The percentage of the patients who had required at least one chest CT scan and the mean number of cCT scans in the NoP group were significantly higher compared with the AFP group. Proven-probable IFIs and relapse-mortality rates were higher in the NoP group compared with the AFP group. Mold-active AFP revealed a significant decrease in the need for cCT scans in children with ALL.

Identification of the molecular etiology in rare congenital hemolytic anemias using next-generation sequencing with exome-based copy number variant analysis.

OBJECTIVES: In congenital hemolytic anemias (CHA), it is not always possible to determine the specific diagnosis by evaluating clinical findings and conventional laboratory tests. The aim of this study is to evaluate the utility of next-generation sequencing (NGS) and clinical-exome-based copy number variant (CNV) analysis in patients with CHA. METHODS: One hundred and forty-three CHA cases from 115 unrelated families referred for molecular analysis were enrolled in the study. Molecular analysis was performed using two different clinical exome panels in 130 patients, and whole-exome sequencing in nine patients. Exome-based CNV calling was incorporated into the traditional single-nucleotide variant and small insertion/deletion analysis pipeline for NGS data in 92 cases. In four patients from the same family, the PK Gypsy variant was investigated using long-range polymerase chain reaction. RESULTS: Molecular diagnosis was established in 86% of the study group. The most frequently mutated genes were SPTB (31.7%) and PKLR (28.5%). CNV analysis of 92 cases revealed that three patients had different sizes of large deletions in the SPTB and six patients had a deletion in the PKLR. CONCLUSIONS: In this study, NGS provided a high molecular diagnostic rate in cases with rare CHA. Analysis of the CNVs contributed to the diagnostic success.

Invasive Fungal Infections in Children With Acute Myeloid Leukemia: A Single-center Experience Over 19 Years.

OBJECTIVE: Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality in children with acute myeloid leukemia (AML). This study aimed to evaluate the incidence, risk factors, etiology, and outcome of IFIs in children with AML and the effect of mold-active antifungal prophylaxis. MATERIALS AND METHODS: We retrospectively reviewed pediatric patients treated for AML between January 2004 and December 2022. Proven, probable, or possible IFIs were defined using standardized definitions of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) classification published at 2008. RESULTS: A total of 298 febrile neutropenia episodes from 78 patients were evaluated. Proven, probable, and possible IFI rates were 3%, 2.6%, and 9.4%, respectively. Profound neutropenia was detected in 18 (58%) and prolonged neutropenia in 20 (64.5%) of the IFI episodes.. Invasive aspergillosis accounted for the majority of IFI episodes; however, non-albicans Candida spp. were the most isolated pathogens in the proven group. Patients with relapsed AML were particularly at risk for the development of IFI ( P =0.02). A significant decrease in IFI episodes was achieved with mold-active antifungal prophylaxis with voriconazole ( P =0.01, odds ratio: 0.288, %95 CI:0.104-0.797). The overall mortality was 35.8%, and the IFI-attributable mortality rate was 25%. In the multivariate analysis, relapsed disease was the most significant risk factor associated with mortality ( P =0.006, odds ratio:4.745; 95% CI: 1.573-14.316). CONCLUSION: Mold-active prophylaxis reduced the rate of IFIs in this cohort however IFI-related mortality was still high as 25% in pediatric AML patients. Relapsed AML was the most significant risk factor associated with mortality.

Central nervous system thrombosis in pediatric acute lymphoblastic leukemia in Turkey: A multicenter study.

BACKGROUND: In patients with acute lymphoblastic leukemia (ALL), the risk of thromboembolism increases due to hemostatic changes secondary to the primary disease and due to treatment-related factors. In this multicenter study, we aimed to research the frequency of central nervous system (CNS) thrombosis occurring during treatment, hereditary and acquired risk factors, clinical and laboratory features of patients with thrombosis, treatment approaches, and thrombosis-related mortality and morbidity rates in pediatric ALL patients. PROCEDURE: Pediatric patients who developed CNS thrombosis during ALL treatment from 2010 to 2021 were analyzed retrospectively in 25 different Pediatric Hematology Oncology centers in Türkiye. The demographic characteristics of the patients, symptoms associated with thrombosis, the stage of the leukemia treatment during thrombosis, the anticoagulant therapy applied for thrombosis, and the final status of the patients recorded through electronic medical records were determined. RESULTS: Data from 70 patients with CNS thrombosis during treatment, out of 3968 pediatric patients with ALL, were reviewed. The incidence of CNS thrombosis was 1.8% (venous: 1.5 %; arterial: 0.03%). Among patients with CNS thrombosis, 47 had the event in the first 2 months. Low molecular weight heparin (LMWH) was the most commonly used treatment with a median of 6 months (min-max: 3-28 months). No treatment-related complications occurred. Chronic thrombosis findings occurred in four patients (6%). In five (7%) patients who developed cerebral vein thrombosis, neurological sequelae (epilepsy and neurological deficit) remained. One patient died related to thrombosis, and the mortality rate was 1.4%. CONCLUSION: Cerebral venous thrombosis and, less frequently, cerebral arterial thrombosis may develop in patients with ALL. The incidence of CNS thrombosis is higher during induction therapy than during other courses of treatment. Therefore, patients receiving induction therapy should be monitored carefully for clinical findings suggestive of CNS thrombosis.

Family Knowledge, Attitudes, and Practices Toward Severe Congenital Neutropenia.

Severe congenital neutropenia is a rare disorder. The survival and quality of life of patients radically improved through infection prevention, use of granulocyte colony-stimulating factor, and the appropriate use of antibiotics during infections. The aim of this study was to evaluate the precautions taken by families to prevent infections, the level of knowledge regarding the disease, and the impact of external factors such as education and economic status on behavior and compliance in patients and caregivers in terms of the following treatment protocols. Questionnaires were designed with the aim of determining how the social, cultural, and economic conditions of the families of children with severe congenital neutropenia affected their behavior and knowledge levels. They were completed using one-on-one video interviews with the caregivers. Thirty-one patients from 25 families were enrolled into the study. No correlations between family disease knowledge, parent education levels, working status of the mother, sibling numbers, economic status, ease of hospital access, and/or residential location were found. An increase in disease knowledge of patients and caregivers, as well as proven approaches to living with the disease, would directly correlate to increased life quality and long-term survival rates of patients.

Risk Factors for Infection and Mortality Associated With Stenotrophomonas maltophilia Bloodstream Infections in Children; Comparison With Pseudomonas aeruginosa Bloodstream Infections.

INTRODUCTION: The increasing incidence of Stenotrophomonas maltophilia ( S. maltophilia ) infections raises concern because of the high fatality/case ratio. This study aimed to evaluate the risk factors for infection and mortality associated with S. maltophilia bloodstream infections (BSIs) in children and compare them with Pseudomonas aeruginosa BSIs. METHODS: All BSIs caused by S. maltophilia (n:73) and P. aeruginosa (n:80) were enrolled in this study between January 2014 and December 2021 at the Medical School of Ege University. RESULTS: Previous Pediatric Intensive Care Unit (PICU) admission, prior glycopeptide, and carbapenem use were significantly more common in patients with S. maltophilia BSIs ( P = 0.044, P = 0.009, and P = 0.001, respectively) than with P. aeruginosa BSIs. C-reactive protein (CRP) levels were significantly higher in S. maltophilia BSIs ( P = 0.002). Multivariate analysis showed that prior carbapenem use was associated with S. maltophilia BSIs ( P = 0.014, adjusted odds ratio [AOR]: 2.710; 95% confidence interval [CI]: 1.225-5.992). PICU admission because of BSI, prior carbapenem and glycopeptide use, neutropenia, and thrombocytopenia were significantly more common in patients with mortality because of S. maltophilia BSIs ( P < 0.001, P = 0.010, P = 0.007, P = 0.008, P = 0.004, respectively), while only PICU admission because of BSI, and prior glycopeptide use were significant in multivariate analysis (AOR, 19.155; 95% CI: 2.337-157.018; P = 0.006 and AOR, 9.629; 95% CI: 1.053-88.013; P = 0.045, respectively). CONCLUSION: Prior carbapenem use is a significant risk factor for developing S. maltophilia BSIs. PICU admission because of BSI and prior glycopeptide use are risk factors associated with the mortality rate in patients with S. maltophilia BSIs. Therefore, S. maltophilia should be considered in patients with these risk factors, and empirical treatment should include antibiotics for S. maltophilia .

Current childhood chronic myeloid leukemia management under tyrosine kinase inhibitor treatment.

Chronic myeloid leukemia (CML) is very rare during childhood. Tyrosine kinase inhibitors (TKI) provide very good results in terms of survival. The medical records of 15 chronic phase (CP)-CML patients in a university hospital pediatric hematology department between 1997 and 2022 were reviewed retrospectively. Complete hematological response was documented in all patients between 20 and 68 (median 30) days of treatment. Major molecular response was achieved in seven patients within 6 months. Median follow-up for the study group was 79 (range 3-330) months and overall survival was 100%. Three patients (2 blastic transformation, 1 therapy resistant) underwent bone marrow transplantation (BMT) and one with blastic transformation is scheduled to undergo BMT. TKI were discontinued in three patients after a median of 86 (range 73-177) months. The complete molecular remission maintenance period before discontinuation of TKI was 81 (range 62-122) months. While no molecular relapse was seen before the last follow-up, the median overall follow-up period was 152 (range 131-300) months. In conclusion, recent advances have led to a very good prognosis for children with CP-CML. With TKI treatment, most patients continue their lives without disease progression. Additionally, in selected patients TKI can be discontinued without molecular relapse.

Clinical Utility of Respiratory Scores at Admission for Estimating the Definitive Microbiological Diagnosis in Lower Respiratory Tract Infections in Infants.

We aimed at determining the clinical utility of respiratory scores and the durations of wheezing or respiratory distress during hospitalization in infants with lower respiratory tract infections (LRTI) at admission for estimating the definitive microbiological diagnosis. We obtained data from a study population of 201 patients, 79 girls and 122 boys. There was a significant divide in the causative agents of LRTI among patients younger and older than 6 months of age (P = .002), and significantly different respiratory score findings were determined in infants with viral LRTI: a low respiratory score in a younger-than-6 month infant suggests Adenovirus as the causative agent and a high respiratory score suggests Parainfluenza 1 or 2; as for infants of 6 months of age or older, a low respiratory score indicates Influenza A or B or a mixed infection, whereas a high respiratory score is likely an indication of Parainfluenza 3 or RSV.

Effect of Breastfeeding and Preterm Births on the Severity of Lower Respiratory Tract Infections and Associated Risk of Hospitalization in Infants and Toddlers.

We studied the effect of duration of breastfeeding and history of prematurity on the duration of hospitalization in infants with lower respiratory tract infections (LRTI) because these may reflect the severity of illness as well as sizable direct and indirect healthcare costs. One hundred twenty-five patients (49 girls, 76 boys; aged 1-24 months) were hospitalized for LRTI during a period of 102 days and studied prospectively. We found a significant difference (P = .045) between the durations of hospitalization of the 92 patients breastfed for at least six months, compared to the other group of 33 patients who were breastfed for less than six months. The durations of hospitalization among the groups with and without a history of prematurity were not statistically different (P = .78). A history of breastfeeding for more than six months had significant effect on the duration of hospitalization, but this was not true for children with a history of preterm birth.

Modern management of iron overload in thalassemia major patients guided by MRI techniques: real-world data from a long-term cohort study.

Monitoring liver and cardiac iron stores by magnetic resonance imaging (MRI) enables identifying patients at risk of organ-specific morbidity and better tailoring of iron chelation therapy in thalassemia. Nevertheless, serum ferritin (SF) remains the only tool for monitoring iron status in most resource-poor regions. In this study, we assessed the impact of using MRI techniques to guide iron chelation therapy on iron overload outcomes in a cohort of 99 patients with thalassemia major (TM, mean age at baselines 20.7 ± 6.9 years) followed from 2006 to 2019. We also assessed the ability of SF trends to predict changes in consecutive liver iron concentration (LIC) and cardiac T2* (cT2*) measurements. The most commonly used chelator was deferasirox at baseline (65%) and final (72%) assessments. Overall, patients with safe LIC values (< 7 mg/g dw) increased from 57 to 77%, and safe cT2* values (> 20 ms) increased from 72 to 86%. We obtained the most significant improvement in patients with severe and moderate liver (p = 0.006 and p < 0.001) and cardiac (p < 0.0013 and p < 0.0001) iron overload at baseline. SF trends were in the same direction in 64% of changes in LIC, but only 42% of changes were proportional. Most of the changes in SF (64%) and LIC (61%) could not predict changes in cT2*. Moreover, downward trends in SF and LIC were associated with worsening cardiac iron in 29% and 23.5% of consecutive cT2* measurements. Liver and cardiac MRI-driven oral iron chelation improved the iron status of subjects with TM and demonstrated the importance of using validated MRI techniques in critical clinical decisions.

Is Monitoring of Cytomegalovirus Disease Required in Nontransplant Pediatric Acute Lymphoblastic Leukemia?

INTRODUCTION: Cytomegalovirus (CMV) infections in developing countries are experienced at an early age. This study was performed to investigate the frequency of reactivation and risk factors of infection acquired at an early age of nontransplant acute lymphoblastic leukemia (ALL) patients receiving immunosuppressive therapy with weekly monitoring of CMV levels in Turkey. MATERIALS AND METHODS: This was a retrospective, single-center study of 172 pediatric patients (102 boys and 70 girls) with ALL. All patients were monitored routinely for CMV-DNA at the initial presentation of leukemia and twice a week during chemotherapy. The CMV immunoglobulin (Ig)M/IgG titers were measured at admission. RESULTS: CMV seropositivity at baseline was 90,11%. The overall prevalence of CMV infection (viremia) was 70.34%, 116 of whom were seropositive for CMV IgG and 5 of whom were negative for CMV at the time of ALL diagnosis. Reactivation was more common than de novo CMV infections (P=0.000). CMV seropositivity at the beginning of the leukemia diagnosis was found to be an independent predictor for developing CMV infection (P=0.001). A total of 60 CMV infection episodes were treated with antivirals. Four of these included organ involvement. The duration of CMV-DNA viremia episodes was longer in patients with CMV-DNA ≥1000 copies/mL (n=45) than in those with lower CMV-DNA levels (P=0.002). Infection was shown not to be associated with chemotherapy phase. CONCLUSION: This study suggests the importance of monitoring for CMV infections in developing countries because of frequent reactivations in seropositive ALL patients. It should be kept in mind that low CMV-DNA levels may also lead to organ involvement.

Aplastic Anemia Frequency and Management in Pediatric Liver Transplantations Due to Non-A-E Hepatitis.

BACKGROUND: Hepatitis-associated aplastic anemia (HAAA) is a rare complication that presented with bone marrow failure after acute hepatitis. HAAA usually occurs in adolescent men within 1-6 months following hepatitis. Most of HAAA's etiology has non-A-E viral hepatitis. METHODS: Our retrospective study included patients with acute fulminant hepatitis who had been treated in Ege University Pediatric Gastroenterology, Hepatology and Nutrition Department and Izmir Kent Hospital Clinical, laboratory, and epidemiological data of the patients were collected from the files. RESULTS: In this study, 499 children underwent liver transplantation (LT) in two pediatric transplantation centers. Sixty-eight (13.6%) out of 499 patients, underwent liver transplantation due to fulminant hepatic failure (FHF). Therefore, a total of 64 patients (34 girls, 30 boys) with a diagnosis of FHF have included in the study. Thirty-two (50.0%) of 64 FHF were due to non-A-E hepatitis and 4 out of the 64 patients (6.2%) with FHF developed HAAA. All of the patients received prednisolone as immunosuppression treatment after LT. Three patients were also given Tacrolimus and 1 received an additional mycophenolate mofetil. One of the patients was given prednisolone and cyclosporine treatment without tacrolimus. Bone marrow transplantation was performed in 1 patient (25.0%). Two of the patients received immunosuppressive treatment including rabbit-derived anti-thymocyte globulin, cyclosporine, and initially prednisolone. CONCLUSION: In children who underwent liver transplantation for non-A-E FHF are at high risk to develop aplastic anemia. The clinicians should be alert after orthotropic liver transplantation patient could develop aplastic anemia and early treatment with immunosuppressive therapies result in a more successful outcome.

Insulin secretion-sensitivity index-2 could be a novel marker in the identification of the role of pancreatic iron deposition on beta-cell function in thalassemia major.

The purpose of this study is to evaluate the impact of insulin secretion-sensitivity index-2 (ISSI-2) in the identification of the role of pancreatic iron deposition on beta-cell function in thalassemia major. Tissue iron stores were measured with magnetic resonance imaging (MRI) in the liver (R2), pancreas (R2*), and heart (T2*). ISSI-2 was assessed as a novel oral glucose tolerance test-based measure of beta-cell function. Also, the Stumvoll index showing the insulin sensitivity and Stumvoll index estimating first and second phase insulin secretion were calculated. Fourteen of the 51 Thalassemia Major patients, aged 8-34 (mean 21.1 ± 7.2) years-old, had either an impaired glucose tolerance test (n = 9, 17.6%) or diabetes mellitus (n = 5, 9.8%)-referred to as the glucose dysregulation (GD) group. The median serum ferritin and the mean liver R2 and cardiac T2* values were not significantly different between the GD and normal glucose tolerance (NGT, n = 37) groups whereas pancreas R2* was significantly higher in the GD group compared to the NGT group (p = 0.004). Patients with GD showed significantly lower ISSI-2 index (p < 0.001) as well as the Stumvoll index and Stumvoll first and second phase indices compared to those with NGT (p < 0.001). All patients with GD displayed a pancreas R2* >50 Hz and ISSI-2 <2. In conclusion, Pancreas R2* MRI combined with ISSI-2 index may be valuable parameters to identify patients at the highest risk for developing glucose dysregulation.

Homozygous c.130-131 ins A (pW44X) mutation in the HAX1 gene as the most common cause of congenital neutropenia in Turkey: Report from the Turkish Severe Congenital Neutropenia Registry.

BACKGROUND: Severe congenital neutropenia is a rare disease, and autosomal dominantly inherited ELANE mutation is the most frequently observed genetic defect in the registries from North America and Western Europe. However, in eastern countries where consanguineous marriages are common, autosomal recessive forms might be more frequent. METHOD: Two hundred and sixteen patients with severe congenital neutropenia from 28 different pediatric centers in Turkey were registered. RESULTS: The most frequently observed mutation was HAX1 mutation (n = 78, 36.1%). A heterozygous ELANE mutation was detected in 29 patients (13.4%) in our cohort. Biallelic mutations of G6PC3 (n = 9, 4.3%), CSF3R (n = 6, 2.9%), and JAGN1 (n = 2, 1%) were also observed. Granulocyte colony-stimulating factor treatment was given to 174 patients (80.6%). Two patients died with infectious complications, and five patients developed myelodysplastic syndrome/acute myeloblastic leukemia. The mean (± mean standard error) follow-up period was 129.7 ± 76.3 months, and overall survival was 96.8% (CI, 94.4-99.1%) at the age of 15 years. In Turkey, severe congenital neutropenia mostly resulted from the p W44X mutation in the HAX1 gene. CONCLUSION: In Turkey, mutation analysis should be started with HAX1, and if this is negative, ELANE and G6PC3 should be checked. Because of the very high percentage of consanguineous marriage, rare mutations should be tested in patients with a negative mutation screen.

Fertility in Patients with Thalassemia and Outcome of Pregnancies: A Turkish Experience

Objective: In recent years, the rates of marriage and pregnancy are increasing in patients with thalassemia major. The aim of the present study was to investigate the fertility rate of thalassemic patients and the course of pregnancies in terms of mother and infant health. Materials and Methods: In this observational study patients with major hemoglobinopathy were evaluated regarding marital status, the need for assisted reproductive techniques, fertility rate, iron status, and pregnancy complications. Results: Seventeen female patients gave birth to 21 healthy infants. About one-third of the patients needed assisted reproductive techniques. Thalassemia major patients showed increased serum ferritin levels from 1203±1206 µg/L at baseline to 1880±1174 µg/L at the end of pregnancy. All babies are still alive and healthy. Conclusion: Pregnancy in patients with thalassemia can be safe for the mother and newborn with close monitoring and a multidisciplinary approach.

The role of cardiac troponin T in detection of cardiac damage and long term mortality in children with chronic renal disease.

Karadas U, Özdemir Karadas N, Bak M, Serdaroglu E, Yilmazer MM, Mese T. The role of cardiac troponin T in detection of cardiac damage and long term mortality in children with chronic renal disease. Turk J Pediatr 2019; 61: 873-878. In this study, we aimed to evaluate the role of cardiac troponin T (cTnT) in detecting myocardial involvement in children with chronic kidney disease (CKD) and to investigate whether it contributes to predicting cardiac involvement and mortality at follow-up. Echocardiographic evaluations were performed on a sample of 69 patients, of which 33 (47.8%) were female, with grade 3, 4 and 5 chronic renal failure and end-stage renal failure. Patients with normal cTnT levels and patients with high cTnT levels were compared. cTnT levels were observed to be high in 13 (19%) of the 69 patients. The comparison between the patients with normal cTnT levels and patients with high cTnT levels with regards to the echocardiographic findings revealed that in the latter group, the average ejection fraction and fractional shortening levels were lower (p=0.003 and p=0.013, respectively), the detection rate of left ventricular systolic dysfunction was 5.5 times higher and the rate of detection of left ventricular hypertrophy (LVH) was 3 times higher (p=0.004, p=0.011). In this study, it was shown that it is possible to obtain information about cardiac effects by examining the serum cTnT level before clinical symptoms occur in children with CKD, and that cTnT can be used for screening purposes.