Small but mighty: Case report and practical guidance for peripheral blood stem cell collection in small infants.

Modern apheresis devices, with increased procedural precision, automation, and monitoring, have been shown to allow for safe delivery of apheresis therapies in young children. Medical advances are increasing demand for apheresis procedures like mononuclear cell collection in infants <10 kg, including stem-cell supported chemotherapy, cell collection for chimeric antigen receptor T cell development, and now ex vivo gene therapies for rare genetic diseases. Nevertheless, safe delivery in small infants involves a range of unique considerations and challenges, beyond just size, and experience will vary between centers. In this case report we describe our experience performing mononuclear cell collection in our smallest patient to date and outline a practice guideline developed following a literature review and discussion with both international experts and device representatives. This case may help to inform other clinicians aiming to provide apheresis care to very small infants in their own centers.

Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry.

BACKGROUND: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. AIMS: To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR. METHODS: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period. RESULTS: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries. CONCLUSIONS: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population.

Effects of dual chelation therapy with deferasirox and deferoxamine in patients with beta thalassaemia major.

BACKGROUND AND OBJECTIVES: Patients with thalassaemia experience complications related to iron overload. In Australia currently, the two main options for iron chelation are deferasirox and deferoxamine. Optimal iron chelation using monotherapy can be limited due to toxicity or tolerability. Dual chelation therapy (DCT) may provide more aggressive iron chelation. MATERIAL AND METHODS: A retrospective, observational study was performed on a state-wide referral centre for patients receiving red cell transfusions for haemoglobinopathies (Monash Health, Australia). All patients prescribed DCT were identified using a local pharmacy dispensing database and were included in the study. Pre-DCT initiation and post-DCT completion were correlated with serum ferritin, cardiac iron loading (based on MRI T2* measurements) and liver iron content (LIC) using Wilcoxon signed-rank test. RESULTS: A total of 18 patients (12 adults, 6 children) were identified as receiving DCT. All patients received a combination of deferasirox and deferoxamine. The median duration of therapy was 23 months (range 2-73). Median serum ferritin reduced by 42% (p = 0.004) and there was a 76% reduction in LIC (p = 0.062). No significant changes were seen in cardiac iron loading. CONCLUSION: DCT over a prolonged period is effective at reducing serum ferritin and may contribute to improvement in liver iron loading.

Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes.

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.

Congenital Methemoglobinemia Type II-Clinical Improvement with Short-Term Methylene Blue Treatment.

We report a case of prophylactic management with methylene blue (MB) in an almost 4-year-old male with congenital methemoglobinemia type II. He has a CYB5R3 compound heterozygote mutation, causing a cytochrome-b(5) reductase deficiency. Since the MB treatment regimen has commenced, his methemoglobin level has been significantly lower. He has shown modest behavioral improvements (as assessed on the Achenbach behavior report scales). There have been no iatrogenic side effects. These findings are encouraging for symptomatic improvement with regular prophylactic MB treatment but represent a single case report, which must be interpreted with caution.

Characterization of core clinical phenotypes associated with recurrent proximal 15q25.2 microdeletions.

A recurrent proximal microdeletion at 15q25.2 with an approximate 1.5 megabase smallest region of overlap has recently been reported in seven patients and is proposed to be associated with congenital diaphragmatic hernia (CDH), mild to moderate cognitive deficit, and/or features consistent with Diamond-Blackfan anemia. We report on four further patients and define the core phenotypic features of individuals with this microdeletion to include mild to moderate developmental delay or intellectual disability, postnatal short stature, anemia, and cryptorchidism in males. CDH and structural organ malformations appear to be less frequent associations, as is venous thrombosis. There is no consistent facial dysmorphism. Features novel to our patient group include dextrocardia, obstructive sleep apnea, and cleft lip.

Hospitalisations for sickle-cell disease in an Australian paediatric population.

AIM: Sickle-cell disease (SCD) is more prevalent in Australia due to increased migration; however, the Australian paediatric SCD population has not been previously described. This study aimed to identify the demographic features of and quantify the hospital resource utilisation in the SCD population at The Royal Children's Hospital in Victoria. METHODS: This was a retrospective chart review of SCD patients who presented to the Royal Children's Hospital over a 10.5-year period. Descriptive analyses were conducted. RESULTS: Thirty-seven SCD patients aged from 0.2 to 18.0 years (mean: 8.5 ± 4.8 years) had 535 admissions over the 10.5-year period. The population was made up of 28 homozygous sickle-cell disease, 1 sickle C disease and 8 sickle-cell beta patients from a variety of ethnic backgrounds. Admissions included 264 unplanned admissions, that is 258 admissions via the emergency department and 6 admissions via outpatients, and 271 planned admissions. Mean length of stay for unplanned admissions was 3.2 ± 2.6 days. Common diagnoses for unplanned admissions were 187 vaso-occlusive crisis (70.8%), 32 infections (12.1%) and 26 anaemic episodes (9.8%). Transfusion therapy (91.9%) accounted for the majority of planned admissions. CONCLUSIONS: Children with sickle-cell disease in an Australian setting require hospitalisation for various reasons related to disease, either unexpected complications or elective procedures. Factors affecting the provision of optimal healthcare to be explored include the multicultural demographics of the SCD population, the timely management of vaso-occlusive crises and the availability of SCD-related protocols.

Common pathway coagulopathy and hemorrhagic edema of infancy.

When screening tests of haemostasis are abnormal, it is important to identify at which point in the coagulation cascade dysfunction may be occurring. This may assist to identify a specific deficiency/dysfunction, the type of bleeding to be anticipated, and replacement therapy if required. Unmasking of an inherited coagulopathy or the development of an acquired coagulopathy may occur in the setting of a second (febrile) illness. Differentiating between inherited and acquired coagulopathies will rely on clinicians taking a thorough personal and family bleeding history, and correlating these findings with the haemostasis screening results.

Using an electronic medical record patient portal for warfarin self-management: Empowering children and parents.

Background: Many children taking warfarin perform their international normalized ratio (INR) at home, with results phoned to a clinician who instructs warfarin dosing. Data suggest that parents can be supported to make warfarin dosing decisions themselves, a process known as patient self-management (PSM). Objectives: This study aimed to determine the suitability and acceptability of warfarin PSM in children using the Epic Patient Portal. Methods: Children currently performing INR patient self-testing were eligible. Participation involved an individualized education session, adherence to the PSM program, and participation in phone interviews. Clinical outcomes (INR time in therapeutic range and safety outcomes), patient portal functionality, and family experience were assessed. The hospital human research ethics committee approved the study and consent was obtained from parents/guardians. Results: Twenty-four families undertook PSM. The median age of children was 11 years and all children had congenital heart disease. A median of 13 INRs was uploaded to the portal per family (range, 8-47) across a 10-month period. Before PSM, the mean time the INR was in therapeutic range was 71%; this increased to 79.9% during PSM (difference: P < .001). No adverse events were encountered. Eight families participated in a phone interview. The major theme identified was empowerment; minor themes that emerged included "gaining knowledge," "trust and responsibility builds confidence," "saving time," and "resources as a safety net." Conclusion: This study demonstrates that communication via the Epic Patient Portal is satisfactory to families and offers a suitable option for PSM for children. Importantly, PSM empowers and builds confidence in families to facilitate management of their child's health.

Guiding warfarin self-management in children: development of a warfarin nomogram.

Background: Warfarin therapy in children is impacted by many variables. To support the implementation of a self-management program within a pediatric anticoagulation service, a pediatric-specific warfarin nomogram was needed. A literature review revealed no published pediatric nomograms; therefore, a nomogram was developed drawing upon an evidence-based "Warfarin Information for Clinicians" hospital guideline. Objectives: This study aimed to evaluate the suitability of a pediatric warfarin nomogram. Methods: A retrospective audit of electronic medical records compared the dosing and international normalized ratio (INR) retest decisions made by hematology clinicians to the dosing and retesting recommended by a new warfarin nomogram at a pediatric hospital. Children (aged 6 months-18 years) receiving warfarin therapy for >6 months were included. Data were collected between September 2019 and February 2020. Descriptive data analysis was performed. The study was approved by the hospital's Human Research Ethics Committee. Results: Warfarin dosing and INR retest decisions for 39 children were included, equating to 521 INRs. The nomogram matched 81.4% of clinicians dosing decisions and 30% of INR retest decisions. Moreover, 59% of the clinician-recommended retest dates were earlier than the nomogram recommendation. In the INR 2.0-3.0 group, 84.4% of dosing decisions and 72% of retest decisions matched the nomogram. Conclusions: These results suggest that this pediatric nomogram is a suitable tool for warfarin dosing, as recommended warfarin doses matched the majority of clinicians' decisions. Modification may be needed to nomogram recommendations for the time to retest. This nomogram can be used to support warfarin self-management and may assist clinicians and patients or families in making evidence-based dosing decisions.

Long-term results using hydroxyurea/phlebotomy for reducing secondary stroke risk in children with sickle cell anemia and iron overload.

Children with sickle cell anemia (SCA) and a primary overt stroke are at high risk of recurrent (secondary) stroke. Chronic transfusion therapy dramatically reduces but does not eliminate this high risk, and inevitably results in transfusion-related hemosiderosis. We previously reported the use of hydroxyurea/phlebotomy as an alternative to transfusions to reduce the risk of secondary stroke and improve management of iron overload in 35 children with SCA. To report long-term results, we retrospectively reviewed clinical and laboratory data through October 2008. With a median of 5.6 years and total of 219 patient-years of follow-up, 10 of 35 patients (29%) had recurrent stroke after switching to hydroxyurea; seven were previously reported and three new strokes occurred during extended follow-up. The overall secondary stroke event rate was 4.6 per 100 patient-years. Children on hydroxyurea received serial phlebotomy and had lower mean serum ferritin values than children on transfusions (591 ng/mL vs. 3410 ng/mL, P = 0.02). In this cohort, long-term hydroxyurea treatment reduced but did not eliminate the risk of stroke recurrence and, uniquely, allowed phlebotomy to reduce iron overload. Long-term assessments of this therapy should evaluate risk factors for secondary stroke and assessments of hemosiderosis, neurocognitive outcome, and health-related quality of life.

Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates.

BACKGROUND: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. AIMS: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. METHODS: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved. RESULTS: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 108 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 108 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 108 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved. CONCLUSIONS: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear.

Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure.

Heterozygous pathogenic variants in SPTB cause autosomal dominant hereditary spherocytosis, an important cause of neonatal nonimmune hemolytic anemia. Biallelic mutations are rarely reported, all with severe neonatal presentation. We describe rapid (68 h) genomic diagnosis of homozygous ß-spectrin deficiency in a newborn with severe transfusion-dependent hemolytic anemia, conjugated hyperbilirubinemia, and progressive liver failure. Trio whole-exome sequencing identified a novel biallelic SPTB variant (c.6119C>T; p.Thr2040Ile) located in the critical spectrin repeat region. Pretransfusion blood film showed marked spherocytosis including microspherocytes and nucleated erythrocytes, and eosin-5-maleimide (E5M) staining was markedly reduced, supporting pathogenicity. Both asymptomatic heterozygous parents demonstrated mildly reduced E5M staining, with occasional spherocytes and elliptocytes. Early molecular diagnosis facilitated hypertransfusion to suppress ineffective erythropoiesis and reverse hepatic dysfunction. This report broadens the genotypic and phenotypic spectrum of spectrin deficiency and highlights the utility of rapid genomic testing in facilitating early diagnosis and informing targeted therapy in critically ill patients.

Point-of-care monitoring of oral anticoagulation therapy in children. Comparison of the CoaguChek XS system with venous INR and venous INR using an International Reference Thromboplastin preparation (rTF/95).

Point-of-care (POC) monitoring of oral anticoagulation has been widely adopted in both paediatric and adult patients. A new POC system, the CoaguChek XS has recently been developed to measure the international normalised ratio (INR) and may offer significant advantages. The CoaguChek XS utilises a new method of electrochemical clot detection based on thrombin generation. This system has not been previously evaluated in children with reference to the laboratory gold standard, the prothrombin time using reference thromboplastin. It was the objective to compare values obtained by the CoaguChek XS system with both the venous INR and the gold standard for anticoagulant monitoring, prothrombin time with reference thromboplastin (rTF/95). To evaluate the impact of testing using the CoaguChek XS on clinical anticoagulant dosing decisions. Fifty paired venous INR and capillary CoaguChek XS results were obtained from 31 children (aged up to 16 years). The laboratory gold standard, a manual prothrombin time with reference thromboplastin (rTF/95) was additionally performed on 26 samples. Correlation between the CoaguChek XS result and the venous INR was r = 0.810. Agreement between the CoaguChek XS result and the reference INR was shown to be higher (r=0.95), in the subset analysed by this method. Correlation between the venous INR and reference INR was r=0.90. Despite changes to the methodology of testing with the CoaguChek XS POC monitoring system, the accuracy of this method when compared with both the venous INR and gold standard reference INR was satisfactory. This resulted in infrequent changes to clinical decision making regarding anticoagulation.

Platelet dysfunction and increased bleeding tendency in McCune-Albright syndrome.

We observed increased bleeding tendency and platelet function abnormalities in 3 boys with McCune-Albright syndrome (MAS). We speculate that platelet dysfunction contributed to excessive blood loss in our patients. This report of platelet dysfunction in MAS highlights the need for assessment of platelet functions in the condition.

Rituximab and protection from vaccine preventable diseases: applying the evidence to pediatric patients.

INTRODUCTION: This article analyses and highlights the challenge of immunization and preventing vaccine preventable diseases in pediatric patients on rituximab. Rituximab is a chimeric anti-CD 20 monoclonal antibody that is an immunosuppressant affecting both cellular and humoral immunity. Children and adolescents on rituximab are at increased risk of infection and vaccine preventable diseases, and require additional strategies to optimize and maximize their protection against such illnesses. Areas covered: This article provides a comprehensive MEDLINE and Pubmed review of existing literature regarding vaccine immunogenicity and safety in patients on rituximab, and assists in providing an evidence base to develop immunization guidelines. Of particular note, the use of live-attenuated vaccines and optimum timing of vaccines post rituximab is considered and discussed. Expert commentary: The increasing use of rituximab in a variety of novel areas within pediatrics must be accompanied by informed discussion around mitigating the risks. These include immunosuppression, and potential susceptibility to infection. Optimizing vaccine status by establishing adequate antibody titers prior to commencement remains the best preventative strategy.