How I manage children with neutropenia Dale, David C.
British journal of haematology,
August 2017, 2017-Aug, 2017-08-00, 20170801, Volume:
178, Issue:
3
Journal Article
Peer reviewed
Open access
Summary
Neutropenia, usually defined as a blood neutrophil count <1·5 × 109/l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life ...the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony‐stimulating factor to treat childhood neutropenia.
Background and importanceUnderreporting in oncology practice is a known phenomenon linked to the predictable toxicity of these drugs. Reporting indicators are often calculated on very large catchment ...areas and this limits the capacity for self-assessment of the performances in each hospital.Aim and objectivesThe purpose of the study was to evaluate the feasibility of the underreporting rate index in a single cancer centre as a process indicator.Material and methodsReports of adverse drug reactions (ADRs), from 1 January 2018 to 31 January 2019 in our institute (230), were collected in a database. The nine most active ingredients reported were subjected to an indepth analysis and their reporting rates were calculated using the formula (number of drug reports X/number of patients treated with drug X)×100 and (number of drug reports X/number of drug administrations X)×100. The expected value was evaluated using the formula (expected frequency×number of patients treated with the drug X)/100, where the expected frequency was calculated by the summary of product characteristics. The rate of underreporting was calculated as a ratio (missing episodes/expected episodes)×100. Only the results of paclitaxel (the most reported drug) are reported in this abstract as an example.ResultsIn the period January 2018 to January 2019, paclitaxel related ADRs were 51 in 412 patients treated (3293 total administrations). The reporting rate for the number of patients treated was 12.4% while the reporting rate by number of administrations was 1.5%. Severe neutropenia represented the main toxicity with an expected incidence of 39%, while the reported incidence was 6.41%.The underreporting rate of ADRs related to paclitaxel were: neutropenia 82.17%, febrile neutropenia 97.22%, transaminite 94.49%, thrombocytopenia 98.46% and diarrhoea 91.02%. Some gastrointestinal and musculoskeletal system reactions were very common reactions (≥1/10) but there were no reports.Conclusion and relevanceThe indicator allowed better identification of the area of underreporting over time in a more precise way than the absolute number of reports. It is feasible, but when the expected frequency of the event decreases to below 10%, the indicator loses reliability for samples <1000 patients. It is therefore mainly a quantitative indicator of frequent events.References and/or acknowledgementsNo conflict of interest.
Summary
This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, ...affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next‐generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events.
Summary
Among 143 patients with elastase, neutrophil‐expressed (ELANE)‐related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic ...neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte‐colony stimulating factor (G‐CSF), on G‐CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem‐cell transplantation. During the disease’s natural history period (without G‐CSF; 1913 person‐years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3), high lymphocyte count (>3000/mm3) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G‐CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.
Neutropenia lasting for at least for 3 months and not attributable to drugs or a specific genetic, infectious, inflammatory, autoimmune or malignant cause is called chronic idiopathic neutropenia ...(CIN). CIN and autoimmune neutropenia (AIN) are very similar and overlapping conditions. The clinical consequences depend upon the severity of neutropenia, but it is not considered a premalignant condition.
Long-term observational studies in children indicate that the disease often lasts for 3-5 years in children, then spontaneously remits, but it rarely remits in adult cases. The value of antineutrophil antibody testing in both children and adults is uncertain. Most recent data suggest that CIN and AIN are immune-mediated diseases, but there are no new clinical or genetic tests to aid in diagnosis. Treatment with granulocyte colony stimulating factor (G-CSF) is effective to increase blood neutrophils in almost all cases; this treatment is reserved, however, for patients with both neutropenia and evidence of recurrent fevers, inflammatory symptoms and infections. There is little or no evidence to indicate that G-CSF treatment predisposes to myeloid malignancies in this population.
It is important to recognize CIN and AIN, the most common causes of chronic neutropenia in both children and adults. If the neutropenia is not severe, that is more than 0.5 × 10/l, most patients can be observed and not treated prophylactically with antibiotics or a growth factor. When neutropenia is severe, treatment with G-CSF is often beneficial.
Febrile neutropenia (FN) is a prevalent and potentially life-threatening complication in patients with lymphoma receiving myelosuppressive chemotherapy. Pegfilgrastim is more effective than ...filgrastim as prophylaxis for FN. However, its usage has been limited because of its higher cost. Pegfilgrastim's value for money remains unclear.
To systematically review the cost-effectiveness of pegfilgrastim compared to filgrastim as a primary or secondary prophylaxis for chemotherapy-induced FN among patients with lymphoma.
A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library databases, and Google Scholar. The most widely used economic evaluations (cost-effectiveness analysis, cost-utility analysis and cost-benefit analysis) were included in the review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards checklist, and the quality of reviewed articles was assessed using the Joanna Briggs Institute (JBI) checklist. Cost-effectiveness data were rigorously summarized and synthesized narratively. Costs were adjusted to US$ 2020.
We identified eight economic evaluation studies (two cost-utility analyses, three cost-effectiveness analyses, and three studies reporting both cost-effectiveness and cost-utility analyses). Half of these studies were from Europe (n = 4), the other half were from Iran, USA, Canada, and Singapore. Six studies met > 80% of the JBI quality assessment criteria. Cost-effectiveness estimates in the majority (n = 6) of these studies were for Non-Hodgkin Lymphoma patients receiving myelosuppressive chemotherapy with high-risk of FN (> 20%). The studies considered a wide range of baseline FN risk (17-97.4%) and mortality rates (5.8-8.9%). Reported incremental cost-effectiveness ratios ranged from US$ 2199 to US$ 8,871,600 per quality-adjusted life-year (QALY) gained, dominant to US$ 44,358 per FN averted, and US$ 4261- US$ 7251 per life-years gained. The most influential parameters were medication and hospitalization costs, the relative risk of FN, and assumptions of mortality benefit.
Most studies showed that pegfilgrastim is cost-effective compared to filgrastim as primary and secondary prophylaxis for chemotherapy-induced FN among patients with lymphoma at a cost-effectiveness threshold of US$ 50,000 per QALY gained. The findings could assist clinicians and healthcare decision-makers to make informed decisions regarding resource allocation for the management of chemotherapy-induced FN in settings similar to those studied.
Despite the overwhelming evidence for the role of granulocyte colony stimulating factors (G-CSF) in managing febrile neutropenia (FN) risk, chemotherapy-induced neutropenia (CIN) and/or FN still ...remain the most common reasons for reducing relative dose intensity (RDI) and/or delaying chemotherapy schedule. The need to maintain RDI to ensure optimal clinical outcomes is one of the key rationales for utilizing G-CSF. There is a high incidence of reduced RDI in both curative and palliative settings, and this observation is especially evidenced in retrospective analyses. Reduced RDI leads to significantly decreased survival outcomes and quality of life in various malignancies at various clinical settings and stages.
Beyond its role as a surrogate prognostic marker, high-grade CIN may have an unexpected predictive role in clinical practice, as illustrated by several data relating CIN occurrence with favorable survival outcomes; this may be due to the fact that body surface area (BSA) – based calculation of dose may not fully account for the pharmacokinetics (PK) of cytotoxic drugs and the fact that there may be variability in drug metabolism between patients treated with same chemotherapy regimens.
Aim
The aim of this study was to provide an overview of foetal/neonatal alloimmune neutropenia (FNAIN), together with advice on the clinical management.
Methods
Neutrophil serology in the Netherlands ...is centralised at Sanquin Diagnostic Services. We examined FNAIN cases between January 1, 1991, and July 1, 2013, to determine the number of cases diagnosed, the relationship with human neutrophil antigen (HNA) antibody, the clinical presentation and therapeutic interventions.
Results
We identified 35 FNAIN cases. The detected HNA antibodies were as follows: anti‐HNA‐1a (n = 7), anti‐HNA‐1b (n = 12), anti‐HNA‐1c (n = 2), anti‐HNA‐2 (n = 8), anti‐HNA‐3a (n = 1), anti‐HNA‐5a (n = 1) and anti‐FcγRIIIb (n = 4). No infections were diagnosed in 14 neonates, and the other 21 neonates suffered from omphalitis (n = 6), urinary tract infection (n = 1), candida mucositis (n = 1), fever of unknown origin (n = 6) and sepsis (n = 7, 20%). Parity, gestational age, birthweight, neutrophil counts and antibody specificity were not significantly different for cases with, and without, infections. All the infected children were treated with antibiotics. No children died.
Conclusion
More than half (21) of the 35 cases of FNAIN presented with infections and most implicated were HNA‐1a, HNA‐1b and HNA‐2. Treatment with antibiotics seemed adequate. A neonatal neutropenia workflow model for use in neonatal intensive care units is presented.
PDF
