Chronic Neutropenia Of Childhood Research Articles

Chronic neutropenia in childhood: experience of a tertiary center

ObjectiveTo assess the prevalence of chronic neutropenia (CN) and the clinical profile of patients with CN aged up to 18 years, followed in the pediatric hematology, rheumatology, or immunology outpatient clinic of a tertiary medical center from May 1, 2018, to 30 April 2019. MethodsRetrospective observational study carried out by collecting data from the patient's medical charts. CN was defined as absolute neutrophil count (ANC) below 1.5 × 109/L lasting over three months. Autoimmune neutropenia (AIN) was defined by clinical criteria and an over twofold increase in ANC after glucocorticoid stimulation. AIN was considered secondary when associated with autoimmune or immunoregulatory disorders. Wilcoxon and Fisher's exact tests were used to compare variables; the significance level was 5 %. ResultsA total of 1,039 patients were evaluated; 217 (20 %) presented CN. Twenty-one (2 %) had AIN, classified as primary in 57 % of the cases. The average age at the onset of symptoms was 38.6 months. During follow-up, patients had 4.2 infections on average; frequency was higher among patients with secondary AIN (p = 003). Isolated neutropenia occurred in 43 % of the patients with AIN. Neutropenia resolved in eight (38 %) of the 21 patients with AIN within 19.6 months on average. Eight patients with secondary AIN met the criteria for Inborn Errors of Immunity. ConclusionAIN prevalence was 2 %. Most cases were first evaluated by a pediatric immunologist or rheumatologist rather than a pediatric hematologist. This study highlights the need for a multidisciplinary approach involving a pediatric immunologist, rheumatologist, and hematologist.

Chronic Neutropenia in Childhood: Laboratory and Clinical Features.

To describe the clinical characteristics of patients with chronic neutropenia. Data of 36 patients with chronic neutropenia, who were followed up in the authors' clinic between May 2013 and May 2020, were analyzed retrospectively. Patients were diagnosed based on their clinical and laboratory characteristics. A total of 36 patients (23 females, 13 males) were included in the study. The mean age at diagnosis was 9.85 ± 9.17 mo while the mean follow-up time was 21.83 ± 20.03 mo. The mean absolute neutrophil count (ANC) at admission was 462.5 ± 388.8 cells/mm3 (median = 375 cells/mm3), and the lowest and highest ANC mean was 241.2 ± 262.1 cells/mm3 (median = 125 cells/mm3), and 1362.9 ± 1127.9 cells/mm3 (median = 925 cells/mm3), respectively. Idiopathic neutropenia was found in 28 (77.8%) patients, autoimmune neutropenia in 6 (16.7%) patients, and congenital neutropenia in 2 (5.6%) patients. Neutrophil normalization was observed in 19 (52.8%) of the patients. Chronic neutropenia is a heterogeneous picture that presents with different clinical symptoms in childhood. The cause of neutropoenia in children is usually benign and resolves spontaneously but especially in those with severe neutropoenia genetic examination should be performed.

Chronic neutropenia in childhood

Die schwere chronische Neutropenie („severe chronic neutropenia“, SCN) umfasst eine heterogene Gruppe von Erkrankungen mit einem gemeinsamen hamatologischen und klinischen Phanotyp, der durch eine absolute Neutrophilenzahl unterhalb 0,5 ⋅ 109/l und ein erhohtes Risiko fur schwere bakterielle Infektionen charakterisiert ist. Die Unterscheidung zwischen angeborener und erworbener Neutropenie sowie die Identifikation ursachlicher Genmutationen sind von immenser Bedeutung fur die Bewertung der Prognose. In den ersten 3 bis 5 Lebensjahren sind die primaren Autoimmunneutropenien die haufigste Ursache einer SCN. Angeborene, vererbte Neutropenien haben trotz ihrer Seltenheit einen erheblichen Wert fur die Erforschung normaler und pathologischer Blutbildung sowie eine fundamentale Bedeutung fur das heutige Verstandnis der Hamatopoese. Bisher konnten mehr als 30 verschiedene Genmutationen beschrieben werden, die mehrheitlich mit einem erhohten Leukamierisiko (bis zu 20 %) assoziiert sind. Durch die Verfugbarkeit und Behandlung mit dem hamatopoetischen Wachstumsfaktor Granulozyten-koloniestimulierender Faktor (G-CSF; Filgrastim/Lenograstim) seit 1987 hat sich die Langzeitprognose von SCN-Patienten dramatisch verbessert: Bakterielle Infektionen werden verhindert, und die Lebensqualitat der Betroffenen hat sich normalisiert.

Chronic Neutropenia in Childhood: Experience From a Single Center.

Chronic neutropenia (CN) is defined as neutropenia that persists for >3 months; it is caused by a heterogeneous group of diseases in children. The aim of the present study was to evaluate the significance and clinical manifestations of CN in children at a single children's hospital. Between October 2004 and April 2014, CN patient data were evaluated retrospectively. Thirty-one patients were assessed in this study. Thirteen of them (41.9%) were younger than 12 months of age at initial diagnosis. There was no difference in the absolute number of neutrophils at diagnosis between the children aged younger than 12 months and those aged 12 months and older at CN onset. Twenty-two of the patients (70.9%) were diagnosed during treatment for acute infections. A total of 11 patients (35.5%) were hospitalized because of recurrent infections. Most of the recurrent infections occurred in the lungs (81.8%). Congenital neutropenia (CoN) was identified in 14 patients (45.1%). Eight of 14 patients (57.1%) required granulocyte-colony stimulating factor treatment, and none of them experienced adverse effects from this treatment. Fifteen patients (48.3%) were diagnosed with idiopathic neutropenia. Comparison between the idiopathic and CoN groups revealed no differences in age, the absolute number of neutrophils, or the presence of infection at diagnosis; however, differences were detected in sex and the rate of spontaneous recovery from neutropenia. Ten of the patients (32.2%) experienced spontaneous recovery from neutropenia during a follow-up period of 7 to 52 months. In current study, we found a higher CoN ratio in the CN patients compared with previous reports, which may be due to the high rate of consanguineous marriages in our country. However, the finding of CN requires several laboratory investigations, prolonged follow-up, and advanced molecular analysis, and its etiology can remain idiopathic.

The Use of Pegylated G-CSF in Chronic Neutropaenia of Childhood. A Single Centre Experience

AbstractAbstract ▪3268▪This icon denotes a clinically relevant abstractChronic Neutropenia of Childhood (CNC) is defined as an absolute neutrophil count that is persistently below 0.5×109/L and leaves patients at risk of severe, systemic bacterial and fungal infections. The standard treatment to raise the neutrophil count is daily injections of recombinant G-CSF to maintain the neutrophil count above 1.0 × 109/L and the child infection free.A long acting Pegylated G-CSF (PEG G-CSF) is available but is unlicensed for use in chronic neutropenia and in children. Concern has been expressed regarding long term exposure to PEG G-CSF and the potential for neutralising antibodies; there is a lack of clinical evidence and experience in its use for CNC. Potential advantages exist in its use including a more stable and sustained neutrophil count and fewer subcutaneous injections; the latter an important consideration in a paediatric population.We report a single centre experience of seven consecutive cases using PEG G-CSF in CNC. Five boys and two girls age range five months to six years had a total of thirty four presentations in Accident and Emergency for bacterial infection; eleven episodes required hospital admission and intravenous antibiotics. All had a history of persistent neutropenia ranging from one to thirty two months. Prophylactic oral anti-infectives; ciprofloxacin and itraconazole were prescribed and once bone marrow examination had excluded evidence for other causes of persistent neutropenia standard G-CSF was commenced.All seven patients were responsive to G-CSF and so following two – four weeks of treatment a switch to PEG G-CSF was made. Neutrophil response kinetics was monitored to tailor individual dose and frequency of injections.In all cases there was an increased longevity of neutrophil response over time. Treatment with PEG G-CSF was required initially every seven days, but the neutrophil count was ultimately sustained by one injection every three to four weeks. We hypothesise that this is due to gradual recruitment of immature precursors and stem cells towards the neutrophil lineage; whereas the initial neutrophil responses are the result of more mature committed precursors.Once on PEG G-CSF there was a marked reduction in serious bacterial infections with a total of only six urgent medical assessments sought. This resulted in one admission each for three of the children. Four children had no further hospital admissions.The neutrophil count responded and was maintained in all seven cases. Prophylactic anti-infectives were discontinued once a stable neutrophil count was achieved. Six patients continued the PEG G-CSF successfully whilst one discontinued its use due to maternal concerns of an associated behaviour change and sleep disturbance, not an expected side effect of PEG G-CSF.These cases demonstrate the effective, safe use of PEG G-CSF in chronic neutropenia of childhood, with a more sustained neutrophil count and thus reduced risk of infection. There was no evidence of a reduced response to PEG C-CSF suggesting no development of neutralising antibodies.The decreased frequency of injections has led to an improved quality of life for these children and their families, with fewer hospital visits for treatment, blood sampling and review. Disclosures:Off Label Use: PEGylated G-CSF used in chronic neutropaenia of childhood.

Eponym

Rolf Kostmann (1909-1982) was a Swedish pediatrician and army doctor. He was the first to describe an inherited form of chronic neutropenia in childhood. In 1956, Kostmann published his article "Infantile genetic agranulocytosis" in Acta Paediatrica. "Infantile agranulocytosis," as Rolf Kostmann named this hereditary syndrome, has been known for more than half a century, yet the underlying genetic mutations have remained unknown for many decades. Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 were found in affected members of the original Kostmann pedigree. Therefore, the eponym "Kostmann disease" best fits this specific mutation and mode of inheritance. The identification of genetic cause now allows the analysis of genotype-phenotype correlations. After the development of recombinant human granulocyte colony-stimulating factor (G-CSF), the prognosis and quality of life improved dramatically. Hematopoietic stem cell transplantation remains the only currently available treatment for refractory cases to G-CSF and patients who have transformed into leukemia.

小児慢性好中球減少症におけるP-100 (CSF-HU)の臨床効果に関する検討

小児慢性好中球減少症におけるP-100 (CSF-HU)の臨床効果に関する検討

Glycosphingolipid expression in acute nonlymphocytic leukemia: common expression of shiga toxin and parvovirus B19 receptors on early myeloblasts

Glycosphingolipids (GSLs) are complex macromolecules on cell membranes that have been shown to play a role in neutrophil differentiation, activation, phagocytosis, and adhesion to both microorganisms and vascular endothelium. Because GSLs are often cryptic antigens on cell membranes, little is known regarding GSL expression in early myelopoiesis. To study the latter, myeloblasts were collected from patients with acute nonlymphocytic leukemia (ANLL) who required therapeutic leukocytopheresis for hyperleukocytosis. The neutral GSLs were isolated and identified by high-performance thin-layer chromatography (HPTLC), HPTLC immunostaining, gas chromatography, nuclear magnetic resonance, and fast atom bombardment-mass spectrometry. Like mature peripheral blood neutrophils, myeloblasts expressed glucosylceramide, lactosylceramide, and the neolacto-family GSLs, lactotriaosylceramide and neolactotetraosylceramide. Unlike neutrophils and chronic myeloid leukemia, most ANLL samples also expressed the globo-series GSLs, globotriaosylceramide and globotetraosylceramide. Globo GSL expression was strongly associated with a myeloblastic (ANLL M0-M2) and monoblastic phenotype (M5). A weak association was also noted with expression of either lymphoid (P <.10) or early hematopoietic markers (terminal deoxynucleotidyl transferase [TdT], CD34; P <.10). Globo-positive ANLL samples bound both shiga toxin and parvovirus B19 on HPTLC immunostaining. Based on these findings, we propose that neolacto and globo GSLs are expressed during early myeloid differentiation. Globotriaosylceramide expression on myeloblasts, and possibly myeloid stem cells, may have important implications for the use of shiga toxin as an ex vivo purging agent in autologous stem cell transplantation. Expression of globotetraosylceramide, the parvovirus B19 receptor, on myeloblasts may also explain the association between B19 infection, aplastic anemia, and chronic neutropenia of childhood.

Serum granulocyte colony-stimulating factor levels in patients with chronic neutropenia of childhood: modulation of G-CSF levels by myeloid precursor cell mass

The serum G-CSF levels of eight patients with severe congenital neutropenia (SCN) were found to be significantly higher than those of 22 patients with chronic benign neutropenia (CBN). The relative number of cells expressing the G-CSF receptor in light density bone marrow cells (LDBMC) was lower in patients with SCN than in patients with CBN or in normal subjects. When recombinant human G-CSF was incubated with LDBMC, G-CSF levels were decreased by LDBMC from normal subjects and CBN patients, but not by those from SCN patients. Serum G-CSF concentrations, which are affected by mature neutrophils, may also be modulated by myeloid precursor cells in the bone marrow.

Serum granulocyte colony‐stimulating factor levels in patients with chronic neutropenia of childhood: modulation of G‐CSF levels by myeloid precursor cell mass

The serum G-CSF levels of eight patients with severe congenital neutropenia (SCN) were found to be significantly higher than those of 22 patients with chronic benign neutropenia (CBN). The relative number of cells expressing the G-CSF receptor in light density bone marrow cells (LDBMC) was lower in patients with SCN than in patients with CBN or in normal subjects. When recombinant human G-CSF was incubated with LDBMC, G-CSF levels were decreased by LDBMC from normal subjects and CBN patients, but not by those from SCN patients. Serum G-CSF concentrations, which are affected by mature neutrophils, may also be modulated by myeloid precursor cells in the bone marrow.

Chronic neutropenia of childhood: frequent association with parvovirus infection and correlations with bone marrow culture studies

Children with neutropenia of more than 3 months duration often have evidence of immune-mediated destruction of mature neutrophils and variable abnormalities of myeloid precursors in their bone marrow. These patients often have anti-neutrophil antibodies which persist for several months. To further investigate the aetiology of neutropenia in such patients, bone marrow cells were evaluated for the presence of common viruses. Fifteen of 19 patients tested had evidence for parvovirus infection by PCR amplification of bone marrow DNA with parvovirus specific primers. Of these 15, six also had serologic evidence of parvovirus infection. Anti-neutrophil antibodies were identified in nine of 12 patients with parvovirus infection. Bone marrow culture studies done on six patients revealed varying degrees of myeloid and erythroid inhibition by patient plasma. These studies indicate that parvovirus may be a common cause of immune-mediated neutropenia in children.

Chronic Neutropenia During Childhood

To evaluate the clinical course and characteristics of children with chronic neutropenia, we reviewed the charts of all such patients seen at our center during a 13-year period. A total of 50 patients with chronic neutropenia were identified. Three patients had documented congenital neutropenia, and two siblings had cyclic neutropenia. The remaining 45 children had chronic neutropenia of unknown origin. All children except two had a remarkably benign course despite markedly reduced granulocyte counts. Of six girls in this group who had abscess or cellulitis of the labia majora, it was a presenting manifestation in three. Resolution of neutropenia was documented in 23 (62%) of 37 patients for whom follow-up information was available, with a median duration of neutropenia of 19 months. No differences were evident between patients with positive antineutrophil antibody test results and those in whom the test yielded negative results or was not performed. Chronic neutropenia in childhood is a relatively uncommon entity, characterized by a benign course and eventual resolution in the majority of patients.

Increases in Neutrophil Counts by Purified Human Urinary Colony-Stimulating Factor in Chronic Neutropenia of Childhood

Clinical effects of purified human urinary colony-stimulating factor (CSFHU) were studied in nine patients with chronic neutropenia of childhood who ranged in age from 1 to 18 years. The patients were given CSFHU at a dose of 6 x 10(6) U/m2/d for seven consecutive days, and their peripheral neutrophil counts were serially followed for 6 to 12 months. In addition, changes in bone marrow morphology and granulocyte-macrophage colony-forming cells (GM-CFUs) were studied. Transient increases in neutrophil counts occurred during the first 4 weeks in all patients except one. Repeated increases were seen in a cyclic fashion in five patients. Three of the patients recovered from the neutropenia after several cycles of fluctuation of neutrophil counts; the counts (per microliter) reached 5,880, 5,640, and 2,000 as compared with pretreatment levels (mean +/- 2 SD) of 80 +/- 164, 182 +/- 250, and 2 +/- 14, respectively. The percentage (mean +/- SE) of marrow neutrophilic cells increased from 30.4% +/- 7.0% to 34.9% +/- 6.9% (P less than .05) and the ratio of the later neutrophil precursors to the earlier ones from 1.02 +/- 0.27 to 1.42 +/- 0.36 (P less than .02) 2 weeks after CSFHU infusion. There were no changes in GM-CFU numbers. These results indicate that CSFHU can increase neutrophil counts by increasing the number and maturity of the marrow neutrophil precursors in some types of childhood chronic neutropenia.

Increases in neutrophil counts by purified human urinary colony- stimulating factor in chronic neutropenia of childhood

Clinical effects of purified human urinary colony-stimulating factor (CSFHU) were studied in nine patients with chronic neutropenia of childhood who ranged in age from 1 to 18 years. The patients were given CSFHU at a dose of 6 x 10(6) U/m2/d for seven consecutive days, and their peripheral neutrophil counts were serially followed for 6 to 12 months. In addition, changes in bone marrow morphology and granulocyte- macrophage colony-forming cells (GM-CFUs) were studied. Transient increases in neutrophil counts occurred during the first 4 weeks in all patients except one. Repeated increases were seen in a cyclic fashion in five patients. Three of the patients recovered from the neutropenia after several cycles of fluctuation of neutrophil counts; the counts (per microliter) reached 5,880, 5,640, and 2,000 as compared with pretreatment levels (mean +/- 2 SD) of 80 +/- 164, 182 +/- 250, and 2 +/- 14, respectively. The percentage (mean +/- SE) of marrow neutrophilic cells increased from 30.4% +/- 7.0% to 34.9% +/- 6.9% (P less than .05) and the ratio of the later neutrophil precursors to the earlier ones from 1.02 +/- 0.27 to 1.42 +/- 0.36 (P less than .02) 2 weeks after CSFHU infusion. There were no changes in GM-CFU numbers. These results indicate that CSFHU can increase neutrophil counts by increasing the number and maturity of the marrow neutrophil precursors in some types of childhood chronic neutropenia.

CLINICAL AND ULTRASTRUCTURAL OBSERVATIONS OF BENIGN NEUTROPENIA OF CHILDHOOD AND NEUTROPENIA ASSOCIATED WITH HYPOGAMMAGLOBULINEMIA

Chronic neutropenia of childhood and neutropenia associated with hypogammaglobulinemia may have autoimmune etiologies. We observed 9 patients with isolated neutropenia and 5 boys with neutropenia associated with hypogammaglobulinemia. Both types of patients presented between 4 and 24 months of age with recurrent otitis media, skin infections caused by S. aureus, P. aeruginosa or Candida and chronic diarrhea. Only the 5 patients with hypogammaglobulinemia developed invasive infections such as bacterial pneumonias and sepsis due to pseudomonas and clostridia. No patients developed an invasive infection while receiving gammaglobulin. No demargination was observed after epinephrine, and no sustained response occurred with steroid therapy. Anti-neutrophil antibodies were not detected in 10 of 12 patients. All patients with hypogammaglobulinemia had elevated percents of T4 lymphocytes. Marrow aspirates showed deficiency of granulocytes beyond the myelocyte or metamyelocyte stage. Ultrastructural studies showed reduction in secondary granules and increased lucency of primary granules. However, myeloperoxidase content was normal by electronmicroscopy. This morphologic appearance may represent accelerated neutrophil senescence. Analysis of both the clinical course and laboratory findings in patients with isolated neutropenia, or with neutropenia associated with hypogammaglobulinemia, thus revealed no distinguishing characteristics. Neutropenia may have a common pathogenesis in both groups of patients.

Morphologic and functional heterogeneity of chronic neutropenia of childhood with normal neutrophil colony formation in vitro

In order to obtain further knowledge of chronic neutropenia of childhood, we studied nine neutropenic infants six to ten months of age by in vitro techniques, including bone marrow culture, electron microscopy, and chemotaxis assay. Eight of the nine patients had a benign clinical course and the bone marrow aspirates showed a reduced number of segmented neutrophils. The ninth patient had a moderately severe course and the bone marrow showed maturation arrest at the promyelocyte stage. Bone marrow cultures demonstrated that the in vitro neutrophil colony formation and production of colony-stimulating activity were normal in all of the eight patients studied. Neutrophils from one of the nine patients had ultrastructural abnormalities such as decrease in number of primary and secondary granules and the presence of myelin figures in primary granules. Neutrophil chemotaxis was defective in three of the nine patients. All of the six patients in whom the neutrophil colony formation in agar, the ultrastructure of neutrophils, and neutrophil chemotaxis were normal recovered from the neutropenia between 11 and 30 months of age. These in vitro parameters appear to be useful for evaluating chronic neutropenia of childhood.

Association of pancreatic insufficiency and chronic neutropenia in childhood.

In childhood, pancreatic exocrine insufficiency is rarely encountered except as one of the features of cystic fibrosis, which is in contrast to the pattern of pancreatic disease in adults, where pancreatitis is common. However, paediatricians recognize that some children with symptoms of pancreatic insufficiency do not have the chronic chest infection and raised levels of electrolytes in the sweat characteristic of cystic fibrosis. Recently Bodian, Sheldon, and Lightwood (1964) have described congenital hypoplasia of the exocrine pancreas in 2 such children. Variable neutropenia and thrombocytopenic purpura occurred in both but did not receive special comment. In 1964 Shwachman, Diamond, Oski, and Khaw reported 5 similar patients, drawing particular attention to the association of haematological and pancreatic abnormalities. These reports stimulated us to review those of our patients whom we knew to have pancreatic exocrine insufficiency but not the other findings of cystic fibrosis, and those children with so-called idiopathic neutropenia. Two of us (C.M.A. and J.H.C.) had recognized as far back as 1946 one patient with both pancreatic insufficiency and chronic neutropenia, but had not pursued this association. A preliminary report of some of the findings in these patients has been published (Colebatch, Anderson, Simons, and Burke, 1965), but further patients have been encountered since that time. In all, 19 children have presented with, initially, at least one of these features, and 11 of them have now been shown to have both. Although the syndrome is rare, we consider it to be the major disorder of pancreatic exocrine function of children in whom cystic fibrosis has been excluded. Associated features are noteworthy in a number of the patients, particularly the radiological changes of metaphysial dysostosis. A familial incidence of the