How I manage children with neutropenia Dale, David C.
British journal of haematology,
August 2017, 2017-Aug, 2017-08-00, 20170801, Letnik:
178, Številka:
3
Journal Article
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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.
We study the evolution of the scaling relations that compare the effective density ( ) and core density ( kpc) to the stellar masses of star-forming galaxies (SFGs) and quiescent galaxies. These ...relations have been fully in place since and have exhibited almost constant slope and scatter since that time. For SFGs, the zero points in and decline by only . This fact plus the narrowness of the relations suggests that galaxies could evolve roughly along the scaling relations. Quiescent galaxies follow different scaling relations that are offset to higher densities at the same mass and redshift. Furthermore, the zero point of their core density has declined by only since , while the zero point of the effective density declines by . When galaxies quench, they move from the star-forming relations to the quiescent relations. This involves an increase in the core and effective densities, which suggests that SFGs could experience a phase of significant core growth relative to the average evolution along the structural relations. The distribution of massive galaxies relative to the SFR-M and the quiescent relations exhibits an L-shape that is independent of redshift. The knee of this relation consists of a subset of "compact" SFGs that are the most likely precursors of quiescent galaxies forming at later times. The compactness selection threshold in exhibits a small variation from z = 3 to 0.5, M kpc−2, allowing the most efficient identification of compact SFGs and quiescent galaxies at every redshift.
The production and deployment of phagocytes are central functions of the hematopoietic system. In the 1950s, radioisotopic studies demonstrated the high prodution rate and short lifespan of ...neutrophils and allowed researchers to follow the monocytes as they moved from the marrow through the blood to become tissue macrophages, histiocytes, and dendritic cells. Subsequently, the discovery of the colony-stimulating factors greatly improved understanding the regulation of phagocyte production. The discovery of the microbicidal myeloperoxidase-H2O2-halide system and the importance of NADPH oxidase to the generation of H2O2 also stimulated intense interest in phagocyte disorders. More recent research has focused on membrane receptors and the dynamics of the responses of phagocytes to external factors including immunoglobulins, complement proteins, cytokines, chemokines, integrins, and selectins. Phagocytes express toll-like receptors that aid in the clearance of a wide range of microbial pathogens and their products. Phagocytes are also important sources of pro- and anti-inflammatory cytokines, thus participating in host defenses through a variety of mechanisms. Over the last 50 years, many genetic and molecular disorders of phagocytes have been identified, leading to improved diagnosis and treatment of conditions which predispose patients to the risk of recurrent fevers and infectious diseases.
Human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal ...lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.
•An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.•The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.
Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to ...leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls (P = NS). Clonal hematopoiesis due to mutations in TP53 was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, P < .001) or patients with SCN (0/40, P < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple TP53 mutations. Conversely, clonal hematopoiesis due to mutations of CSF3R was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand TP53-mutated HSPCs, suggesting that acquisition of TP53 mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.
•Hematopoietic stem/progenitor mutation burden is not increased in SCN.•Clonal hematopoiesis due to mutations of TP53 is present in the majority of patients with SDS.
Neutropenia absolute neutrophil count (ANC) less than 1.5 × 10(9)/l is a common hematological finding, and severe neutropenia, that is, ANC less than 0.5 × 10(9)/l is a well known risk factor for ...susceptibility to bacterial infections. This review provides a succinct clinical approach to the diagnosis and treatment of neutropenia with specific recommendations on the treatment of severe chronic neutropenia with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF).
Experts agree that patients with acute febrile neutropenia should be treated with antibiotics and that patients at high risk of severe neutropenia (>20% risk) after myelosuppressive chemotherapy should be treated prophylactically with a myeloid growth factor, usually G-CSF. The diversity of causes and consequences of chronic neutropenia make the diagnosis and management of these patients more complicated.
The review provides a stepwise approach to neutropenia focusing first on reaching a provisional diagnosis and treatment plan then steps to a final diagnosis. It also provides specific recommendations on the treatment of severe chronic neutropenia with G-CSF.
An antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD).
To assess the ...efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD.
This 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1.
A total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 SD, 1.43 L 0.45; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference SE, 67 ml 32). Reduced sputum neutrophil count was observed among the 122 patients examined; P = 0.003 (3 mo) and P = 0.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. George's Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5 × 10(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups.
Treatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).
Studying giant star-forming clumps in distant galaxies is important to understand galaxy formation and evolution. At present, however, observers and theorists have not reached a consensus on whether ...the observed "clumps" in distant galaxies are the same phenomenon that is seen in simulations. In this paper, as a step to establish a benchmark of direct comparisons between observations and theories, we publish a sample of clumps constructed to represent the commonly observed "clumps" in the literature. This sample contains 3193 clumps detected from 1270 galaxies at 0.5 ≤ z < 3.0 . The clumps are detected from rest-frame UV images, as described in our previous paper. Their physical properties (e.g., rest-frame color, stellar mass ( M * ), star formation rate (SFR), age, and dust extinction) are measured by fitting the spectral energy distribution (SED) to synthetic stellar population models. We carefully test the procedures of measuring clump properties, especially the method of subtracting background fluxes from the diffuse component of galaxies. With our fiducial background subtraction, we find a radial clump U − V color variation, where clumps close to galactic centers are redder than those in outskirts. The slope of the color gradient (clump color as a function of their galactocentric distance scaled by the semimajor axis of galaxies) changes with redshift and M * of the host galaxies: at a fixed M * , the slope becomes steeper toward low redshift, and at a fixed redshift, it becomes slightly steeper with M * . Based on our SED fitting, this observed color gradient can be explained by a combination of a negative age gradient, a negative E(B − V) gradient, and a positive specific SFR gradient of the clumps. We also find that the color gradients of clumps are steeper than those of intra-clump regions. Correspondingly, the radial gradients of the derived physical properties of clumps are different from those of the diffuse component or intra-clump regions.
Randomized controlled trials (RCTs) of prophylactic granulocyte colony-stimulating factors (G-CSF) have demonstrated a significant reduction in febrile neutropenia (FN) after systemic chemotherapy. ...Several RCTs have been published recently that investigate the impact of G-CSF on mortality and relative dose-intensity (RDI).
A comprehensive systematic review and meta-analysis of all reported RCTs comparing primary prophylactic G-CSF with placebo or untreated controls in adult solid tumor and malignant lymphoma patients was undertaken without language restrictions, using electronic databases, conference proceedings, and hand-searching techniques. Two reviewers extracted data independently. Summary estimates of relative risk (RR) with 95% CIs were estimated based on the method of Mantel-Haenszel and DerSimonian and Laird.
Seventeen RCTs were identified including 3,493 patients. For infection-related mortality, RR reduction with G-CSF compared with controls was 45% (RR = 0.55; 95% CI, 0.33 to 0.90; P = .018); for early mortality (all-cause mortality during chemotherapy period), it was 40% (RR = 0.60; 95% CI, 0.43 to 0.83; P = .002); and for FN, it was 46% (RR = 0.54; 95% CI, 0.43 to 0.67; P < .001). Average RDI was significantly higher in patients who received G-CSF compared with control patients (P < .001). Bone or musculoskeletal pain was reported in 10.4% of controls and 19.6% of G-CSF patients (RR = 4.03; 95% CI, 2.15 to 7.52; P < .001). Significant reductions in FN with G-CSF were observed in studies allowing secondary G-CSF prophylaxis in controls and in the three trials with concurrent prophylactic antibiotics in both treatment arms.
Prophylactic G-CSF reduces the risk of FN and early deaths, including infection-related mortality, while increasing RDI and musculoskeletal pain. There are insufficient data to assess the impact of G-CSF on disease-free and overall survival.
Objectives To investigate the range of clinical presentations for Shwachman–Diamond syndrome (SDS) with the long-term goal of improving diagnosis. Study design We reviewed the North American ...Shwachman–Diamond Syndrome Registry. Genetic reports of biallelic Shwachman–Bodian–Diamond syndrome mutations confirming the diagnosis of SDS were available for 37 patients. Results Neutropenia was the most common hematologic abnormality at presentation (30/37, 81%); however, only 51% (19/37) of patients presented with the classic combination of neutropenia and steatorrhea. Absence of pancreatic lipomatosis on ultrasound or computed tomography scan, normal fecal elastase levels, and normal skeletal survey do not rule out the diagnosis of SDS. SDS was diagnosed in 2 asymptomatic siblings of SDS probands. Twenty-four of 37 patients (65%) had congenital anomalies. Conclusion Our cohort reveals a broad range of clinical presentation for SDS. Clues to the underlying diagnosis of SDS included cytopenias with a hypocellular marrow, congenital anomalies, family history, and myelodysplasia with clonal abnormalities frequently found in SDS. Reliance on classic clinical criteria for SDS would miss or delay diagnosis of a significant subset of patients with SDS.
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