Clinical and immunological features in ACKR1/DARC-associated neutropenia.

ABSTRACT: ACKR1/DARC-associated neutropenia (NP; ADAN; Online Mendelian Inheritance in Man 611862), caused by a variation in the ACKR1/DARC gene (rs2814778), is common in persons of African or Middle Eastern descent. In a cohort of 66 genetically confirmed subjects with ADAN, we show that absolute neutrophil counts (ANCs) may occasionally be lower than previously recognized (0.1 × 109-0.49 × 109/L for 9% of the subjects), which is similar to ANCs in severe congenital NP (SCNP). ANCs often normalized during inflammation, even mild. Individuals with ADAN (of 327 observed person-years) showed no cases of myelodysplastic syndrome (MDS), which is frequently encountered in SCNP. Unexpectedly, 22% presented with autoantibodies to neutrophils, compared with <1% in controls. Compared with healthy donors, subjects with ADAN demonstrated significantly lower human cationic antimicrobial protein-18/pro-leucin leucin-37 plasma levels; higher levels of nonclassical, proinflammatory, 6-sulfo LacNac-expressing monocytes; and differentially expressed plasma levels of 28 of the 239 analyzed cytokines related to immunity/inflammation, cell signaling, neutrophil activation, and angiogenesis. Collectively, more severe neutropenia in ADAN than previously assumed may complicate differential diagnoses compared with other SCNPs, and various (auto)immune/inflammatory reactions with a distinct profile may be a cause or consequence of this hereditary neutropenia.

Hypogammaglobulinemia in children after allogeneic hematopoietic stem cell transplantation: a cytokine mediated immunoglobulin isotype class switch arrest?

BACKGROUND: Hypogammaglobulinemia (hypo-IgG) is common early post-HSCT in children, occasionally necessitating long-term immunoglobulin (Ig) G replacement therapy. IgG replacement may not reduce mortality, although infectious complications are decreased PROCEDURE: Clinical data and samples from 86 children were analyzed retrospectively with the aim to identify risk factors for developing long-term hypo-IgG (i.e., requiring ≥ 3 months IgG replacement) post-HSCT and studying the underlying biology. Laboratory studies covered serum cytokines, IGHG2 genotyping and routine laboratory investigations. Results were analyzed statistically. RESULTS: Forty-eight percent of the children developed long-term hypo-IgG. These children were younger (<5 years) and had higher acute GvHD incidence, but had better overall survival (88% vs. 69%, P = 0.036). Significantly lower Ig levels post-HSCT but equal immune cell recovery were seen in patients with long-term hypo-IgG compared with those of transient or no hypo-IgG. Pre-HSCT IL-6 and -7 and post-HSCT BAFF and APRIL levels were significantly higher in the long-term hypo-IgG group. CONCLUSIONS: Findings suggests an unfavorable cytokine milieu for graft-derived immune recovery, possibly inducing Ig isotype class switch arrest. Younger age, acute GvHD, and higher pre-HSCT IL-6 levels were identified as significant risk factors for long-term hypo-IgG. Long-term hypo-IgG post-HSCT does not need to be unfavorable and could be an effect of deteriorated cytokine signaling.

Neutropenia in childhood: a 5-year experience at a tertiary center.

UNLABELLED: Clinical characteristics corroborated by laboratory investigations are essential to determine the etiology in cases of childhood neutropenia and the level of future health-care needs. Here the presentation, findings, and need of interventions in different types of neutropenia in children followed at our center from 2007 to 2012 were investigated retrospectively. Children with congenital and autoimmune neutropenia presented at a significantly younger age and with lower absolute neutrophil granulocyte counts than those with other types of neutropenia (p < 0.01-0.05). The duration of neutropenia, in case of remission, was shorter in post-infection and drug-induced cases compared to autoimmune and chronic idiopathic neutropenias (p = 0.001). Least affected from infections were children with ethnic and post-infection neutropenias compared to the others (p = 0.01-0.05). With the exception of congenital and autoimmune neutropenias, neutropenic children had few clinical infections and few hospital admissions even though the outpatient visit frequency was similar among the groups. A vast majority of the patients received no antibiotic prophylaxis. CONCLUSION: The majority of patients with pediatric neutropenia, apart from congenital types, display a benign clinical course. Our data suggest that most neutropenic children need neither antibiotic prophylaxis nor extensive medical attention.

Folinic acid supplementation in higher doses is associated with graft rejection in pediatric hematopoietic stem cell transplantation.

Folinic acid is widely used in hematopoietic stem cell transplantation (SCT), mainly to reverse antifolate effects of such drugs as methotrexate and cotrimoxazole but also empirically to reduce toxicity and support hematopoietic recovery. However, concerns have been raised in oncohematology about reduced curative rates associated with folinic acid administration. The clinical impact of folinic acid with regard to graft-versus-host disease (GVHD), relapse, and rejection in pediatric SCT is largely undetermined. In this single-center retrospective study we investigated folinic acid administration in 87 children undergoing SCT between 2007 and 2010. Data on folinic acid dosage and duration were analyzed along with SCT parameters using univariate and multivariate statistics. Folinic acid treatment was not correlated with relapse or GVHD grades ≥ II. However, significantly higher folinic acid doses until day +21 post-SCT had been administered to patients rejecting their grafts (P < .005). In a subanalysis of nonmalignant disease and reduced-intensity conditioning (RIC) SCTs, higher total folinic acid doses were found to be associated with rejection (P = .015 and P = .026). Multivariate analysis identified RIC (odds ratio, 19.9; P < .01) and an early total folinic acid dose of >185 mg/m(2) (odds ratio, 11.4; P = .03) as risk factors for graft rejection. Late folinic acid treatment had no impact on relapse, GVHD, and rejection. To conclude, administration of folinic acid in pediatric SCT seems safe in terms of relapse and GVHD. However, it should be carried out with caution, especially in patients with nonmalignant conditions and those receiving RIC to avoid graft rejection.