Congenital neutropenia

Congenital neutropenia is strictly defined as neutropenia present at birth. However, it is more generally used to describe neutropenia secondary to inherited genetic mutations. This review will discuss the presentation of such children and the various causes of congenital neutropenia. In particular, it will focus on severe congenital neutropenia (SCN) and the recent discovery of mutations in the gene encoding neutrophil elastase in the majority of cases of SCN. The potential mechanisms of pathogenesis and of transformation to leukaemia will be discussed. Shwachman-Diamond Syndrome and other less common causes of congenital neutropenia will also be reviewed. Finally, an approach to the child with potential congenital neutropenia will be presented.     

Recent advances in the understanding of genetic defects of neutrophil number and function

Neutrophils are amongst the first immune cells to arrive at sites of infection and play an important role as the host’s first line of defence against invading pathogens. Defects of neutrophil number or function are usually recognized clinically by recurrent infections that often are life‐threatening. Over the last few years, a number of genetic mutations have been discovered to be the basis for congenital neutropenia, adding to our understanding of the molecular basis of these diseases. While many genetic mutations that cause severe congenital neutropenia result in a differentiation block at the promyelocyte stage, defects of neutrophil function are more heterogeneous on clinical, genetic and mechanistic levels. In this review we discuss recent advances in our understanding of the genetic and molecular basis of human neutrophil disorders.     

Severe congenital neutropenia unresponsive to G-CSF

Summary Severe congenital neutropenia (SCN) is an inherited disorder characterized by severe neutropenia and recurrent infections from an early age, with bone marrow showing a maturational arrest of granulopoiesis at the promyelocyte stage. Since the introduction of G-CSF therapy the prognosis for affected children has improved dramatically. We describe two patients with SCN who were clinically unresponsive to G-CSF therapy. The results of in-vitro colony assays from these two patients are presented together with the results from the mother of one of these patients who also has a chronic neutropenia, and a further child with SCN who responded to treatment with G-CSF.     

Otitis Media in Children with Congenital Immunodeficiencies

Otitis media represents one of the most common infections in childhood. Within the first 3 years of life, up to 80% of children experience at least one episode of otitis media. It is often resolved with supportive therapies and consequently not considered a worrisome problem. However, it may be an early manifestation of a severe underlying disease. Primary immunodeficiencies are rare congenital defects of the immune system that often remain unrecognized, or diagnosis can be delayed, sometimes resulting in fatal consequences for the child. Patients suffer from recurrent, prolonged, and/or unusual infections leading to local sequelae, failure to thrive, developmental delays, and systemic infections with severe courses. This review provides a brief insight into primary immunodeficiencies and an overview of leading findings that should result in further evaluation of the immune system in cases of otitis media. A stepwise diagnostic approach is proposed to facilitate early and accurate diagnosis and, consequently, effective and timely therapy to improve the patient’s outcome and quality of life.     

Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias

Summary . Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44, cyclic n = 10) treated for 4–6 years. A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients. Two patients required an increase of > 25% in dose to maintain a clinical response; one patient became refractory to therapy. A significant decrease in the incidence of severe infections and the need for intravenous antibiotics was noted. Significant adverse events noted which may or may not be related to therapy included: osteopenia ( n = 15), splenomegaly ( n = 12), hypersplenism ( n = 1), vasculitis ( n = 2), glomerulonephritis ( n = 1), BM fibrosis ( n = 2), MDS/leukaemia ( n = 3), and transient inverted chromosome 5q with excess blasts ( n = 1). R-metHuG-CSF has been well tolerated in the majority of patients and resulted in a longterm improvement in their clinical status.     

Pathophysiology and treatment of severe chronic neutropenia

 Severe chronic neutropenia (SCN) include a heterogeneous group of diseases characterized by blood neutrophil counts chronically less than 0.5×10⁹/L. In phase I–III studies in SCN patients, treatment with recombinant human granulocyte colony stimulating factor (r-metHuG-CSF; Filgrastim) resulted in a rise in the absolute neutrophil counts (ANC) to above 1.0×10⁹/L associated with a reduction in bacterial infections. Long-term treatment with filgrastim up to 8 years demonstrate a sustained ANC response, a significant reduction of the need for intravenous antibiotics and a dramatic improvement in the quality of life. In 1994 an international registry for severe chronic neutropenia (SCNIR) was established to improve care for chronic neutropenia and for further understanding the pathophysiology of this rare disease. Three-hundred and ten patients have been enrolled to this registry so far. Worldwide phase I–III studies with filgrastim and SCNIR provide information on 424 patients with severe chronic neutropenia. Adverse events include the development of acute myeloid leukemia in approximately 7% of the patients within the cohort of patients with congenital neutropenia (Kostmann's syndrome) suggesting that congenital neutropenia is a preleukemic syndrome. None of the patients with cyclic of idiopathic neutropenia developed leukemia suggesting that filgrastim is not involved in the development of leukemia. Received: 19 December 1995 / Accepted: 21 December 1995     

How I investigate neutropenia

Neutropenia is a common laboratory finding in adults and children. Its underlying causes are extremely heterogeneous and include benign conditions, autoimmune disorders, infections, and malignancies. The clinical laboratory plays a central role in the diagnosis of these disorders, including data derived from hematology, microbiology, molecular biology/cytogenetics, and clinical chemistry. The purpose of this review is to (a) highlight the clinical, hematologic, and molecular genetic features of the major entities resulting in neutropenia and (b) outline an algorithm‐based approach to permit the classification of neutropenias.     

Severe neutropenia associated with IgG2 subclass deficiency and bone marrow T-lymphocyte infiltration

Patients with selective IgG2 subclass deficiency (IgG2 SD) usually suffer from recurrent respiratory infections. The occurrence of cytopenia is extremely rare in these patients. We report on two patients with isolated IgG2 SD who experienced unexplained severe neutropenia associated with T-lymphocyte proliferation. IgG2 SD clearly preceded the occurrence of neutropenia in one patient. In the other patient, the long-standing history of recurrent respiratory infections prior to diagnosis of agranulocytosis suggests that IgG2 SD also preceded the occurrence of neutropenia. Analysis of bone marrow biopsy in both patients and skin tissue lesions in one patient showed massive infiltration with CD4+ and CD8+ T-lymphocytes. The pathological feature did not suggest any malignant lymphoproliferative disorder. Neutropenia was refractory to i.v. Ig in both patients and to recombinant G-CSF, steroids, and cyclophosphamide in one patient. Severe cellulitis led to death in one patient. In summary, we reported herein a heretofore undescribed syndrome characterized by the association of IgG2 SD with severe neutropenia and tissue T-cell infiltration. It suggests that bone marrow analysis as well as determination of serum IgG subclasses need to be performed in patients with unexplained neutropenia. Am. J. Hematol. 57:241–244, 1998. © 1998 Wiley-Liss, Inc.     

Fièvre et cancer : éléments de diagnostic pour une prise en charge adaptée

Fever is defined as a body temperature above 37.8 °C in the absence of antipyretic drug. It is a frequent and potentially severe event and its interpretation can be difficult in patients with solid tumors. It is usually alleged that more than half of cancer patients will be affected by the occurrence of this event during the course of their disease. Underlying causes are multiple but most frequent and severe causes include infections, the most life-threatening causes being, firstly, febrile neutropenia and secondly, healthcare-associated infections and more particularly infections related to catheter. Opportunistic infections are much less frequent than in hematology oncology but clinicians should be aware of two severe opportunistic infections: systemic candidiasis and Pneumocystis jiroveci pneumonia. Fever related to paraneoplastic or tumor necrosis complicates the diagnosis process. Other common causes of fever include venous thromboembolic disease or more rarely treatment related fever. We aim at examining the optimal diagnostic and therapeutic strategies when facing a cancer patient with fever.     

Primäre und sekundäre Neutropenie

Severe chronic neutropenia (SCN) comprises a heterogeneous group of disorders with a common hematological and clinical phenotype characterized by absolute neutrophil counts (ANC) below 0,5???10⁹/l and increased risk of severe bacterial infections. The differentiation between primary and secondary neutropenia and the identification of causative gene mutations is of great importance for the estimation of prognosis. During childhood primary autoimmune neutropenia is the most frequent diagnosis, while secondary neutropenia predominates in adulthood. Despite the rarity, congenital, genetic neutropenias are of great value for research on normal and pathological hematopoiesis and have a fundamental impact on the current knowledge on hematopoiesis. To date mutations in more than 10 genes have been described which are mainly associated with an increased risk for leukemia. The treatment with hematopoietic growth factors has improved the long-term prognosis of SCN patients dramatically: Bacterial infections can be prevented and a normal participation in everyday life is possible.     

Osteoporosis in severe congenital neutropenia treated with granulocyte colony-stimulating factor

Recombinant human granulocyte colony-stimulating factor (G-CSF) has substantially improved life expectancy for children with severe congenital neutropenia (SCN). Severe osteoporosis, reported in this population, may relate to the disease process, or be a therapeutic side-effect. This report details bone loss, quantitated absorptiometrically and histomorphometrically, in a child with SCN and vertebral collapse, and the positive response to anabolic steroid and bisphosphonate therapy.     

Neutropenia and anaemia associated with T-cell large granular lymphocyte leukaemia responds to fludarabine with minimal toxicity

T-cell large granular lymphocyte leukaemia (T-LGL) is a clonal disorder of T cells associated with neutropenia and anaemia. The clinical consequences are recurrent infections and transfusion dependence. The optimum treatment for severely affected patients remains to be defined. Current therapies require long-term administration to maintain an effect. We report the reversal of severe neutropenia and/or anaemia in four patients treated with fludarabine which has been maintained since stopping treatment. The therapeutic side-effects were restricted to one episode of fever not associated with neutropenia. We conclude that fludarabine is effective in T-LGL, may be given safely despite severe neutropenia and induces durable treatment-free remissions.     

Huge pulmonary artery aneurysm

Pulmonary artery aneurysms (PAAs) are uncommon entities. PAAs are caused mostly by trauma (often iatrogenic), infections and Behcet’s disease (BD). Less common causes are pulmonary hypertension, congenital heart disease and neoplasm. BD is a multisystem disorder presenting with recurrent oral and genital ulcerations, as well as ocular involvement, and PAA is one of its rare complications. A case of huge PAA, in which the usual criteria for the clinical diagnosis of BD were present, is described. Transcatheter embolization resulted in clinical improvement.     

Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy

Severe congenital neutropenia (SCN) is characterized by profound neutropenia, recurrent severe bacterial infections and maturation arrest in the myeloid lineage. Granulocyte colony-stimulating factor (G-CSF) treatment results in clinical improvement in over 90% of cases. Point mutations of the G-CSF receptor (G-CSFR) have been implicated in the progression of SCN to acute myeloid leukaemia (AML). Data are presented here on the 9-year follow-up of seven patients and the further screening of 18 other cases. One of the two original cases with a G-CSFR mutation has improved clinically; nevertheless, mutant DNA could still be detected at a very low level > 8 years after identification. The second child with a mutation progressed to myelodysplasia/AML 5 years after her mutation was detected. No mutations were found in the 18 new cases. One of three transformed cases had a G-CSFR mutation. This work is in agreement with the suggestion that G-CSFR mutations may provide a survival advantage to haemopoietic stem cells, but argues against the inevitability of leukaemic progression in their presence. Furthermore, the low frequency of G-CSFR mutations in SCN and the importance of regular screening and close clinical and laboratory follow-up if a mutation is found were demonstrated.     

Rates of neutropenia in adults with influenza A or B: a retrospective analysis of hospitalised patients in South East Queensland during 2015

Neutropenia in adult patients is often attributed to intercurrent viral infections; however, there are limited data describing the frequency or natural history of this phenomenon. We examined all patients presenting to three large hospitals in the Metro South region of South East Queensland with laboratory‐confirmed influenza A or B throughout the 2015 influenza season (January–October). Four hundred and thirty‐six patients were studied and 15.3% of this cohort were neutropenic (absolute neutrophil count <2.0 × 10⁹/L) with no identifiable cause other than the influenza. Importantly, the majority of cases were mild, with absolute neutrophil count remaining >1.0 × 10⁹/L. The incidence of neutropenia was significantly higher in association with influenza B than influenza A (18.3% vs 10.3%). We conclude that mild, transient neutropenia is common among patients with influenza infection and advise that it should not cause alarm or invite specific investigation unless severe or prolonged.     

Hemopoietic marrow function in chronic neutropenia of blacks: cure of aplastic anemia by allogeneic marrow transplantation from a neutropenic sibling donor

A black patient with severe aplastic anemia is described who underwent successful bone marrow transplantation from a sibling with chronic neutropenia. During an evaluation to identify a suitable donor, it was found that the majority of family members tested had neutropenia, with no familial history of significant infections or related hospitalizations. In vitro hemopoietic culture studies of marrow from the patient's HLA-MLC-matched siblings showed normal numbers of pluripotential and committed hemopoietic progenitors; in vitro hemopoietic colony formation from the patient was markedly subnormal, consistent with the clinical picture of severe aplastic anemia. Following appropriate conditioning therapy, marrow transplanted from one of these neutropenic sibs produced full hematopoietic reconstitution. Posttransplant marrow culture studies of the patient showed restoration of a normal pattern of in vitro hemopoiesis. The in vitro culture studies and clinical experience in this patient support the concept that chronic neutropenia of blacks is not primarily a marrow progenitor cell disorder but, more likely, a manifestation of a genetically determined alteration in granulocyte kinetics.     

Human ‘knockouts’ of CSF3 display severe congenital neutropenia

Colony-stimulating factor 3 (CSF3) is a key factor in neutrophil production and function, and recombinant forms have been used clinically for decades to treat congenital and acquired neutropenia. Although biallelic inactivation of its receptor CSF3R is a well-established cause of severe congenital neutropenia (SCN), no corresponding Mendelian disease has been ascribed to date to CSF3. Here, we describe three patients from two families each segregating a different biallelic inactivating variant in CSF3 with SCN. Complete deficiency of CSF3 as a result of nonsense-mediated decay (NMD) could be demonstrated on RT-PCR using skin fibroblasts-derived RNA. The phenotype observed in this cohort mirrors that documented in mouse and zebrafish models of CSF3 deficiency. Our results suggest that CSF3 deficiency in humans causes a novel autosomal recessive form of SCN.     

Model analysis of the contrasting effects of GM-CSF and G-CSF treatment on peripheral blood neutrophils observed in three patients with childhood-onset cyclic neutropenia

Human cyclic neutropenia (CN) is a rare haematological disorder characterized by regular fluctuation in the serial count of blood neutrophils. The oscillations occur at subnormal levels with a stable 3-week period. To reduce the risk of serious infections during the severe neutropenic nadir phases (<0.25 ×10⁹ neutrophils/l) patients are usually treated with recombinant growth factors. Compared with G-CSF, which has been shown to enhance the amplitudes substantially, the response to GM-CSF is poor: neutrophil numbers are not amplified, the cycles remain unchanged or are dampened. However, two cases with a modest neutrophil increase have been reported in the literature. In a recently published clinical study the different effects of GM-CSF and G-CSF application have been investigated in the same patients. Based on a mathematical model of CN we previously proposed, the detailed neutrophil data measured in this study are analysed by simulation. The contrasting clinical results can be quantitatively explained by the model concept of regulatory control together with possible individual feedback defects, i.e. abnormally reduced mitotic responsiveness of granulopoietic progenitor cells to GM-CSF and G-CSF.     

Diagnostic yield of bronchoscopic sampling in febrile neutropenic patients with pulmonary infiltrate and haematological disorders

Background: The development of pulmonary infiltrate in neutropenic patients is potentially life‐threatening, and requires early diagnosis and treatment. Bronchoscopic sampling is an established form of investigation in such patients. Aim: The aim of the study is to determine the diagnostic yield and complication rate of bronchoscopic sampling in patients with a haematological disorder presenting with febrile neutropenia and pulmonary infiltrate. Methods: Medical records and laboratory investigations were retrospectively reviewed for all patients with a haematological disorder who underwent flexible bronchoscopy and bronchoalveolar lavage (BAL) or bronchial washing (BW) at Auckland City Hospital, New Zealand, after presenting with febrile neutropenia and pulmonary infiltrate between January 2008 and December 2009. Demographic, clinical, radiological and microbiological data, procedure‐related complications and treatment were recorded. Modifications to treatment regimens as a result of bronchoscopy and 30‐day mortality were recorded. Results: Out of 678 bronchoscopies performed during this period, 26 were in patients with a haematological disorder presenting with febrile neutropenia and pulmonary infiltrate. Most patients had a haematological malignancy (19/26). Two (7.7%) patients reported minor haemoptysis. No biopsies were performed. Positive microbiological samples were obtained with BAL/BW in 23% of patients. The most common organisms identified were Aspergillus species (15.4%); other organisms were Candida (11.6%) and Streptococcus pneumoniae (3.9%). The bronchoscopic results altered the clinical management of 10 (38.4%) patients. The 30‐day mortality rate was 19.2%, but no deaths were related to the procedure. Conclusions: In haematology patients presenting with febrile neutropenia and pulmonary infiltrate, bronchoscopy is a safe procedure that plays a significant role in management.