Do ribosomopathies explain some cases of common variable immunodeficiency?

The considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bone-marrow failure disorders such as Diamond-Blackfan anaemia (DBA) and Shwachman-Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders.

Clinical outcomes and health-related quality of life (HRQOL) following haemopoietic stem cell transplantation (HSCT) for paediatric leukaemia.

BACKGROUND: Haemopoietic stem cell transplantation (HSCT) is a life-saving but intensive procedure associated with potentially severe adverse late effects. We aimed to determine morbidity and health-related quality of life (HRQOL) in a sample of survivors aged 8-18 years at least 1 year post HSCT for paediatric acute leukaemia, compared with a non-transplanted group of survivors matched for age, gender, initial disease and time since treatment. METHODS: Families (N = 54; HSCT n= 29) recruited from four UK centres completed measures of child behaviour and school attendance, HRQOL and finances. Mothers completed measures of their own well-being. Clinical outcome data were extracted from medical records. RESULTS: Children in the HSCT group had significantly more late effects and had received more tests for vision, bone, dental and skin health, and thyroid, lung, and gonadal function than the non-transplanted group. HRQOL scores for the HSCT group were significantly lower in all domains compared with the non-transplanted group and population norms, but were not significantly related to clinical indices. Mothers in the HSCT group had significantly poorer mental well-being than population norms. CONCLUSION: Significant morbidity and compromised HRQOL was found in survivors of HSCT. The burden of caring for a child after HSCT has a continuing toll on mothers' well-being.The importance of counselling families about possible long-term consequences is emphasized.

Health-related quality of life and financial impact of caring for a child with Thalassaemia Major in the UK.

BACKGROUND: Thalassaemia Major (TM) is a serious condition characterized by life-long dependence on blood transfusions and chelation therapy. Our aim was to determine health-related quality of life (HRQOL) in children with TM living in the UK, and the impact of caring for a child receiving National Health Service treatment on family finances. METHODS: This was a cross-sectional assessment of HRQOL in children (n= 22) with TM aged 8-18 years. Children were recruited from three UK Paediatric Haematology and Bone Marrow Transplant centres. Mothers completed measures of their child's HRQOL [PedsQL 4.0 (Measurement Model for the Pediatric Quality of Life Inventory, James W. Varni PhD, PedMetrics, Quantifying the Qualitative SM, Copyright 1998-2009)] and behaviour (Strengths and Difficulties questionnaire), and the impact of caring for the child on family finances. RESULTS: Child behaviour was within the normal range but child HRQOL was significantly lower than population norms. Family financial concerns associated with TM were associated with poorer child HRQOL (P= 0.020). CONCLUSIONS: Thalassaemia Major poses a considerable challenge to child HRQOL, well documented in areas of the world where TM is prevalent. Despite the availability of National Health Service care and financial benefits our study suggests a similar burden in the UK.

A unified call to action from Australian nursing and midwifery leaders: ensuring that Black lives matter.

Nurses and midwives of Australia now is the time for change! As powerfully placed, Indigenous and non-Indigenous nursing and midwifery professionals, together we can ensure an effective and robust Indigenous curriculum in our nursing and midwifery schools of education. Today, Australia finds itself in a shifting tide of social change, where the voices for better and safer health care ring out loud. Voices for justice, equity and equality reverberate across our cities, our streets, homes, and institutions of learning. It is a call for new songlines of reform. The need to embed meaningful Indigenous health curricula is stronger now than it ever was for Australian nursing and midwifery. It is essential that nursing and midwifery leadership continue to build an authentic collaborative environment for Indigenous curriculum development. Bipartisan alliance is imperative for all academic staff to be confident in their teaching and learning experiences with Indigenous health syllabus. This paper is a call out. Now is the time for Indigenous and non-Indigenous nurses and midwives to make a stand together, for justice and equity in our teaching, learning, and practice. Together we will dismantle systems, policy, and practices in health that oppress. The Black Lives Matter movement provides us with a 'now window' of accepted dialogue to build a better, culturally safe Australian nursing and midwifery workforce, ensuring that Black Lives Matter in all aspects of health care.

Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.

Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guérin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought. A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As a result, IFN-gamma production by lymphocytes was markedly impaired. This is the first discovered human disease resulting from a cytokine gene defect. It suggests that IL-12 is essential to and appears specific for protective immunity to intracellular bacteria such as mycobacteria and salmonella.

Increased acute GvHD and higher transplant-related mortality in non-caucasians undergoing standard sibling allogeneic stem cell transplantation.

We conducted a retrospective study to compare outcome in Caucasians and non-Caucasians undergoing standard sibling allogeneic SCT. End points of the study were to compare graft-versus-host disease (GvHD) occurrence and transplant-related mortality (TRM). There were 251 patients, 43 non-Caucasian and 208 Caucasian. A higher proportion of non-Caucasian patients developed acute GvHD (aGvHD) grade 2 or greater as compared to the Caucasian group (48 vs 26%, respectively) P = 0.02. With a median follow-up of 27 months, 26% (11/43) of non-Caucasians and 14% (29/208) of Caucasian patients had died from TRM, which accounted for 55% of all deaths in the non-Caucasian group compared to 33% in Caucasians, P = 0.02. Overall survival 12 months post transplant was 64 vs 69% in the non-Caucasian and Caucasian groups, respectively (P = 0.43). Although there were higher numbers of CMV-positive patients in the non-Caucasian group, there were no deaths from CMV reactivation in this subgroup. We conclude that there is increased TRM and aGvHD following standard sibling allograft in the non-Caucasian population and this could be due to either differences in tumour biology or extrinsic factors such as socio-economic factors, nutritional status, post transplant care or presenting with late stage disease.

Molecular analysis of single colonies reveals a diverse origin of initial clonal proliferation in B-precursor acute lymphoblastic leukemia that can precede the t(12;21) translocation.

The pathogenesis of pediatric B-precursor acute lymphoblastic leukemia is largely unknown, and even with nonrandom chromosomal translocations present, the precise order of clonal molecular events is undefined. We developed an in vitro system using cytokines interleukin (IL)-3, IL-7, IL-10, and FMS-like tyrosine kinase 3 ligand with CD40 ligand-expressing fibroblasts to obtain single blast colonies from which clonal immunoglobulin heavy chain (IgH), T-cell receptor delta gene rearrangements, and, in t(12;21)-positive cases, TEL-AML1 fusion transcripts could be simultaneously PCR amplified. The proliferation of early tumor progenitors increased subclone detection enabling us, in seven diagnostic samples, to determine the stage of differentiation at which each leukemia occurred. Four were derived from the stage before initiation of IgH rearrangement, one during recombination of variable, joining, and diversity segments of the heavy chain gene VDJ(H), and two after completion of IgH rearrangement. Furthermore, analysis of a t(12;21)-positive leukemia with unusually late onset, identified both TEL-AML1-positive and -negative colonies carrying a clonal T-cell receptor delta rearrangement, inferring the presence of clonal expansion before the occurrence of the t(12;21). In contrast, in a typical, early onset t(12;21)-positive leukemia, the t(12;21) appeared to be the first clonal event. In both leukemias, the t(12;21) occurred before recombination of variable, joining and diversity segments of the heavy chain gene VDJ.

Migration of CD18-deficient neutrophils in vitro: evidence for a CD18-independent pathway induced by IL-8.

Neutrophils isolated from a child with severe leukocyte adhesion deficiency 1 (LAD1) had a complete absence of expression of the CD11/CD18 beta2 integrin family of adhesion molecules, and were shown to be deficient in the in vitro adhesion and migration properties. However, we found that interleukin-8 (IL8), a potent chemoattractant for neutrophils, and sputum sol phase induced these LAD1 neutrophils to migrate through an endothelial cell layer in vitro, and confirmed that this migration was CD18-independent. These findings add to evidence of CD18-independent mechanisms of neutrophil recruitment, in particular neutrophil infiltration into the lungs, where IL8 may be an important recruitment factor.

Successful HSCT using nonradiotherapy-based conditioning regimens and alternative donors in patients with Fanconi anaemia--experience in a single UK centre.

Seven children with Fanconi anaemia (FA) (five female, two male), who had not undergone transformation, received nine haemopoietic stem cell transplantation (HSCT) between 2000 and 2004. Conditioning regimen was: fludarabine 25-30 mg/m2/day for 5 days, antilymphocyte globulin 12.5 mg/kg/day for 3 days and cyclophosphamide 5-7.5 mg/kg/day for 4 days. Radiation was not used. One male patient who had multiple HSCT and one female who was retransplanted, received slightly different conditioning regimens. Four patients received fully matched unrelated umbilical cord blood (UCB), two matched unrelated peripheral blood stem cell (PBSC) grafts, and three haploidentical T-cell-depleted (TCD) PBSC grafts. None of the patients had any significant conditioning-related toxicity or severe infections. All engrafted within 2-3 weeks. One patient rejected her first HSCT after 10 weeks and had a second successful transplant from the same donor. One male patient rejected his TCD haploidentical HSCT from his mother, and subsequently had a successful fully matched unrelated UCB transplant. Rejection rate was 22%. Acute and chronic graft-versus-host disease (GVHD) was seen in 77 and 22% patients. In all, 57% patients developed autoimmune complications, all of which have resolved. All patients are well with stable or full donor chimerism after a median follow-up of 37 months (range 13-54).

Clonal diversity, measured by heterogeneity of Ig and TCR gene rearrangements, in some acute leukaemias of childhood is associated with a more aggressive disease.

The pattern of immune system gene rearrangements in acute leukaemias of childhood is heterogeneous. The biological significance of this heterogeneity in childhood acute leukaemia is still poorly understood. In this study, we analysed 49 children with acute leukaemia (29 B-precursor acute lymphoblastic leukaemia (ALL), 5 relapsed cALL, 6 T-ALL, 7 acute non-lymphocytic (ANLL) and 2 mixed lineage leukaemias), for the presence of different immune system gene rearrangements (Ig JH, C kappa, C lambda, TCR J gamma, C beta, J delta and J alpha) by Southern blot hybridisation. The most prominent heterogeneity of immune system gene rearrangements was observed in the group of B-precursor ALL. The results from our study suggest that the heterogeneity of immune system gene rearrangement reflects clonal diversity in approximately one-third of patients with B-precursor ALL at presentation and in most patients in relapse. The observed association of clonal diversity with high white blood cell count, pre-B immunophenotype and age under 1 year in B-precursor ALL may have clinical significance. There was a significantly shorter disease-free survival in the group of B-precursor ALL patients with clonal diversity compared with those without clonal diversity. Clonal diversity may, therefore, be a mechanism of disease progression common to different types of aggressive B-precursor ALL.

Rapid production of diversity during the progression of a mixed lineage leukaemia.

A leukaemia presenting with two morphologically different blast populations failed to respond to either antimyeloid or antilymphoid treatment and showed a rapid clinical progression. Immunophenotyping provided good evidence for two blast populations, one lymphoid and the other lymphoid with granulocyte monocytic markers. Two different gene rearrangements within JH were also observed with band densities corresponding to the sizes of the two blast cell populations. A t(19; 22) translocation was observed in almost all cells at presentation one of which evolved into a subclone, becoming dominant in the terminal phase of the disease. We show here both the clonal evolution and clonal competition that occurred in this leukaemia and suggest that the potential of the tumour stem line for rapidly producing diversity was the reason for the resistance to treatment.

Experience with quinupristin/dalfopristin in treating infections with vancomycin-resistant Enterococcus faecium in children.

BACKGROUND: The emergence and spread of vancomycin-resistant Enterococcus faecium (VREF) has presented serious therapeutic difficulties because of the lack of reliably active antibiotics. Quinupristin/dalfopristin is a new injectable streptogramin antibiotic that is active against most strains of VREF. Experience with this agent in adults with VREF infections is well-documented; however, there are few reports of its use in children. We report on eight children with VREF infections who received quinupristin/dalfopristin under a compassionate use protocol. METHODS: Quinupristin/dalfopristin was administered according to the manufacturer's recommendations. Clinical and laboratory data were recorded for each patient. RESULTS: The infections treated comprised six cases of bacteremia and two of peritonitis. All patients had serious underlying conditions. Seven patients recovered fully. One patient died, having experienced a relapse of his infection after quinupristin/dalfopristin was discontinued. None of the patients experienced side effects or other adverse events. CONCLUSION: Quinupristin/dalfopristin was well-tolerated and generally effective in children with infections caused by VREF. There is increasing evidence that it may be more effective than other currently available antibiotics in some such patients.

'Clustering'--real or apparent? Probability maps of childhood cancer in the West Midlands Health Authority region.

The West Midlands Regional Children's Tumour Registry collects detailed information on all cases of childhood cancer in the West Midlands Health Authority Region (WMHAR). The distribution by electoral ward of all cases diagnosed in the WMHAR between 1980 and 1984 has been determined. Analysis has also been performed for leukaemias/non-Hodgkin's lymphomas alone. We suggest that this latter grouping should be universally employed, owing to the difficulty of accurately separating out cases of leukaemia. Both spatial analyses showed several wards with significantly excessive rates on the basis of their cumulative Poison probability. Observed/expected ratios of 3-35 were seen for cases in significant wards, which are similar to the ratios seen in analysis of incidence around nuclear installations. However, further detailed consideration of these individual significance levels in the light of the number of statistically significant wards which would occur by chance alone, due to the multiple use of the test, accounted completely for the number of wards obtained in each of the groups considered. Thus, apparent 'clustering' of cases could be mere statistical artefact. In the WMHAR, therefore, using the technique of probability mapping, no true spatial pattern of incidence was found, other than that which would occur by chance alone. This, in a large area without nuclear installations and an even mix of rural and industrialised regions, could be seen as control data for those studies which have considered cases of childhood leukaemia around nuclear facilities, where the observation of single point clusters associated with suspected sites restricts assessments of spatial pattern in the rest of the area.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of donor lymphocytes in extramedullary relapse of childhood acute lymphoblastic leukaemia following bone marrow transplantation.

Relapse is the commonest cause of treatment failure following bone marrow transplantation for malignant haematological disease. Treatment options are limited and often unsuccessful, with remissions, if achieved, being short-lived. Donor lymphocyte infusions have been used in the treatment of relapsing CML for several years, with good results being obtained. Use of this form of adoptive immunotherapy however, has been much less successful in patients with acute leukaemias, with acute lymphoblastic leukaemia appearing to be particularly resistant. We report the successful use of a donor lymphocyte infusion in a patient with isolated extramedullary relapse of acute lymphoblastic leukaemia post bone marrow transplantation.

Use of idarubicin in pre-transplant conditioning in children with high-risk acute leukaemia.

The major cause of treatment failure following allogeneic bone marrow transplantation for acute leukaemia is disease relapse. In an attempt to reduce post- transplant relapse in 33 children with high-risk acute leukaemia who received a related or unrelated bone marrow transplant, the pre-transplant conditioning regimen was intensified by the addition of idarubicin. Its toxicity and effects on survival were evaluated over a 57-month period. Toxicity, largely gastrointestinal, was increased but acceptable, and there was no specific regimen-related toxicity. Relapse rates were low (24%) in this high risk group, but mortality was increased in those receiving unrelated donor grafts, largely due to sepsis. Idarubicin does appear to have a role to play in the conditioning regimen of patients with high-risk acute leukaemia undergoing BMT, and may reduce relapse rates without increasing transplant-related mortality.

Partially matched related donor peripheral blood progenitor cell transplantation in paediatric patients adding fludarabine and anti-lymphocyte gamma-globulin.

Twenty-one paediatric patients (11 males and 10 females) received a CD34-selected partially matched related donor transplant for malignant (16 cases) and non-malignant conditions (five cases). The average cell dose was 11.13 x 10(6)/kg. Fifteen of 16 patients with malignant conditions and one with non-malignant disease received total body irradiation plus cyclophosphamide. Three of 5 patients with non-malignant conditions and one with leukaemia, received busulphan plus cyclophosphamide. One patient with Fanconi anaemia received 100 mg/kg of cyclophosphamide. Fludarabine (25 mg/m(2)/day for 5 days) was administered prior to all these regimens. Additionally, anti-lymphocyte gamma-globulin (12.5 mg/kg/day) was administered from day -2 to day +2. Three (15%) patients failed to achieve complete chimaerism (CC). These patients received a second cell infusion. Two of them achieved CC. In the third patient, the percentage of donor cells was increased. The likelihood for engraftment was not related to the cell dose received. Acute graft-versus-host disease (GVHD) occurred in nine patients but only one developed GVHD >grade II. Eight patients developed active viral infections, which resolved after treatment. Patients receiving cell doses higher than our average had a significantly faster CD3 and CD4 cell recovery and experienced a lower incidence of viral infections. After 480 +/- 255 days of median follow-up, 16/21 patients are alive and well and have CC. Three patients died of leukaemic relapse and a fourth from progression of his disease (adreno-leuko-dystrophy). We conclude that partially matched related donors are a feasible source of haemopoietic progenitor cells for transplantation for patients without matched familial or unrelated donors.

Disseminated BCG infection in severe combined immunodeficiency presenting with severe anaemia and associated with gross hypersplenism after bone marrow transplantation.

An infant with severe combined immunodeficiency (SCID) is described, who presented with severe anaemia and hepatosplenomegaly due to disseminated Bacillus Calmette-Guérin (BCG) infection involving the bone marrow, liver and spleen. After BMT, huge splenic enlargement occurred, presumably due to proliferation of engrafted donor lymphocytes, leading to severe hypersplenism. Peripheral blood cell consumption was resolved by splenectomy, but gradual loss of the marrow graft followed.

Autografting in Philadelphia (Ph)+ chronic myeloid leukaemia using cultured marrow: an update of a pilot study.

Incubation of CML marrow in long-term culture (LTC) conditions may result in selection of normal (Ph-) LTC-initiating cells (LTC-IC) as early as 10 days, and in production of Ph- clonogenic cells and mature end cells within 5 weeks. This was the rationale for using marrow cells from 10-day-old LTC to autograft nine chronic phase CML patients, ineligible for HLA-matched sibling donor transplant, and who were selected on the basis of a pre-transplant screening LTC test. Of the transplanted patients three died; two of graft failure and one of therapy-related toxicity with 97% Ph- cells 16 months following the autograft. The reconstituting haemopoietic cells in the seven engrafted patients were 100% Ph- in four, > or = 90% Ph- in two and 71% Ph- in the seventh, with a duration of complete cytogenetic response of 6-12 months. Three patients reverted to chronic phase and 100% Ph+ haemopoiesis 27-36 months post-autograft. The other three patients remain in continuous haematological remission with 22% Ph- cells in one and complete cytogenetic remission in the other two 3-4 years post-autograft. IFN therapy was generally introduced on the first evidence of recurrence of Ph+ cells or of cytogenetic deterioration. Further strategies to modulate immune surveillance in vivo may improve the outcome of cultured marrow autografts which give an initial and rather prolonged bias towards Ph- haemopoiesis.

Granular acute lymphoblastic leukaemia of childhood: a morphological phenomenon.

Three hundred and twenty consecutive children with lymphoblastic leukaemia (ALL), treated on the Medical Research Council UKALL VIII schedule, had their Romanowsky stained diagnostic marrows reviewed for the presence of azurophil granules in blast cell cytoplasm. Twenty patients (7%) had greater than 5% blasts showing this feature; 19 had the cell phenotype of "common ALL." Male children and those with French-American-British (FAB) L2 morphology predominantly showed this feature. There was also a strong correlation between granularity and non-diffuse acid phosphate positivity, but no obvious difference between the 20 patients in their response to treatment emerged during a minimum follow up of 15 months. The "granular" variant occurs in around 7% of children with ALL, but has no clear prognostic importance. Morphologists should be aware of its existence and incidence to avoid confusion with acute myeloid leukaemia.

Changes in cytomorphology of childhood lymphoblastic leukaemia at the time of disease relapse. Childhood Leukaemia Working Party of the United Kingdom Medical Research Council.

AIMS: Children in a United Kingdom national trial for relapsed non-B lymphoblastic leukaemia (ALL) had their diagnostic and relapse marrow cytomorphology compared to see what changes occur during the evolution of the disease. METHODS: Each relapse slide was assessed blindly for French American British (FAB) type and other morphological features by a panel of three independent microscopists without reference to each other or any diagnostic material. Diagnostic slides had been assessed by the same panel on an earlier occasion. RESULTS: A total of 134 consecutive children was studied. Six (5%) were classified as FAB type L2 at diagnosis, compared with 18 (13%) at relapse (a difference of 9%). Twenty two (16%) changed their FAB type, 17 (13%) from L1 to L2 and five (4%) from L2 to L1. The FAB score fell at relapse in 34 children and rose in 14, a difference of 14%. Cell size was the commonest feature to change (increasing in 22 and diminishing in nine) followed by prominent nucleoli (appearing in 21 and disappearing in six). Forty four (33%) children had vacuolated blasts at diagnosis, compared with 48 (36%) at relapse. Twenty five changed their vacuole score substantially, 14 gaining > 10% and 11 falling < 10%. CONCLUSIONS: These findings reflect the variability of lymphoblast cytomorphology, but also show a trend for cells to have more prominent nucleoli and greater size at relapse. Factors controlling these features of the FAB type are unknown, but they may simply be related to the growth fraction of a particular disease and not to any lineage specific biological feature.