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Summary:Haemopoietic stem cell transplants (HSCT) cure increasing numbers of primary immunodeficiencies (PID): residual recipient T-cell function increases risk of incomplete or decreasing immune reconstitution, which may resolve following a second, unconditioned, infusion from the same donor (boost infusion). We assessed the outcome of 20 boost infusions in 19/139 patients transplanted for PID patients at our centre since 1987. Boost infusion was given 64-1226 days after the original HSCT. Follow-up was 4-124 months. In all, 12 of 19 patients cleared viral infection (6), or showed sustained increase in donor chimerism, T- and B-cell numbers and function, or other markers (6). In 7/12 patients, immunoglobulin replacement has been discontinued. Four were partially successful with stable low-level chimerism (two patients) or improved T-cell function, but not B cell function (two patients). Four failed with no change in donor chimerism or cell number. No significant association with donor source, T-cell depletion, conditioning regimen, boost infusion stem cell dose or time from original HSCT to boost was found. One patient developed grade III acute graft-versus-host disease despite cyclosporine, and one developed severe pneumonitis; both have recovered. Boost infusion was successful or partially successful in 84%of patients. The risk of adverse effects is low.Bone Marrow Transplantation (2005) 35, 683-689. doi:10.1038/sj.bmt.1704872 Published online 21 February 2005 [ABSTRACT FROM AUTHOR]

We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease (HVOD) following bone marrow transplantation is potentially fatal. Criteria for diagnosis and starting treatment are mainly based on adult studies. Recombinant tissue plasminogen activator (rtPA) has been used with variable success. rtPA and heparin were given to 12 children (nine with immunodeficiency, two malignancy, one thalassaemia) with moderate to severe HVOD. Of the 12, 10 responded with a fall in bilirubin concentration; eight survived with complete resolution of HVOD. Four of the five patients with associated multiorgan failure (MOF) died despite rtPA treatment. One child suffered significant, and one minor, bleeding during rtPA treatment. A scoring system for quantifying the severity of HVOD in children is proposed, incorporating the criteria used to diagnose HVOD, risk factors for its development and also parameters reflective of the patient's general condition. This will facilitate early diagnosis and management of those cases which, if not treated promptly, are likely to deteriorate with an adverse outcome. Our experience suggests rtPA and heparin are an effective treatment for HVOD in children, with relatively little toxicity provided therapy is started before MOF develops.Bone Marrow Transplantation (2003) 31, 591-597. doi:10.1038/sj.bmt.1703881 [ABSTRACT FROM AUTHOR]

Bone marrow transplantation is the only curative treatment for children with severe combined immunodeficiency (SCID). In the absence of an HLA-identical sibling, haploidentical parental donor marrow can be used provided it is depleted of T cells to prevent otherwise inevitable GVHD. Campath 1M has been successfully used for this procedure in several centres. In our centre 17 SCID patients plus one with combined immunodeficiency (CID) were transplanted with Campath 1M T cell-depleted bone marrow. Progenitor cell recovery, before and after T cell depletion, was monitored using granulocyte–macrophage colony-forming cell assays (GMCFU) and CD34 analysis. The numbers of GMCFU/kg transplanted correlated with engraftment and survival post-transplant and monitoring CD34+ cell numbers in the T cell-depleted marrow pretransplant may be an additional indicator of successful engraftment. Use of a buffy coat marrow preparation with restriction of the number of T cells to <5 × 105/kg was associated with graft failure in four and death in five of eight children, probably because too few stem cells were infused. T cell depletion of a mononuclear cell preparation of donor marrow with no arbitrary ceiling of infused T cells is highly effective at preventing clinically important GVHD and cured nine out of 10 children transplanted with such material. [ABSTRACT FROM AUTHOR]

Patients with chronic mucocutaneous candidiasis (CMC) present with persistent infections with the opportunistic yeast Candida. Impaired cell-mediated responses to Candida have been documented in CMC patients, but the defect remains poorly understood. The importance of Th1 cytokines in resistance and Th2 in susceptibility to Candida infections has recently been demonstrated in murine models. In our studies we evaluated production of IL-2 and IFN-γ (markers of Th1 type responses) as well as IL-4 and IL-6 (Th2 type markers) following stimulation with two kinds of Candida antigens (CAgs), polysaccharide antigens, tetanus toxoid and pokeweed mitogen. Our results demonstrate that CMC patients have impaired cytokine production upon in vitro stimulation with CAgs resulting in low or absent IL-2, increased IL-6 and either absent or increased IFN-γ production. Cytokine production following stimulation by other antigens was unaltered. The overall cytokine-producing capacity assessed through mitogen stimulation was also intact. Addition of IFN-α or IFN-γ to culture in an attempt to modify cytokine production did not have significant effects. Levels of soluble IL-6 receptors were not increased and could not account for increased IL-6 production. Our studies support the hypothesis that Candida antigens trigger a predominantly Th2 instead of a Th1 cytokine response in patients with CMC. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about hemophagocytosis during fludarabine-based stem cell transplantation for systemic juvenile adiopathic arthritis in the 2006 issue.

Congenital immunodeficiency in hyper IgE syndrome is characterised by a markedly raised IgE level, recurrent staphylococcal skin infection and pneumatoceles. Standard treatments include anti-staphylococcal antibiotics. We report a severely affected patient in whom successful bone marrow transplantation was followed by reappearance of the immunodeficiency. We conclude that bone marrow transplantation does not cure the immunological features of the hyper IgE syndrome. Bone Marrow Transplantation (2000) 25, 1303–1305. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To analyze available evidence on vaccinations in paediatric patients with rheumatic and autoinflammatory diseases. This evidence formed the basis of the recently constructed European League against Rheumatism (EULAR) recommendations for vaccination of these patients. Methods: A systematic literature review in the MEDLINE and EMBASE databases was conducted using various terms for vaccinations, paediatric rheumatic and autoinflammatory diseases and immunosuppressive drugs. Only papers on paediatric patients (<18years of age) were selected. A panel of 13 experts in the field graded methodological quality and extracted data using predefined criteria. Results: 27 papers were available. No studies were found on autoinflammatory diseases. 14 studies considered live-attenuated vaccines. Evidence so far supports the safety and immunogenicity of non-live composite vaccines, although studies were underpowered to accurately assess safety. Live-attenuated vaccines did not cause disease flares or severe adverse events, not even in patients on methotrexate and low dose glucocorticosteroids. Seven patients on anti-TNFalpha therapy were described receiving the live-attenuated measles, mumps, rubella (n =5) or varicella (n =2) booster without severe adverse events. Conclusions: Data on safety and efficacy of vaccinations in paediatric patients with rheumatic diseases is reassuring, but too limited to draw definite conclusions. More research is needed on the safety and efficacy of especially live-attenuated vaccines in patients with rheumatic and autoinflammatory diseases using high dose immunosuppressive drugs. [Copyright &y& Elsevier]

Abstract: Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαβ+CD4−CD8− double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID. [Copyright &y& Elsevier]

Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1. [ABSTRACT FROM AUTHOR]

Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1–10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti- Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients. [ABSTRACT FROM AUTHOR]

Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-γ, IL-2, tumour necrosis factor (TNF)-α, IL-6, transforming growth factor-β, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-γ, TNF-α and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients. [ABSTRACT FROM AUTHOR]

More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are associated with T–B + NK + SCID phenotype. Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia. Hypomorphic recombination activating genes 1 and 2 mutations were first described in patients with Omenn syndrome. More recently, defects in Artemis, RMRP, IL7Rα and common gamma chain genes have been described. We describe four patients with mutations in CHD7, who had clinical features of CHARGE syndrome and who had T–B + NK + SCID (two patients) or clinical features consistent with Omenn syndrome (two patients). Immunodeficiency in patients with DiGeorge syndrome is well recognized − CHARGE syndrome should now be added to the causes of T–B + NK + SCID, and mutations in the CHD7 gene may be associated with Omenn-like syndrome. [ABSTRACT FROM AUTHOR]

Pulmonary infection, often insidious, is frequent in primary immunodeficiency (PID) and acquired immunodeficiency. Pulmonary complications are serious obstacles to success of haematopoietic SCT (HSCT) for these conditions. Bronchoalveolar lavage (BAL) permits identification of lower respiratory tract pathogens that may direct specific treatment and influence prognosis. There are no reports about the utility of pre-HSCT BAL for immunodeficient patients. We prospectively studied the value of ‘routine’ BAL before commencing transplantation in patients undergoing HSCT for severe immunological disease. Routine non-bronchoscopic BAL was performed under general anaesthetic, a few days before commencing pre-HSCT cytoreductive chemotherapy. Patients were categorized as symptomatic or asymptomatic with respect to pulmonary disease or infection. Samples were sent for microbiological processing. Complications arising from the procedure, pathogens isolated and treatments instituted were recorded. Results were available from 69/75 patients transplanted during the study period; 26 (38%) had pathogens identified (six asymptomatic patients), 10 (14.5%) developed complications post-procedure (two asymptomatic patients)—all recovered, 21 had management changes. There was no statistically significant difference in the number of positive isolates from severe combined or other immunodeficient patients, or of symptomatic or asymptomatic patients. Routine non-bronchoscopic BAL is safe in immunodeficient patients about to undergo HSCT, and leads to management changes.Bone Marrow Transplantation (2007) 40, 529–533; doi:10.1038/sj.bmt.1705776; published online 16 July 2007 [ABSTRACT FROM AUTHOR]

Aims: To evaluate outcome following neonatal bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) when there is a family history of a previously affected sibling, and to compare results with those published for in utero BMT.Methods: A retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD) complications after BMT, and T and B lymphocyte function. Thirteen patients received 18 stem cell transplants: four whole marrow, one cord blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide.Results: All are alive and well (six months to 11.5 years after BMT). Six had grade I-II acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT for poor T cell function, one had a third BMT for graft failure and chronic GvHD, and one had a third BMT for graft failure. Twelve have good in vitro proliferation to T cell mitogens, and all have normal serum IgA levels. Three receive intravenous immunoglobulin; for one of these, it is less than one year since BMT. Nine are above the 2nd centile, and 10 of 12 old enough to be assessed have normal neurodevelopment.Conclusion: These results are better than those published for in utero BMT for SCID. Early postnatal BMT should be the preferred option in neonatal SCID. [ABSTRACT FROM AUTHOR]

Summary:Primary immunodeficiencies (PID) are an important cause of childhood mortality. Haematopoietic stem cell transplantation (HSCT) is the best treatment for many PID. Umbilical cord stem cells are an alternative source of HSC. There is little data regarding outcome of umbilical cord stem cell transplantation (UCSCT) for PID. Our single centre experience is reported. A retrospective study of 14 of 148 patients transplanted for PID, who have received 15 UCSCT was performed, with specific regard to graft-versus-host disease (GvHD) and immune reconstitution. Eight patients with severe combined immunodeficiency (SCID), and six with other combined immunodeficiencies were treated. Of the patients, 12 received unrelated cords, and two had sibling transplants. Median age at transplant was 3.5 months, median nucleated cell dose was 0.8 × 108/kg. All engrafted. Median time to neutrophil engraftment was 22 days, median time to platelet engraftment was 51 days. One developed significant grade III GvHD post transplantation. In total, 11 patients had full donor T and six full donor B-cell chimerism, six of nine patients >1 year post-BMT had normal IgG levels and specific antibody responses to tetanus and Hib vaccines; two are being assessed. Two patients died of multi-organ failure related to pre-existing infection and inflammatory complications respectively. UCSCT should be considered for patients requiring stem cell therapy for PID.Bone Marrow Transplantation (2005) 36, 295–299. doi:10.1038/sj.bmt.1705054; published online 20 June 2005 [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome, is characterized clinically by developmental abnormalities, growth retardation, progressive bone marrow failure, pancytopenia, and pronounced cancer predisposition. Nijmegen Breakage Syndrome (NBS) is a related disorder that shares overlapping clinical features, principally, developmental delay, microcephaly, and cancer predisposition. The diagnosis has relied on chromosomal instability following exposure to DNA cross-linking agents in FA and to ionizing radiation (IR) in NBS. We describe two patients who clinically had FA, but showed sensitivity to both DNA cross-linking agents and ionizing radiation, and who were found to have a rare mutation in the NBS gene. The importance of genetic diagnosis with respect to treatment and prognosis is discussed. [Copyright &y& Elsevier]

Summary:Thyroid dysfunction, a common long-term complication following bone marrow transplantation (BMT), is frequently associated with total body irradiation (TBI) given in the pre-BMT conditioning protocol. We report our preliminary observation of the prevalence of thyroid dysfunction in children transplanted for primary immunodeficiency (PID) who were given cytoreductive conditioning with busulphan and cyclophosphamide, but without TBI. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (fT4) in 83 survivors transplanted between 1987 and 2002. We found nine children (10.8%) with clinical and/or biochemical thyroid dysfunction at 4 months to 4.5 years post-BMT of which three had positive antithyroid microsomal antibodies. Two patients were classified as primary and seven as compensated hypothyroidism (hyperthyrotropinaemia). Four patients with clinical features of hypothyroidism received replacement thyroxine, while five of the seven patients with compensated hypothyroidism remain off thyroxine because we suspect this may be a transient phenomenon.Abnormalities of thyroid function including severe primary hypothyroidism may occur post-BMT in children receiving chemotherapy conditioning without TBI. Thyroid function should be assessed regularly in this group of patients.Bone Marrow Transplantation (2004) 33, 949-953. doi:10.1038/sj.bmt.1704456 Published online 8 March 2004 [ABSTRACT FROM AUTHOR]

Summary:Established treatment of severe combined immunodeficiencies (SCID) and other primary immunodeficiencies (PID) is bone marrow transplantation (BMT). Normal lymphocyte numbers and protein antigen responses are present within 2 years of BMT, polysaccharide antibody responses appear last. Streptococcus pneumoniae infection causes significant morbidity and mortality post-BMT. Previous studies have shown good protein antigen responses post-BMT for SCID and PID, but had not examined the polysaccharide responses. We retrospectively analysed pneumococcal polysaccharide (PPS) responses in our patient series.In total, 22 SCID and 12 non-SCID PID were evaluated, all >2 years post BMT: 17 SCID, 12 PID received chemotherapy conditioning; 17 SCID, three PID had T-cell depleted (TCD) BMT, others had nonconditioned whole marrow BMT. All had normal Haemophilus influenza B and tetanus antibody responses. Of 22 SCID, 13 vs 11/12 PID responded to PPS vaccine (P=0.05). There was no association with donor age, GvHD, B-cell chimerism, or IgG2 level. Fewer TCD marrow recipients responded to PPS (P=0.04). Analysis of the SCID group showed no association of PPS response with type of marrow received. This is the first study to specifically examine PPS antibody responses following SCID and PID BMT. Pneumococcal conjugate vaccine antibody responses should be examined in these children.Bone Marrow Transplantation (2003) 32, 225-229. doi:10.1038/sj.bmt.1704109 [ABSTRACT FROM AUTHOR]

Background: Transplantation of allogeneic haemopoietic stem cells can cure several primary immunodeficiencies. This European report focuses on the long-term results of such procedures done between 1968 and December, 1999, for primary immunodeficiencies.Methods: The report includes data from 37 centres in 18 countries, which participated in a European registry for stem-cell transplantation in severe combined immuno deficiencies (SCID) and in other immunodeficiency disorders (non-SCID). 1082 transplants in 919 patients were studied (566 in 475 SCID patients, 512 in 444 non-SCID patients; four procedures excluded owing to insufficient data). Minimum follow-up of 6 months was required.Findings: In SCID, 3-year survival with sustained engraftment was significantly better after HLA-identical than after mismatched transplantation (77% vs 54%; p=0.002) and survival improved over time. In HLA-mismatched stem-cell transplantation, B(-) SCID had poorer prognosis than B(+) SCID. However, improvement with time occurred in both SCID phenotypes. In non-SCID, 3-year survival after genotypically HLA-matched, phenotypically HLA-matched, HLA-mismatched related, and unrelated-donor transplantation was 71%, 42%, 42%, and 59%, respectively (p=0.0006). Acute graft versus host disease predicted poor prognosis whatever the donor origin except in related HLA-identical transplantation in SCID.Interpretation: The improvement in survival over time indicates more effective prevention and treatment of disease-related and procedure-related complications--eg, infections and graft versus host disease. An important factor is better prevention of graft versus host disease in the HLA-non-identical setting by use of more efficient methods of T-cell depletion. For non-SCID, stem-cell transplantation can provide a cure, and grafts from unrelated donors are almost as beneficial as those from genetically HLA-identical relatives. [ABSTRACT FROM AUTHOR]

Background: Although severe T cell immunodeficiency in DiGeorge anomaly is rare, previous studies of humoral function in these patients have found no antibody abnormalities but have not examined the response to polysaccharide antigens. Isolated cases of autoimmunity have been reported. Several patients with 22q11.2 deletion attending our immunology clinic suffered recurrent sinopulmonary infection or autoimmune phenomena.Aims: To investigate humoral immunodeficiency, particularly pneumococcal polysaccharide antibody deficiency, and autoimmune phenomena in a cohort of patients with 22q11.2 deletion.Methods: A history of severe or recurrent infection and autoimmune symptoms were noted. Lymphocyte subsets, immunoglobulins, IgG subclasses, specific vaccine antibodies, and autoantibodies were measured. Subjects were vaccinated with appropriate antigens as indicated.Results: Of 32 patients identified, 26 (81%) had severe or recurrent infection, of which 13 (50%) had abnormal serum immunoglobulin measurements and 11/20 >/=4 years old (55%) had an abnormal response to pneumococcal polysaccharide. Ten of 30 patients (33%) had autoimmune phenomena; six (20%) were symptomatic.Conclusions: Humoral immunodeficiency is more common than previously recognised in patients with 22q11.2 deletion. Normal T cell function and immunoglobulin levels do not exclude poor specific antibody responses. Patients should be referred for formal immunological assessment of cellular and humoral immune function. [ABSTRACT FROM AUTHOR]

Aims -- To evaluate outcome following neonatal bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) when there is a family history of a previously affected sibling, and to compare results with those published for in utero BMT. Methods -- A retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD) complications after BMT, and T and B lymphocyte function. Thirteen patients received 18 stem cell transplants: four whole marrow, one cord blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide. Results -- All are alive and well (six months to 11.5 years after BMT). Six had grade I-II acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT for poor T cell function, one had a third BMT for graft failure and chronic GvHD, and one had a third BMT for graft failure. Twelve have good in vitro proliferation to T cell mitogens, and all have normal serum IgA levels. Three receive intravenous immunoglobulin; for one of these, it is less than one year since BMT. Nine are above the 2nd centile, and 10 of 12 old enough to be assessed have normal neuro- development. Conclusion -- These results are better than those published for in utero BMT for SCID. Early postnatal BMT should be the preferred option in neonatal SCID. [ABSTRACT FROM AUTHOR]

Background: CD40 ligand (CD40L) deficiency is a rare X linked immunodeficiency disorder leading to recurrent bacterial infection, with cryptosporidial enteritis and subsequent hepatic cirrhosis. Bone marrow transplantation offers the only cure.Objective: To analyse retrospectively the outcome of bone marrow transplantation for this condition in one centre.Design: A retrospective case note analysis was performed, identifying all patients with CD40L deficiency who had undergone bone marrow transplantation between May 1988 and December 2000. Details of pre-existing infection, pretransplantation immunological and infective data, transplant procedure (particularly donor type and HLA match), conditioning regimen, and marrow manipulation were analysed. Post-transplantation data including infective episodes, engraftment details, immune function, complications, and outcome were recorded.Results: Eight boys (age 1-14 years, median 5.75) had transplants. Six received T cell depleted unrelated donor marrow. Four survive and have normal immune function. Six had previous Pneumocystis carinii pneumonia and three had histological liver damage. Survival was associated with younger age at transplantation and normal liver histology.Conclusions: Bone marrow transplantation can be curative in CD40L deficiency. Better outcome is associated with younger age at transplantation and normal liver histology. [ABSTRACT FROM AUTHOR]

Background: SCID can be cured by BMT. Depletion of mature T cells from BM has enabled HLA non-identical stem-cell transplantation. We report the outcome of 30 patients treated with 37 T-cell depleted BMT procedures using CAMPATH-1M in vitro between 1987-98 in a single center. Methods: Immune reconstitution and quality-of-life were assessed in 19 longterm survivors. All but two received pre-transplant conditioning. T- and B-cell chimerism, numbers and function were analyzed during a median follow-up of 5.3 years (range 1.33-12). Results: The overall engraftment rate was 59%, six children required repeated BMT and the survival rate was 63%. All have donor T cells, 58% normal T-cell numbers and 74% normal T-cell function. Of 17 evaluated, 16 patients (94%) have normal IgM and IgG levels, and production of specific Abs to protein Ags, but only 5/16 (31%) have a good response to pneumococcal polysaccharide. Early and late post-BMT complications were rare and there were no delayed deaths. Only one child continues on long-term i.v. Ig 4-years post-BMT. Eleven children died (37%). Discussion: CAMPATH-1M T-cell depleted BMT for SCID resulted in 63% survival. Deaths of 11 children were mainly due to pre-existing infections. Seventeen of 19 long-term survivors have normal immune function and good quality-of-life. [ABSTRACT FROM AUTHOR]

Respiratory viral infections are major causes of morbidity and mortality in children with SCID and other primary immunodeficiencies who require BMT. Twenty-two of 73 (30%) such children were admitted with respiratory viral infections, of whom 13/22 (59%) died. All viruses were detected in nasopharyngeal aspirate (NPA). Virus was only found in BAL in those with LRTI. Eleven of 22 (50%) had paramyxovirus infections, all with severe viral pneumonitis which worsened post BMT. Five of 11 (45.5%) survived overall. All 11 received aerosolised ribavirin; five of 11 received additional inhaled immunoglobulin and corticosteroid. Three of 5 (60%) survived compared with two of six (33.3%) not thus treated. Three of 22 (13.6%) had adenoviruses; one died of disseminated disease, including pneumonia despite intravenous ribavirin. Eleven patients had rhinovirus detected; nine of 11 (82%) were asymptomatic or coryzal and survived. Two patients with additional severe lung pathologies had LRT rhinovirus and died. All patients received intravenous immunoglobulin. No treatments resulted in viral clearance without successful T cell engraftment. Respiratory viruses, particularly paramyxoviruses and adenoviruses are common, significant pathogens in these patients, significantly worsening outcome of BMT. NPA is an ideal specimen for diagnosis and monitoring of infection. Aggressive treatments may reduce viral replication and damage. Nebulised immunoglobulin and corticosteroid in LRTI may improve respiratory function and outcome. Bone Marrow Transplantation (2000) 26, 1097–1102. [ABSTRACT FROM AUTHOR]

Patients with chronic mucocutaneous candidiasis (CMC) succumb to persistent infections with the opportunistic yeast Candida. Impaired cell-mediated responses to Candida have been repeatedly reported while antibody responses were mostly found to be normal. The underlying defect remains poorly understood. It has recently been shown that CMC patients are also susceptible to infections with encapsulated bacteria, and may have associated IgG2 and IgG4 deficiency. Our previous studies demonstrated altered cytokine production in CMC patients. As cytokines can influence production and isotype of specific antibody, in 10 patients with CMC we measured the levels and isotype distributions of serum antibodies to Candida antigens (CAg). pneumococcal polysaccharide (PPS) and tetanus toxoid (TT) antigens. Peripheral blood lymphocytes were also stimulated in culture and the antibodies made in vitro were measured. Our data demonstrated that in vivo, CMC patients had very high levels of IgG and IgA CAg-specific antibodies. CAg-specific and PPS specific IgG1 was markedly higher than in controls. Children but not adults with CMC had significantly lower levels of IgG2-specific antibody to CAg and PPS compared with age-matched controls. Patients had significantly higher levels of IgG3-specific antibody to all three antigens tested. These findings were in accordance with increased total IgG and IgG3 levels seen in CMC patients. In vitro, CMC patients, particularly children, did not respond as frequently to antigen stimulation as did their healthy controls. The level of specific antibody produced was also lower lo all antigens tested, as was the amount of total immunoglobulins following antigenic and particularly mitogenic stimulation. Addition of interferon-alpha (IFN-α) or IFN-β lo cultures had variable, sometimes marked, effects. Our results demonstrate that CMC patients manifest subtle alterations in specific antibody responses to CAg, PPS and TT, which are most pronounced in children. This may relate to altered cytokine production also seen in these patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the mutation in FOXP3 in patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome who are undergoing haematopoietic stem cell transplantation (SCRT) between 2003 and 2010.

There is an increase in the number of patients with systemic lupus erythematosus (SLE) reported as developing progressive multifocal leukoencephalopathy (PML) while on intensive immunosuppressive therapy. A 39-year-old HIV-negative woman with a 10-year history of SLE presented with progressive left-side weakness while on maintenance therapy with oral prednisone and mycophenolate mofetil (MMF). On several occasions low CD4+ T-lymphocyte counts were found (68/µL). Brain magnetic resonance imaging (MRI) revealed a large lesion in the right subcortical fronto-parietal region and a smaller one in the left frontal subcortex, corresponding to the PML. In cerebrospinal fluid, polymerase chain reaction (PCR) for JC virus (JCV) was negative, but anti-JCV antibodies were highly positive. Diagnosis of probable PML was made and MMF was withdrawn. The patient's condition improved with marked reduction of left-side weakness and an increase in CD4+ T-lymphocyte count (141/µL). Follow-up MRI showed regression of lesions and over the next 6 months the patient remained stable. In spite of the grave prognosis associated with PML, SLE patients can have an excellent outcome if immunosuppressants are discontinued as soon as the correct diagnosis is made. SLE patients with associated low CD4+ T-lymphocyte counts should be monitored for the development of PML during immunosuppressive therapy in particular. [ABSTRACT FROM AUTHOR]

This article presents a report on the postmortem diagnosis of chronic granulomatous disease (CGD). This report is in the form of a case study. The subject of this study was an 11 year old boy, who was admitted to hospital with right upper lobe pneumonia. He Was prescribed amoxicilin, followed after a week by erythromycin. In spite of aggressive and supportive care he died. The granulomatous inflammation of the lungs, liver and spleen seen on postmortem histopathology. Because of the fulminant disease course no immunological investigations were performed before death. However, 20 percent of the mother's neutrophils had reduced oxidative burst activity, suggesting a carrier state for X linked CGD.

Chronic granulomatous disease (CGD) causes growth failure, inflammatory lung damage and often early death. Prophylactic cotrimoxazole improves medium-term survival, but cannot prevent inflammatory sequelae. We report the first patient with CGD who underwent successful HLA identical sibling umbilical cord stem cell transplantation (UCSCT) after myeloablative conditioning. The patient presented with colitis, confirmed as CGD at 2 years of age. Following BU16/CY200 conditioning, he had UCSCT from his unaffected HLA identical sister. A year post-transplant, his colitis had resolved clinically and on radioisotope scan growth has improved. Neutrophil oxidative burst was 92% normal with full donor lymphocyte reconstitution.Bone Marrow Transplantation (2003) 31, 403-405. doi:10.1038/sj.bmt.1703863 [ABSTRACT FROM AUTHOR]

Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency disorder with an estimated overall frequency of 1 in 75 000 live births. Bone marrow transplantation is the only curative treatment available. Using T cell-depleted HLA non-identical bone marrow requires preconditioning with a short course of cytotoxic chemotherapy. We report severe dental developmental anomalies in three such patients under long-term follow up. Bone Marrow Transplantation (2000) 25, 1007–1009. [ABSTRACT FROM AUTHOR]

Discusses the role of the gene encoding nuclear factor kappa-beta essential modulator in anhidrotic ectodermal dysplasia and immunodeficiency. Essential role of the protein in the activation of the transcription factor that affects human development, skin homeostasis and immunity; Implications on acute pediatrics.

The article describes the case of a 13-year old girl with a history of left limb movement and falls presumed to be vasovagal faints. The girl suffered from left arm weakness and speech difficulties following a collapsed. Medical record shows the girl's mood swings, self-harming behaviors, development of a right hand preference having previously been left hand dominant, inability to walk upstairs, appeared confused and wandered about the house looking for objects which she thought had been lost.

Summary:Since 1997, autologous stem cell transplantation (ASCT) had been applied to more than 40 children with polyarticular or systemic juvenile idiopathic arthritis (JIA). For this review, results of the follow-up are available from 25 children with systemic JIA and six with polyarticular JIA that were reported in detail from eight different pediatric European transplant centers. Before ASCT all children had progressive disease despite the use of corticosteroids, methotrexate (MTX) up to 1?mg/kg/week, cyclosporin (2.5?mg/kg/day) and/or anti-TNFa therapy. The clinical follow-up of these children ranges from 8 to 60 months (median 33 months).Bone Marrow Transplantation (2003) 32, S61-S64. doi:10.1038/sj.bmt.1703946 [ABSTRACT FROM AUTHOR]