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A R Gennery

Publications and source records attributed to A R Gennery.

35 records · Page 2Linked to original sources
PubMed2001

Characterization of the impaired antipneumococcal polysacharide antibody production in immunosuppressed pediatric patients following cardiac transplantation.

We previously have demonstrated impaired pneumococcal polysaccharide IgG antibody responses in children immunosuppressed following cardiac transplantation in early childhood. We have further characterized the antibody defect. To further investigate the production of antibody, antipneumococcal polysaccharide (PPS) specific IgM, IgG, IgG subclasses, and IgA were measured in postvaccination sera by enzyme-linked immunosorbent assay. Two groups were studied: posttransplant children who made pneumococcal antibody in vivo following natural exposure or PPS immunization (R) and those with an impaired response (NR). There was no difference in IgM or IgA levels between R and NR. IgG and IgG2 levels were higher in R than NR (P = 0.002), even after adsorption of nonspecific common cell wall antigen antibody. Differences in anti-pneumococcal antibody levels suggest that immunoglobulin isotype switching from IgM to IgG and particularly IgG2 is impaired in patients immunosuppressed at a young age. These findings confirm data regarding the effect of immunosuppressive agents derived from animal models in humans.

Adolescent↗
PubMed2001

CAMPATH-1M T-cell depleted BMT for SCID: long-term follow-up of 19 children treated 1987-98 in a single center.

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.

Alemtuzumab↗
PubMed2001

Bone marrow transplantation for CD40 ligand deficiency: a single centre experience.

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.

Adolescent↗
PubMed2001

Neonatal bone marrow transplantation for severe combined immunodeficiency.

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.

Acute Disease↗
PubMed2001

Diagnosis of severe combined immunodeficiency.

Early diagnosis of severe combined immunodeficiency (SCID) is important to enable prompt referral to a supraregional centre for bone marrow transplantation before the occurrence of end organ damage secondary to infective complications. This review outlines clinical, microbiological, and immunopathological clues that aid the diagnosis of SCID and emphasises the multidisciplinary approach needed to diagnose and treat these infants.

Bone Marrow Transplantation↗
PubMed2000

Bone marrow transplantation does not correct the hyper IgE syndrome.

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.

Bone Marrow Transplantation↗
PubMed1999

Posttransplantation B lymphoblastic leukemia with Burkitt-like features.

BACKGROUND: Posttransplantation Epstein-Barr virus-associated lymphoproliferative disease (PTLPD) occurs as a spectrum of disease ranging from benign, polyclonal, localized lymphoid hyperplasia to malignant, monoclonal, disseminated lymphoma, sometimes involving the bone marrow. To our knowledge, PTLPD has not been previously reported to present as acute lymphoblastic leukemia. METHODS: We report the case of a boy who developed PTLPD in the form of acute lymphoblastic leukemia 6 years after cardiac transplantation. He had greater than 90% bone marrow invasion by Epstein-Barr virus-positive B lymphoblasts with Burkitt-like features and a t(8;14) translocation. RESULTS: He was successfully treated with combination chemotherapy but unfortunately died, 6 months after completing treatment, from ischemic heart disease. CONCLUSIONS: B lymphoblastic leukemia may occur as a manifestation of PTLPD and should be included in the classification of these diseases. Bone marrow examination should be an essential part of the investigation of patients suspected of having PTLPD.

Administration, Oral↗
PubMed1999

Significance of Epstein-Barr virus status and post-transplant lymphoproliferative disease in pediatric thoracic transplantation.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a serious complication of organ and bone marrow transplantation. The importance of EBV matching between recipient and donor remains unclear. Between October 1987 and December 1997, 64 pediatric cardio-pulmonary transplants were performed at this center (58 hearts, two heart/lungs, four sequential single lungs). The EBV viral capsid antigen (VCA) immunoglobulin G (IgG) status of both donor and recipient was determined at the time of transplant. Of 56 patients from whom paired sera was available for analysis, 27 (50%) were recipient and donor EBV IgG positive, four (7%) were recipient EBV IgG positive and donor EBV IgG negative, and 12 (20%) were recipient EBV IgG negative and donor EBV IgG negative. The remaining 13 (23%) patients were EBV IgG negative but received organs from EBV IgG-positive donors. The EBV immunoglobulin M (IgM) status was determined from 6 weeks post-transplant in the 11 mismatches who survived for longer than 28 d. Seven became EBV IgM positive, two remained EBV IgM negative; the status of the remaining two remains unknown. The EBV IgM status was also determined retrospectively in patients who were EBV IgG negative pretransplant and received organs from EBV IgG-negative donors. Nine became EBV IgM positive; the rest remained negative. PTLD was diagnosed in two of 56 patients from whom paired sera was available; one was donor and recipient EBV IgG negative; the other was donor and recipient EBV IgG positive. No cases of PTLD were diagnosed in the remaining eight patients from whom paired sera was not available. Our experience suggests that PTLD does not occur with any greater frequency in the 'mismatch' group, and does not justify EBV matching in pediatric thoracic transplantation where there is a higher proportion of EBV-negative recipients than in adults.

Adolescent↗
PubMed1999

Changing cyclosporin A formulation: an analysis in paediatric cardiac transplant recipients.

Cyclosporin A is the primary immunosuppressive agent used in cardiac transplantation to maintain chronic immunosuppression. Absorption may be erratic and major side-effects include nephrotoxicity. A recently introduced formulation (Neoral) improves absorption in cystic fibrosis heart-lung transplant recipients, but episodes of rejection have been reported on conversion from the oil-based formulation. A retrospective analysis of 21 paediatric cardiac transplant recipients who had been converted from the oil-based formulation to the micro-emulsified formulation was performed. No clinical rejection episodes occurred following conversion. There was a significant reduction in dose following conversion (p < 0.001). The mean trough level was less on the new formulation (p = 0.04), but there was no difference in coefficient of variation or standard deviation. Mean glomerular filtration rate (GFR) was significantly less, but there was no difference in the rate of change of GFR on the new formulation. Erratic absorption and deteriorating renal function remain as significant problems in paediatric cardiac transplant recipients despite conversion to the new formulation.

Adolescent↗
PubMed1998

Effect of immunosuppression after cardiac transplantation in early childhood on antibody response to polysaccharide antigen.

BACKGROUND: Three children who had cardiac transplantation before age 4 years later presented with recurrent sinopulmonary infection caused by organisms including Streptococcus pneumoniae, in which capsular polysaccharide plays an important part, one developed bronchiectasis. We therefore studied responses to polysaccharide antigen after immunosuppression started in early childhood. METHODS: Antibodies against pneumococcal and haemophilus polysaccharides, and total IgG, IgG1, IgG2, and IgA concentrations were measured in 33 cardiac-transplant recipients transplanted before the age 4 years (group 1) and after that age (group 2). Patients with low pneumococcal and haemophilus antibody concentrations were immunised with 23 polyvalent pneumococcal and tetanus-haemophilus conjugate vaccines and antibody responses were measured. FINDINGS: Five patients from group 1 and seven from group 2 were transplanted for congenital heart disease and ten patients in each group had heart transplants because of cardiomyopathy; none were asplenic. Group 1 (16 patients) were aged 2-10 years when investigated, group 2 (17 patients), were 6-16 years. Four of 16 patients in group 1 responded to pneumococcal polysaccharide vaccine compared with 14 of 17 in group 2 (p=0.0016). This difference remained when those in group 1, aged less than 4 years at investigation, were excluded (p=0.0060). Response to haemophilus-conjugate vaccine was similar in both groups (14 of 16 vs 14 of 17, p=1.0). Significantly more patients who failed to respond to pneumococcal vaccine had low IgG2 concentrations (p=0.0269). INTERPRETATION: Children who had a transplantation and immunosuppression in early childhood before they had developed antibody responses to pneumococcal polysaccharide, still failed to show a response when older-ie, when such responses are the norm. Ongoing immunosuppression prevents the maturation of antipolysaccharide responses leaving children susceptible to severe and recurrent damaging infection.

Aging↗
PubMed1998

Thiamine deficiency mimicking acute rejection following cardiac transplantation.

We describe a recipient of an orthotopic cardiac transplant who developed severe ventricular dysfunction following an episode of sepsis. He had normal cardiac biopsies and responded to treatment with thiamine. Causes other than rejection should be considered in patients who have received a cardiac transplant and who present in cardiac failure.

Acute Disease↗
PubMed1998

Benign transient hyperphosphatasemia of infancy and early childhood following cardiac transplantation.

The phenomenon of a transient very high rise in serum alkaline phosphatase, associated with either trivial illness or no symptoms, in early childhood has been described previously in otherwise normal children. We describe here what we believe are the first published reports in two children who have previously undergone orthotopic cardiac transplantation. They were found to have a very high serum alkaline phosphatase, with features consistent with a diagnosis of transient hyperphosphatasemia of infancy and early childhood. The importance of early recognition and avoidance of overinvestigation are discussed.

Alkaline Phosphatase↗
PubMedDate not supplied

An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome.

Around 15-20 hereditary disorders associated with impaired DNA damage response mechanisms have been previously described. The range of clinical features associated with these disorders attests to the significant role that these pathways play during development. Recently, three new such disorders have been reported extending the importance of the damage response pathways to human health. LIG4 syndrome is conferred by hypomorphic mutations in DNA ligase IV, an essential component of DNA non-homologous end-joining (NHEJ), and is associated with pancytopaenia, developmental and growth delay and dysmorphic facial features. Radiosensitive severe combined immunodeficiency (RS-SCID) is caused by mutations in Artemis, a protein that plays a subsidiary role in non-homologous end-joining although it is not an essential component. RS-SCID is characterised by severe combined immunodeficiency but patients have no overt developmental abnormalities. ATR-Seckel syndrome is caused by mutations in ataxia telangiectasia and Rad3 related protein (ATR), a component of a DNA damage signalling pathway. ATR-Seckel syndrome patients have dramatic microcephaly and marked growth and developmental delay. The clinical features of these patients are considered in the light of the function of the defective protein.

Ataxia Telangiectasia Mutated Proteins↗