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Biomedical subjects

R A Seger

Publications and source records attributed to R A Seger.

At least 19 recordsLinked to original sources
PubMed2003

Nonmyeloablative allogeneic hematopoietic stem cell transplantation for treatment of Dyskeratosis congenita.

We describe the treatment of a 10-year-old girl with autosomal recessive Dyskeratosis congenita (DC), neutropenia, thrombocytopenia and combined immunodeficiency by nonmyeloablative hematopoietic stem cell transplantation. The conditioning regimen consisted of fludarabine 30 mg/m(2)/day (days -5, -4, -3) and 2 Gy TBI (0.07 Gy/min; day 0). For graft-versus-host disease (GVHD) prophylaxis a course of intravenous MMF and CSA was administered. At 2 years after transplantation of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells from a healthy 11-year-old HLA-identical brother, peripheral blood counts and T- and B-cell functions have completely normalized and donor chimerism was 100% in all cell lineages. No GVHD occurred. Neurological examination and lung function remained normal. The current transplantation regimen appears suitable, safe and efficacious in patients with DC.

Child↗
PubMed2003

Quality control of a national bone marrow donor registry: results of a pilot study and proposal for a standardized approach.

Unrelated hematopoietic stem cell transplantation (HSCT) is a recognized therapy for hematological diseases and over 8 million HLA-typed donors are ready to donate. Increased international exchanges and rapid requests through the Bone Marrow Donor Worldwide (BMDW) ask for standardized quality assurance. Since no such standards have been established to date, we tested a pilot program in order to evaluate donor availability and quality of HLA typing of the Swiss Registry. The 18500 donors of the registry have been analyzed by serology for HLA-AB and by molecular typing for HLA-DR. Through three successive annual quality control (QC) exercises, a total of 114 donor requests were sent to 13 blood transfusion centers responsible for donor recruitment asking for a blood sample. Donors were randomly selected according to recruitment periods (1988-1993; 1994-1997; 1998-2000), and to homozygosity for HLA-A and/or -B antigens. An additional 80 frozen blood samples from the repository corresponding to the three periods (n=26) and to the 2001 period (n=54) were also included in the HLA study. HLA-AB typings were done by polymerase chain reaction-sequence specific primers (PCR-SSP) and all discrepancies were retyped. The results showed that 79 samples provided by 69.3% of the requested donors were received within 14 days, and 19 samples (16.7%) were received in >14 days. Altogether, an 86% rate of donor availability was observed, independent of the recruitment period. Among the requested donors, 16 (14%) were not available: for medical reasons (two), for personal reasons (eight), for loss (one), and for an unknown reason (five). The HLA-A/B DNA typing results of 166 homozygous and 12 heterozygous blood samples showed that 437/439 (99.5%) of the assigned A/B antigens were correct. However in 36/178 donors (20.2%) an HLA-A or -B antigen had been missed (34 donors) or misassigned (two donors) by serology, with a decreasing discrepancy rate of 30% (1988-1993) to 18.5% in 2001. Assuming that HLA-A or -B homozygotes are found in 10-15% of the donors and that correct assignments have been observed in nearly 100% of the donors, an overall error rate of 4-5% would be expected for the national registry HLA-AB typing. These data show that standardized quality control for donor availability and HLA typing is feasible, and we propose that this model could be applied to the registries participating in bone marrow donor worldwide.

Bone Marrow Transplantation↗
PubMed2001

Diagnostic and therapeutic impact of whole body positron emission tomography using fluorine-18-fluoro-2-deoxy-D-glucose in children with chronic granulomatous disease.

AIMS: To compare whole body positron emission tomography (PET) using fluorine-18-fluoro-2-deoxy-D-glucose (FDG) with computed tomography (CT) in detecting active infective foci in children with chronic granulomatous disease. METHODS: We performed 22 whole body FDG PET studies in seven children with X linked (n = 6) or autosomal recessive (n = 1) CGD. All had clinical signs of infection and/or were evaluated prior to bone marrow transplantation (BMT). Nineteen PET studies were also correlated with chest and/or abdominal CT. All PET scans were interpreted blinded to the CT findings. Diagnoses were confirmed histologically and bacteriologically. RESULTS: We detected 116 lesions in 22 FGD PETs and 126 lesions on 19 CTs. Only two of the latter could be classified reliably as active lesions by virtue of contrast enhancement suggesting abscess formation. PET excluded 59 lesions suspicious for active infection on CT and revealed 49 infective lesions not seen on CT. All seven active infective lesions were identified by PET, allowing targeted biopsy and identification of the infective agent followed by specific antimicrobial treatment, surgery, or subsequent BMT. CONCLUSIONS: Identification of infective organisms is more precise if active lesions are biopsied. CT does not discriminate between active and inactive lesions. Whole body FDG PET can be used to screen for active infective lesions in CGD patients.

Adolescent↗
PubMed2000

Evaluation of a clinical algorithm involving serum eosinophil cationic protein for guiding the anti-inflammatory treatment of bronchial asthma in childhood.

A pilot study was performed to investigate a clinical algorithm using serum-eosinophil cationic protein level (S-ECP) as an objective parameter for tapering the anti-inflammatory treatment in chronic childhood asthma. We studied 21 outpatient asthmatic children (6 girls and 15 boys, mean age 9 yr, range 3-12 yr, all with initial S-ECP > or = 15 microg/l) over a period of 12 months at monthly intervals. At each visit a short history, clinical examination, blood sample for S-ECP and eosinophil count, lung function tests and drug compliance were assessed. According to the initial S-ECP, patients were allocated to two anti-inflammatory treatment groups: patients with S-ECP between 15 microg/l and 30 microg/l were treated with Budesonide 200 microg twice daily, while patients with S-ECP of 30 microg/l and above received Budesonide 400 microg twice daily. After this induction treatment the anti-inflammatory medication was tapered at monthly intervals according to actually measured S-ECP: patients with S-ECP < 15 microg/l received sodium cromoglycate (SCG) 10 mg twice daily per inhalation via spacer, patients with S-ECP > or = 15 microg/l and < 30 microg/l received Budesonide 200 microg twice daily via spacer, and patients with S-ECP > or = 30 microg/l received Budesonide 400 microg twice daily. Prior to inhalation of topical steroids or SCG all patients had to inhale 500 microg Terbutaline twice daily for optimal bronchodilatation. The use of medication was assessed by weighing the metered dose inhaler containers each month. Our results showed a decrease in symptoms (p = 0.0001) and in S-ECP (p= 0.02) and MEF50% predicted (p= 0.02) after the initial month of Budesonide treatment. During a total of 246 months of investigation there was no need for emergency room treatment or hospital admission, and no need for oral steroids. During the whole study period there was a tendency for inhaled steroids to be more effective than SCG in reduction of markers of airway inflammation, improvement of symptoms and lung function. Inadequate use of medication was related to an increase in S-ECP in all treatment groups. From this open pilot study it is concluded that a clinical algorithm including S-ECP for tapering the anti-inflammatory treatment may be helpful in childhood asthma. These first observations should be confirmed by a controlled long-term study.

Algorithms↗
PubMed1999

Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by exocrine pancreas insufficiency, metaphyseal dysostosis and bone marrow dysfunction. Recurrent severe bacterial infections and susceptibility to leukaemia are the major causes of morbidity and mortality occurring preferentially in patients with pancytopenia and features of myelodysplasia. Here we report a patient with SDS leading to recurrent bacterial infections and a deteriorating condition since early infancy. Extensive investigations disclosed severe pancytopenia, myelodysplasia and a clonal cytogenetic abnormality, inv(14)(q11q32), as risk factors of leukaemic transformation. He therefore underwent allogeneic geno-identical bone marrow transplantation which resulted in correction of all haematological and immunological abnormalities within an 18-month follow up period. Conclusion Bone marrow transplantation may be considered early as a valuable treatment option especially in high risk Schwachman-Diamond syndrome patients anticipating malignant transformation, life-threatening severe infections or further organ damage.

Bone Marrow Diseases↗
PubMed1998

Successful treatment of invasive aspergillosis in chronic granulomatous disease by bone marrow transplantation, granulocyte colony-stimulating factor-mobilized granulocytes, and liposomal amphotericin-B.

X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency with complete absence or malfunction of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the phagocytic cells. Life-threatening infections especially with aspergillus are common despite optimal antimicrobial therapy. Bone marrow transplantation (BMT) is contraindicated during invasive aspergillosis in any disease setting. We report an 8-year-old patient with CGD who underwent HLA-genoidentical BMT during invasive multifocal aspergillus nidulans infection, nonresponsive to treatment with amphotericin-B and gamma-interferon. During the first 10 days post-BMT, the patient received granulocyte colony-stimulating factor (G-CSF)-mobilized, 25 Gy irradiated granulocytes from healthy volunteers plus G-CSF beginning on day 3 to prolong the viability of the transfused granulocytes. This was confirmed in vitro by apoptosis assays and in vivo by finding nitroblue tetrazolium (NBT)-positive granulocytes in peripheral blood 12 and 36 hours after the transfusions. Clinical and biological signs of infection began to disappear on day 7 post-BMT. Positron emission tomography with F18-fluorodeoxyglucose (FDG-PET) and computed tomography (CT) scans at 3 months post-BMT showed complete disappearance of infectious foci. At 2 years post-BMT, the patient is well with full immune reconstitution and no sign of aspergillus infection. Our results show that HLA-identical BMT may be successful during invasive, noncontrollable aspergillus infection, provided that supportive therapy is optimal.

Amphotericin B↗
PubMed1998

Protective immunogenicity of Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine in children who failed to respond to prior invasive H. influenzae type b disease.

UNLABELLED: A polyribosylribitol phosphate (polysaccharide)-tetanus protein conjugate vaccine (PRP-T) against Haemophilus influenzae type b (Hib) was evaluated for protective immunogenicity in 25 previously PRP-unimmunized children who had failed to develop protective PRP antibody levels (< 1 microg/ml) after prior invasive Hib disease at median age 10 months. Children under 21 months of age at time of PRP-T immunization received one, two or three doses. Serum was obtained for total PRP antibody, complement mediated bactericidal activity and specific IgG1 and IgG2 PRP antibodies before (n = 25), 1 to 2 months (n = 24) and > 5 months (n = 13) after completed vaccination. One to 2 months after immunization, all but one patient developed > 1 microg/ml of antibody (geometric mean level 50.7 microg/ ml). The non-responder developed protective antibody levels when tested at 6 months after vaccination. Twenty out of 22 sera had detectable complement mediated bactericidal activity (median dilution titer 1:24), 1-2 months after vaccination. Three patients failed to demonstrate PRP antibodies in the IgG1 or IgG2 subclasses, although two of them had protective (> 1 microg/ml) total antibody levels. The second post immunization sera showed persistence of the total PRP antibody levels (geometric mean level 38.2 microg/ml) as well as of the bactericidal activity (median dilution titer 1:32). CONCLUSION: PRP-T conjugate vaccine is able to elicit a protective immune response in children who have low or unmeasurable PRP antibody levels after a systemic Hib infection.

Antibodies, Bacterial↗
PubMed1998

The relationship of serum-eosinophil cationic protein and eosinophil count to disease activity in children with bronchial asthma.

BACKGROUND: The serum-eosinophil cationic protein level (S-ECP) has been promoted as a biomarker of asthma that reflects the degree of bronchial eosinophilic inflammation. PATIENTS AND METHODS: To investigate whether S-ECP is indeed a clinically useful objective parameter, especially in mild or moderate chronic childhood asthma, we studied 100 outpatient children with chronic asthma symptoms (63 boys and 37 girls, aged three to 15 years, median of age eight) and 25 controls (12 boys and 13 girls aged three to 15 years, median of age eight). Symptom scores, lung function parameters and atopy were compared with S-ECP determined by commercially available tests and eosinophils measured by an autoanalyser. RESULTS: Asthma symptom scores in the patient group ranged between one and 13 (median of 8), S-ECP between 2.1 and 75.6 microg/l (median of 13.3 microg/ l), and eosinophils between 30/microl and 2002/microl (median of 314). Symptom scores and S-ECP were correlated significantly (P < 0.001) as were symptom scores and eosinophils (P = 0.001). S-ECPs were significantly higher in children with chronic asthma symptoms compared with non-asthmatic, non-atopic children (P = 0.005 for non-atopic chronic asthmatics and P < 0.001 for atopic asthmatics); similar results were found comparing eosinophils in these groups. There was no difference in S-ECP between atopic and non-atopic asthmatic children, but the 25 polysensitised asthmatic children especially with sensitisations to mite, pollen and pet allergens were found to have significantly higher S-ECP compared to 15 monosensitised children (P = 0.002). Similar results were found when correlating eosinophil numbers with atopy. Polysensitised (mite, pollen, pet) asthmatics had significantly higher eosinophil counts compared with monosensitised (pollen) asthmatics (P = 0.01); there was, however, a better discrimination between atopic and non-atopic asthmatics (P = 0.001). Non-asthmatic, non-atopic controls had significantly lower eosinophil counts compared with asthmatics (P < 0.001 for both non-atopic and atopic asthmatics). No correlation between S-ECP or eosinophils and any of the lung function parameters measured (FEV1, FEV1/FVC, MEF50, airway resistance and ITGV) was found. SUMMARY: Our data thus indicate that 1) S-ECP is higher than normal in children with asthma symptoms and correlates with asthma symptom score. 2) S-ECP is better correlated to symptom score than to lung function parameters especially in children with mild and moderate asthma symptoms. 3) Raised S-ECP appears to reflect the extent of allergen sensitivity and may also reflect current allergen exposure. 4) Similar correlations were seen when measuring eosinophil number by an autoanalyser instead of S-ECP. CONCLUSIONS: Although S-ECP and eosinophils are not diagnostic of asthma they are useful inflammation markers especially in the context of clinical studies. However, both methods are not yet suitable for use in daily practice because they require extensive procedures and special equipment.

Adolescent↗
PubMed1997

Adenosine deaminase deficiency in adults.

Adenosine deaminase (ADA) deficiency typically causes severe combined immunodeficiency (SCID) in infants. We report metabolic, immunologic, and genetic findings in two ADA-deficient adults with distinct phenotypes. Patient no. 1 (39 years of age) had combined immunodeficiency. She had frequent infections, lymphopenia, and recurrent hepatitis as a child but did relatively well in her second and third decades. Then she developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease; she died of viral leukoencephalopathy at 40 years of age. Patient no. 2, a healthy 28-year-old man with normal immune function, was identified after his niece died of SCID. Both patients lacked erythrocyte ADA activity but had only modestly elevated deoxyadenosine nucleotides. Both were heteroallelic for missense mutations: patient no. 1, G216R and P126Q (novel); patient no. 2, R101Q and A215T. Three of these mutations eliminated ADA activity, but A215T reduced activity by only 85%. Owing to a single nucleotide change in the middle of exon 7, A215T also appeared to induce exon 7 skipping. ADA deficiency is treatable and should be considered in older patients with unexplained lymphopenia and immune deficiency, who may also manifest autoimmunity or unexplained hepatobiliary disease. Metabolic status and genotype may help in assessing prognosis of more mildly affected patients.

Adenosine Deaminase↗
PubMed1997

Adenovirus-mediated gene transfer into monocyte-derived macrophages of patients with X-linked chronic granulomatous disease: ex vivo correction of deficient respiratory burst.

The underlying cause of X-linked chronic granulomatous disease (X-CGD) is mutations in the gp91phox coding gene. Gp91phox is the larger subunit of the cytochrome b558, the membrane-bound terminal redox centre of the respiratory burst oxidase (NADPH oxidase). We have constructed a recombinant adenovirus which contains a functional copy of the human gp91phox cDNA under the control of the cytomegalovirus (CMV) enhancer/promoter region. This vector was used to infect monocyte-derived macrophages of gp91phox-deficient CGD patients. Expression of the gp91phox transgene resulted in ex vivo reconstitution of the respiratory burst activity. Nitroblue-tetrazolium staining indicated that 74% of the patient cells could be phenotypically corrected when compared with a corresponding control culture of normal monocyte-derived macrophages. Adenoviral gene transfer may become a promising tool and gain therapeutical potential by the targeting of autologous monocytes. Genetically corrected autologous monocytes may be used for supportive treatment of X-CGD patients to overcome acute life-threatening infections. Establishment of adenovirus-mediated reconstitution of gp91phox-deficient monocytes therefore represents a first step towards the development of a clinically applicable supportive transient somatic gene therapy in CGD.

Adenoviridae↗
PubMed1997

Greater omentum flaps and granulocyte transfusions as combined therapy of liver abscess in chronic granulomatous disease.

We report the case of a 17-year-old boy with gp91phax-deficient chronic granulomatous disease who developed a liver abscess due to Staphylococcus aureus. Despite treatment with appropriate antibiotics and gamma interferon for three months as well as incision and drainage, the abscess persisted unchanged in size. After surgical debridement, the abscess cavity was filled with two pedunculated greater omentum flaps as a direct feeder road of granulocytes to the infectious focus. An average of 48.5 x 10(9) granulocytes a day harvested from G-CSF-prestimulated donors were transfused for a total of 8 days without side effects. Ultrasound 3 months later showed no residual abscess. Combination of greater omentum flaps and transfusion of G-CSF-prestimulated granulocytes may be the optimal treatment for liver abscesses refractory to conventional therapy.

Adolescent↗
PubMed1996

RAG mutations in human B cell-negative SCID.

Patients with human severe combined immunodeficiency (SCID) can be divided into those with B lymphocytes (B+ SCID) and those without (B- SCID). Although several genetic causes are known for B+ SCID, the etiology of B- SCID has not been defined. Six of 14 B- SCID patients tested were found to carry a mutation of the recombinase activating gene 1 (RAG-1), RAG-2, or both. This mutation resulted in a functional inability to form antigen receptors through genetic recombination and links a defect in one of the site-specific recombination systems to a human disease.

B-Lymphocytes↗
PubMed1996

Bone marrow transplantation in cartilage-hair hypoplasia: correction of the immunodeficiency but not of the chondrodysplasia.

UNLABELLED: We diagnosed cartilage-hair hypoplasia (CHH) in a female child with prenatal-onset short stature, metaphyseal chondrodysplasia, and severe combined immunodeficiency leading to recurrent, severe respiratory tract infections. The patient required several hospital admissions during her 1st year of life and failed to thrive in spite of antimicrobial therapy and hypercaloric nutrition. Bone marrow transplantation (BMT) from an HLA-identical sister was performed at age 16 months after conditioning with busulphan and cyclophosphamide, using 9 x 10(8) nucleated bone marrow cells/kg body weight. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. The post-transplantation period was uneventful. She developed full and sustained chimerism as demonstrated by DNA analysis of granulocytes and mononucleated cells on days 44, 69 and 455 post BMT. Cellular immunity was completely reconstituted at 4 months, humoral immunity at 15 months post BMT. The patient is alive and well 24 months post BMT without medication, but the radiological osseous changes persist, and longitudinal growth remains markedly below the 10th percentile for CHH standards; her height at age 3 years 4 months is 66 cm. CONCLUSION: In this patient with unusually severe CHH, bone-marrow transplantation has fully corrected the immune deficiency but has had no influence on the course of the chondrodysplasia.

Bone Marrow Transplantation↗
PubMed1995

T-cell death by apoptosis in vertically human immunodeficiency virus-infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors?

One mechanism proposed to play a role in T-cell depletion in human immunodeficiency virus (HIV) infection is apoptosis (activation-induced cell death). We assessed whether apoptosis is related to activation of T cells in vivo and its possible triggers. DNA was extracted from peripheral blood mononuclear cells (PBMC) taken from 16 vertically HIV-infected children and 9 HIV-negative children born to HIV-positive mothers (controls) and tested by agarose gel electrophoresis for the presence of DNA fragments specific for apoptosis. Signs of apoptosis were found on in vitro culture of PBMC from 12 of 16 HIV-infected children, but not in PBMC from the nine controls. Eleven of the 12 HIV-infected children with apoptosis showed an elevated (> 15%) proportion of CD3+/HLA-DR+ cells. This was due to an increased proportion of CD8+/HLA-DR+ cells, as shown in 7 of 7 further tested patients. In none of the probands an increased (> 5%) proportion of IL-2 receptor expressing CD3+ cells was found. T cells undergoing apoptosis were preferentially of the CD8+ phenotype. Expansion of circulating CD8+/interleukin-2 receptor (IL-2R)-/HLA-DR+ T cells is known to occur during active infection with herpes viruses. To investigate the possible role of herpes viral coinfections for apoptosis in HIV infection, we focused on Epstein-Barr virus (EBV) as an example for a herpes virus usually acquired during childhood. In 10 of 12 patients with apoptosis, we found increased levels of EBV genome in PBMC and/or tissues, indicating active EBV replication. By contrast, no increased burden of EBV was found in the four HIV-infected patients without apoptosis or in the controls. Our data indicate that in children the occurrence of apoptosis in HIV infection is closely related to activation of CD8+ T cells. Furthermore, primoinfection with or reactivation of herpes viruses, such as EBV, may substantially contribute to such T-cell activation and the ensuing apoptosis. Additional studies are warranted to evaluate the contribution of herpes virus-triggered apoptosis to the T-cell loss leading to the acquired immunodeficiency syndrome.

Apoptosis↗
PubMed1995

Recombinant human interferon-gamma in patients with chronic granulomatous disease--European follow up study.

This was an uncontrolled, open-label follow up study of a previous 12-month, randomized, double-blind, placebo-controlled trial performed to assess the long-term efficacy and safety of Recombinant Human Interferon Gamma (rIFN-gamma) in patients with chronic granulomatous disease (CGD). In two centres, 28 patients (24 male, 4 female) with a mean age of 16 years (range 3-37) entered the open-label phase. The patients were treated for a mean of 880 days (range 97-1375 days). Visits were scheduled every 180 days and patients completed one to six visits. rIFN-gamma was administered subcutaneously three times weekly at a dose of 0.05 mg per m2. During the open-label phase of the study 12 patients experienced a serious infection requiring hospitalization within 880 days. The median infection-free time was 993 days. No obvious increase of infections over time was seen. Phagocyte superoxide anion production and phagocyte staphylococcal killing were not influenced by therapy. Seven patients were withdrawn from the study, one because of an adverse reaction, three on their own wish and the other three because they changed to another trial. No patient died during the study. Conclusion. Treatment of patients with CGD with intracellular active antibiotics and additional interferon gamma as infection prophylaxis is safe and justified.

Adolescent↗