An open, prospective trial investigating the pharmacokinetics and safety, and the tolerability of escalating infusion rates of a 10% human normal immunoglobulin for intravenous infusion (IVIg), BT090, in patients with primary immunodeficiency disease.

BACKGROUND AND OBJECTIVES: Pharmacokinetics, safety and tolerability of escalating infusion rates of BT090, a 10% intravenous immunoglobulin (IVIg), were studied in patients with primary immunodeficiency disease. MATERIALS AND METHODS: In Part A, patients (n = 30) received 3 infusions of BT090 at their pretrial dose and dosing interval; the infusion rate of BT090 was increased from 0·3 to 1·4 to 2·0 ml/kg/h for each infusion in each patient initially at 30-min intervals. Pharmacokinetics was evaluated at the 3rd infusion (n = 24). At the 4th infusion, infusion rates were to be gradually escalated from 0·3 to 1·4 to 4·0 to a maximum of 8·0 ml/kg/h initially at 30-min intervals to establish the maximum tolerated infusion rate per patient. RESULTS: The pharmacokinetic characteristics and safety profile of BT090 were comparable with those of other IVIgs, including Intratect(®) . Escalation of infusion rates was well tolerated, allowing identification of individual patient's maximum tolerated infusion rate. At subsequent infusions, all patients tolerated their individually defined maximum infusion rate: 17 patients (68·0%) tolerated infusion rates of 6·0 or 8·0 ml/kg/h and four patients (16%) had maximum tolerated infusion rates of <4·0 ml/kg/h at subsequent infusions. Escalation of infusion rates shortened infusion time from a median of around 2·5 h to around 1·6 h. SAEs were reported in three patients, but none was related to BT090 treatment. CONCLUSIONS: Shortening infusion time may reduce overall healthcare spending, for example nursing time needed, and also minimize disruption of patients' daily routine, especially for those patients in work or school settings.

Antibody response to Haemophilus influenzae type-b conjugate vaccine in children and young adults with congenital asplenia or after undergoing splenectomy.

Absence of the spleen constitutes a risk of infection caused by encapsulated bacteria. The aim of our study was to determine the immune response to Haemophilus influenzae type-b (Hib) conjugate vaccine (HibCV) in asplenic individuals, considering the cause of asplenia, the age when splenectomy was carried out, and previous Hib vaccinations. Twenty asplenic patients, aged five to 25 years, were immunized with a single dose of HibCV. The specific antibody concentrations against HibCV were measured by enzyme-linked immunosorbent assay. Before vaccinations, the geometric mean antibody concentration (GMC) had an average value of 3.21 µg/ml and was comparable for all of the patients, regardless of the causes of asplenia. After vaccinations, the GMC was significantly higher, with an average of 6.78 µg/ml. Further, 4.5 years after vaccinations, the GMC was comparable to that of previously unvaccinated children. Moreover, 17/20 patients had GMC ≥ 1.0 µg/ml, which included all of the children with congenital asplenia, children splenectomized before the age of six years, and only 57% of children splenectomized after that age. HibCV gives asplenic patients long-term protection. Hence, HibCV should be administered regardless of previous vaccinations and time from splenectomy, even if antibody evaluation is not available.

Efficacy and safety of Hizentra(®) in patients with primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous replacement therapy.

A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra(®), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra(®) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra(®) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra(®)-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra(®) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections.

Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies.

Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2-<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies.

Liver transplantation for severe hepatic graft-versus-host disease in two children after hematopoietic stem cell transplantation.

Chronic graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). After the skin, the liver is the second, most frequent target of GVHD, which presenting with hyperbilirubinemia, elevated liver enzymes, and coagulopathy. Progressive destruction of small intrahepatic bile ducts causes vanishing bile duct syndrome and leads to end-stage liver disease. We report 2 successful cases of orthotopic liver transplantation performed in children with severe GVHD after hematopoietic stem cell transplantation from a matched unrelated donor (HSCT-MUD).

A multi-centre study of efficacy and safety of Intratect®, a novel intravenous immunoglobulin preparation.

We studied the efficacy, safety and pharmacokinetic profiles of Intratect®, a recently developed polyvalent intravenous immunoglobulin (IVIG) preparation. Fifty-one patients (aged 6-48 years) with primary immunodeficiencies (PID) and established replacement therapy using a licensed IVIG were enrolled and treated for 12 months with Intratect®. Retrospective patient data served as prestudy controls. The primary efficacy variable was the annual rate of acute serious bacterial infection (ASBI) per patient. Secondary parameters were annual rate of acute relevant infection (ARI), days with antibiotic use, fever, absence from school/work and hospitalization. The average IVIG dose was 0·49 g/kg, with an average infusion rate of 2·4 ml/kg/h. The annual ASBI rate/patient was 0·02 and ARIs were detected 128 times during the 630 adverse events in 40 patients, specified mainly as bronchitis, sinusitis, respiratory tract infection, rhinitis and pharyngitis. The annual rate of respiratory ARIs/patient was 2·0 and the rates/patient for days with fever >38°C, school/work absence and hospitalization were 1·81, 3·99 and 0·36, respectively. A total of 630 adverse events (AEs) were observed in 50 of 51 (98·0%) of patients. In 46 of 51 patients the AEs were not related to infusion. Pharmacokinetic studies after the first infusion revealed a mean elimination half-life of 50·8 ± 30·3 days. During this study, 19 of 649 (2·9%) IgG trough levels were below 6 g/l, better than that of reference IVIGs during the 6 months before study start (10 of 201). These data suggest that Intratect® is a well tolerated, safe and effective IgG concentrate for the treatment of patients with PID.

Immune response to the 7-valent pneumococcal conjugate vaccine in 30 asplenic children.

The aim of the study was to determine the concentration of pneumococcal antibodies after a dose of 7-valent pneumococcal conjugate vaccine (PCV7) in 30 asplenic children between 4 months and 19 years of age. Fifteen children had received pneumococcal polysaccharide vaccine (PPV) approximately 5 years prior to vaccination with PCV7. The antibody concentrations against serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F were measured by ELISA before and after the PCV7 vaccination. Before vaccination with PCV7, the antibody concentrations were similar in children who had or had not received PPV previously. A dose of PCV7 stimulated a good immune response in asplenic patients. Prior immunization with PPV did not affect the antibody concentration after the vaccination with PCV7. In conclusion, asplenic children vaccinated with PPV may need revaccination with PPV earlier than the recommended 3-5 years after the first dose. PCV7 induces a satisfactory immune response in asplenic patients and should be considered as an alternative vaccine in that patient group.

ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is an early onset autosomal recessive ataxia associated with characteristic chromosomal aberrations, cell cycle checkpoint defects, cancer susceptibility, and sensitivity to ionizing radiation. We utilized the protein truncation test (PTT), and single strand conformation polymorphism (SSCP) on cDNA, as well as denaturing high performance liquid chromatography (dHPLC) on genomic DNA (gDNA) to screen for mutations in 24 Polish A-T families. Twenty-six distinct Short Tandem Repeat (STR) haplotypes were identified. Three founder mutations accounted for 58% of the alleles. Three-quarters of the families had at least one recurring (shared) mutation, which was somewhat surprising given the low frequency of consanguinity in Poland. STR haplotyping greatly improved the efficiency of mutation detection. We identified 44 of the expected 48 mutations (92%): sixty-nine percent were nonsense mutations, 23% caused aberrant splicing, and 5% were missense mutations. Four mutations have not been previously described. Two of the Polish mutations have been observed previously in Amish and Mennonite A-T patients; this is compatible with historical records. Shared mutations shared the same Single Nucleotide Polymorphism (SNP) and STR haplotypes, indicating common ancestries. The Mennonite mutation, 5932 G>T, is common in Russian A-T families, and the STR haplovariants are the same in both Poland and Russia. Attempts to correlate phenotypes with genotypes were inconclusive due to the limited numbers of patients with identical mutations.

Pharmacokinetics of total immunoglobulin G and immunoglobulin G subclasses in patients undergoing replacement therapy for primary immunodeficiency syndromes.

BACKGROUND AND OBJECTIVES: Careful evaluation of the pharmacokinetic properties of a new immunoglobulin G (IgG) preparation is necessary to ensure that the product will not deviate significantly from existing products, in terms of pharmacological activity. MATERIALS AND METHODS: A prospective, open and uncontrolled trial was performed in 16 patients with primary immunodeficiency syndromes. Patients who had been under replacement therapy with licensed preparations prior to study inclusion, received 280 +/- 60 mg/kg of a solution of IgG, ready for intravenous administration, every 3 weeks for 6 months. Trough and peak plasma levels were measured immediately before and 1 h after each infusion, respectively. Pharmacokinetic parameters were calculated for total IgG and IgG subclasses. RESULTS: Total IgG, IgG1, IgG2 and IgG3 declined mono-exponentially in contrast to IgG4 which showed a bi-exponential decline. Half-lives which were highly variable among patients were similar for total IgG, IgG1 and IgG2 (35.9 +/- 10.8, 36.3 +/- 9.2, and 37.1 +/- 13.9 days, respectively) and shorter for IgG3 and IgG4 (28.6 +/- 10.4 and 15.6 +/- 4.5 days, respectively). CONCLUSIONS: The decline of IgG4 probably reflected a complex catabolic pathway specific for this subclass. As the plasma level of IgG4 is low, the decline of total IgG remained unaffected. Pharmacokinetic properties were consistent with results reported elsewhere in patients undergoing replacement therapy for primary immunodeficiency syndromes.

[Immunity to infection. Infection in primary immunodeficiency]. / Udzial ukladu odpornosci w eliminacji zakazen. Zakazenia u dzieci z pierwotnymi niedoborami odpornosci.

The human body has an elaborate system of local and systemic, immune (cellular, humoral) and nonimmune (skin, mucous membranes) defense mechanisms to protect itself against microbal invaders. Disorders of this intricate system of host defense may generally be classified as primary or secondary. Unusual pathogens infect immunocompromised hosts. Ubiquitous organisms can become opportunistic pathogens. Reactivation of latent organisms is common in this group of patients. Despite their unusual features, infections in the primary immunodeficiency do not occur in a haphazard fashion but rather are predictable depending on the type of immune defects.

Four novel mutations in the gene encoding gp91-phox of human NADPH oxidase: consequences for oxidase assembly.

The superoxide-forming nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase of human phagocytes comprises membrane-bound and cytosolic proteins, which, upon cell activation, assemble on the plasma membrane to form the active enzyme. Patients with chronic granulomatous disease (CGD) are defective in one of the phagocyte oxidase (phox) components, p47-phox or p67-phox, which reside in the cytosol of resting phagocytes, or gp91-phox or p22-phox, which constitute the membrane-bound cytochrome b(558). In four X-linked CGD patients we have identified novel missense mutations in CYBB, the gene encoding gp91-phox. These mutations were associated with normal amounts of nonfunctional cytochrome b(558) in the patients' neutrophils. In phorbol-myristate-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, the association of p47-phox and p67-phox with the membrane fraction of the cells with Cys369-->Arg, Gly408-->Glu, and Glu568--> Lys substitutions was strongly disturbed. Only a Thr341-->Lys substitution, residing in a region of gp91-phox involved in flavin adenine dinucleotide (FAD) binding, supported a normal translocation. Thus, the introduction or reversal of charge at residues 369, 408, and 568 in gp91-phox destroys the correct binding of p47-phox and p67-phox to cytochrome b(558). Based on mutagenesis studies of structurally related flavin-dependent oxidoreductases, we propose that the Thr341-->Lys substitution results in impaired hydride transfer from NADPH to FAD. Because we found no electron transfer in solubilized neutrophil plasma membranes from any of the four patients, we conclude that all four amino acid replacements are critical for electron transfer. Apparently, an intimate relation exists between domains of gp91-phox involved in electron transfer and in p47/p67-phox binding. (Blood. 2000;95:666-673)

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA. Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site. A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified. Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.

A European phase II study of recombinant human granulocyte colony-stimulating factor (lenograstim) in the treatment of severe chronic neutropenia in children. Lenograstim Study Group.

UNLABELLED: We conducted a multicentre, open-label prospective study to evaluate the efficacy and tolerability of lenograstim (human-identical glycosylated rHuG-CSF) in the prevention of infectious episodes of severe chronic neutropenia in 19 patients. The median follow up period was 54.6 months. Lenograstim was administered subcutaneously at a starting dosage of 5 microg/kg per day. Neutrophil recovery was achieved in all patients at induction dosages of 5 (n = 15), 10 (n = 2), 15 (n = 1) or 20 microg/kg per day (n = 1) and occurred at a median 7 days after therapy initiation. Alternate-day administration of double-dose lenograstim was feasible in 7 of 17 patients. Lenograstim treatment significantly (P = 0.012) reduced the incidence of treated infections and hospitalization for infection compared with the pre study period and significantly (P < 0.001) improved perceived health and disease-related symptoms. One patient discontinued treatment because of adverse events (pustulosis) initially related to lenograstim therapy but not confirmed. One patient withdrew by personal choice and was therefore only treated occasionally. One patient committed suicide after 45 months because of social difficulties. One patient was lost during follow up, and three patients presented with a spontaneous neutrophil recovery after 9, 15 and 27 months, respectively. Moderate and transient side-effects related to lenograstim were observed (thrombocytopenia, n = 2; splenomegaly, n = 2; moderate anaemia (without transfusion requirement), n = 5; bone pain, n = 2; increased of alkaline phosphatase, n = 5). CONCLUSION: Lenograstim produced a sustained neutrophil recovery in patients with severe chronic neutropenia, reduced the incidence and severity of infection, and improved quality of life.

[Antibody deficiency in obstructive lung diseases]. / Antikörperdefizienz bei obstruktiven Lungenerkrankungen.

Severe chronic chest disease is the most serious complication in patients with antibody deficiency syndromes. IgG-subclass-deficiencies were a frequent finding in patients with obstructive lung disease and in patients with sinopulmonary infections. In the patient population referred to us for immunological investigation recurrent infection of the upper and lower respiratory tract was the most common reason to suspect undue susceptibility to infection. In 1034 pediatric patients analyzed 299 were found to be deficient in one of several IgG subclasses. In a group of 30 children, all of whom had severe lung disease and normal concentrations of serum IgG, IgA and IgM, airway-obstruction has been diagnosed in 19. 20 of the 30 patients had IgG-subclass-deficiency. The large percentage of IgG-subclass-deficiencies in this group of patients indicates that immunological disregulation is likely to contribute to the pathogenesis of chronic lung disease.

Interaction of campylobacter species with antibody, complement and phagocytes.

The opsonisation of four different campylobacter species for human neutrophils was studied using a chemiluminescence system and electron microscopy. Opsonisation of Campylobacter fetus, Campylobacter coli, and Campylobacter jejuni was mediated by antibody and enhanced by complement. Antibody was not, however, required for the phagocytosis of Campylobacter pylori because it activates the classical pathway of complement directly. This unusual property may be important in the pathogenesis of C pylori associated gastritis and duodenal ulcer.

Primary immunodeficiency diseases in children treated in the Children's Memorial Hospital, Poland.

One hundred and three cases of primary immunodeficiency diseases were diagnosed among children suffering mainly from chronic and severe infections in the period 1980-1987. Predominantly antibody defects were recognized in 48 patients (46.6%), combined immunodeficiencies in 36 patients (35%), phagocytic disorders in 12 patients (11.6%), complement defects in 6 patients (5.8%), and cell-mediated disease (Di George syndrome) in 1 patient. Allergic complications were observed in 25 patients (24.2%) and malignancy-in 3 patients (2.9%). More detailed immunological studies were performed in children with X-linked agammaglobulinemia in the course of intravenous immunoglobulin therapy and in children with ataxia telangiectasia.