Immunization with Haemophilus influenzae type b conjugate vaccine in children given bone marrow transplantation: comparison with healthy age-matched controls.

Forty-seven patients (age range, 7 months-18 years) with malignant (38 cases) and nonmalignant (9 cases) disorders given an allogeneic or an autologous bone marrow transplantation (BMT) were immunized with Haemophilus influenzae type b (Hib) polysaccharide-diphtheria toxoid conjugate vaccine administered in a single dose at different time points after transplantation. Results were compared with those of 13 healthy children matched for age and sex who received the same immunization schedule. Serum and saliva samples for measurement of total IgG subclass and specific antibody levels were obtained from patients and healthy controls before and 3 weeks after vaccination. Twenty-five of the 47 patients (53%) had a specific anti-Hib IgG response, while an effective IgA and IgM response was mounted by 23 (49%) and 11 (23%) children, respectively. In the control group, 13 of 13 subjects mounted a specific IgG antibody production (P < 0.005 in comparison to the patients' response rate), while an IgA and IgM response was demonstrated in 12 (92%; P < 0.01 compared to transplanted patients) and 7 (54%; P < 0.05 in comparison to BMT recipients) children, respectively. Lapse of time from BMT to immunization was the most important factor predicting antibody response, as proved by an effective increase in prevaccination specific IgG levels in the majority of patients vaccinated after 2 years from transplant. Our data demonstrate that BMT recipients have a reduced capacity to mount an antibody response to polysaccharide antigens compared to normal controls, even when a protein-conjugated vaccine is employed. Since time after transplant is the major factor influencing the recovery of immune reactivity to polysaccharide antigens, the ontogeny of the B cell repertoire seems to follow a predetermined sequential program of development.

Infusion of donor-derived peripheral blood leukocytes after transplantation of cord blood progenitor cells can increase the graft-versus-leukaemia effect.

We describe the case of a child affected by acute lymphoblastic leukaemia who received adoptive immunotherapy after cord blood transplantation (CBT). The patient, transplanted in second relapse resistant to chemotherapy, still showed lung and costal leukaemic nodular lesions 2 months after CBT. For this reason, three infusions of donor peripheral blood leukocytes 1 x 10(7)/kg each were administered on days +60, +80 and +100. The procedure was well tolerated by both patient and donor, and a complete disappearance of the lung lesions was documented 2 months after the last infusion. The patient remains in continuous complete haematological remission 13 months after CBT. This experience suggests that adoptive immunotherapy may be safely employed after CBT in order to increase the contribution of immune-mediated anti-leukaemia effect.

Use of recombinant human granulocyte colony-stimulating factor in children given allogeneic bone marrow transplantation for acute or chronic leukemia.

The role of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in myeloid recovery of children given an allogeneic bone marrow transplant (BMT) from an HLA-identical sibling for acute leukemia was evaluated in a retrospectively historically controlled study, involving 20 consecutive treated patients and 30 historical controls. In order to investigate the efficacy of rHuG-CSF in patients given a matched unrelated BMT with methotrexate as part of graft-versus-host disease (GVHD) prophylaxis, we also analyzed the kinetics of engraftment in eight further children with acute or chronic leukemia, transplanted using a volunteer donor. Patients were treated with 5 micrograms/kg/day of rHuG-CSF by 1-h intravenous infusion from day +5 until the absolute neutrophil count (ANC) was > or = 2 x 10(9)/l. No adverse effect related to treatment was observed in any patients. Children transplanted from an HLA-identical sibling and treated with rHuG-CSF reached an ANC count greater than 0.5 x 10(9)/l, 1 x 10(9)/l and of 2 x 10(9)/l in a significantly shorter time than the control group (day +9, +10 and +12, vs day +15, +22 and +29, respectively). An accelerated granulocyte production was also observed in patients receiving an unrelated transplant after a GVHD prophylaxis schedule including methotrexate, the median time to neutrophil recovery above 0.5 x 10(9)/l, 1 x 10(9)/l and 2 x 10(9)/l being +14, +15 and +17 days, respectively. In comparison to historical controls, all rHuG-CSF-treated patients had fewer days of fever, of antibiotic therapy and, only for children with HLA-compatible siblings, of hospitalization, whereas in the three groups the duration and severity of mucositis were comparable. No difference between the rHuG-CSF-treated patients and the historical controls given BMT from HLA-identical sibling was seen with regard to incidence of acute or chronic GVHD, relapse rate and actuarial event-free survival at day +100 and 1 year after transplantation. Our data suggest that in children given allogeneic BMT for acute or chronic leukemia, rHuG-CSF reduces duration of neutropenia, without increasing the rate of relapse or the incidence and severity of GVHD.

Organ- and non-organ-specific auto-antibodies in children with hypopituitarism on growth hormone therapy.

UNLABELLED: Serum non-organ-specific antibodies (NOSA) against nuclear, mitochondrial (AMA), smooth muscle, liver/kidney microsomal (LKM), reticulin, ribosomal, and organ-specific antibodies (OSA) against pituitary gland, gonads (testis, ovary) adrenal cortex, thyroid (thyroglobulin and microsomal), pancreas islet cells, gastric parietal cells and intestinal epithelial cells were evaluated in 45 patients with hypopituitarism (mean age 12.4 +/- 4.0 years). In 22 of them, 9 with isolated growth hormone (GH) deficiency (IGHD) and 13 with multiple pituitary hormone deficiency, MRI showed anterior pituitary hypoplasia with structural stalk abnormality and ectopic posterior pituitary. Twelve had isolated small anterior pituitary and IGHD and 11 had normal morphology of pituitary gland and IGHD. Controls were healthy age-sex-matched subjects. Thyroid antibodies were detected by a passive haemagglutination test while indirect immunofluorescence was used for the others. The auto-antibodies were found in 7/45 asymptomatic patients, a frequency not significantly different from that in controls; 5 were type NOSA and 2 type OSA. Pituitary antibodies were positive in 1 girl with IGHD and normal pituitary morphology. One girl developed hyperthyroidism during the follow up. Autoantibodies were equally distributed between the three groups and the frequency was not dissimilar from that in controls; this suggests that these patients are not at a higher risk of developing auto-immune disease, at least during the first two decades. CONCLUSION: Pituitary insufficiency in children with different MRI features seems unlikely to be secondary to an auto-immune process.

Antibody response to pneumococcal vaccine in children receiving bone marrow transplantation.

Fifty-three pediatric patients given an allogeneic or an autologous bone marrow transplantation (BMT) were immunized with a polyvalent pneumococcal capsular polysaccharide vaccine (Pneumovax II). Vaccine was administered six months or more after BMT and the pneumococcal IgM, total IgG, and IgG subclasses levels were evaluated before and three weeks after immunization. Immunization promoted a significant rise in antibody serum levels (P < 0.000001), and all children vaccinated more than two years after transplantation responded to pneumococcal polysaccharides, whereas only 20-30% and 50% of patients given BMT between six months and one year and one and two years, respectively, mounted an effective antibody production (P < 0.0001). In univariate analysis, lapse of time from BMT to vaccination, chronic graft-versus-host disease occurrence, and female sex influenced the response rate. However, in multivariate analysis, only time between marrow transplant and immunization was a powerful predictor of response. Interestingly, four of 11 patients with IgG2 deficiency before immunization normalized serum levels of this IgG subclass after the pneumococcal antigenic challenge. Our study suggests that time after transplant is the major factor influencing the recovery of immune reactivity to polysaccharide antigens. This seems to confirm the hypothesis that ontogeny of the B-cell repertoire follows a predetermined sequential program in which polysaccharide antigens are some of the last to evoke an antibody response.

Juvenile chronic myelogenous leukemia: in vitro characterization before and after allogeneic bone marrow transplantation.

In previously published studies on patients with juvenile chronic myelogenous leukemia (JCML), excessive proliferation of malignant monocyte-macrophage elements and impaired growth of normal hematopoietic progenitors were demonstrated. A selective hypersentivity of granulocyte-macrophage progenitors (CFU-GM) to granulocyte-macrophage colony stimulating factor (GM-CSF) seems to represent the main pathogenetic mechanism. Allogeneic bone marrow transplantation (BMT) has been demonstrated to be the only curative strategy for patients with JCML. In this study, we evaluated the growth of peripheral blood hematopoietic progenitors in semisolid cultures in two children with JCML before and after allogeneic BMT. Serum levels of GM-CSF, interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) were also assessed. IL-1-beta, GM-CSF and TNF-alpha serum levels of the patients before and after BMT did not differ significantly from those obtained in 45 healthy controls. After marrow transplant, the engraftment of donor hematopoietic stem cell was associated with the disappearance of both pretransplant GM-CSF hypersensitivity and CFU-GM spontaneous growth. The inhibitory effect on the growth of normal hematopoietic progenitors also resolved. This confirms that the substitution of the pathological hematopoietic progenitors represents the basis for the curvative effect of allogeneic BMT in the treatment of JCML, abolishing both the excessive responsiveness of JCML progenitor cells even to very low concentrations of GM-CSF and the growth-inhibitory effect on normal hematopoiesis.