S. Blanche

Allogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis

Chez un nourrisson de 25 mois presentant une lymphohistiocytose erythrophagocytaire refractaire au traitement medicamenteux, la transplantation de moelle osseuse compatible de son frere aine, associee a la chimiotherapie, a permis une remission complete stable

Treatment of Severe Epstein-Barr Virus-Induced Polyclonal B-Lymphocyte Proliferation by Anti-B-Cell Monoclonal Antibodies: Two Cases After HLA-Mismatched Bone Marrow Transplantation

We treated two children who developed Epstein-Barr virus-induced polyclonal B-cell proliferation after HLA-mismatched bone marrow transplantation for congenital immunodeficiency with two monoclonal anti-B-cell antibodies. Lymphoproliferative syndrome occurred between 50 and 60 days after bone marrow infusion, and was diagnosed by the presence of spontaneously growing B cells containing Epstein-Barr-nuclear antigen in the blood and bone marrow. The mouse monoclonal anti-B-cell antibodies used were a CD21-specific antibody recognizing the CR2 receptor on B cells (BL13, IgG1) and a CD24-specific antibody binding B cells at all steps of differentiation (ALB9 IgG1). Both antibodies were given intravenously (0.2 mg/kg/body weight.d for 10 days). All clinical and biological manifestations resolved within 3 weeks of treatment. Recurrence was not seen at 18- and 15-month follow-ups. T-cell function developed normally; B-cell function remained partially deficient in one patient 21 months after bone marrow transplantation. These results suggest that monoclonal anti-B-cell antibodies could be useful in controlling severe polyclonal lymphoproliferative syndrome in profoundly immunodeficient patients after bone marrow transplantation.

Treatment of Omenn syndrome by bone marrow transplantation.

We report the outcome of allogeneic bone marrow transplantation (BMT) in nine consecutive patients with Omenn syndrome treated between 1980 and 1989. Five patients received unmanipulated marrow from a related matched donor, and four received T cell-depleted marrow from a haploidentical donor. The patients were conditioned with cyclophosphamide (200 mg/kg) and, except in one case, busulfan (16 mg/kg). Antithymocyte globulin and etoposide were given to three patients each; three recipients of T cell-depleted haploidentical marrow also received intravenous injections of an anti-leukocyte function-associated antigen type 1 antibody as graft rejection prophylaxis. All the patients were fed parenterally for 1 to 5 months before BMT to improve nutritional status and received topical corticosteroids (n = 8), systemic steroids (n = 2), etoposide (n = 1), or cyclosporine (n = 1) to control T-cell activation. Engraftment occurred in four of five recipients of human leukocyte antigen (HLA)-identical marrow and three of four recipients of HLA-haploidentical marrow. One patient died with cytomegalovirus infection. The other six patients are alive 4 to 11 years after BMT, with full chimerism in all but one case. Chronic graft-versus-host disease persists in one patient; the other five survivors have fully restored immune function and have no manifestations of Omenn syndrome, including failure to thrive. We conclude that both HLA-identical and haploidentical BMT can cure Omenn syndrome, provided that parenteral nutrition and immunosuppressive therapy are given before transplantation.

Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors

Summary:Hematological inherited diseases can be cured by hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling donor (MSD), but the outcome of unrelated donors (URD) or haploidentical donors (HMD) has been a cause of concern. In all, 94 children affected with inherited diseases underwent HSCT at a single center using MSD (group A, n=31), URD (group B, n=23) or HMD (group C, n=40). There was no difference in the rate of engraftment or in the incidence of grades III–IV acute graft-versus-host disease (GVHD) between the groups. Survival rate was 80.6% in group A, 62.5% in group B and 47.5% in group C (P=0.023). In group B, survival rate was 73.7% in the subgroup with zero or one class I mismatch, and 25% in the subgroup with two or more class I mismatches (P=0.04). In group C, survival rate was 83.3% in the 9/10-identical subgroup, 64.3% in the seven or 8/10 subgroup, and 25% in the five or 6/10 subgroup (P=0.0007). Thus, engraftment, incidence of GVHD and survival are similar in recipients of grafts from MSD, URD with 0–1 class I-mismatch, or HMD with at least 7/10 HLA matches. The low success of HSCT using more disparate donors suggests reserving them for patients with very poor prognosis.

Treatment of central nervous system B lymphoproliferative syndrome by local infusion of a B cell-specific monoclonal antibody

&NA; A 9-month-old infant developed Epstein-Barr virusinduced lymphoproliferative syndrome with mediastinal and central nervous system localizations, associated with mediastinal tuberculosis, 5 months after heart transplantation. As a combination of anti—B cell antibodies (CD21− and CD24-specific) and recombinant interferon alpha 2b, given intravenously, was not effective on the central nervous system disease, the anti-CD21 antibody was infused intrathecally via an Ommaya reservoir. High local concentrations of monoclonal antibodies were achieved, with no adverse effects. A dramatic clinical response was obtained, with clearance of abnormal cells from the cerebrospinal fluid and a clear reduction in the abnormalities on the brain images. The patient is well 7 months later. This observation indicates that treatment of B lymphoproliferative syndrome with central nervous system localization is feasible using a nontoxic, local B cell—specific approach.

A Prospective Study of Infants Born to Women Seropositive for Human Immunodeficiency Virus Type 1

Assessment of the risks of transmission of infection with human immunodeficiency virus type 1 (HIV-1) from mother to newborn is difficult, partly because of the persistence for up to a year of maternal antibodies transmitted passively to the infant. To determine the frequency of perinatal transmission of HIV infection, we studied from birth 308 infants born to seropositive women, 62 percent of whom were intravenous drug abusers. Of 117 infants evaluated 18 months after birth, 32 (27 percent) were seropositive for HIV or had died of the acquired immunodeficiency syndrome (AIDS) (n = 6); of the 32, only 2 remained asymptomatic. Another 76 infants (65 percent) were seronegative and free of symptoms, whereas 9 (8 percent) were seronegative but had symptoms suggestive of HIV-1 infection. The infants infected with HIV-1 did not differ from the others at birth with respect to weight, height, head circumference, or rate of malformations, but as compared with newborns who were seronegative at 18 months, their serum IgM levels were higher (78 +/- 81 mg per deciliter vs. 38 +/- 39 mg per deciliter; P less than 0.03) and their CD4 lymphocyte counts were lower (2054 +/- 1221 per cubic millimeter vs. 2901 +/- 1195 per cubic millimeter; P less than 0.006). Neither maternal risk factors nor the route of delivery was a predictor of seropositivity at 18 months; however, 5 of the 6 infants who were breast-fed became seropositive, as compared with 25 of 99 who were not (P less than 0.01). We conclude that approximately one third of the infants born to seropositive mothers will have evidence of HIV-1 infection or of AIDS by the age of 18 months, and that about one fifth of this group will have died.

Does haploidentical transplantation in children with primary immunodeficiencies have the potential to exploit donor NK cell alloreactivity

Summary:Donor potential to exert NK cell alloreactivity has been shown to confer survival advantage in haploidentical hematopoietic cell transplantation for hematological malignancies. We investigated killer immunoglobulin receptor (KIR) ligand incompatibility in 40 children receiving haploidentical transplantation for primary immunodeficiencies. The conditioning regimen consisted of busulfan and cyclophosphamide. T-cell depletion of the graft used complement-dependent lysis or CD34+ selection. Two patients died in the first month. The remaining 38 patients were divided into those with (n=13) and those without (n=25) donor potential to exert NK cell alloreactivity. Engraftment was similar in the two groups (61.5 and 64%, respectively). The incidence of grade II–IV acute graft-versus-host disease (GVHD) tended to be lower in the group with donor potential to exert NK cell alloreactivity, but the difference was not significant. In conclusion, in this series of patients with primary immunodeficiencies, donor potential to exert NK cell alloreactivity was not associated with significant advantages in engraftment and prevention of acute GVHD.

Specific T cells for the treatment of cytomegalovirus and/or adenovirus in the context of hematopoietic stem cell transplantation.

from the CHS for parental stress measures. L.A.FANS did not use validated stress measures; therefore, we chose psychosocial stressors that pertain to the adolescent’s physical surroundings or family functioning that have previously been associated either with a stress response or with reduced lung function (for detailed discussion of selected stressors, see the Discussion section in this article’s Online Repository at www.jacionline.org). Psychosocial stressors, which often cluster in economically deprived neighborhoods, may explain some of the adverse effects on respiratory health observed with measures of socioeconomic status. The biologic underpinnings for synergisms between air pollution and stress on lung function may be found in the immune response and inflammatory reactions. Many air pollutants consist of free radicals, which in the lung tissue result in oxidative stress that generates an inflammatory response, releasing additional free radicals that ultimately damage lung tissue. Psychosocial stressors, acting through the hypothalamic-pituitary-adrenal axis modifications, also heighten inflammatory activity and modulate immune function, potentially increasing susceptibility to environmental insults. This pathway may contribute to some of the differential pulmonary vulnerability to air pollutants observed in those with higher levels of psychosocial stress. Briefly, strengths of our study include the use of adolescent self-reported psychosocial stressors. In addition, our spirometry estimates were sensitive to the effects of air pollution and both measures were similar to estimates obtained for air pollutants and pulmonary function from the CHS. However, validated or more psychometrically sound instruments would have been preferential to the stress measures that we used. Although we chose psychosocial stressors based on empirical evidence of cortisol activity in other research, without such biomarkers, we do not know whether reported psychosocial stressors caused a stress response in the adolescent. Our findings of paternal absence are difficult to interpret, as the adolescents were not further queried about their own feelings about the familial composition or related stress. In addition, our sample size did not allow us to analyze pulmonary function as a change from predicted value from a standard population, nor was our sample size large enough to calculate our own standard reference. Thus, we have reported absolute changes in pulmonary function values. Healthy growth and development of pulmonary function in childhood and adolescence is instrumental for respiratory health in adulthood. Our findings contribute modest evidence to the hypothesis that psychosocial stress modifies the effects of air pollutants on lung function, and we hope they may inspire researchers to measure stress when conducting research on respiratory health. Gretchen Bandoli, PhD Ondine von Ehrenstein, PhD Jo Kay Ghosh, PhD Beate Ritz, MD, PhD From the Departments of Epidemiology and Community Health Sciences, Fielding School of Public Health, University of California, Los Angeles, Calif; Independent Researcher, Los Angeles, Calif. E-mail: gbandoli@ucla.edu. The collection of spirometry and air pollution data was funded by the California Air Resources Board (04-323). The National Institute of Environmental Health Sciences (NIEHS) provided additional funding for the analysis and manuscript preparation (grant no. R03ES025908-01). RAND Corporation collected all other data (RAND Center for Population Health and Health Disparities (NIEHS grant no. 1P50 ES012383). California Air Resources Board, RAND Corporation, and NIEHS had no involvement in the design, analysis, or preparation of this manuscript. Disclosure of potential conflict of interest: The authors have received research support from the California Air Resources Board (04-323), RAND Center for Population Health and Health Disparities (National Institute of Environmental Health Sciences [NIEHS] grant no. 1P50 ESO12383), and the NIEHS (grant no. R03 ES025908-01).

Relation of the Course of HIV Infection in Children to the Severity of the Disease in Their Mothers at Delivery

MatemaI lgG1 aod IgA antibody to V3 loop coosensus seqwnce and matemaI-infant HIV-1 trtmsmissioa Markham R.B.; Coberly J.; Ruff A.J.; Hoover D.; Gomez J.; Holt E.; Desormeaux J.; Boulos R.; Quinn T.C.; Halsey N.A. USA LANCET 1994 343/8894 (390-391) Maternal-infant transmission of HIV-I occurs in l3-40% of pregnancies. Studies of transmission of maternal immunity to HIV antigens have used antigens from viruses not represented of clinical isolates and have been conflicting. Using a consensus peptide sequence based on HIV isolates found in Haiti, we found that Haitian mothers who transmitted infection to their offspring had significantly higher mean concentrations of IgGl antibodies to the V3 loop of the primary neutralising domain of the viral envelope (gp 160) than non-transmitters (P = 0.02). Concentrations of IgA antibody to this domain were similar in transmitters and non-transmitters.

Transfusion-related adverse events are decreased in pregnant women with sickle cell disease by a change in policy from systematic transfusion to prophylactic oxygen therapy at home: A retrospective survey by the international sickle cell disease observato

Sickle cell disease (SCD) in pregnancy can be associated with adverse maternal and perinatal outcomes. Furthermore, complications of SCD can be aggravated by pregnancy. Optimal prenatal care aims to decrease the occurrence of maternal and fetal complications. A retrospective, French, two‐center study compared two care strategies for pregnant women with SCD over two time periods. In the first study period (2005‐2010), the women were systematically offered prophylactic transfusions. In the second study period (2011‐2014), a targeted transfusion strategy was applied whenever possible, and home‐based prophylactic nocturnal oxygen therapy was offered to all the pregnant women. The two periods did not differ significantly in terms of the incidence of vaso‐occlusive events. Maternal mortality, perinatal mortality, and obstetric complication rates were also similar in the two periods, as was the incidence of post‐transfusion complications (6.1% in 2005‐2010 and 1.3% in 2011‐2014, P = .15), although no de novo alloimmunizations or delayed hemolysis transfusion reactions were observed in the second period. The results of this preliminary, retrospective study indicate that targeted transfusion plus home‐based prophylactic nocturnal oxygen therapy is safe and may decrease transfusion requirements and transfusion‐associated complications.