Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

BACKGROUND: Since 1968 it has been known that bone marrow transplantation can ameliorate severe combined immunodeficiency, but data on the long-term efficacy of this treatment are limited. We prospectively studied immunologic function in 89 consecutive infants with severe combined immunodeficiency who received hematopoietic stem-cell transplants at Duke University Medical Center between May 1982 and September 1998. METHODS: Serum immunoglobulin levels and lymphocyte phenotypes and function were assessed and genetic analyses performed according to standard methods. Bone marrow was depleted of T cells by agglutination with soybean lectin and by sheep-erythrocyte rosetting before transplantation. RESULTS: Seventy-seven of the infants received T-cell-depleted, HLA-haploidentical parental marrow, and 12 received HLA-identical marrow from a related donor; 3 of the recipients of haploidentical marrow also received placental-blood transplants from unrelated donors. Except for two patients who received placental blood, none of the recipients received chemotherapy before transplantation or prophylaxis against graft-versus-host disease. Of the 89 infants, 72 (81 percent) were still alive 3 months to 16.5 years after transplantation, including all of the 12 who received HLA-identical marrow, 60 of the 77 (78 percent) who were given haploidentical marrow, and 2 of the 3 (67 percent) who received both haploidentical marrow and placental blood. T-cell function became normal within two weeks after transplantation in the patients who received unfractionated HLA-identical marrow but usually not until three to four months after transplantation in those who received T-cell-depleted marrow. At the time of the most recent evaluation, all but 4 of the 72 survivors had normal T-cell function, and all the T cells in their blood were of donor origin. B-cell function remained abnormal in many of the recipients of haploidentical marrow. In 26 children (5 recipients of HLA-identical marrow and 21 recipients of haploidentical marrow) between 2 percent and 100 percent of B cells were of donor origin. Forty-five of the 72 children were receiving intravenous immune globulin. CONCLUSIONS: Transplantation of marrow from a related donor is a life-saving and life-sustaining treatment for patients with any type of severe combined immunodeficiency, even when there is no HLA-identical donor.

Complete DiGeorge syndrome: persistence of profound immunodeficiency.

OBJECTIVE: DiGeorge syndrome is characterized by developmental defects of the heart, parathyroid glands, and thymus. The objective of this study was to determine whether T-cell function spontaneously improves in patients with DiGeorge syndrome who have profoundly depressed T-cell proliferative responses to mitogens at presentation, regardless of the T-cell count. STUDY DESIGN: We conducted a retrospective chart review of eight patients with DiGeorge syndrome who had no proliferative responses to mitogens on presentation. RESULTS: Despite lack of responsiveness of the patients' peripheral blood lymphocytes to mitogens, T cells were occasionally detected, and the patients' cells often responded to IL-2 and in mixed lymphocyte reactions. Unresponsiveness to mitogens and clinical immunodeficiency persisted without immune-based therapy. One patient is alive and well after immunoreconstitution from thymic transplantation. The others either died early of complications of their disease such as gastroesophageal reflux with aspiration (2 patients) or infection (2 patients) or died after attempts at immunorestorative therapy with IL-2, thymus transplantation, or bone marrow transplantation (3 patients). CONCLUSION: Eight patients with DiGeorge syndrome who were first seen with no mitogen responsiveness did not improve spontaneously. We recommend HLA-identical bone marrow transplantation or thymic transplantation for these patients as soon as the diagnosis is confirmed.

Gastroesophageal reflux and severe combined immunodeficiency.

BACKGROUND: Gastrointestinal and respiratory symptoms and failure to thrive not associated with infections or medications were noted in patients with severe combined immunodeficiency. OBJECTIVE: The aim of our study was to determine the frequency of gastroesophageal reflux in patients with severe combined immunodeficiency. METHODS: We studied the case histories of 73 pediatric patients who had been treated at Duke University Medical Center for severe combined immunodeficiency between 1982 and 1995. Charts were reviewed for documentation of gastroesophageal reflux on the basis of clinical course and results of barium swallow, esophageal pH probe monitoring, or endoscopy. To compare the incidence of gastroesophageal reflux in patients with severe combined immunodeficiency to known high-risk populations, we additionally tabulated the underlying diagnoses in an age-matched group of patients who underwent Nissen fundoplication from 1990 to 1995. RESULTS: We found clinically significant gastroesophageal reflux in 15 of the 73 patients (20.5%), much higher than has been reported in the normal population (0.1% to 0.3%, p < 0.001). Of patients treated between 1990 and the present, 10 of 36 (27.7%) had significant gastroesophageal reflux compared with five of 37 patients (13.5%) in the previous years. Thus with greater recognition and improved methods for diagnosis, the observed incidence of gastroesophageal reflux has increased greatly. The clinical presentations were not different from those of patients with other well-documented underlying diagnoses. Seven of the 15 patients (46.6%) did not respond to medical treatment with antacids, H2-blockers, and prokinetic agents and underwent surgical treatment. Indications for surgery included persistent esophagitis, vomiting, pneumonia, and growth failure. CONCLUSIONS: The reason for the high incidence of gastroesophageal reflux in patients with severe T-cell disorders remains unclear. Considering the frequency of this association, early recognition and treatment is important to enable adequate nutrition and prevent damage to the esophagus and lungs.

Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants.

OBJECTIVE: To determine the relative frequencies of the different genetic forms of severe combined immunodeficiency (SCID) and whether there are distinctive characteristics of the particular genotypes. STUDY DESIGN: The demographic, genetic, and immunologic features of 108 infants with SCID who were treated consecutively at Duke University Medical Center were analyzed. RESULTS: Eighty-nine subjects were boys and 19 were girls; there were 84 white infants, 16 black infants, and 8 Hispanic infants. Forty-nine had X-linked SCID with mutations of common cytokine receptor gamma chain (gamma c), 16 had adenosine deaminase (ADA) deficiency, 8 had Janus kinase 3 (Jak3) deficiency, 21 had unknown autosomal recessive mutations, 1 had reticular dysgenesis, 1 had cartilage hair hypoplasia, and 12 (all boys) had SCID of undetermined type. Deficiency of ADA caused the most profound lymphopenia; gamma c or Jak3 deficiency resulted in the most B cells and fewest natural killer (NK) cells; NK cells and function were highest in autosomal recessive and unknown types of SCID. CONCLUSIONS: Different SCID genotypes are associated with distinctive lymphocyte characteristics. The presence of NK function in ADA-deficient, autosomal recessive, and unknown type SCIDs, and low NK function in a majority of gamma c and Jak3 SCIDs indicates that some molecular lesions affect T, B, and NK cells (gamma c and Jak3), others primarily T cells (ADA deficiency), and others just T and B cells.

Multicenter crossover comparison of the safety and efficacy of Intraglobin-F with Gamimune-N, Sandoglobulin, and Gammagard in patients with primary immunodeficiency diseases.

The safety and clinical efficacy of a liquid, beta-propiolactone-stabilized intravenous gamma-globulin, Intraglobin-F, was evaluated in a multicenter, double-blind study comparing Intraglobin-F to Gamimune-N, Sandoglobulin, or Gammagard. beta-Propiolactone stabilizes the IgG molecule to decrease aggregate formation and is a potent virucidal agent that reduces the risk of viral transmission by intravenous gamma-globulin (IVIG) preparations. Twenty-seven patients with primary immunodeficiency diseases were enrolled at three centers. Each patient received 6 months of therapy with either Intraglobin-F or the IVIG preparation that they had received during the preceding 3 months, then crossed over to the other preparation. Twenty-three patients completed the study. One patient withdrew because of an adverse event, generalized urticaria. A second patient withdrew because of fatigue and perceived decreased efficacy. Adverse reactions were comparable and occurred in 8.7% of the infusions of Intraglobin-F and 6% of the infusions with Sandoglobulin. None were severe or life-threatening. There was no discernible difference in efficacy between any of the products. The number of days when patients noted symptoms in their diaries was similar for Intraglobin-F and the comparison preparations, 4158 vs 4143. Similarly, there were no differences in the number of physician visits (33 vs 22), days missed from work or school (405 vs 404), days with fever (41 vs 47), or days of prophylactic antibiotics (675 vs 642). There was an increase in the number of days when antibiotics were given therapeutically (578 vs 451); most of the difference was attributable to one patient. There also was a difference in the number of days of hospitalization (21 vs 0), but 19 of the days were accounted for by two patients. When the patients were asked to score their feeling of well-being on a scale of 1 to 5, with 1 being entirely well, the mean score for the patients on Intraglobin-F was 1.86 (range, 1.0 to 3.0), compared to 1.85 (range, 1.0 to 3.2) for patients while on the comparison preparations. Trough IgG levels were slightly lower during the period when patients were treated with Intraglobin-F compared to the other products. There were no abnormalities in blood chemistries or hematologic parameters. Thus, Intraglobin-F is comparable to three of the marketed IVIG preparations in efficacy and safety, as well as patient acceptability, and offers the additional benefit of an extra virucidal step to reduce further the risk of transmitting viral infections.

Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions.

Carboplatin is the drug of choice for the treatment of nonresectable astrocytomas in children, but patients who are intolerant may require cranial irradiation which is associated with significant morbidity. Hypersensitivity reactions, including urticaria, bronchospasm, and hypotension, have been reported in 1% to 30% of patients treated with carboplatin. Although a few patients have attempted to continue therapy following pretreatment with antihistamines and corticosteroids, most have had recurrent severe reactions and have discontinued therapy. Two children with a history of severe systemic reactions to carboplatin were pretreated with 1 to 2 mg/kg of oral prednisolone the night before and the morning of their infusion. The initial desensitization was carried out in the intensive care unit (ICU) using doses of 1, 2.5, 5, 10, 25, and 50 mg of carboplatin infused at 1 mg/min every 15 minutes. This was well-tolerated and the remainder of the dose was infused at the standard rate of 200 mg/hr. One patient continued to receive infusions in the clinic without any difficulty. The other patient tolerated a second infusion, but during his third he experienced a systemic reaction that required discontinuation of the infusion and treatment with diphenhydramine. Desensitization was repeated in the ICU with pretreatment with prednisolone, diphenhydramine, and ranitidine, starting with 0.1 mg of carboplatin, and increasing more slowly than in the first protocol. This was well-tolerated, and subsequent infusions have been administered beginning with 1 mg doses without adverse effects. Both boys continued therapy with carboplatin; their astrocytomas are stable and they are clinically well. The use of the desensitization protocol enabled them to avoid cranial irradiation and improved their chances for normal neurologic development.

Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency.

From May 1992 to March 1993, 50 infants with severe combined immunodeficiency (SCID) were given bone marrow transplants at Duke University Medical Center. None received chemotherapy for conditioning or for graft-versus-host disease (GVHD) prophylaxis. Forty-one received haploidentical parental marrow depleted of T cells by soybean lectin and sheep red blood cell resetting, and nine received HLA-identical marrow. Forty (80%) survived from 1 week to almost 11 years posttransplantation, including nine of nine (100%) HLA-identical marrow recipients and 31 of 41 haploidentical recipients. T-cell function was present within 2 weeks after transplantation of unfractionated HLA-identical marrow, but not until 3 to 4 months after T-cell-depleted haploidentical marrow stem cells. All 37 patients who are more than 4 months posttransplantation have good T-cell function, and all but one have 100% donor T cells. B-cell function developed slowly or not at all in some recipients of haploidentical marrow. Fourteen (four HLA-identical and 10 haploidentical recipients) have some donor B cells; 19 patients are receiving intravenous immune globulin (IVIG) therapy.

Rapid infusion of Sandoglobulin in patients with primary humoral immunodeficiency.

We studied 16 patients with primary disorders of humoral immunity to determine the practicality of infusing intravenous gamma globulin at rates of infusion and concentrations higher than the 4 mg/kg/min and 6% currently recommended. In the first portion of the study, the concentration of Sandoglobulin was increased from 6% to 12%. In the second portion, the flow rate was increased to 5 mg/kg/min, and if no reactions occurred, the time of each successive infusion was decreased by 10 minutes until infusions were completed in 15 to 20 minutes or vasomotor reactions occurred. Thirteen of the 16 patients completed the study; six patients achieved reaction-free rates greater than 15 mg/kg/min, and the other patients achieved rates ranging from 7.1 to 12 mg/kg/min. Seven patients had infusion times less than 30 minutes, with four patients completing infusions in 15 minutes. In the 13 patients who completed the study, there were 14 reactions in 159 infusions, mostly fever and chills, and often at the end or after the infusion. Only one infusion could not be completed because of an adverse reaction. Three patients were not able to complete the study because of adverse reactions; there were seven reactions in 11 infusions in these three patients, although none of the reactions were considered serious. Overall, in this study, most immunodeficient patients (13/16) were able to tolerate infusion rates of Sandoglobulin two to 10 times higher than the standard rates now recommended. The maximal rate of infusion must be individualized, but for carefully selected patients, infusions of 400 mg/kg can be completed in 1 hour or less.(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective study on the hepatitis safety of intravenous immunoglobulin, pH 4.25.

Recent reports of transmission by intravenous gamma-globulin preparations of non-A non-B hepatitis (NANBH), including several cases that progressed to severe liver damage and death, have raised concerns about the safety of intravenous gamma-globulin. However, the problem does not seem to be widespread. To assess this issue, we previously reported the results of liver function tests monitored in 41 patients with primary immunodeficiency treated with intravenous immunoglobulin (IGIV), pH 4.25 over periods ranging from 6 to 15 months. Eighteen of these patients at two of the three centers have now had serial serum glutamic pyruvic transaminase (SGPT) levels performed regularly at intervals of 1-5 weeks while continuing monthly intravenous infusions of nonmodified IGIV, pH 4.25 for an additional 14-26 months. The standard dosage was 400 mg per kg body weight IGIV, pH 4.25. Six lots of IGIV, pH 4.25 were used. Transient minor SGPT elevations were observed in 5 of the patients on a total of 8 occasions. None of the elevations was considered indicative of NANBH or of any chronic hepatic disease. All patients remained negative for hepatitis B surface antigen throughout the study.

Non-A non-B hepatitis and the safety of intravenous immune globulin, pH 4.2: a retrospective survey. Preliminary communication.

Evidence for transmission of non-A non-B hepatitis (NANB) was sought in 41 patients with primary immune deficiency who were receiving human intravenous immune globulin (IGIV) over periods ranging from 6 to 15 months at a monthly dosage of 400 mg/kg body weight. One lot of a reduced and alkylated IGIV and three lots of a nonmodified preparation stabilized at pH 4.2 were used. No evidence of NANB was found, although transient elevations in serum glutamic pyruvic transaminase (alanine aminotransferase) were found in 6 of the patients. The possible causes of the elevated levels in these 6 patients are discussed.

Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients.

The courses of six patients with adenosine deaminase (ADA) and two with purine nucleoside phosphorylase (PNP) deficiencies were evaluated before and after therapy. The heterogeneity of immunologic and clinical parameters was striking in each enzyme deficiency. In both PNP and ADA deficiency, some patients had very low immunoglobulin levels, while others had normal levels. T-cell function was always low in patients with ADA deficiency. In the two patients with PNP deficiency, contrary to the classical descriptions of this disorder, T-cell function fluctuated with time. Five ADA-deficient patients were treated with irradiated normal red-cell transfusions as a form of enzyme replacement and showed no lasting benefit. Three of the ADA-deficient patients and one of the PNP-deficient patients were given transplants of haploidentical parental bone marrow stem cells without pretransplant immunosuppression. In the PNP-deficient patient, chimerism has not been documented on enzymatic testing. One ADA-deficient patient has demonstrated long-term engraftment with good B- and T-cell function. Haploidentical bone marrow transplantation is currently the preferred therapy for enzyme-deficient patients with absent T-cell function who do not have an HLA-identical donor, as it may result in a lasting reconstitution of immune function. In those patients with unsatisfactory responses to transplantation, however, specific enzyme replacement or gene therapy may be considered in the future.

Half-life and clearance of pH 6.8 and pH 4.25 immunoglobulin G intravenous preparations in patients with primary disorders of humoral immunity.

The half-life (t1/2) and clearance of IgG and three antibodies--to tetanus, pneumococcus type 3, and pneumococcus type 7--were evaluated in 38 patients who participated in a multicenter, double-blind, crossover study comparing two immunoglobulin G intravenous preparations, IGIV pH 6.8 and the new IGIV pH 4.25. IgG metabolism was evaluated after the sixth infusion by measuring the decline in concentration of IgG and specific antibody. The t1/2 values of IgG varied greatly, but the mean values of 32 and 37 days are comparable to those determined in previous studies with use of radiolabeled IgG and are longer than those reported in normal volunteers. The t1/2 values for specific antibodies, especially those to tetanus, tended to be shorter than those for IgG. The clearance of IgG and antibodies also varied widely, but even though there was some relationship between the clearance and t1/2 in individual patients, the poor correlation (R2 less than .5) suggested that other factors, such as redistribution or loss of damaged molecules, are as important as the catabolic rate. Thus, clearance may be a more reliable parameter than t1/2 in evaluating the metabolism of IgG.

Alterations in the half-life and clearance of IgG during therapy with intravenous gamma-globulin in 16 patients with severe primary humoral immunodeficiency.

Published studies of the metabolism of human IgG using trace amounts of radiolabeled IgG demonstrated that the elimination of native IgG followed first-order kinetics but that the half-life of IgG was shortest in patients with the highest serum concentrations of IgG. To evaluate the effect of increasing the serum concentration of IgG on the metabolism of IgG, we determined the half-life and clearance of IgG and tetanus antibody in 16 patients with severe primary humoral immunodeficiency diseases while they received several doses of intravenous gamma-globulin (IVIG). Each patient received 100 mg/kg of IVIG each month and the half-life and clearance of IVIG were determined by following the decline in the serum IgG concentration. The dose of IVIG was adjusted to give a minimum IgG level of 200 mg/dl and the half-life was reevaluated. The dose was again adjusted to give minimum concentrations of 450 mg/dl and two additional studies were performed. Mean doses of IVIG infused increased from 100 to 346 mg/kg. The mean trough serum IgG concentration was 191 mg/dl on the standard dose and increased to 427 mg/dl at the highest dose. The serum half-lives of IgG were highly variable, ranging from 22 to 96 days. The mean decreased from 43 days in the first to 33 days in the third and fourth studies, and the clearances of IgG increased from 1.8339 to 2.4302 mg/kg/day, but the differences were not statistically significant. Patients with the highest serum IgG concentrations tended to have the longest half-lives, suggesting that intrinsic IgG production might falsely prolong the calculated half-life of IgG.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation.

Recent advances in the prevention of graft-vs-host disease (GVHD) have allowed the use of haploidentical bone marrow cells for correction of lethal genetic defects of the immune system. Sequential analyses of blood lymphocyte phenotypes and functions were done before and after transplantation of haploidentical marrow stem cells into 17 infants with severe primary T cell deficiencies. The marrow was depleted of post-thymic T cells and most other mature marrow cells by soy lectin agglutination and sheep erythrocyte rosetting. The studies were performed to define the time course and extent of appearance of immune function, and to identify factors leading to resistance to engraftment. No pretransplant immunosuppression was used. T cell function was detected between 34 and 287 days after transplantation, but a sharp rise usually occurred between 84 and 115 days, and normal function was reached between 113 and 210 days. Fifteen of the patients are alive from 6 to 41 mo post-transplantation, 12 have improved or have normal T lymphocyte function, and nine have proven T cell chimerism. Increased immunoglobulins of several isotypes have been noted in 11 patients and specific antibodies in seven patients, although B cell chimerism has been detected in only one patient. B cell function required 2 to 2.5 yr for normalization. No GVHD occurred in 14 patients, and the other three had only transient mild skin rashes. Two patients died of viral infections. Failure to engraft was correlated with some pre-transplant lymphocyte responses to mitogens and allogeneic cells (three cases), but not with the presence of pre-transplant natural killer cell function (five cases) nor with the presence of purine salvage pathway enzyme deficiencies (four cases). The latter, however, was associated with poor lymphoid function in two patients. These studies indicate that the thymic microenvironment of most infants with severe combined immunodeficiency disease is capable of differentiating donor stem cells to mature and functioning T lymphocytes which can cooperate with apparently normal host B cells for antibody production.

Individualizing the dose of intravenous immune serum globulin for therapy of patients with primary humoral immunodeficiency.

The availability of safe and effective IgG preparations for replacement therapy for patients with primary disorders of humoral immunity allows almost unlimited doses of IgG to be used. Thus, knowledge of the optimal dose and serum concentration of IgG to be achieved is of practical importance. In a multicenter study of a reduced and alkylated IgG preparation (MISG), it was shown that the MISG was well tolerated and as effective as the intramuscular immune serum globulin (ISG) used for more than 30 years. During the course of this study, we observed that the standard dose of 100 mg/kg/month resulted in a wide range of IgG levels. We began a study using another intravenous IgG preparation to determine whether the variable IgG levels were due to variability in the half-life of IgG in these patients and whether an individualized dose of IgG could be calculated based on the half-life for each patient. The half-life was greatly prolonged, ranging from 26 to 86 days compared with 21 days in normal individuals. However, there was no correlation between the half-life and the serum IgG concentration over the range of concentrations measured. When patients were treated with higher doses of IgG, based on the amount calculated to raise the serum IgG concentration to 200 mg/dl, only 1 patient actually achieved that level and only 3 had a significant increase in the serum concentration despite the higher dose. Failure to achieve the predicted levels could not be explained by a shortened half-life and seemed to be related to increased losses in the early, redistribution, phase. The half-life was not reduced in patients who did achieve higher serum IgG concentrations, suggesting that the half-life is characteristic for each patient and not directly dependent on the serum IgG concentration. However, only modest increases were observed and additional studies using much higher doses of IgG will be necessary before this issue can be settled. Similarly, we did not see an additional benefit in those patients receiving higher doses of IgG, and further studies will be necessary before it can be determined whether higher levels of IgG can reduce the incidence of chronic infections and justify the increased time and expense. The results of the completed study have been published elsewhere [7].