Original Article
Intravenous Immune Globulin for the Prevention of Bacterial Infections in Children with Symptomatic Human Immunodeficiency Virus Infection
N Engl J Med 1991; 325:73-80July 11, 1991
- Abstract
- Abstract
Background.
Serious recurrent bacterial infections are a major cause of morbidity and mortality in children infected with the human immunodeficiency virus (HIV). Because intravenous immune globulin has been shown to prevent bacterial infection in patients with primary immunodeficiency and in uncontrolled studies of HIV-infected children, we undertook a multicenter study of its safety and efficacy in children with symptomatic HIV infection.
Methods.
In a double-blind trial, 372 HIV-infected children (mean age, 40 months) with clinical or immunologic evidence of HIV disease were randomly assigned to receive either intravenous immune globulin (400 mg per kilogram of body weight) or placebo (0.1 percent albumin) every 28 days. The children were stratified into two groups according to CD4+ lymphocyte count at entry into the study and the clinical classification of the Centers for Disease Control. The median length of follow-up was 17 months.
Results.
For children in either group with CD4+ counts ≥0.2×109 per liter (≥200 per cubic millimeter) at entry, treatment with intravenous immune globulin significantly increased the time free from serious infection; estimated infection-free rates after 24 months were 67 percent for children receiving immune globulin as compared with 48 percent for those receiving placebo (P = 0.01 ). In addition, immune globulin was associated with an overall reduction in the number of both serious and minor bacterial infections (relative risk, 0.68; P = 0.01) and in the number of hospitalizations for acute care (relative risk, 0.65; P = 0.03). No such benefits were seen for children with CD4+ counts below 0.2×109 per liter at entry. For group 1 overall, there was a trend toward a difference in serious bacterial infection between immune globulin and placebo (24-month infection-free survival, 31 percent for intravenous immune globulin vs. 25 percent for placebo; P = 0.10). For group 2, the estimates of survival without serious infection were 73 percent with intravenous immune globulin as compared with 53 percent with placebo (P = 0.04). There was no effect of treatment on mortality for any group or CD4+ count at entry. Adverse reactions, noted for less than 1 percent of infusions, were minor.
Conclusions.
In symptomatic HIV-infected children the prophylactic use of intravenous immune globulin is safe, and it significantly increases the time free from serious bacterial infections for those entering treatment with CD4+ lymphocyte counts ≥0.2×109 per liter. (N Engl J Med 1991; 325:73–80.)
Media in This Article
Figure 1
Probability of Remaining Free of Laboratory-Proved and Clinically Diagnosed Serious Bacterial Infections after Entry into the Study, in the Children Assigned to Intravenous Immune Globulin (Solid Line) or Placebo (Dashed Line).Article Activity
- Article
AS early as 1987, the acquired immunodeficiency syndrome (AIDS) was the ninth leading cause of death in U.S. children from one through four years of age.1 , 2 Children with human immunodeficiency virus (HIV) infection may have profound dysfunction in humoral and cellular immunity.3 4 5 6 One of the consequences of this immune dysfunction is a markedly increased rate of serious, potentially life-threatening recurrent bacterial infections in some HIV-infected children.7 8 9
Previous studies10 11 12 13 14 15 16 17 have suggested that the use of immune globulin in HIV-infected children may result in clinical and immunologic improvement. Two studies in such children suggested that survival improved after treatment with immune globulin.10 , 15 These studies, however, involved only small numbers of children, had inadequate controls, used widely varying regimens of immune globulin, and did not present data to document the reported improvement in survival.
Methods
Study Design and Entry Criteria
The intravenous immune globulin trial of the National Institute of Child Health and Human Development was a randomized, double-blind, placebo-controlled study conducted in 28 clinical centers to determine whether intravenous immune globulin administered to HIV-infected children every 28 days in a dose of 400 mg per kilogram of body weight would substantially reduce the proportion of the treatment group that had at least one serious bacterial infection or died over a projected two-year study period, as compared with placebo.
The children eligible for the study were those under 13 years of age without hemophilia who had laboratory evidence of HIV infection and clinical or immunologic evidence of HIV disease that met the criteria for pediatric HIV disease of class P2 (symptomatic infection) or class PIB (asymptomatic infection with abnormal immune function) as defined by the Centers for Disease Control (CDC).18 Patients were ineligible if they were clinically asymptomatic with normal or unknown immunologic function; had hemophilia; had an HIV-related cancer (CDC class P2E disease); were receiving continuous antimicrobial chemoprophylaxis (except prophylaxis for Pneumocystis carinii pneumonia); were receiving anti-retroviral therapy at entry into the study; had hypogammaglobulinemia or idiopathic thrombocytopenic purpura requiring therapy with intravenous immune globulin; or had known hypersensitivity to intravenous immune globulin. Previous use of intravenous immune globulin was allowed if 90 days or more had elapsed between the treatment and entry into the study. A lapse of seven or more days was required between the completion of previous antiviral or antibiotic therapy and entry into the study. The initiation of anti-retroviral therapy and prophylaxis for P. carinii pneumonia (trimethoprim–sulfamethoxazole on three consecutive days per week) was permitted at any time after entry into the study.
The study patients were divided into two groups on the basis of their CD4+ lymphocyte counts at entry and their infection history, and they were randomly assigned to receive either intravenous immune globulin or placebo within each group. Group 1 included children with one or more of the following: a CD4+ count below 0.2×109 per liter (200 per cubic millimeter) at entry or disease of CDC class P2D1 (a history of AIDS-defining opportunistic infection) or P2D2 (a history of AIDS-defining serious recurrent bacterial infection). Group 2 included children with a CD4+ count ≥0.2×109 per liter at entry and disease of CDC class P1B (with immunologic abnormalities only) or class P2 in one or more of the following subclasses: P2A (nonspecific HIV-related findings), P2B (progressive neurologic disease), P2C (lymphoid interstitial pneumonitis), P2D3 (other specified infectious diseases), or P2F (other possibly HIV-related disease). The treatment assignments were blocked according to clinic with a minimization technique.19
Treatment Protocol
The study protocol and informed-consent forms were reviewed and approved by the institutional review board at each participating center. Written informed consent was obtained from each child's parent or legal guardian before randomization. Patients assigned to treatment with immune globulin (Gamimune N, Cutter Biological, Miles Laboratories, Berkeley, Calif.)20 received 400 mg of intravenous immune globulin per kilogram every 28 days. The initial and maximal infusion rates were those recommended by the manufacturer.21 The study placebo was a preparation of 0.1 percent albumin without preservatives in 10 percent maltose, visually indistinguishable from the study drug and administered in an identical fashion. All the patients were treated according to prevailing medical standards, as determined by their physicians with the consent of the parents or guardians. The children were seen every 28 days by study personnel to collect information about all intercurrent infections, medications, and hospitalizations.
Definition of Outcomes
The primary study end points were death or the occurrence of one or more serious bacterial infections. The infections were classified as either laboratory-proved or clinically diagnosed. Laboratory-proved infections were defined as meningitis, bacteremia, pneumonia, osteomyelitis, septic arthritis, acute sinusitis, acute mastoiditis, or the abscess of an internal organ, as confirmed by bacteriologic culture or antigen assay. Clinically diagnosed infections were defined as episodes of acute pneumonia or sinusitis without a defined microbiologic cause that met rigorous predetermined clinical and radiologic criteria.22 All reported episodes of pneumonia or sinusitis were reviewed independently and classified as acute and laboratory-proved, acute and clinically diagnosed, or neither. Bacterial infections and deaths occurring within seven days of the first infusion were excluded a priori as outcomes.
The secondary end points included minor laboratory-proved bacterial or clinically diagnosed infections (including reported episodes of pneumonia and sinusitis that did not meet the study criteria for the primary end points; otitis media; urinary tract infection; and infections of skin or soft tissue) and the number and duration of hospitalizations for acute care. Hospitalizations for acute care were defined as hospitalizations lasting more than 1 but less than 45 days that did not have the provision of social services as the sole reason for admission.
Statistical Analysis
The study was designed to detect a 50 percent reduction in the risk of serious bacterial infections or deaths in each group, with an alpha of 0.05 (two-sided) and 80 percent power, with independent sample sizes calculated for groups 1 and 2. The times to death and the first serious infection in the intravenous immune globulin and placebo arms were compared by nonparametric techniques of survival analysis.23 The statistical significance of differences between treatment and placebo in the overall distribution of the times to an event was assessed with the log-rank test.24 Comparisons at specific times were assessed for significance with an approach based on Greenwood's formula for estimating the variance of the estimated proportion surviving to a particular time.24 These analyses were conducted every six months. These time points for the analysis were selected in advance, without regard to the eventual shapes of the observed survival distributions. All P values are two-sided. Since the comparisons of infections, hospitalizations, and numbers of hospital days per 100 patient-years were calculated as the differences between ratios of dependent random variables, standard errors for these statistics were estimated with the jackknife method.25
Results
Study Population
A total of 372 patients were enrolled, 115 in group 1 and 257 in group 2. Among the 28 centers, enrollment ranged from 4 to 46 patients. Ninety-one percent of the patients had vertically acquired HIV infection. The mean age at the time of enrollment was 40 months (range, 2 months to 11 years); 78 percent were under 5 years of age at entry into the study. The majority of the patients (88 percent) had clinical evidence of HIV disease (CDC class P2) at entry; 12 percent were asymptomatic with abnormal immune function (CDC class P1B). Fifteen percent were receiving prophylaxis for P. carinii pneumonia at entry, and 49 percent were receiving it by the end of the study; 39 percent began zidovudine treatment after entry into the study.
The characteristics of the patients according to clinical stratum and treatment arm are shown in Table 1Table 1
Characteristics of the Study Children According to Clinical Stratum and Treatment Arm.*. The children receiving intravenous immune globulin and placebo differed only in group 1, with more children under the age of two years, more boys, and more children with CD4+ counts below 0.2 ×109 per liter randomly assigned to placebo, and all nine children with neonatal transfusion-acquired HIV randomly assigned to receive intravenous immune globulin.Because a CD4+ lymphocyte count below 0.2 × 109 per liter at entry was found post hoc to be the most important determinant of the response to treatment with intravenous immune globulin, the characteristics of the children in group 1 according to treatment arm were examined with the children divided into two subgroups on the basis of the CD4+ lymphocyte count at entry. The group 1 patients with a CD4+ count below 0.2× 109 per liter were designated group 1A; those with a CD4+ count ≥0.2× 109 per liter were designated group IB. In group 1A, the mean age at entry was 60.4 months among the children assigned to intravenous immune globulin, as compared with 50.1 months among the children assigned to placebo; in group IB, the mean age at entry was 41.0 and 42.8 months in the intravenous immune globulin and placebo arms, respectively. Six children in group 1A and three in group 1B had transfusion-acquired HIV infection.
Serious Bacterial Infections
One hundred thirty-three study children had 214 serious bacterial infections that were laboratory-proved or clinically diagnosed (Table 2Table 2
Serious Infections and Mortality during the Study.*). Clinically diagnosed infections were 2.3 times more frequent than laboratory-proved infections. Four serious infections (three clinically diagnosed and one laboratory-proved) that occurred in four children within seven days of the first infusion were excluded from the analysis; one child was in the placebo arm, and three were in the intravenous immune globulin arm.There was a significant difference in group 1B (P = 0.005) between the two study arms with regard to the time free from serious infection (Fig. 1Figure 1
Probability of Remaining Free of Laboratory-Proved and Clinically Diagnosed Serious Bacterial Infections after Entry into the Study, in the Children Assigned to Intravenous Immune Globulin (Solid Line) or Placebo (Dashed Line).A). The median time to the development of laboratory-proved or clinically diagnosed infection in group 1B was approximately one year longer with intravenous immune globulin than with placebo (583 vs. 221 days). In group 1 A, however, there was no such difference in the time to infection or the number of children with serious infections. For four children who were placed in group 1 because of a history of AIDS-defining infections (CDC class P2D1 or P2D2) and were assigned to placebo, CD4+ counts were not made at entry, and these children were not included in the subgroup analysis of group 1. Two of these children had a total of three episodes of clinically diagnosed serious infection.Because of the age imbalance between the study arms in group 1B, additional analyses with a proportional-hazards model were conducted to control for age at entry into the study, using age as a continuous variable. A significant treatment effect for intravenous immune globulin was still seen after adjustment for age in group 1B (relative risk, 0.47; 95 percent confidence interval, 0.23 to 0.96; P = 0.04). The results for group 1 overall (groups 1A and 1B combined) showed a trend toward a treatment effect (P = 0.10) both before and after adjustment for age at entry and the CD4+ count.
In group 2, although the proportion of children with serious infections was smaller than in group 1, there was also a significantly longer time free from infection in those treated with intravenous immune globulin (relative risk, 0.60; 95 percent confidence interval, 0.40 to 0.97; P = 0.035). The treatment effect in group 2 was evident only after approximately 12 months of intravenous immune globulin therapy (Fig. 1B). For all children with CD4+ counts ≥0.2×l09 per liter at entry (groups 1B and 2 combined), treatment with intravenous immune globulin significantly prolonged the time free from serious infection (relative risk, 0.58; 95 percent confidence interval, 0.39 to 0.86; P = 0.009) (Fig. 1C). For all children in the study (groups 1 and 2 combined), the time free from serious infection was significantly longer in the intravenous immune globulin arm (P = 0.02; data not shown).
Serious Laboratory-Proved Infections
An analysis confined to laboratory-proved serious bacterial infections showed a beneficial effect of intravenous immune globulin for children with CD4+ counts ≥200 per cubic millimeter at entry (data not shown). Fewer of the serious bacterial infections were laboratory-proved than were clinically diagnosed. Fifty-one study children had 66 laboratory-proved infections (Table 2).
With intravenous immune globulin as compared with placebo, there was a significant difference in the time free from laboratory-proved serious bacterial infections in group 1B (P = 0.04) but not in group 1A. Proportionally fewer children had laboratory-proved serious bacterial infections in group 2 than in group 1. Thirty such infections occurred in 22 children in group 2, with a trend toward a longer infection-free interval (P = 0.09) in the intravenous immune globulin arm. For all children with CD4+ counts ≥0.2× 109 per liter at entry (groups 1B and 2 combined), the time to a laboratory-proved serious bacterial infection was significantly longer (P = 0.02) with intravenous immune globulin.
Sites and Types of Serious Infections
Acute pneumonia accounted for the majority (64 percent) of the clinically diagnosed serious infections (Table 2), with 35 episodes in 26 children assigned to intravenous immune globulin and 63 episodes in 53 children assigned to placebo. The numbers of episodes of clinically diagnosed acute sinusitis were similar for all groups in both study arms.
Primary bacteremia accounted for the majority (70 percent) of the laboratory-proved serious bacterial infections (Table 2), with 16 episodes in 15 children who received intravenous immune globulin and 30 episodes in 25 children who received placebo. Of 20 children with central venous catheters, 5 had a total of six positive blood cultures. The reasons for catheter placement in these children were unrelated to the infusions of the study drug. No difference in bacteremia associated with the use of a central venous catheter was observed between the study arms.
Streptococcus pneumoniae accounted for 21 of 66 episodes of laboratory-proved serious infection (15 episodes of primary bacteremia, 5 of pneumonia and bacteremia, and 1 of meningitis). Four recipients of intravenous immune globulin had 5 episodes of invasive pneumococcal disease, as compared with 16 episodes in 14 recipients of placebo. In group 2, there were no episodes in the recipients of intravenous immune globulin, as compared with 11 in the recipients of placebo. Serious infections with other species of bacteria were too few for meaningful comparison (Table 3Table 3
Bacterial Isolates from Children with Serious Laboratory-Proved Infections.*).Mortality
Sixty-two of the 372 children (17 percent) died during the study (including 1 child assigned to placebo who died within seven days of entry into the study). For both study arms, mortality was higher in group 1 than in group 2 and was highest in group 1A. There was no difference in mortality between study arms, with 31 deaths in each. Survival analyses indicated no difference in the time to death between study arms in group 2 or in group 1, analyzed as a whole or according to CD4+ count at entry. The 24-month estimated survival rates for recipients of intravenous immune globulin were 29 percent in group 1A, 80 percent in group 1B, and 93 percent in group 2, as compared with 26 percent, 72 percent, and 93 percent, respectively, for the recipients of placebo.
Bacterial Infections Overall
When all reported bacterial infections were combined (serious and minor, laboratory-proved and clinically diagnosed), a reduction in their numbers was observed among the children treated with intravenous immune globulin (Table 4Table 4
All Reported Episodes of Bacterial Infection and Acute Care Hospitalizations during the Randomized Trial.*). Overall, these children had 25 percent fewer reported bacterial infections than the children assigned to placebo (473 vs. 633; relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.89; P = 0.03). There were significantly fewer bacterial infections reported per 100 patient-years with intravenous immune globulin in group 2 (144 vs. 232; P = 0.002), with a similar trend in group 1B (238 vs. 335; P = 0.12) but not in group 1A. Among the children with CD4+ counts ≥0.2×l09 per liter at entry (groups 1B and 2 combined), there were 78 fewer bacterial infections per 100 patient-years reported with intravenous immune globulin than with placebo (168 vs. 246; relative risk, 0.68; 95 percent confidence interval, 0.49 to 0.87; P = 0.01).Hospitalization for Acute Care
Treatment with intravenous immune globulin was associated with a reduced rate of hospitalization for acute care among children with CD4+ counts ≥0.2×109 per liter at entry (Table 4). In group 2, there were significantly fewer hospitalizations per 100 patient-years with intravenous immune globulin than with placebo (47 vs. 85; P = 0.01), with a similar trend in group 1B (118 vs. 170; P = 0.25) but not in group 1A. There were 35 fewer hospitalizations per year per 100 children assigned to intravenous immune globulin who had CD4+ counts ≥0.2 × 109 per liter at entry into the study (groups 1B and 2 combined) than for the corresponding children assigned to placebo (64 vs. 99; relative risk, 0.65; 95 percent confidence interval, 0.38 to 0.91; P = 0.03).
For the children with CD4+ counts ≥0.2× 109 per liter at entry who received intravenous immune globulin, the average number of days spent in the hospital for acute care each year was reduced, but not significantly. Trends toward fewer average annual inpatient hospital days for acute care were seen with intravenous immune globulin treatment in group 2 (4.1 vs. 7.5; P = 0.07) and group 1B (12.3 vs. 14.9; P = 0.63) but not in group 1A. There were 278 fewer hospital days annually for acute care per 100 children assigned to intravenous immune globulin who had CD4+ counts ≥0.2×l09 per liter (groups 1B and 2 combined).
Adverse Reactions
Adverse reactions to infusions of the study drug accompanied 17 of 3199 infusions of intravenous immune globulin (0.5 percent) and 19 of 3203 infusions of placebo (0.6 percent). The adverse reactions were minor and were similar in nature in the two study arms. In one child receiving intravenous immune globulin, therapy was discontinued because of an adverse reaction to the infusion. No children receiving placebo required the cessation of therapy.
Possible Confounding Factors
To examine whether concomitant use of other medications or loss to follow-up might explain the effects seen for intravenous immune globulin, we compared the proportion of patients in both study arms who received prophylaxis for P. carinii pneumonia at or after the time of entry into the study, the time to the initiation of such prophylaxis, the proportion of patients receiving zidovudine after entry into the study, the time to the initiation of zidovudine therapy, and the loss to follow-up before and after the occurrence of a study end point. The proportion of patients receiving prophylaxis for P. carinii pneumonia at entry was similar among those assigned to intravenous immune globulin (15 percent) and those assigned to placebo (14 percent), as was the proportion that eventually received prophylaxis (48 percent and 49 percent, respectively). There was no difference between the study arms in the length of time until the start of prophylaxis, regardless of the CD4+ count at entry or study-group assignment. When the children who received prophylaxis for P. carinii pneumonia were stratified according to CD4+ count at entry, those who had counts ≥0.2 × 109 per liter continued to show benefit from intravenous immune globulin therapy. The proportions of patients who had serious infection were similar among the children receiving prophylaxis at entry and those not receiving such prophylaxis (41 percent and 34 percent, respectively).
Although no patients were receiving antiretroviral therapy when they entered the study, zidovudine use was permitted at any time thereafter. The proportions of patients who received zidovudine were nearly identical in the two study arms. In group 1B, 38 percent of the children assigned to intravenous immune globulin and 35 percent of those assigned to placebo received zidovudine; in group 2, the numbers were 40 percent and 43 percent, respectively. The median duration of zidovudine treatment was under six months in both study arms. As with prophylaxis for P. carinii pneumonia, the time to the initiation of zidovudine therapy was evaluated, and no differences were seen. Beneficial effects of similar magnitude were seen with intravenous immune globulin treatment, whether or not serious infections occurring after the initiation of zidovudine therapy were included in the analysis.
Overall, the loss to follow-up was minimal (8 percent) and was evenly distributed between the study arms. During the study, several treatment protocols for children with HIV infection became available at certain study sites, presenting parents and physicians with the option of transferring children enrolled in this study to one of the other protocols. Such transfers were evenly distributed between the study arms, and there were no significant differences in the time of transfer or the proportion of children who had an infection before transfer.
Discussion
This randomized, double-blind, controlled trial found that the administration of intravenous immune globulin every 28 days significantly increased the interval free of serious infection in children with clinical or immunologic evidence of HIV disease and an initial CD4+ lymphocyte count ≥0.2 × 109 per liter. The effect of intravenous immune globulin in preventing serious infections was noted primarily against invasive pneumococcal disease and clinically diagnosed acute pneumonia. Similar effects of intravenous immune globulin prophylaxis are seen in chronic lymphocytic leukemia, in which the treatment predominantly reduces the incidence of clinically diagnosed pneumonia and laboratory-proved infections with S. pneumoniae and Haemophilus influenzae.26 In addition, the recipients of intravenous immune globulin with CD4+ counts ≥0.2×l09 per liter at entry had significantly fewer total reported bacterial infections, both serious and minor, and had reductions in the frequency of acute care hospitalization. Toxicity was minimal, as noted in other studies of intravenous immune globulin.26 , 27 Adverse reactions were infrequent and were similar for the two study arms.
It is important to note some limitations of the benefit from intravenous immune globulin therapy. There was no improvement in survival with intravenous immune globulin in this study. Although this treatment delayed the occurrence of serious infections in all study children with initial CD4+ counts ≥0.2 ×l09 per liter and substantially reduced the frequency of serious infections in the children in group 2, infections were not completely prevented. In group 2, an increase in the period free of infection was not apparent with intravenous immune globulin until 12 months into the study. This may be related to the lower incidence early in the study of outcome events in these children, who entered the study with less advanced disease, and to the fact that the likelihood of infectious complications increases as HIV-related immunologic deterioration progresses.5 , 28 Previous studies of intravenous immune globulin in HIV-infected children have not specified the length of time before a clinical response, although some suggest that several months is needed to achieve responses in laboratory measures.12 , 13 , 17 , 29 Because the half-life of IgG is reduced in hypergammaglobulinemic states,30 a protective effect of intravenous immune globulin in HIV-infected children may be delayed as compared with that in patients with primary immunodeficiency, in whom serum IgG levels after a monthly infusion of intravenous immune globulin show a stepwise increase in trough and peak levels after the first four to six infusions, before reaching a protective plateau.31
Although intravenous immune globulin was effective in prolonging the period without invasive pneumococcal disease and acute pneumonia, the incidence of sinusitis was not affected. Passive immunoprophylaxis has been reported to be less effective for infections such as sinusitis, which involve mechanical abnormalities resulting from chronic tissue injury (e.g., bronchiectasis and chronic otitis media).32 Finally, the efficacy of intravenous immune globulin in delaying or reducing the incidence of serious infections was not demonstrated in HIV-infected children with CD4+ counts below 0.2 × 109 per liter at entry. However, the limited number of children studied who had such CD4+ counts at entry decreases the power of this study to detect such a difference.
Intravenous immune globulin is a relatively expensive therapy, costing approximately $154 to $228 for a 5-g vial of drug.33 The monthly cost of the drug (at a dose of 400 mg per kilogram) for a four-year-old child weighing 20 kg would average approximately $306. In addition, the costs of administering the drug (which was given in this study over a three-to-four-hour period on an outpatient basis) must be considered. Data from this study indicate that the children treated with intravenous immune globulin who had CD4+ counts ≥0.2 × 109 per liter at entry required fewer days of hospitalization for acute care. However, the costs of hospitalization and other medical expenses, such as office visits and antibiotic therapy, were not completely assessed. A further evaluation of data from this and other studies is needed to identify better the children most likely to benefit from intravenous immune globulin before a valid cost-benefit analysis can be conducted. Recent studies have demonstrated that infusion of intravenous immune globulin can be accomplished safely at home, at a substantial savings in cost, in both adults and children with primary immunodeficiency.34 35 36 This option may not be viable for all the children in this study, but it would be possible for some. In addition, evaluation of alternative, lower-cost methods of preventing serious bacterial infection, such as daily prophylaxis with a low-dose antibiotic, may be warranted.
The results of this clinical trial should not be interpreted as indicating that all HIV-infected children should receive intravenous immune globulin. The study population did not include HIV-infected children with hemophilia or cancers. The majority of the children enrolled in this study had vertically acquired HIV infection, and 78 percent were under five years of age. All the children in the study had overt clinical or immunologic HIV-related disease. Whether therapy with intravenous immune globulin benefits asymptomatic children remains to be answered. Although the use of standard regimens for prophylaxis against P. carinii pneumonia and zidovudine therapy during the study did not affect the results, the trial was not designed to evaluate the efficacy of intravenous immune globulin in children already receiving zidovudine. AIDS Clinical Trials Group protocol 051 specifically addresses the safety and efficacy of intravenous immune globulin and zidovudine in combination. A more direct assessment of immune function in relation to intravenous immune globulin, using data from the present study, is under way. Further evaluation of these and other ongoing studies may better define the subgroup of HIV-infected children most likely to benefit from intravenous immune globulin therapy.
*Members of the study group are listed in the Appendix.
We are indebted to the children and parents who volunteered to participate in this effort; to the members of the clinical-trial centers and the research staff of Westat, Inc., for managing the data for the study; to Drs. E. Connor, J. Oleske, E.R. Stiehm, S. Nicholas, and K. Krasinski for serving on the protocol-development committee; to Dr. R. Schwartz and Cutter Biological, Miles Laboratories, for donating the intravenous immune globulin and placebo preparations; and to Drs. G. Peter, J. Jason, J. Gale, and T. Gordon for serving on the data safety monitoring board.
Source Information
Address reprint requests to Dr. Lynne M. Mofenson at the Pediatric, Adolescent and Maternal AIDS Branch, National Institute of Child Health and Human Development, Executive Plaza South, Rm. 450W, 9000 Rockville Pike, Bethesda, MD 20892.
Appendix
The following persons and institutions constituted the National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group: National Institute of Child Health and Human Development, Bethesda, Md. — A. Willoughby, M.D., M.P.H, L.M. Mofenson, M.D., R. Nugent, Ph.D., and J. Moye, M.D. (from the Pediatric, Adolescent and Maternal AIDS Branch), and H.W. Berendes, M.D., M.H.S., and J.G. Rigau-Perez, M.D., M.P.H. (from the Division of Prevention Research); Westat, Inc., Rockville, Md. — S. Durako, C.Jordan, R.N., K. Rust, Ph.D., R. Hirschhorn, M.A., and J. Bethel, Ph.D.; Lincoln Hospital Center, Bronx, N.Y. — K. Shah, M.D., and J. Chow, M.D.; Cornell Medical Center-New York Hospital, New York — P. Edelson, M.D., and D. Sanders, M.D.; Schneider Children's Hospital—Queens Hospital Center of Long Island Jewish Medical Center, New Hyde Park, N.Y. — V. Bonagura, M.D., and D. Valacer, M.D.; Beth Israel Medical Center, New York — W. Henley, M.D.; Metropolitan Hospital Center, New York — M. Bamji, M.D.; New York Medical College, Valhalla — A. Gupta, M.D., and K.I. Li, M.D.; Harlem Hospital Center, New York — E J. Abrams, M.D.; State University of New York Health Science Center, Brooklyn — S. Fikrig, M.D.; St. Luke's/Roosevelt Hospital Center, New York — S.S. Bakshi, M.D.; North Shore University Hospital, Manhassett, N.Y. — S. Pahwa, M.D.; New York University Medical Center—Bellevue Hospital Center, New York — K. Krasinski, M.D.; Babies Hospital, New York —J. Pitt, M.D.; Albert Einstein College of Medicine, Bronx, N.Y. — L. Bernstein, M.D., and A. Rubinstein, M.D.; University of Connecticut Health Center, Hartford — G. Johnson, M.D.; Boston City Hospital, Boston — E.R. Cooper, M.D.; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick — L. Frenkel, M.D.; St. Christopher's Hospital, Philadelphia — H.W. Lischner, M.D., and S.A. Raphael, M.D.; University of Maryland, Baltimore—J.P. Johnson, M.D.; Children's Hospital National Medical Center, Washington, D.C. — T. Rakusan, M.D.; Emory University School of Medicine, Atlanta — S. Nesheim, M.D., A. Nahmias, M.D., and H. Keyserling, M.D.; Children's Memorial Hospital, Chicago — R. Yogev, M.D., and E. Chadwick, M.D.; University of Illinois College of Medicine, Chicago — K. Rich, M.D.; Texas Children's Hospital, Houston — W.T. Shearer, M.D., Ph.D., and I.C. Guerra-Hanson, M.D.; Children's Hospital Medical Center, Oakland, Calif. — A. Petru, M.D.; University of Puerto Rico, San Juan — C. Diaz, M.D., and J.L. Colon Santini, M.D.; San Juan City Hospital, San Juan, P.R. — E.Jimenez, M.D.; Ramon Ruiz Arnau University Hospital, Bayamon, P.R.— D. GarciaTrias, M.D., and C. Acantilado, M.D.; and Cutler Biological, Miles, Inc., Berkeley, Calif. — R. Schwartz, M.D.
- References
References
1
Novello
Web of Science | Medline2
Gayle 3
Bernstein
CrossRef | Web of Science | Medline4
Borkowsky
CrossRef | Web of Science | Medline5
Blanche
CrossRef | Web of Science | Medline6
Pahwa
Medline7
Bernstein
CrossRef | Medline8
Krasinski
CrossRef | Web of Science | Medline9
Scott
Full Text | Web of Science | Medline10
Siegal FP, Oleske JM. Management of the acquired immune deficiency syndrome: is there a role for immune globulins? In: Morrell A, Nydegger UE, eds. Clinical use of intravenous immunoglobulins: proceedings of a conference held at Interlaken, September 15–18. 1985. London: Academic Press, 1986:373–84.
11
Silvcrman
CrossRef | Web of Science | Medline12
Gupta
Web of Science | Medline13
Wood
CrossRef | Web of Science | Medline14
Calvelli
CrossRef | Web of Science15
Schaad
CrossRef | Web of Science | Medline16
Williams
CrossRef | Web of Science17
Hague
CrossRef | Web of Science | Medline18
Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age . MMWR 1987; 36:225–30, 235.
Medline19
Taves
Web of Science | Medline20
Schwartz
CrossRef | Web of Science | Medline21
Physicians' desk reference. 45th ed. Oradell, N.J.: Medical Economics, 1991:1521–2.
22
Mofenson LM, Rigau-Perez JG, Nugent R, Cadden C. Pneumonia diagnosis in HIV-infected children in a clinical trial of intravenous immunoglobulin. In: Program and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21–24. Washington, D.C.: American Society for Microbiology, 1990:168. abstract.
23
Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 2nd ed. Littleton, Mass.: PSG Publishing, 1985.
24
Kalbfleisch JK, Prentice RL. The statistical analysis of failure time data. New York: John Wiley, 1980.
25
Miller
Web of Science26
Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia: a randomized, controlled clinical trial . N Engl J Med 1988;319:902–7
Full Text | Web of Science | Medline27
Sullivan
Full Text | Web of Science | Medline28
Stiehm ER, Wara D. Immunology of HIV. In: Pizzo PA, Wilfert CM, eds. Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents. Baltimore: Williams & Wilkins, 1991:95–112.
29
Silverman
CrossRef | Web of Science | Medline30
Morell
CrossRef | Web of Science | Medline31
Ochs
CrossRef | Web of Science | Medline32
Pirofsy
CrossRef | Web of Science33
Mofenson LM, Willoughby A. Passive immunization. In: Pizzo PA, Wilfert CM, eds. Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents. Baltimore: Williams & Wilkins, 1991:633–50.
34
Ochs
CrossRef | Web of Science | Medline35
Ryan
CrossRef | Web of Science | Medline36
Kobayashi
Web of Science | Medline
- Citing Articles (84)
Citing Articles
1
Daniele Pastori, Antonella Esposito, Ivano Mezzaroma. (2011) Immunomodulatory Effects of Intravenous Immunoglobulins (IVIGs) in HIV-1 Disease: A Systematic Review. International Reviews of Immunology 30:1, 44-66
CrossRef2
Avinash K. Shetty, Yvonne A. Maldonado. 2011. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in the Infant. , 622-660.
CrossRef3
Shaye Kivity, Uriel Katz, Natalie Daniel, Udi Nussinovitch, Neophytos Papageorgiou, Yehuda Shoenfeld. (2010) Evidence for the Use of Intravenous Immunoglobulins—A Review of the Literature. Clinical Reviews in Allergy & Immunology 38:2-3, 201-269
CrossRef4
Heather J. Zar, Michael R. Bye. 2009. Pulmonary Manifestations of Human Immunodeficiency Virus (HIV) Infection. , 28-48.
CrossRef5
Martha M. Eibl. (2008) History of Immunoglobulin Replacement. Immunology and Allergy Clinics of North America 28:4, 737-764
CrossRef6
Maria Garcia-Lloret, Sean McGhee, Talal A. Chatila. (2008) Immunoglobulin Replacement Therapy in Children. Immunology and Allergy Clinics of North America 28:4, 833-849
CrossRef7
Avi Deener, Ami Mehra, Larry Bernstein, Jenny Shliozberg, Arye Rubinstein. (2008) Intravenous Gammaglobulin Treatment in HIV-1 Infection. Immunology and Allergy Clinics of North America 28:4, 851-859
CrossRef8
Daniel R. Couriel. (2008) Ancillary and supportive care in chronic graft-versus-host disease. Best Practice & Research Clinical Haematology 21:2, 291-307
CrossRef9
Heather J. Zar, Michael R. Bye. 2008. Human Immunodeficiency Virus Infection. , 575-588.
CrossRef10
GALIA GRISARU-SOEN, WENDY LAU, CHERYL ARNESON, DEBORAH LOUCH, ARI BITNUN, DEREK STEPHENS, STANLEY E. READ, SUSAN M. KING. (2007) Randomized controlled trial of short-term withdrawal of i.v. immunoglobulin therapy for selected children with human immunodeficiency virus infection. Pediatrics International 49:6, 972-977
CrossRef11
Anette Debes, Maria Bauer, Sybille Kremer. (2007) Tolerability and safety of the intravenous immunoglobulin Octagam®: a 10-year prospective observational study. Pharmacoepidemiology and Drug Safety 16:9, 1038-1047
CrossRef12
Andromachi Scaradavou, Susanna Cunningham-Rundles, John L. Ho, Claudia Folman, Howard Doo, James B. Bussel. (2007) Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIV-thrombocytopenia: Results of a small, randomized prospective comparison. American Journal of Hematology 82:5, 335-341
CrossRef13
Kamran Darabi, Omar Abdel-Wahab, Walter H. Dzik. (2006) Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion 46:5, 741-753
CrossRef14
Daniel Couriel, Paul A. Carpenter, Corey Cutler, Javier Bolaños-Meade, Nathaniel S. Treister, Juan Gea-Banacloche, Paul Shaughnessy, Sharon Hymes, Stella Kim, Alan S. Wayne, Jason W. Chien, Joyce Neumann, Sandra Mitchell, Karen Syrjala, Carina K. Moravec, Linda Abramovitz, Jerry Liebermann, Ann Berger, Lynn Gerber, Mary Schubert, Alexandra H. Filipovich, Daniel Weisdorf, Mark M. Schubert, Howard Shulman, Kirk Schultz, Barbara Mittelman, Steven Pavletic, Georgia B. Vogelsang, Paul J. Martin, Stephanie J. Lee, Mary E.D. Flowers. (2006) Ancillary Therapy and Supportive Care of Chronic Graft-versus-Host Disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biology of Blood and Marrow Transplantation 12:4, 375-396
CrossRef15
Yvonne A. Maldonado. 2006. Acquired Immunodeficiency Syndrome in the Infant. , 667-692.
CrossRef16
L. M. Mofenson, J. Oleske, L. Serchuck, R. Van Dyke, C. Wilfert. (2005) Treating Opportunistic Infections among HIV-Exposed and Infected Children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. Clinical Infectious Diseases 40:Supplement 1, S1-S84
CrossRef17
C Chintu, GJ Bhat, AS Walker, V Mulenga, F Sinyinza, K Lishimpi, L Farrelly, N Kaganson, A Zumla, SH Gillespie, AJ Nunn, DM Gibb. (2004) Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. The Lancet 364:9448, 1865-1871
CrossRef18
(2003) Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. The Lancet 362:9396, 1605-1611
CrossRef19
LM Mofenson, DR Harris, J Moye, J Bethel, J Korelitz, JS Read, R Nugent, W Meyer. (2003) Alternatives to HIV-1 RNA concentration and CD4 count to predict mortality in HIV-1-infected children in resource-poor settings. The Lancet 362:9396, 1625-1627
CrossRef20
Lucy Civitello. (2003) Neurologic aspects of HIV infection in infants and children: Therapeutic approaches and outcome. Current Neurology and Neuroscience Reports 3:2, 120-128
CrossRef21
M. Ballow, M. Berger, F. A. Bonilla, R. H. Buckley, C. H. Cunningham-Rundles, P. Fireman, M. Kaliner, H. D. Ochs, S. Skoda-Smith, M. T. Sweetser, H. Taki, C. Lathia. (2003) Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunextm, 10%). Vox Sanguinis 84:3, 202-210
CrossRef22
Flavia Ferrantelli, Regina Hofmann-Lehmann, Robert A Rasmussen, Tao Wang, Weidong Xu, Pei-Lin Li, David C Montefiori, Lisa A Cavacini, Hermann Katinger, Gabriela Stiegler, Daniel C Anderson, Harold M McClure, Ruth M Ruprecht. (2003) Post-exposure prophylaxis with human monoclonal antibodies prevented SHIV89.6P infection or disease in neonatal macaques. AIDS 17:3, 301-309
CrossRef23
P. Matejtschuk, K. Chidwick, A. Prince, J. E. More, D. Goldblatt. (2002) A direct comparison of the antigen-specific antibody profiles of intravenous immunoglobulins derived from US and UK donor plasma. Vox Sanguinis 83:1, 17-22
CrossRef24
K. NAKATANI, S. TAKESHITA, H. TSUJIMOTO, I. SEKINE. (2002) Intravenous immunoglobulin (IVIG) preparations induce apoptosis in TNF-α-stimulated endothelial cells via a mitochondria-dependent pathway. Clinical & Experimental Immunology 127:3, 445-454
CrossRef25
S. W. Nicholas, E. J. Abrams. (2002) Boarder Babies With AIDS in Harlem: Lessons in Applied Public Health. American Journal of Public Health 92:2, 163-165
CrossRef26
Shabir A. Madhi, Anas Madhi, Karen Petersen, Manikant Khoosal, Keith P. Klugman. (2001) Impact of human immunodeficiency virus type 1 infection on the epidemiology and outcome of bacterial Meningitis in South African children. International Journal of Infectious Diseases 5:3, 119-125
CrossRef27
Sheldon L. Kaplan. (2001) Prevention of pneumococcal respiratory infections. Pediatric Pulmonology 32:S23, 82-85
CrossRef28
Sheldon L. Kaplan. (2001) Prevention of pneumococcal respiratory infections. Pediatric Pulmonology 26:S23, 82-85
CrossRef29
WAYNE M. DANKNER, JANE C. LINDSEY, MYRON J. LEVIN. (2001) CD4 Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. The Pediatric Infectious Disease Journal 20:1, 40-48
CrossRef30
Stanley H. Shapiro, Charles Weijer, Benjamin Freedman. (2000) Reporting the study populations of clinical trials. Journal of Clinical Epidemiology 53:10, 973-979
CrossRef31
Moallem, Kalayci, Homel, Fikrig, Chice, Durkin, Michl. (2000) Expression of Fcgammar1 (CD64) on Polymorphonuclear Leucocytes during Progression to Acquired Immunodeficiency Syndrome in Perinatally Human Immunodeficiency Virus-Infected Children. Scandinavian Journal of Immunology 52:2, 184-189
CrossRef32
JENNIFER S. READ, KENNETH C. RICH, JAMES J. KORELITZ, LYNNE M. MOFENSON, D. ROBERT HARRIS, JOHN H MOYE, WILLIAM A. MEYER, SAVITA G. PAHWA, JAMES W. BETHEL, ROBERT P. NUGENT. (2000) Quantification of human immunodeficiency virus type 1 p24 antigen and antibody rivals human immunodeficiency virus type 1 RNA and CD4+ enumeration for prognosis. The Pediatric Infectious Disease Journal 19:6, 544-551
CrossRef33
ALAN S. KARSTAEDT, MANIKANT KHOOSAL, HEATHER H. CREWE-BROWN. (2000) Pneumococcal bacteremia during a decade in children in Soweto, South Africa. The Pediatric Infectious Disease Journal 19:5, 454-457
CrossRef34
K. S. R. Sivasai, T. Mohanakumar, D. Phelan, S. Martin, M. E. Anstey, D. C. Brennan. (2000) Cytomegalovirus immune globulin intravenous (human) administration modulates immune response to alloantigens in sensitized renal transplant candidates. Clinical and Experimental Immunology 119:3, 559-565
CrossRef35
Chong Eun Chang, Ho Gueon Eo, Yoon Sung Lee, Soon Kwan Chung, Jeong Sup Shin, Yoon Kyung Lah, Chan Woo Park, Jin Taek Jung, Jae Wook Huh, Soung Min Lee. (2000) Human Intravenous Immunoglobulin Preparation and Virus Inactivation by Pasteurization and Solvent Detergent Treatment. Preparative Biochemistry and Biotechnology 30:3, 177-197
CrossRef36
M.C Rousseau, J Moreau, J Delmont. (1999) Vaccination and HIV: a review of the literature. Vaccine 18:9-10, 825-831
CrossRef37
Anna Nowak-Wegrzyn, Howard M Lederman. (1999) Supply, use, and abuse of intravenous immunoglobulin. Current Opinion in Pediatrics 11:6, 533-539
CrossRef38
Milind D. Khare, Mike Sharland. (1999) Pulmonary manifestations of pediatric HIV infection. The Indian Journal of Pediatrics 66:6, 895-904
CrossRef39
JENNIFER S. READ, JAMES BETHEL, D. ROBERT HARRIS, WILLIAM A. MEYER, JAMES KORELITZ, LYNNE M. MOFENSON, JOHN MOYE, SAVITA PAHWA, KENNETH RICH, ROBERT P. NUGENT. (1999) Serum vitamin A concentrations in a North American cohort of human immunodeficiency virus type 1-infected children. The Pediatric Infectious Disease Journal 18:2, 134-142
CrossRef40
Lynne M. Mofenson, D. Robert Harris, Kenneth Rich, William A. Meyer, Jennifer S. Read, John Moye, Robert P. Nugent, James Korelitz, James Bethel, Savita Pahwa. (1999) Serum HIV-1 p24 antibody, HIV-1 RNA copy number and CD4 lymphocyte percentage are independently associated with risk of mortality in HIV-1-infected children. AIDS 13:1, 31-39
CrossRef41
Takata, Seki, Dobashi, Takeshita, Nakatani, Kamezawa, Hiraide, Sekine, Yoshioka. (1998) Inhibition of IL-12 synthesis of peripheral blood mononuclear cells (PBMC) stimulated with a bacterial superantigen by pooled human immunoglobulin: implications for its effect on Kawasaki disease (KD). Clinical and Experimental Immunology 114:2, 311-319
CrossRef42
LYNNE M. MOFENSON, RAM YOGEV, JAMES KORELITZ, JAMES BETHEL, KEITH KRASINSKI, JOHN MOYE, ROBERT NUGENT, JOSE G. RIGAU-PEREZ. (1998) Characteristics of acute pneumonia in human immunodeficiency virus-infected children and association with long term mortality risk. The Pediatric Infectious Disease Journal 17:10, 872-880
CrossRef43
J. Gray. (1997) HIV in the neonate. Journal of Hospital Infection 37:3, 181-198
CrossRef44
JACOBO ABADI, ZHAOJING ZHONG, JOANNA DOBROSZYCKI, LIISE-ANNE PIROFSKI. (1997) Fc??RIIa Polymorphism in Human Immunodeficiency Virus-Infected Children with Invasive Pneumococcal Disease. Pediatric Research 42:3, 259-262
CrossRef45
E. RICHARD STIEHM. (1997) Human intravenous immunoglobulin in primary and secondary antibody deficiencies. The Pediatric Infectious Disease Journal 16:7, 696-707
CrossRef46
RICHARD M. RUTSTEIN, STUART E. STARR. (1997) Immunizing the HIV-Infected Child. AIDS Patient Care and STDs 11:3, 149-160
CrossRef47
Akos Kovacs, Howard L. Leaf, Michael S. Simberkoff. (1997) BACTERIAL INFECTIONS. Medical Clinics of North America 81:2, 319-343
CrossRef48
Martin L. Lee, PhD, CStat, Robert Peter Gale, MD, PhD, Peng Lee Yap, MD. (1997) USE OF INTRAVENOUS IMMUNOGLOBULIN TO PREVENT OR TREAT INFECTIONS IN PERSONS WITH IMMUNE DEFICIENCY. Annual Review of Medicine 48:1, 93-102
CrossRef49
F. Maggiolo, A. Taras, F. Suter, Maria Grazia Pravettoni, Manuela Leone, Antonella Ingrosso. (1997) Zidovudine and thymus humoral factor gamma-2 in the treatment of HIV infection: Preliminary clinical experience. Infection 25:1, 35-38
CrossRef50
EDWARD N. JANOFF, JEFFREY B. RUBINS. (1997) Invasive Pneumococcal Disease in the Immunocompromised Host. Microbial Drug Resistance 3:3, 215-232
CrossRef51
Alan J Chaput, Robin D'Ambrosio, Gene D Morse. (1996) In vitro protein-binding characteristics of delavirdine and its N-dealkylated metabolite. Antiviral Research 32:2, 81-89
CrossRef52
Atul Shah, William Moss, Susan Champion, Elaine J. Abrams. (1996) NONMENSTRUAL TOXIC SHOCK SYNDROME IN A YOUNG CHILD WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION. The Pediatric Infectious Disease Journal 15:7, 639-641
CrossRef53
E. Richard Stiehm. (1996) Appropriate therapeutic use of immunoglobulin. Transfusion Medicine Reviews 10:3, 203-221
CrossRef54
STEVEN R. NESHEIM. (1996) The Diagnosis and Management of Perinatal HIV Infection. Clinical Obstetrics and Gynecology 39:2, 396-410
CrossRef55
StevenK Obaro, M.C Steinhoff, N Shahid, G Siber. (1996) Serum, breast milk, and infant antibody after maternal immunisation with pneumococcal vaccine. The Lancet 347:8995, 192-193
CrossRef56
D. A. Watson, D. M. Musher, J. Verhoef. (1995) Pneumococcal virulence factors and host immune responses to them. European Journal of Clinical Microbiology & Infectious Diseases 14:6, 479-490
CrossRef57
(1995) Prophylactic Immune Globulin in Children with HIV Disease. New England Journal of Medicine 332:11, 750-752
Full Text58
EMILIO BOUZA, PATRICIA MUÑOZ. (1995) Penicillin-Resistant Pneumococci in Adult Disease with Special Reference to AIDS Patients. Microbial Drug Resistance 1:1, 9-28
CrossRef59
Baziel G.M. van Engelen, Willy O. Renier, Corry M.R. Weemaes, Fons J.M. Gabreels, Harry Meinardi. (1994) Immunoglobulin treatment in epilepsy, a review of the literature. Epilepsy Research 19:3, 181-190
CrossRef60
Spector, Stephen A.Gelber, Richard D.McGrath, NualaWara, DianeBarzilai, AsherAbrams, ElaineBryson, Yvonne J.Dankner, Wayne M.Livingston, Robert A.Connor, Edward M.the Pediatric AIDS Clinical Trials Group. (1994) A Controlled Trial of Intravenous Immune Globulin for the Prevention of Serious Bacterial Infections in Children Receiving Zidovudine for Advanced Human Immunodeficiency Virus Infection. New England Journal of Medicine 331:18, 1181-1187
Full Text61
SW Nicholas. (1994) The opportunistic and bacterial infections associated with pediatric Human Immunodeficiency Virus disease. Acta Paediatrica 83:s400, 46-50
CrossRef62
E Ruga, C Giaquinto, S Cozzani, A Giacomelli, A Pagliaro, A Mazza, A Manzini, AM Laverda, R D'Elia. (1994) The use of antibiotics in the treatment and prevention of infection in HIV-infected children. Acta Paediatrica 83:s400, 70-72
CrossRef63
T Español, I Caragol, JM Bertran. (1994) Evolution of immunological abnormalities in HIV infection by vertical transmission. Acta Paediatrica 83:s400, 35-38
CrossRef64
Stephen M. Arpadi, Sara Back, James O'Brien, Edward N. Janoff. (1994) Antibodies to pneumococcal capsular polysaccharides in children with human immunodeficiency virus infection given polyvalent pneumococcal vaccine. The Journal of Pediatrics 125:1, 77-79
CrossRef65
R.I. Schiff. (1994) Intravenous gammaglobulin: pharmacology, clinical uses and mechanisms of action. Pediatric Allergy and Immunology 5:2, 63-87
CrossRef66
H. Nielsen. (1994) Immunoglobulin preparations for intravenous administration.. Allergy 49:2, 69-75
CrossRef67
(1994) Features of children perinatally infected with HIV-1 surviving longer than 5 years. The Lancet 343:8891, 191-195
CrossRef68
James J. Rusthoven. (1994) Biological response modifiers and infectious diseases: Actual and potential therapeutic agents. International Journal of Antimicrobial Agents 3:4, 223-243
CrossRef69
ARYE RUBINSTEIN, THERESA CALVELLI, R. RUBINSTEIN. (1993) Intravenous Gammaglobulin for Pediatric HIV-1 Infection: Effects on Infectious Complications, Circulating Immune Complexes, and CD4 Cell Decline. Annals of the New York Academy of Sciences 693:1 Pediatric AID, 151-157
CrossRef70
WILLIAM T. SHEARER, HOWARD M. ROSENBLATT, MARK D. SCHLUCHTER, LYNNE M. MOFENSON, THOMAS N. DENNY, THE NICHD IVIG CLINICAL TRIAL GROUP, . (1993) Immunologic Targets of HIV Infection: T Cells. Annals of the New York Academy of Sciences 693:1 Pediatric AID, 35-51
CrossRef71
T. Güngör, M. Funk, R. Linde, I. Kynast, A. Allendorf, C. Lotz, S. Ehrenforth, D. Hofmann, B. Kornhuber, W. Kreuz. (1993) Combined therapy in human immunodeficiency virus-infected children —a 4-year experience. European Journal of Pediatrics 152:8, 650-654
CrossRef72
C. F. Davison, F. J. Holland, M. L. Newell, C. N. Hudson, C. S. Peckham. (1993) Screening for HIV infection in pregnancy. AIDS Care 5:2, 135-140
CrossRef73
R. Blasczyk, U. Westhoff, H. Grosse-Wilde. (1993) Soluble CD4, CD8, and HLA molecules in commercial immunoglobulin preparations. The Lancet 341:8848, 789-790
CrossRef74
T. Saint-Marc, J-L. Touraine, N. Berra. (1992) Beneficial effects of intravenous immunoglobulins in AIDS. The Lancet 340:8831, 1347
CrossRef75
Baker, Carol J., Melish, Marian E., Hall, Robert T., Casto, Daniel T., Vasan, Ushanalini, Givner, Laurence B., the Multicenter Group for the Study of Immune Globulin in Neonates . (1992) Intravenous Immune Globulin for the Prevention of Nosocomial Infection in Low-Birth-Weight Neonates. New England Journal of Medicine 327:4, 213-219
Full Text76
(1992) Manipulating the Immune System with Immune Globulin. New England Journal of Medicine 326:24, 1636-1638
Full Text77
A.A.M. Todd, P.L. Yap. (1992) Applications of intravenous immunoglobulin in haematology. Blood Reviews 6:2, 105-117
CrossRef78
Kimberly P. Dunsmore, Henry S. Friedman, Joanne Kurtzberg. (1992) The uses of intravenous immunoglobulin in pediatrics. Critical Reviews in Oncology/Hematology 12:2, 67-90
CrossRef79
Oates, John A., Wood, Alastair J.J., , Dwyer, John M., . (1992) Manipulating the Immune System with Immune Globulin. New England Journal of Medicine 326:2, 107-116
Full Text80
G. Zuin, N. Principi, R. Tornaghi, S. Paccagnini, M. Re, E. Massironi, M.C. Ragni. (1992) Impaired response to hepatitis B vaccine in HIV infected children. Vaccine 10:12, 857-860
CrossRef81
Carol Levine. (1991) Children in HIV/AIDS Clinical Trials: Still Vulnerable after All These Years. The Journal of Law, Medicine & Ethics 19:3-4, 231-237
CrossRef82
Stiehm, E. Richard, . (1991) New Uses for Intravenous Immune Globulin. New England Journal of Medicine 325:2, 123-125
Full Text83
Oates, John A., Wood, Alastair J.J., , Buckley, Rebecca H., Schiff, Richard I., . (1991) The Use of Intravenous Immune Globulin in Immunodeficiency Diseases. New England Journal of Medicine 325:2, 110-117
Full Text84
(1991) Immunoglobulin therapy. The Lancet 338:8760, 157-158
CrossRef
