IgG antibody response to polyethylene glycol-modified adenosine deaminase in patients with adenosine deaminase deficiency.

Polyethylene glycol (PEG)-modified bovine adenosine deaminase (ADA) is used for replacement therapy of severe combined immunodeficiency disease due to inherited ADA deficiency. We monitored IgG anti-ADA antibody in 17 patients treated by intramuscular injections of PEG-ADA for 1 to greater than 5.5 yr. ELISA-detectable anti-ADA IgG appeared in 10 patients, usually between the third and eighth months of treatment. Anti-ADA levels did not correlate with trough plasma ADA activity, which averaged 1.8-5 times normal blood (erythrocyte) ADA activity, depending on dose (15-60 U/kg per wk). ELISA-detectable anti-ADA antibodies were directed primarily at bovine-specific peptide (rather than PEG-containing) epitopes. Enhanced enzyme clearance, mediated by antibody that directly inhibited native and PEG-modified bovine ADA, and native, but not PEG-modified human ADA, occurred in two patients. In one, tolerance was induced; in the second, twice weekly injections of PEG-ADA compensated for accelerated clearance. We speculate that inhibitory antibodies recognize conserved, relatively PEG-free epitope(s) encompassing the active site, and that in human, but not bovine, ADA a PEG-attachment site "shields" the active site from immune recognition. We conclude that PEG-modification largely prevents the development of high affinity, or high levels of clearing antibodies to bovine ADA, and that PEG-modified human ADA should be further investigated as a possible treatment for ADA deficiency.

The Wiskott-Aldrich syndrome. Results of transfer factor therapy.

12 patients with Wiskott-Aldrich syndrome were treated with therapeutic doses of transfer factor in an attempt to induce cellular immunity. Clinical improvement was noted after transfer factor therapy in 7 of the 12 patients treated. Because this disease has a variable course and temporary spontaneous improvement can occur, the observed improvement cannot necessarily be attributed to the transfer factor. However, in two patients repeated remissions consistently followed transfer factor administration on repeated occasions. This included freedom from infections, regression of splenomegaly, and clearing of eczema. An unexpected finding was a decrease in bleeding in 3 of the 10 patients who had bleeding. Conversion of skin reactivity was obtained in all seven patients who clinically seemed to respond to transfer factor. In vitro studies performed after the administration of transfer factor demonstrated that the lymphocytes of the patients now produced migration inhibitory factor in response to appropriate test antigens, but did not undergo increased radioactive thymidine incorporation in response to the same antigens. A defect in the monocyte IgG receptors has been found in certain patients with the disease, and the current study shows that all patients with defective monocyte IgG receptors responded to transfer factor, whereas only one patient with normal receptors showed any response. This test may thus prove to be useful in predicting the results of transfer factor therapy in patients with Wiskott-Aldrich syndrome, although evaluation of a larger series of patients will be necessary to confirm this point. We conclude that cellular immunity can be induced, that there appears to be clinical benefit in certain patients with Wiskott-Aldrich syndrome by the use of transfer factor, and that this mode of therapy warrents trial in these patients and others with defects of cellular immunity.

Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.

We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe than in the usual, early-onset disorder. Six patients were compound heterozygotes; 7 of 10 mutations found were novel, including one deletion (delta 1019-1020), three missense (Arg156 > His, Arg101 > Leu, Val177 > Met), and three splicing defects (IVS 5, 5'ss T+6 > A; IVS 10, 5'ss G+1 > A; IVS 10, 3'ss G-34 > A). Four of the mutations generated stop signals at codons 131, 321, 334, and 348; transcripts of all but the last, due to delta 1019-1020, were severely reduced. delta 1019-1020 (like delta 955-959, found in one patient and apparently recurrent) is at a short deletional hot spot. Arg156 > His, the product of which had detectable activity, was found in three patients whose second alleles were unlikely to yield active ADA. The oldest patient diagnosed was homozygous for a single base change in intron 10, which activates a cryptic splice acceptor, resulting in a protein with 100 extra amino acids. We speculate that this "macro ADA," as well as the Arg156 > His, Arg101 > Leu, Ser291 > Leu, and delta 1019-1020 products, may contribute to mild phenotype. Tissue-specific variation in splicing efficiency may also ameliorate disease severity in patients with splicing mutations.

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team.

OBJECTIVE: To evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DESIGN: Risk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. METHODS: HIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. RESULTS: Eighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34; P < 0.001], multiple gestation (OR, 6.02; P = 0.011), antenatal alcohol use (OR, 1.91; P = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24; P = 0.022) or pre-eclampsia (OR, 6.36; P = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08; P = 0.014) and pre-eclampsia (OR, 5.25; P = 0.049), and baseline HIV culture titer (OR, 1.41; P = 0.037). IUGR was associated with multiple gestation (OR, 8.20; P = 0.010), antenatal cigarette use (OR, 3.60; P = 0.008), and pre-eclampsia (OR, 12.90; P = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Metabolic correlates of immune dysfunction in malnourished children.

Mononuclear cells of malnourished children contain diminished activity of phosphoglycerate kinase and pyruvate kinase (PK). The PK activity of these cells correlates well with the percentage of circulating thymus-derived lymphocytes (T-cells). Phytohemagglutinin causes an immediate increase in PK activity of mononuclear cells of malnourished patients. The correlation of PK activity with T-cells and the response of PK activity to phytohemagglutinin are in distinct contrast to observed perturbations of neonatal mononuclear cell metabolism. The relationship of the metabolic alterations to the pathophysiology of the immune system in malnutrition has not yet been defined.

Biochemical evidence of thiamin deficiency in young Ghanian children.

Detailed biochemical studies for nutritional status were carried out on 146 Ghanaian children ages 6 months to 6 years over a 2-year period. Study children comprised three main groups: severe protein-calorie malnutrition; mild to moderate protein-calorie malnutrition and apparently healthy children. Erythrocyte transketolase activity and the percentage of erythrocyte transketolase pyrophosphate effect were also determined. In the first year of the study elevated percentage of transketolase pyrophosphate effect indicative of thiamin deficiency was found in all three of the above-mentioned groups, with the most widespread deficiency in the normal groups. In year 2, repeat studies of the severely malnourished group after 2 weeks of nutritional therapy with the administration of vitamin capsules, which included thiamin, resulted in the normalization of transketolase pyrophosphate effect. Apoenzyme activity was comparable in all groups studied. There were no obvious clinical signs of thiamin deficiency, although sensory testing was not performed. A relatively large number of children with high percentage of transketolase pyrosphosphate effect also had serum folic acid deficiency. This evidence of widespread biochemical thiamin deficiency is indicative of an at-risk population among young children for clinical thiamin deficiency. Further studies are needed to identify whether the problem is inadequate thiamin intake, destruction of thiamin by thiaminases or food preparation methods, or malabsorption of thiamin.

Activation and differentiation antigens on T cells of healthy, at-risk, and HIV-infected children.

We examined the T-lymphocyte phenotypes of 67 human immunodeficiency virus (HIV)-infected children (P-1 or P-2) and 65 age-matched, healthy, control children stratified into four groups from < 1 to > or = 5 years of age to determine expression of antigens associated with cell activation/differentiation. Immunophenotyping was performed by laser flow cytometry using two-color immunofluorescent labeling. Although the control children showed a decline in total CD4 cell percent with age, the HIV-infected children in all age groups showed significantly decreased CD4 cell numbers compared with the age-matched controls. However, the slope of the CD4 cell decline with age was not significantly different in HIV-infected and control children. The CD4 cell decrease in infected children was reflected in both the CD45RA+ (naive) and CD45RA- (memory) CD4 cell subsets, although the CD45RA+ cells were decreased in greater proportion. Results assessing CD4 cells for expression of the L-selectin (Leu8) molecule were similar to those for CD45RA. The overall CD8 cell percentage was significantly increased in HIV-infected children compared with controls in all age groups. This was due primarily to increases in CD8 cells that were CD38+, CD57+, HLA-DR+, or CD45RA-. In a retrospective analysis of data from 23 P-0 children, we compared phenotype results from 5 children who were HIV+ with those 18 who were HIV-. Although the phenotypic changes seen in the 5 HIV+ children paralleled those described above for P-1 and P-2 subjects, there was no significant difference in the values for HIV+ compared with HIV P-0 children. Although the phenotypic alterations described did not appear to be diagnostic markers in P-0 children, they may serve as useful adjuncts for the evaluation of HIV-infected children.

Purification and properties of porcine polymorphonuclear cells.

A method for the rapid separation of highly purified populations of porcine polymorphonuclear cells from whole blood is described. Porcine blood, anti-coagulated with EDTA, was layered over a discontinuous Percoll gradient (62.5% and 75%) and then centrifuged at 400 X g for 25 min. This results in the formation of a band of cells at the interface of the two Percoll layers which is greater than 99% granulocytes (93.8 +/- 1.8% neutrophils and 5.3 +/- 1.8% eosinophils) with a 77% recovery. The mononuclear cells remain above the 62.5% Percoll layer, and most erythrocytes pellet to the bottom of the tube. The isolated porcine granulocytes were found to respond to opsonized zymosan, phorbol myristate acetate (20 ng/ml), and the calcium ionophore A23187 (10(-5) M) in chemiluminescence assays with kinetics similar to those of human granulocytes. The porcine cells did not respond to the chemotactic peptide N-formyl-methionyl-leucyl-phenalanine (FMLP; 10(-6) M) unlike the human granulocytes which display a very rapid response to FMLP. Both porcine and human granulocytes readily changed shape by elongating and developing pseudopods when exposed to zymosan-activated serum, but only human granulocytes changed on exposure to FMLP. Thus, porcine granulocytes may be rapidly isolated on discontinuous Percoll gradients with little mononuclear cell contamination. Porcine and human PMN have similar oxidative and chemotactic responses, but porcine PMN differ from human granulocytes in the inability of porcine granulocytes to respond to FMLP.

Purification and properties of peritoneal eosinophils from pediatric dialysis patients.

Peritoneal eosinophilia frequently occurs in patients undergoing peritoneal dialysis. We have devised a method for isolating large numbers of these peritoneal eosinophils from pediatric patients on continuous peritoneal dialysis. Patients were selected on the basis of previous high peritoneal eosinophil counts and had an age range of 1.5-11 years. The unfractionated peritoneal fluid contained 7.9 +/- 3.7% neutrophils, 3.8 +/- 1.0% lymphocytes, 11.0 +/- 3.7% monocytes/macrophages, and 77.3 +/- 6.3% eosinophils (based on Wright stain) and up to 2 x 10(9) cells could be recovered from 1 liter of peritoneal dialysate. The cells were concentrated by centrifugation and the cell suspension then layered over a discontinuous Percoll gradient consisting of layers of 45%, 55%, 65%, and 75% Percoll. The gradients were centrifuged resulting in the formation of bands of cells at the interfaces of the layers. The densest band of cells (above 75% Percoll) contained 94.7 +/- 1.8% eosinophils (mean with median of 98%) and 4.3 +/- 16% neutrophils. The eosinophil counts were 72.2 +/- 7.1% above the 65% layer, 57.1 +/- 8.7 above 55%, and 40.9 +/- 10.9% above 45%. The monocyte/macrophage count increased from 0.1% above the 75% layer to 42.9% above the 45%. The denser eosinophils (above 75% and 65%) had the appearance of normal blood eosinophils and comparable function to blood eosinophils in cytotoxic and oxidative assays. This method provides a means of obtaining large numbers of very pure eosinophils for study of eosinophil function, eosinophil subpopulations, or eosinophil granule constituents.

Therapy of chronic mucocutaneous candidiasis.

Clinical observations made on a group of six children and three adults indicate that ketoconazole is a safe and effective fungistatic agent that is useful for both initial and long-term maintenance therapy of mucocutaneous lesions due to infection by sensitive strains of Candida in patients with chronic mucocutaneous candidiasis.

Basophil releasability in the newborn: factors limiting immunoglobulin E-mediated histamine release.

Cord basophil preparations from 53 term neonates were studied for various factors affecting immediate hypersensitivity reactions including: basophil IgE receptor density and histamine releasability following incubation with calcium ionophore A23187, zymosan-activated serum (C5a), and anti-IgE. Basophil histamine content (geometric mean, 0.4 pg/basophil, with content in 14/28 cord blood samples below 0.2 pg/cell) is considerably below that of atopic and nonatopic individuals (geometric mean, 2.3 pg/basophil). Histamine release is normal with both A23187 (range 33% to 88%) and C5a (range 11% to 58%). Normal release with anti-IgE was shown in five of nine cord blood samples (range 13% of 52%), but four of five cell preparations required IgE preincubation. Indirect evidence indicates that basophils from newborns contain less than 30,000 total IgE receptors/cell. IgE-mediated histamine release in basophils from newborns is minimized by suboptimal IgE binding. Optimal IgE binding is not favored in basophils from neonates because of low serum IgE and low IgE receptor density. Serum IgE and IgE receptors increase to a variable degree as the child grows older and may determine the clinical onset of allergic disease.

Cellular (T cell) immunity in the human newborn.

The cellular immune system of the human newborn, like the rest of the immunologic apparatus, is anatomically intact, antigenically inexperienced, and functionally deficient. The latter is suggested by the newborns' enhanced susceptibility to infection, diminished delayed cutaneous hypersensitivity reactions, and selective abnormalities (when compared to adults) of measures of cellular immunity in vitro. These include impaired proliferative response to ubiquitous antigens, depressed lymphotoxin, migration inhibition factor, and immune interferon production, and diminished cytotoxic reactions including cell-mediated lympholysis. By contrast, other aspects of neonatal T cell function, such as to mitogens or allogeneic lymphocytes, natural interferon and leukocyte inhibition factor production, and number and percentage of E-rosette-forming cell are generally normal. These decreased functional properties may provide an explanation for the newborns' susceptibility to infection and for the occasional occurrence of engraftment of foreign cells from either the mother or from prenatal or neonatal blood transfusion.

Aspirin intolerance in chronic childhood asthma: Detected by oral challenge.

Most previously reported individuals with acetylsalicylic acid (aspirin, ASA)-induced asthma have been adults. This study was undertaken to define the prevalence of ASA intolerance among children with intractable asthma. Fifty children (34 boys and 16 girls) ranging in age from 6 to 18 years with extrinsic (atopic) asthma were studied. None had a history of ASA sensitivity or nasal polyps; all required continuous medication including cromolyn sodium and daily or intermittent steroids. Anti-asthmatic medications were stopped 12 hours prior to testing. At the same time of day, each subject, in a doubleblind manner, on two separate days, ingested either 300 mg of ASA or 100 mg of lactose (placebo). Measurements of FVC, FEV1, and FEF25-75 were obtained prior to challenge and one half, one, two, three, and four hours after. ASA intolerance required a decrease of 30% in lung function with ASA as compared to placebo. Fourteen of 50 (28%) were ASA-intolerant; a greater number were girls, and they had more sinusitis and an onset of disease prior to 2 years of age. Steroid dependency, frequency of eczema, nasal eosinophilia, serum IgE levels, and peripheral eosinophil counts did not differ between the two groups. The use of aspirin in childhood asthma should be limited.

Decreased bactericidal activity of leukocytes of stressed newborn infants.

Previous studies have established that leukocyte phagocytosis and intracellular killing are normal in term and low-birthweight newborns who are well. To determine the effect of stress or illness on newborn leukocyte function, the phagocytic and bactericidal activity of leukocytes from 40 sick newborns was compared with that of leukocytes from 12 newborns and 23 normal adults. To eliminate abnormal phagocytosis resulting from serum opsonic defects in newborn sera, pooled adult sera were used in all assays. Twenty-five of the 40 stressed newborns (63%) had decreased in vitro activity against either Staphylococcus aureus 502A or Escherichia coli, or both, compared with decreased activity in two of 12 well infants (17%) and in four of 23 adult controls (17%). The mean bactericidal activity (percentage of organisms killed after two hours) of leukocytes from stressed newborns against S. aureus (83% +/- 2 [SEM]) and E. coli. (87% +/- 4 [SEM]) was significantly less than in the combined well infant and adult control group (94% +/- 1 for S. aureus and 97% +/- .5 for E. coli). Although the more severely ill infants had an increased incidence of impaired antibacterial activity, the degree of impairment was not related to the severity of illness. No consistent relationship of decreased activity to birthweight, gestational age, age when studied, or specific diagnosis was seen. The leukocyte abnormality in stressed infants against S. aureus was principally a killing defect, while against E. coli both phagocytosis and killing were abnormal. This study indicates that a wide variety of neonatal disorders may affect one or more of the steps required for normal bacterial killing. The lability of leukocytic antibacterial function under stress is an additional mechanism for the newborn's increased susceptibility to infection.

Serum enzyme abnormalities in juvenile rheumatoid arthritis.

Elevated serum transaminases, particularly SGOT, as a result of acetylsalicylic acid (ASA) therapy have been reported in patients with juvenile rheumatoid arthritis (JRA). In order to evaluate the possibilities that these elevated transaminases may result from JRA itself or from concomitant muscle injury, we correlated liver function tests and a specific test for muscle damage, creatine phosphokinase (CPK), with ASA therapy in 37 patients. These JRA patients were evaluated serially; 20 took ASA continuously, 6 took it intermittently, and 11 were on no therapy. Thirty-five healthy children were also studied to establish normal control values for the serum enzyme tests. Mean SGOT and SGPT in the 11 untreated subjects were significantly (P less than.001) higher than normal controls while CPK and alkaline phosphatase (AP) were not elevated. Mean SGOT and SGPT were also significantly (P less than .001) elevated in 20 children receiving ASA continuously; CPK was normal and AP less (P less than .05) than normal. CPK was elevated in 13 patients. Elevation of enzymes was sporadic and there was no correlation with serum salicylate, sex, age, disease duration, type, or activity. We conclude that mild abnormalities of SGOT and SGPT in JRA patients are common, but that they occur sporadically and elevated values appear to be unrelated to ASA therapy.

Evaluation of congenital neutropenic disorders by in vitro bone marrow culture.

The congenital neutropenias are a heterogenous group of diseases whose etiology and pathogenesis are largely unknown. We studied nine neutropenic patients from seven families. Evaluation included peripheral blood cell and differential cell counts, epinephrine and typhoid vaccine stimulation studies. Rebuck skin windows, and bone marrow aspirations for morphological assessment and for in vitro culture in liquid suspension and in agar plates. Parallel cultures were set up with and without colony-stimulating activity (CSA), and peripheral leukocytes were assayed for cellular production of CSA. Patients were initially classified on the basis of their clinical course: benign, mild, moderately severe, or severe disease. One patient in the moderately severe group had an immunoglobulin disorder. Morphologically normal mature granulocytes were seen in bone marrow aspirates of two patients, and maturational defects of varying degree were seen in the remaining seven. Colony formation in agar was markedly reduced below normal in three of seven, moderately reduced in two of seven, and greater than normal in two patients. Colonies in six of seven patients consisted exclusively of macrophages. Marrow from all but one of the nine patients demonstrated poor neutrophil development in suspension culture, and addition of CSA did not result in augmented granulocytic proliferation or maturation. A scheme of normal neutrophil maturation is proposed, and the nine patients were categorized according to this scheme. Four patterns of congenital neutropenia emerged: type 1 was the most benign form of disease with essentially normal clinical and in vitro parameters, and a defect considered to be due to a small committed stem cell pool, abnormal release, or excessive utilization peripherally; type 2 had mild disease with presumed defective committed stem cell differentiation along the granulocyte line; type 3 included benign to severe clinical expression with an apparent defect at the level of the committed granulocyte precursor more severe than in type 2; type 4 disease had varied clinical expression but evidence for a defect at the level of the pluripotent stem cell.

Candida esophagitis and laryngitis in chronic mucocutaneous candidiasis.

Five children (aged 11 to 19 years) with lifelong chronic mucocutaneous candidiasis had 12 episodes of esophageal and/or laryngeal candidiasis documented by endoscopy. Symptoms included hoarseness (8/12), dysphagia (6/12), and hemoptysis (1/12). There was poor correlation between oral lesions and esophageal or laryngeal involvement. On fiberoptic endoscopy, the esophagus was involved alone in four episodes (33%), the larynx in two episodes (17%), and both structures in six episodes (50%). In six of eight instances, the esophagram was nondiagnostic or markedly underestimated the extent of inflammation. Intravenous amphotericin B or miconazole resulted in the resolution of these infections for variable periods of time. Repeat endoscopy was used to follow the course of the disease. Aerosolized amphotericin B was effective on one occasion in clearing candidal lesions of the larynx and one small area of the left mainstem bronchus. Oral topical therapy was not beneficial. Since the signs and symptoms of laryngitis or esophagitis are often minimal or absent and complications, including strictures, may arise from chronic inflammation, periodic endoscopy and systemic therapy may be necessary.

T-cell reconstitution by thymus transplantation and transfer factor in severe combined immunodeficiency.

Reconstitution of cell-mediated immunity was achieved in a 5-month old female infant with severe combined immunodeficiency by fetal thymus transplant given simultaneously with two units of transfer factor. Thymus was obtained from a 15-week gestational age male fetus, and the two units of transfer factor from the lymphocytes of 500 ml of peripheral blood. Three weeks after transplantation, two nel HL-A antigens were detected on the infant's lymphocytes, one of which was present in the mother of the thymus donor; at the same time, some of the infant's own HL-A antigens disappeared. Thereafter, the percent of rosette-forming cells (T-cells) increased and the in vitro response to phytohemagglutinin and allogeneic lymphocytes became normal, and delayed skin tests became positive. Karyotyping of peripheral blood lymphocytes posttransplantation reveals an XY (male) pattern. These results suggest lymphocyte re-population as a result of the thymus-transfer factor therapy. Five months after transplantation, the patient has normal cellular immunity but persistent hypogammaglobulinemia. She is free of infection and growing normally on gammaglobulin injections.

Immunodeficiency as a component of recognizable syndromes.

Immunodeficiency occurs in numerous genetic syndromes. While it is the dominant manifestation in primary immunodeficiencies, immune deficits may also be seen in a variety of other recognizable syndromes. Immunodeficiency has been reported in 64 such conditions, adding to the 45 recognized primary immunodeficiencies. These uncommon syndromes with immune defects can present with: (a) growth deficiency (11 syndromes with disproportionate or proportionate short stature), (b) specific organ system dysfunction (18 with gastrointestinal, dermatologic, or neurologic abnormalities), (c) inborn errors of metabolism (13), (d) miscellaneous anomalies (10), or (e) chromosome anomalies (12). In most of the disorders, only some of the affected patients have immune defects. However, in 27 syndromes, immunodeficiency is a constant finding. We briefly review the clinical manifestations of each syndrome and delineate the specific associated immune defects. In most syndromes, the connection between the immune and other defects is unknown. Recognition of these conditions involving both the immune and other organ systems may facilitate accurate diagnosis and management as well as yield information regarding genes critical for the development of the involved systems.

Human intravenous immunoglobulin in primary and secondary antibody deficiencies.

IVIG is of value in patients with primary and secondary antibody deficiencies. High dose IVIG therapy is usually the treatment of choice for patients with primary antibody deficiency disease. Sufficient IVIG should be given to maintain IgG trough levels of > 500 mg/dl; this usually requires a dose of 400 to 500 mg/kg/month. Adverse side effects to IVIG has been described; the two most common serious side effects are hepatitis C and aseptic meningitis. New procedures to inactivate hepatitis C (and other viruses) are now in place. Aseptic meningitis is usually associated with high IVIG doses given rapidly to patients with autoimmune and inflammatory disease; its cause is not known. Subcutaneous infusions of IG or IVIG at weekly intervals has been shown to be clinically efficacious, well-tolerated and a less expensive alternative to monthly IVIG infusions. IVIG has been used with encouraging results in selected pediatric patients with HIV infection. The benefit is primarily in patients with CD4 counts > 200 cells/mm2 who receive no P. carinii pneumonia prophylaxis. IVIG may also be of value in preventing or ameliorating infection in other secondary antibody deficiencies including patients with malignancies; patients with protein-losing enteropathy and nephrotic syndrome; severely ill care patients with shock, trauma or surgery; premature infants and patients undergoing transplantation procedures; and severely burned patients. Guidelines for selecting patients for IVIG are offered.