Arthur J. Ammann

Perinatal Transmission of Human Immunodeficiency Virus Type 1 by Pregnant Women with RNA Virus Loads <1000 Copies/mL

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

Thymosin Activity in Patients with Cellular Immunodeficiency

An extract of calf thymus, thymosin, induces an increase in percentage of T-cell rosettes when incubated in vitro with sheep erythrocytes and lymphocytes from patients with primary immunodeficiency diseases or viral illness. Precursor lymphocytes are required for this increase to occur. The percentage of T-cell rosettes, when they are normal, is not increased further upon incubation with thymosin. A patient with thymic hypoplasia and immunoglobulin synthesis was selected to receive thymosin in vivo when her T-cell rosettes had increased from 15 to 48 per cent after in vitro incubation with thymosin. During therapy, she clinically improved, the percentage of T-cell rosettes gradually increased to normal, and positive delayed hypersensitivity skin tests developed. Thymosin may be useful clinically for partial reconstitution of cellular immunity. An increased percentage of T-cell rosettes after incubation with thymosin in vitro may predict which patients will respond to thymosin therapy in vivo.

Deoxyguanosine Triphosphate as a Possible Toxic Metabolite in the Immunodeficiency Associated with Purine Nucleoside Phosphorylase Deficiency

Purine nucleoside phosphorylase (PNP) deficiency is associated with a severe defect in thymus-derived (T)-lymphocyte function combined with normal bone marrow-derived (B)-lymphocyte function. To investigate the role of this enzyme deficiency in the resulting immune dysfunction, we measured the levels of ribonucleoside and deoxyribonucleoside triphosphates in erythrocytes from two unrelated PNP-deficient, T-lymphocyte-deficient patients. Both PNP-deficient patients have abnormally high levels of deoxyguanosine triphosphate (deoxy-GTP) in their erythrocytes (5 and 8 nmol/ml packed erythrocytes). In contrast, normal controls and adenosine deaminase-deficient, immunodeficient patients do not have detectable amounts of deoxyGTP (<0.5 nmol/ml packed erythrocytes). We propose that deoxyguanosine, a substrate of PNP, is the potentially lymphotoxic metabolite in PNP deficiency. The mechanism of toxicity involves phosphorylation of deoxyguanosine to deoxyGTP, which acts as a potent inhibitor of mammalian ribonucleotide reductase.

Acquired immune dysfunction in homosexual men: immunologic profiles.

Homosexual men with Kaposi sarcoma, lymphadenopathy syndrome, opportunistic infection, and nonhomosexual traditional Kaposi sarcoma were evaluated for B cell, T cell, and complement immunity and compared to normal controls and homosexual controls. No significant immunologic abnormalities were found in the traditional Kaposi group. All homosexual groups, including the homosexual controls, had a significant decrease in the helper/suppressor cell ratio. Functional abnormalities of T-cell immunity were observed in the homosexual Kaposi sarcoma, lymphadenopathy syndrome, and opportunistic infection groups. Significant elevations of IgG, IgM, IgA, and IgE were found in the lymphadenopathy group, while only IgG and IgA were elevated in the Kaposi sarcoma group. C3, C4, and immune complexes were normal, while total hemolytic complement activity was increased in the Kaposi sarcoma and lymphadenopathy syndrome groups.

Abnormal Purine Metabolism and Purine Overproduction in a Patient Deficient in Purine Nucleoside Phosphorylase

To delineate the normal function of purine nucleoside phosphorylase and to understand the pathogenesis of the immune dysfunction associated with deficiency of this enzyme, we studied purine metabolism in a patient deficient in purine nucleoside phosphorylase, her erythrocytes and cultured fibroblasts. She exhibited severe hypouricemia and hypouricosuria but excreted excessive amounts of purines in her urine, the major components of which were inosine and guanosine. Her urine also contained deoxyinosine, deoxyguanosine and uric acid 9-N riboside. The patients erythrocytes but not her cultured fibroblasts contained increased concentrations of phosphoribosylpyrophosphate and inosine. The metabolic abnormalities resembled those in the erythrocytes of patients with the Lesch-Nyhan syndrome. Purine nucleoside phosphorylase is a necessary component of the major, if not the sole, pathway for the conversion of purine nucleosides and nucleotides to uric acid. The increased intracellular concentrations of inosine may, by inhibiting adenosine deaminase, be related to the immunologic dysfunction.

Use of intravenous γ-globulin in antibody immunodeficiency: Results of a multicenter controlled trial☆

Abstract A 2-year corssover study was performed in 34 patients with antibody-deficiency disorders characterized by normal T-cell function. Each patients was treated for 1 year with either ISG or MISG and then treated for an additional year with the other preparation. There were no significant differences in acute or chronic infections in the categories of otitis media, bronchitis, sinusitis, gastrointestinal tract, skin, or conjunctival infections. Although there were attendant increases in the number of mild side effects and the number of apparent acute upper respiratory tract illnesses during MISG treatment, the modified preparation was as effective as ISG in preventing life-threatening infections in these patients with antibody-deficiency syndromes. MISG appears to be suitable for the treatment of patients who require large amounts of intravenous γ-globulin, of individuals in whom a rapid increase in antibody levels is required, of patients with bleeding disorders such as the Wiskott-Aldrich syndrome, and of severely debilitated patients in whom intramuscular γ-globulin administration would be difficult.

Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases☆

To assess safety and efficacy of high-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency syndromes we treated a group of 19 patients with a monthly dose of 400 mg/kg of reduced and alkylated, maltose-containing immunoglobulin (Gamimune, Cutter Biological, Berkeley, California) and compared their responses with a group of 16 patients receiving 100 mg/kg per month intravenously. Side effects observed were mild to moderately severe and similar in both groups. In one adult patient receiving the high dose a severe enough reaction developed during the first infusion to exclude her from the study. Serum IgG levels of patients receiving high-dose immunoglobulin showed a stepwise increase in both trough and peak values until a new plateau was reached after four to six infusions. None of the patients receiving the low dose showed such a stepwise increase. On average, serum IgG levels rose by approximately 250 mg/dl for each 100 mg/kg immunoglobulin infused. The mean catabolic rate of the infused IgG was estimated to be 26 days in patients receiving high-dose immunoglobulin infusions. We demonstrated that 400 mg/kg immunoglobulin given intravenously every four weeks to patients with immunodeficiency results in a substantial increase in serum IgG during the postinfusion period, suggesting persistence of specific antibody throughout the interval between infusions.

The Antibody Responses to Pneumococcal Capsular Polysaccharides in Aged Individuals

Abstract A population of elderly individuals was studied following immunization with the pneumococcal capsular polysaccharides of types 3 and 8. The antibody responses, determined by indirect hemagglutination (IHA) and by radioimmunoassay (RIA), before and 2 weeks following immunization were compared to those in young adults. Immunoglobulin levels were measured prior to immunization. The numbers of individuals showing a significant increase in antibodies to the polysaccharides of pneumococcal types 3 and 8 were comparable in both age groups when assayed by IHA and RIA. In addition, the mean fold increases in levels of antibodies measured by IHA and by RIA were not significantly lower to either polysaccharide in the elderly group. Postimmunization levels of antibody in the elderly, determined by RIA, were lower to both polysaccharides studied than in young adults, but only those to pneumococcal polysaccharide type 3 differed at a stastically significant level. Comparison of immunoglobulin levels in elderly responders and nonresponders suggested an association between low values of serum IgM and IgA and lack of responsiveness to immunization with pneumococcal polysaccharides.

PEDIATRIC ACQUIRED IMMUNODEFICIENCY SYNDROME

Approximately 40 to 50 infants and children with similar epidemiologic, clinical, and laboratory features of AIDS have been described. The occurrence of significant numbers of patients with PAIDS in geographic areas that are associated with similar risk factors and clinical features of AIDS suggests a common cause. Immunologic evaluation reveals hypergammaglobulinemia, decreased or absent antibody responses after immunization, normal to decreased T-cell numbers, decreased helper/suppressor cell ratios, and abnormal results of functional studies of T-cells. None of the patients described has the clinical or laboratory features of well-established congenital immunodeficiency disorders. No consistent viral agent has been documented except for antibody to ARV and HTLV III. The frequent finding of T-cell abnormalities in the mothers of infants with PAIDS is in contrast to the absence of such abnormalities in the mothers of infants with congenital immunodeficiency disorders. Future studies in PAIDS should be directed toward uncovering the etiology and risk factors as well as determining the response to treatment with various methods of immunologic reconstitution.

Acquired immune deficiency syndrome in childhood

The acquired immunodeficiency syndrome has been observed with increasing frequency in children with associated hemophilia, high-risk environmental backgrounds, and blood transfusions. AIDS should be considered in the differential diagnosis of childhood immunodeficiency, and it must be distinguished from congenital disorders. We emphasize the importance of epidemiologic, clinical, and laboratory data in diagnosis and aggressive management of infectious complications. The relationship between human retrovirus infection and AIDS remains to be precisely defined, especially with regard to cofactors that may play a role in the development of severe immunodeficiency following exposure to the agent.