Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials.

BACKGROUND: This study assessed the immunogenicity of pegvaliase (recombinant Anabaena variabilis phenylalanine [Phe] ammonia lyase [PAL] conjugated with polyethylene glycol [PEG]) treatment in adults with phenylketonuria (PKU) and its impact on safety and efficacy. METHODS: Immunogenicity was assessed during induction, upward titration, and maintenance dosing regimens in adults with PKU (n = 261). Total antidrug antibodies (ADA), neutralizing antibodies, immunoglobulin (Ig) M and IgG antibodies against PAL and PEG, IgG and IgM circulating immune complex (CIC) levels, complement components 3 and 4 (C3/C4), plasma Phe, and safety were assessed at baseline and throughout the study. Pegvaliase-specific IgE levels were measured in patients after hypersensitivity adverse events (HAE). FINDINGS: All patients developed ADA against PAL, peaking by 6 months and then stabilizing. Most developed transient antibody responses against PEG, peaking by 3 months, then returning to baseline by 9 months. Binding of ADA to pegvaliase led to CIC formation and complement activation, which were highest during early treatment. Blood Phe decreased over time as CIC levels and complement activation declined and pegvaliase dosage increased. HAEs were most frequent during early treatment and declined over time. No patient with acute systemic hypersensitivity events tested positive for pegvaliase-specific IgE near the time of the event. Laboratory evidence was consistent with immune complex-mediated type III hypersensitivity. No evidence of pegvaliase-associated IC-mediated end organ damage was noted. INTERPRETATION: Despite a universal ADA response post-pegvaliase administration, adult patients with PKU achieved substantial and sustained blood Phe reductions with a manageable safety profile. FUND: BioMarin Pharmaceutical Inc.

Hiperferritinemia como factor pronóstico de inmunosupresión en pacientes con síndrome de inmunodeficiencia adquirida / Hyperferritinemia as a prognostic factor for immnosuppression in patients with acquired immnodeficiency syndrome

Se realiza una investigación prospectiva con el objetivo de determinar si la hiperferritinemia es un factor pronóstico de inmunosupresión en pacientes con síndrome de inmunodeficiencia adquirida (SIDA). La población estuvo conformada por 40 pacientes hospitalizados en el Hospital Universitario de Maracaibo, durante los meses de Enero a Octubre del 2010. 27 (67,50%) pacientes fueron de sexo masculino y 13 (32,50%) femeninos. El 55,00% presentó hiperferritinemia. 22,50% presentaron contaje de linfocitos T CD4+ entre 200-400 cel/mm³ con un promedio de ferritina de 144,2 ± 127,1 ng/mL y, el 77,50% contaje de linfocitos T CD4+ < 200 cel/mm³ con un promedio de ferritina de 1100,0 ± 984,7 ng/mL (p = 0,01). Se demostró una correlación inversamente negativa entre niveles elevados de ferritina con niveles bajos de contaje de linfocitos T CD4+ (r = 0,3135, p = 0,030), cifras bajas de leucocitos (r= 0, 7458, p= 0,012), cifras bajas de proteínas (r= 0,5814, p= 0,01) y una relación directamente proporcional con el aumento de la VSG (r = 0,7422, p= 0,001). En los pacientes fallecidos el promedio de ferritina (1180,0 ± 1.072) estadísticamente (p= 0,018) fue más elevado en comparación con el promedio de ferritina (474 ±440,2) de los pacientes que sobrevivieron. Se concluye que se puede tomar en cuenta a la hiperferritinemia como factor pronóstico de inmunosupresión en pacientes con diagnóstico de SIDA

A prospective study was carried out to determine if hyperferritinemia is a predictive factor for immunosuppression in patients with acquired immunodeficiency syndrome (AIDS). The population consisted of 40 patients hospitalized at the University Hospital of Maracaibo (Hospital Universitario de Maracaibo), from January to October, 2010. Twenty-seven (67.50%) patients were male and 13 (32.50%) were female. 22.50% had a T CD4+ lymphocyte count between 200-400 cells/mm³ with a mean ferritin of 144.2 ± 127.1 ng/mL; 77.50% had a T CD4+ lymphocyte count of <200 cells/mm³ and a ferritin average of 1100.0 ± 984.7 ng/mL (p = 0.01). An inverse negative correlation was found between high ferritin levels and low T CD4+ lymphocyte count (r = 0.3135, p = 0.030), low numbers of leukocytes (r = 0, 7458 p = 0.012), low levels of protein (r = 0.5814, p = 0.01), and a directly proportional relation with the increase of ESR (r = 0.7422, p = 0.001). In patients who died, the mean ferritin level (1180.0 ± 1,072) statistically (p = 0.018) was higher compared with the average ferritin level (474 ± 440.2) of patients who survived. Conclusions are that these results are sufficiently relevant to take hyperferritinemia into account as a prognostic factor for the immunosuppression of diagnosed AIDS patients

Immune function in children with classical phenylketonuria and tetrahydrobiopterin deficiencies.

BACKGROUND: An increased susceptibility to infections has been observed in some patients with phenylketonuria (PKU), which is not well known whether it is due to alterations of plasma essential amino acid concentrations or to some other factors. OBJECTIVE: This study is designed to establish B cell and T cell functions in 44 children with classical PKU and tetrahydrobiopterin (BH4) deficiencies and the effects of too high plasma phenylalanine (PA) concentrations (16.53 to 30.54 mg/dL) on the same parameters. DESIGN: B and T cell functions of 33 children with classical PKU (divided into two groups based on fasting mean plasma PA concentrations: Group-I = 20.9 +/- 3.7 mg/dL, Group-II = 3.8 +/- 1.02 mg/dL), and 11 children with BH4 deficiencies (Group III) were studied. The results were compared between the groups and referenced with previously reported values from healthy controls. RESULT: Delayed type skin hypersensitivity responses to purified protein derivative (PPD) in Group I and phytohaemagglutinin (PHA) in Group I, III were lower than the other groups and healthy controls. Plasma IgG and IgM concentrations of Group I was lower than the reference values. Although mean serum zinc and iron levels of all patients were lower than published values of healthy children, zinc and iron deficiencies in Group I, III were much more prominent as compared to Group II. CONCLUSION: The somewhat low plasma IgG concentrations in Group I may be related to the very high plasma PA levels, however the role of zinc deficiency as a causal factor can not be ruled out. BH4 metabolism defects do not appear to affect the same parameters. Impaired delayed skin hypersensitivity responses in Group I and III can be explained by severe serum zinc deficiency. In the light of this study, we conclude that in order to establish a causal relationship between PKU and immune functions, further studies need to be conducted after the correction of micro-nutrient status of such children.

Immunological evidence for a bacterial toxin aetiology in sudden infant death syndrome.

Toxin-specific antibodies to clostridial, enterobacterial and staphylococcal toxins implicated in sudden infant death syndrome were studied in sera from sudden infant death syndrome infants and a comparison group of infants (babies with phenylketonuria). The results indicated a higher proportion of sera from sudden infant death syndrome infants contained IgA that bound to clostridial and enterobacterial toxins but a higher proportion of sera from the phenylketonuria comparison group contained IgA that bound staphylococcal toxins. The higher proportion of serum samples with IgG and IgM in the healthy comparison babies serum probably indicated immunity in this group of babies to these toxins. The effect of gender and age had a minimal effect on the incidence of these antibodies. The presence of toxin-specific antibodies in sudden infant death syndrome and the of comparison infants suggests that all infants are exposed to these toxins and most babies successfully overcome the toxic challenge. Some infants with predisposing risk factors (temperature change, smoking, infection, immune development, sleeping position, etc.) that could affect the baby's immune competency could succumb to these and possibly other toxins. This immunological evidence further strengthens the view that bacterial toxins are a significant cause of sudden infant death syndrome.

Immune status of children with phenylketonuria.

OBJECTIVE: To determine the effect of differences in plasma phenylalanine (Phe) concentrations (< 363 umol/L, 363 to 605 umol/L, and > 605 umol/L) on hematological and immunological parameters in 22 children with phenylketonuria (PKU). METHODS: Children with PKU were divided into one of three groups based on fasting plasma Phe levels. Hematologic and immunologic parameters of the children with PKU were compared between the groups and also compared with published values from age-matched children without PKU. RESULTS: Hematologic and immunologic parameters did not differ among children with different plasma Phe concentrations. Specifically, no significant differences between groups of PKU children with differing plasma Phe levels were found for plasma levels of albumin, hemoglobin, amino acids, IgM, complement C3, interleukins 1 and 2, erythrocyte, leukocyte and differential cell counts, hematocrit, percentages and numbers of CD4+, CD8+, CD3+ and total lymphocytes, or CD4 to CD8 ratio. Mean plasma IgG and IgA concentrations of the PKU children were, however, significantly lower than values from similar aged children. Moreover, positive correlations were obtained between plasma albumin and percentages and numbers of CD3+ and CD4+, between plasma IgG and interleukins 1 and 2, and between intakes of energy, protein, iron and plasma IgG levels. No correlations were found between plasma Phe and immunological parameters. CONCLUSION: While differences in plasma Phe concentrations up to concentrations of 866 umol/L do not appear to affect selected immune system parameters, further studies are needed to investigate the relationship between dietary nutrient intake, nutritional status, antibody biosynthesis and cytokine production. Assessment of plasma and cell membrane lipids and trace mineral status of PKU children would be helpful to determine if relationships exist between these nutrients and antibody production.

PKU-related dysgammaglobulinaemia: the effect of diet therapy on IgE and allergic sensitization.

The effect of diet on the development of immunoallergic signs and symptoms in children with phenylketonuria (PKU) was evaluated. Immunological indices of 58 children with PKU treated with diets were compared to the immunological indices of 58 healthy (non-PKU) children. In the PKU group, 39 children had been placed on diet therapy within the first month of life; 19 children had been placed on diet therapy after 6 months of age. Total circulating lymphocytes; CD3+, CD4+, CD8+ circulating lymphocytes; and serum IgA, IgM, IgG and total IgE levels were measured for each child. Skin prick tests were performed for common inhalant and food allergens. Every 3 months over the 2-year period of this study, the signs and symptoms of eczema, allergic rhinitis and asthma were recorded. The PKU group had lower IgG levels (p = 0.004) and higher total IgE levels (p = 0.0001) than the control group. Significantly lower IgE levels were found in children started on diet therapy within the first month of life compared with those started on diet therapy after 6 months of age (p = 0.0001). Allergic sensitization was significantly more frequent in the PKU group (24/58 vs 13/58, z = 2.00, p < 0.05), but no significant difference in the incidence of eczema and allergic rhinitis was found. Asthma was less frequent in the PKU group than in the control group (5/58 vs 14/58, z = 2.09, p < 0.05). Thus, diet appeared to prevent the development of immunoallergic signs and symptoms.

In vitro OKT3-induced mitogenesis in selenium-deficient patients on a diet for phenylketonuria.

Patients with phenylketonuria (PKU) are frequently deficient in the essential trace element selenium (Se), because of their very low protein diet. Using two approaches to investigate T-cell response to proliferative signaling, viz, mitogenesis caused by the monoclonal antibody OKT3 and the plant lectin phytohaemagglutinin (PHA), we demonstrated significantly reduced responses to optimal concentrations of OKT3 in a group of PKU patients with reduced serum Se compared with a normal group (p = 0.0005) and with a group of PKU patients whose serum Se was normal (p = 0.0023). The response of the Se-deficient group to optimal levels of PHA did not differ from that of the normal controls or from that of Se-normal PKU patients. A dose-dependent relationship between serum Se levels and mitogenic response was evident for OKT3 (r = 0.34, p = 0.0154), but not for PHA (r = -0.02, p = 0.9086). We suggest that the reduced response to OKT3 mitogenesis in Se-deficient PKU patients is possibly the consequence of impaired Se-dependent metabolic activity, which affects mitogenic signaling via the T cell antigen receptor (TCR/CD3) complex.

[Dynamics of the humoral immunity indices in children with phenylketonuria against a background of diet therapy and after its discontinuance]. / Dinamika nekotorykh pokazatelei gumoral'nogo immuniteta u detei, bol'nykh fenilketonuriei, na fone dieticheskogo lecheniia i posle ego otmeny.

The paper concerns variations in some parameters of humoral immunity in children with phenylketonuria examined at varying time (in the presence of specific dietetics and after its discontinuation). It is concluded that in children over 5 years of age, the hyperphenylalaninemia newly occurring after discontinuation of dietetics does not exert any material effect on the function of the mature enough immune system.

Immunologic studies in phenylketonuria.

Significantly reduced immunoglobulins were found in 22 patients with phenylketonuria. Tests of cellular immune function which included delayed skin hypersensitivity, T rosettes and PHA transformation were normal. Escherichia coli antibodies and the booster response to tetanus toxoid were also normal.