Role of immunoglobulin supplementation for secondary immunodeficiency associated with chylothorax after pediatric cardiothoracic surgery.

OBJECTIVE: To evaluate whether intravenous immunoglobulin was linked to a reduction in sepsis in patients with prolonged chylothoraces postpediatric cardiothoracic surgery. DESIGN: Retrospective observational cohort study. SETTING: Tertiary pediatric cardiac surgical center. PATIENTS: Children with chylothoraces postcardiothoracic surgery from 1998 to 2006 divided into two groups: with and without intravenous immunoglobulin supplementation. INTERVENTION: Intravenous immunoglobulin supplementation. MEASUREMENTS AND MAIN RESULTS: Thirty-seven with chylothoraces (median duration 14 days; interquartile range, 10-32 and median maximum chyle drainage 1.9 mL/kg/hr; interquartile range, 1-3) were included, and 16 (43%) received intravenous immunoglobulin. The degree of lymphopenia was worse with longer duration of chylothorax (p = .005). There was a trend toward immunoglobulin depletion-IgG (p = .07) and IgM (p = .07) with higher volume chyle loss. Twenty-two of 37 (59%) developed bloodstream infection and 24 of 37 (65%) developed sepsis related to other organ systems. The rate of bloodstream infection and of sepsis in other organ systems was high at 25 (95% confidence interval 17-39) and 23 (95% confidence interval 15-34) episodes per 1,000 intensive care unit days, respectively. Intravenous immunoglobulin was not related to the bloodstream infection rate: adjusted hazard ratio 0.88 (95% confidence interval 0.20-3.94; p = .87) or rate of sepsis in other organ systems: hazard ratio 2.31 (95% confidence interval 0.21-24.29; p = .49) or the proportion surviving to hospital discharge (p = .37). CONCLUSION: Patients with prolonged, large-volume chyle loss had greater secondary immunodeficiency. Although the sample size was small and therefore able to detect only a large treatment effect from intravenous immunoglobulin, infectious outcomes were equal between the two groups.

IgG subclasses in smokers with chronic bronchitis and recurrent exacerbations.

BACKGROUND: Tobacco smokers have lower serum levels of IgG than non-smokers. IgG subclass deficiency is common in patients with recurrent respiratory infections. Recurrent bronchial infections are common in smokers with chronic bronchitis (CB). We have investigated whether susceptibility to recurrent exacerbations in smokers with CB is associated with altered IgG subclass levels or IgG subclass deficiency. METHODS: Serum levels of IgG, IgA, IgM, and IgG subclasses 1-4 were determined by radial immunodiffusion in 100 subjects: 33 smokers with stable CB and recurrent exacerbations, 24 asymptomatic smokers, and 43 healthy never smokers. Systemic tobacco exposure was verified and excluded using a serum cotinine ELISA. Immunoglobulin data were log transformed to enable use of parametric statistical methods. RESULTS: Compared with never smokers, both patients with CB and asymptomatic smokers had significantly lower levels of IgG (median 9.7 g/l (range 5.6-15.2) and 9.9 (6.1-12.1) g/l v 12.0 (6.9-18.5) g/l) and IgG2 (2.8 (0.9-5.9) g/l and 2.5 (1.0-6.3) g/l v 4.0 (1.7-10.2) g/l). The estimated ratio of median values between the patients with CB and never smokers was 0.78 (95% confidence interval (CI) 0.69 to 0.89) for IgG and 0.65 (95% CI 0.50 to 0.83) for IgG2. The corresponding ratios between asymptomatic smokers and never smokers were 0.79 (95% CI 0.69 to 0.91) and 0.60 (95% CI 0.50 to 0.83), respectively. There were no significant differences between the smoking groups. CONCLUSIONS: Susceptibility to recurrent exacerbations in smokers with CB is not associated with lower levels of IgG subclasses than can be accounted for by smoking per se.

[Polyclonal B lymphocytosis and hyper-IgM: immunodeficiency and/or benign lymphoid proliferation associated with tobacco?]. / Hyperlymphocytose B polyclonale et hyper-IgM: déficit immunitaire et/ou prolifération lymphoïde bénigne associé(s) au tabac?

PURPOSE: To study the association of polyclonal B-cell lymphocytosis with binucleated lymphocytes with clinical manifestations suggesting the existence of an immunodeficiency, to evaluate the effect of cigarette smoking on this 'benign lymphoid proliferation', to analyze the clonality of lymphocytes, to determine the levels of immunoglobulins (Ig) G, A, M. METHODS: Description and analysis of the results obtained in four patients and literature review. RESULTS: Polyclonal B-cell lymphocytosis is associated with both a decrease in IgA and IgG and an increase in IgM. Recurrent infectious episodes (bronchitis) were observed in two patients. Transient smoking cessation allowed a decrease in lymphocytosis and IgM levels in two patients. No hematological malignancy occurred during the follow-up, while biological abnormalities persisted. CONCLUSION: Persistent polyclonal B-cell lymphocytosis may be associated with minor clinical features of immunodeficiency. Smoking cessation may sometimes lead to a decrease in lymphocytosis and IgM.

Heterogeneity of serum IgG subclass deficiencies in B chronic lymphocytic leukemia.

The occurrence of abnormally low serum immunoglobulin (Ig) levels is well-known in B chronic lymphocytic leukemia (CLL), but published data on IgG subclass levels are virtually absent. We measured serum IgG subclass levels in 52 B CLL outpatients, most in stage A and untreated, using an indirect immunoenzymatic assay with monoclonal antibodies. Mean levels of all Ig isotypes were lower than in normal controls in the whole group of patients, except for IgG2 in those studied at diagnosis. Levels of IgG1, IgG2, IgA, and IgM were lower in patients with a long disease duration than in those studied earlier. IgG subclass deficiencies occurred in 54% of cases and the most frequently affected isotype was IgG1. Every possible combination of IgG subclass and Ig class deficiencies from the selective deficiency of a single subclass to a combined deficiency of all isotypes was observed. This marked heterogeneity argues against the occurrence of isolated defects of one of the cytokines involved in Ig switching as a cause of hypoimmunoglobulinemia in CLL.

Humoral immunodeficiency in patients after bone marrow transplantation.

Ex vivo IgG production was determined in 17 children and adolescents and in 14 adult patients between 10 months and 6 years after BMT. Twenty-four patients received allogeneic transplants. Seven patients were transplanted with autografts. Seven patients received immunosuppressive therapy. B cells were purified by positive selection with a CD20 antibody. After IL-2 or IL-10 stimulation, IgG production of SAC-preactivated B cells in patients with immunosuppression (median/range: 11/4-15 ng/ml or 14210-29 ng/ml) was significantly reduced compared with patients receiving allogenic (30/3-860 ng/ml or 33/2-3431 ng/ml; P < 0.01) or autologous transplants (75/7-1431 ng/ml or 269-/7-13600 ng/ml, P < 0.01). In 14/31 patients ex vivo IgG production was defective. Investigations of B cell function in patients with defective IgG production was performed significantly earlier after BMT compared with patients with normal IgG production ex vivo (2 +/- 1 years vs 3.3 +/- 1.5 years; P < 0.05). In addition, only patients with a B cell deficiency received immunosuppression. However, patients ex vivo IgG produced by B cells was decreased, but IgG production/sIgG+ B cells was within range of healthy volunteers. The number of IgG-committed B cells in these patients was significantly reduced compared to patients without deficiency (23/19-45/microliter vs 100/14-336/microliter; P < 0.05), indicating an in vivo switching defect. Although IL-10 is known to induce IgG-isotype switching in vitro, production of IL-10 by anti-CD3 activated MNCs obtained from patients with a switching defect did not differ from patients without B cell defects (1699/400-2662 pg/ml vs 724-112-1826 pg/ml). In nine patients IgG production and IgG production/sIgG+ B cells were impaired. The number of sIgG+ B cells was not decreased compared with patients without B cell deficiency (115/18-288/microliter), indicating a defective terminal differentiation of IgG-committed B cells to plasma cells. Although autocrine IL-6 is essential for plasma cell formation of isotype-determined B cells, it was comparable in patients with a terminal deficiency and without deficiency (3838/583-5967 pg/ml vs 2423/1643-6184 pg/ml). However, IL-10 production by anti-CD3 activated MNCs in patients with a terminal B cell defect (426/54-2262 pg/ml, P < 0.05) was significantly lower than in patients without deficiency, indicating a deviant cytokine production by T cells which might in part account for the B cell defect. Defective isotype switching as well as impaired terminal differentiation of B cells were found. Further analysis of factors regulating isotype-switching in vivo as well as cytokine receptor expression or signalling processes of differentiation factors in activated B cells might help to characterize the nature of these B cell deficiencies after BMT.

IgG2 deficiency in primary Sjögren's syndrome and hypergammaglobulinemic purpura.

Total IgG and IgG subclasses were studied in 34 patients with primary Sjögren's syndrome and 4 with hypergammaglobulinemic purpura. Total IgG was elevated in 30/34 patients with Sjögren's syndrome. IgG1 increase was responsible for the main part of total IgG increase, contrasting with low levels of IgG2. The difference in IgG1/IgG2 ratio between 38 patients as a group and 40 normal controls was statistically highly significant, but was not seen in all patients. Six patients had markedly low levels of IgG2, but only two had severe repeated respiratory infections. These observations probably reflect selective autoantibody restriction to the IgG1 subclass. We conclude that patients with Sjögren's syndrome may be IgG2 subclass deficient despite elevated levels of total IgG, but also that such deficiency in most instances does not cause a tendency to infections. IgG subclass analysis may be of value to characterize polyclonal IgG increase, since IgG1 subclass predominance often indicates autoimmune disease.

Transfer by BMT of IgG2 deficiency involving an immunoglobulin heavy chain constant region deletion and a silent IgG2 gene.

A patient suffering from ALL who underwent allogeneic BMT developed complete IgG2 deficiency after BMT. When the donor Ig serum levels were examined, it was found that he also lacked detectable levels of IgG2. The IGHC genes were investigated and a heterozygous 50-70 kb deletion encompassing the genes coding for IgG2 (G2) and IgG4 (G4) (del G2-G4) was found in the white blood cells. The patient had IgG2 levels in the low normal range before BMT. When the patient's fibroblasts were examined to determine his original genotype, they were found to carry the same deletion haplotype, but in combination with a different G2 allele than that present in the transplanted BM cells. The combination of Ig heavy chain constant region gene alleles found in the transplant has also been inherited by a third brother also lacking IgG2. The hemizygous G2 allele present in the donated BM cells was thus 'silent' and the complete IgG2 deficiency had been transferred by the BMT.

[Immunodiagnosis of retinoblastoma]. / Ob immunodiagnostike retinoblastomy.

To improve the accuracy of early diagnosis of retinoblastoma, the authors have examined a number of cellular and humoral immunity parameters in 188 children with retinoblastomas, in 57 ones with nontumorous conditions of the eyes, and in healthy controls. Stages III-IV retinoblastoma was found associated with reduced blood levels of IgG and IgA and a still more marked reduction of both in the lacrimal fluid (4-fold), with reduced blood T lymphocyte count (by 1.5 times), decreased lymphocyte blastogenesis response to phytohemagglutinin (by 8-9 times), reduced leukocyte migration activity (MI = 79 +/- 10%), reduced serum thymic activity (by 2.5 times). The early (I-II) stage of the disease involves a lowering of only lacrimal fluid IgA (2-fold) and of the leukocyte migration index (MI) (89 +/- 2%). This index was found to be an important specific indicator for the early preoperative diagnosis of retinoblastoma. Leukocyte migration inhibition (MI less than 95%) by retinoblastoma antigens was observed only if this tumor was present. In cases with the nontumorous conditions and in health retinoblastoma antigens as a rule stimulated the leukocyte migration (MI over 95%).