Change in referral diagnoses and diagnostic delay in hypogammaglobulinaemic patients during 28 years in a single referral centre.

BACKGROUND: The classical clinical manifestation of untreated immunoglobulin deficiency comprises predominantly recurrent and complicated respiratory tract infections. Before the 1980s, little was known about the clinical manifestation of immunodeficiency in the general medical population, and also the availability of serum immunoglobulin laboratory determination was not sufficient, leading to a significant diagnostic delay. METHODS: We have analysed the diagnostic delay and referral diagnoses in patients in whom any form of primary hypogammaglobulinaemia had been diagnosed at our department, which was established in 1981. RESULTS: Comparing the diagnostic delay in the 1980s (19 patients, median 5.5 years), the 1990s (37 patients, median 3.5 years) and the years 2001-2008 (33 patients, median 1 year), a significant decrease was observed (p < 0.05, Spearman's correlation coefficient). Also, the median number of pneumonia episodes during the diagnostic delay decreased from 5 in the 1980s, to 1 in the 1990s and to 0 in the period of 2001-2008 (p < 0.05, Spearman's correlation coefficient). While in the 1980s 17 of the 19 patients had pneumonia in their past history, in the period of 2001-2008 only 13 of the 33 patients were concerned. CONCLUSIONS: Our observation documents improved awareness of immunodeficiencies among physicians. It is supposed that earlier diagnosis will prevent complications, improve the quality of life and even survival of hypogammaglobulinaemic patients.

Interleukin-6 May Contribute to Mortality in Parkinson's Disease Patients: A 4-Year Prospective Study.

Objectives. The association between abnormal serum immunomarkers and mortality in 53 consecutive Parkinson's disease patients was studied. Materials and Methods. The plasma level of specific inflammatory cytokines was investigated: mannan-binding lectin (MBL), interleukin- (IL-) 6, and tumor necrosis factor-alpha (TNF-α). The baseline serum immunomarkers obtained from patients who died (n = 16) during a four-year follow-up period were compared with the data of patients who survived (n = 37). Results. The baseline level of IL-6 was significantly higher in the deceased patients than in the survivors. Elevated IL-6 levels and age were major independent contributors to disease mortality. Differences between other plasma cytokine level abnormalities were not significant. Conclusion. This study showed that IL-6 elevation may be a marker of increased mortality risk in Parkinson's disease patients. The inflammation may act in association with other factors and comorbidities in progressive neurodegenerative pathology.

Anti-Gal IgM, IgA and IgG natural antibodies in childhood.

The target for the most abundant xenoreactive natural antibodies in humans is the α-Gal epitope. Anti-Gal could provide natural immune defense against pathogens that express the α-Gal epitope. Anti-Gal natural antibodies are usually studied in adult individuals. Data demonstrating the incidence and concentration of anti-Gal natural antibodies in childhood are in short supply and incomplete. In the present study we prospectively quantified anti-Gal IgM, IgA and IgG levels in different age groups of children from delivery to 24 months of age and compared these levels to the level of these antibodies in their respective mothers. Measurement of anti-Gal antibodies may broaden the spectrum of specific antibodies that are available for determination of specific antibody responses in physiological and pathological conditions in children. Plasma was collected from umbilical cord blood of full term newborn, from blood of infants at age 6, 12 and 24 months and from their respective mothers at time of delivery. Quantitative determination of anti-Gal antibodies IgM, IgA and IgG were made with the enzyme immunoassays Human Anti-Alpha Galactosyl IgM ELISA, IgG ELISA and IgA ELISA. Hemagglutination activity was titrated against rabbit erythrocytes. The kinetic processes for the formation of natural antibodies in the first two years of life, in general, compared with the kinetics for the formation of total immunoglobulins IgM, IgA and IgG. There were no detectable anti-Gal IgM and IgA in the cord blood, whereas anti-Gal IgG were found at similar levels in both neonate cord blood and peripheral blood of their respective mothers. When comparing the percentage of natural antibodies in the plasma of children, the level of natural antibodies in children at the age of two years was approximately 37% for IgM, 25% for IgG and 15% for IgA. The titration of antibodies required for agglutination of rabbit red blood cells over the 24 month period followed the same trend observed for the formation of natural antibodies. Our study demonstrates the kinetics of formation of anti-Gal IgM, IgA and IgG natural antibodies in the first two years of life. The relative lack of these antibodies in this period should be taken into account when assessing for humoral immunodeficiencies, particularly with regards to the potential for children to mount an anti-carbohydrate response.

Antibody forming cells and plasmablasts in peripheral blood in CVID patients after vaccination.

Common variable immunodeficiency (CVID), the most frequent primary antibody disorder, is characterized by hypogammaglobulinaemia and impaired antibody production. Poor vaccination response is essential for the diagnosis of CVID. Their under laying defects remain to be elucidated. Routine determination of antibody production in serum from CVID patients after vaccination and investigation of B cell function in vivo is complicated due to substitution therapy. Therefore we investigated antibody production on the B-cell level by ELISPOT and characterized changes in B-cell subpopulations in CVID patients, including plasmablasts, in peripheral blood by flow cytometry after vaccination for specification of the diagnosis. Thirty-seven CVID patients and eighty healthy volunteers were immunized with tetanus toxoid and pneumococcal polysaccharide vaccines. Specific antibody levels and B cell subpopulations were measured before vaccination and on day 7 after vaccination by ELISPOT assay and flow cytometry respectively. Of the thirty-seven well defined CVID patients studied, thirty lacked detectable spot forming cells producing specific IgG, IgA or IgM antibodies against employed vaccines and seven had only weak responses compared to controls. In the control group, an increase in circulating plasmablasts on day 7 post immunization corresponded with the appearance of antibody forming cells. In contrast, CVID patients failed to increase plasmablasts significantly in peripheral blood after antigen challenge. Our findings indicate that CVID patients have a block in terminal B-cell differentiation and that flow based assessment of plasmablasts in peripheral blood after vaccination serves as a surrogate diagnostic marker for assessing in vivo antibody responses in patients suspected to have CVID.