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Results WP1: The Natural Course and Phenotype of PAD

The objective for Workpackage 1 was to better describe the natural phenotype of primary antibody deficiencies. To this end, we used the existing database of the European Society for Primary Immune Deficiencies (ESID), which has been developed with help of the European Framework 6 Program and commercial funding during the years 2004 to 2006, and local pre-existing national registries such as the Italian IPInet registry. During the funding period of EURO-PADnet, we increased the total number of PAD patients in the ESID Registry from 3,369 in May 2008 to 5,554 in August 2009 by 2,185 patients. This has further increased to 7,466 patients as of April 2011. The total increase over the three-year period hence was 4,099 patients, or 122%. We aimed at better describing the T and B cell phenotype in antibody deficiencies, to identify pathogenic and clinically relevant patterns of dysregulation, and to improve current classification schemes based on a large European cohort of patients with PAD. Data of 411 patients have been collected from 6 centres and are currently evaluated for the association of changes in T and B cell phenotype with the clinical manifestation of splenomegaly, lymphadenopathy, autoimmune disease, granulomatous disease, opportunistic infection, conventional infection of the respiratory and gastrointestinal tract, bronchiectasis and interstitial lung disease. Statistical evaluation is under way. Data is posted on www.ipidnet.org. As an example shall serve the following published study: We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinemia. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+) CD45RO(+) and CD4(+) CD45RO(+) CXCR5(+) cells. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the obesrved paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans.

EURO-PADnet researchers also accompanied a prospective clinical study on the natural course of antibody deficiencies over a cumulative follow-up period of 1,365 patient-years. This study was carried out by centres in Italy. It revealed that for X-linked agammaglobulinemia, the only co-morbidity risk factor for pneumonia was the presence of bronchiectasis. In common variable immunodeficiency (CVID), the data allowed us to identify a clinical phenotype characterised by a high pneumonia risk: patients with low IgG and IgA levels at diagnosis; patients who had IgA level <7 mg/dL and who had bronchiectasis. Patients with pneumonia did not have significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400 mg/dL. Based on a cohort of paediatric (n=232) and adult (n=73) patients (mean age 36.5, SD 17.7, range 1.6 to 79.3 years) with CVID who underwent chest CT, the overall prevalence of structural bronchial pathology was 72%, with bronchiectasis present in 63%. Parenchymal pathology, such as lines, bands and nodules, was detected in 76%. A pathological lung function as indicated by a forced expiratory volume in 1 second (FEV1) of <80% predicted was present in 39.5% of the patients who underwent lung function analysis (n=185). Importantly, 55% of the patients with a normal lung function had bronchiectasis. Air trapping was evident in up to 30%.

The consortium established an international, multidisciplinary expert group, the "Chest CT in ADS Group", with 26 immunologists, 13 radiologists and 7 pulmonologists from 20 academic centres from 9 countries, www.chest-ct-group.eu. The Chest CT in ADS Group plans to hold a European meeting consensus conference on the use of chest CT scans in primary antibody deficiencies by January, 2012. To link the data in the clinical databases, our centres collected biological samples of the documented patients for research. The centre in Brescia has collected 150 PID patients, 150 sIgA patients and 15 PID families; the Karolinska Institute has collected 250 CVID samples, 1200 sIgAD samples and 100 samples with other PIDs; INSERM in Paris has collected 98 samples with class switch recombination defects. Rome has collected approximately 1,450 samples, Freiburg about 660; and London more than 864 samples. These sample collections provided a huge resource for future projects and collaborations and put each of the centres into a unique position. This collection of samples is unprecedented in the world.