Anna Maria Pesce

LONG-TERM FOLLOW-UP AND OUTCOME OF A LARGE COHORT OF PATIENTS WITH COMMON VARIABLE IMMUNODEFICIENCY

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

Health Related Quality of Life in Common Variable Immunodeficiency

Purpose To quantify the health related quality of life in primary immunodeficiency patients. Materials and Methods We used generic health status and general psychological health questionnaires to determine the range of issues that needed to be considered in examining the burden of common variable immunodeficiency (CVID). Results The health status of patients with CVID was lower than that observed in normal subjects. Overall, Role-Physical and General Health scales correlated with a poorer clinical status. Surprisingly, the duration of disease did not influence health status. Being female, older, General Health Questionnaire-positive and alexithymic proved to be major risk factors associated with a poor health status. Patients with chronic lung disease and chronic diarrhea had the lowest values on the Medical Outcome Study, Short Form SF-36 (SF-36) scales. Disease severity perception was associated with the General Health Questionnaire and alexithymia status. Limitations in daily activities as a result of lower physical health were the major problems facing common variable immunodeficiency patients. Conclusion Our data underlined the importance of conducting a periodical health related quality of life assessment on patients with primary antibody deficiencies and, moreover, stressed the necessity of providing psychological support to at risk patients.

Quantification of IgM and IgA Anti-Pneumococcal Capsular Polysaccharides by a New ELISA Assay: a Valuable Diagnostic and Prognostic Tool for Common Variable Immunodeficiency

PurposeExisting ways of assessing CVID patients at risk of pulmonary infections are not universally accepted. The need to identify additional prognostic factors allowed us to evaluate the anti-polysaccharide IgA and IgM responses in 125 CVID patients immunized with the 23-valent pneumococcal polysaccharide (PS) vaccine (Pneumovax®).MethodsWe used a new anti-PS23 IgM and IgA ELISA assay, which evaluates a global response to all 23 polysaccharides contained in Pneumovax®.ResultsAnti-PS23 IgM and/or IgA antibodies were detectable in a minority of CVID patients. Antibody responses were correlated to B cell subpopulations and serum immunoglobulin concentrations. The non responders had a higher incidence of pneumonia and bronchiectasis and responders had the lowest incidence of respiratory complications.ConclusionsThis new ELISA assay allows for studying vaccine response in patients on Ig replacement therapy. This test also is an additional method of evaluation of specific antibody responses representing a valuable contribution to identify prognostic marker in CVID patients.

Hemolysis in patients with antibody deficiencies on immunoglobulin replacement treatment

Immunoglobulin (Ig)G replacement with intravenous or subcutaneous immunoglobulins is a lifelong substitutive therapy in patients with primary antibody deficiencies (PADs). Hemolysis after immunoglobulin therapy was described in patients receiving high immunoglobulin dosages. The issue of hemolysis after immunoglobulin administration at replacement doses has been considered of little clinical significance.

Lung Magnetic Resonance Imaging with Diffusion Weighted Imaging Provides Regional Structural as well as Functional Information Without Radiation Exposure in Primary Antibody Deficiencies

PurposePrimary antibody deficiency patients suffer from infectious and non-infectious pulmonary complications leading over time to chronic lung disease. The complexity of this pulmonary involvement poses significant challenge in differential diagnosis in patients with long life disease and increased radio sensitivity. We planned to verify the utility of chest Magnetic Resolution Imaging with Diffusion-Weighted Imaging as a radiation free technique.MethodsProspective evaluation of 18 patients with Common Variable Immunodeficiency and X-linked Agammaglobulinemia. On the same day, patients underwent Magnetic Resonance Imaging with Diffusion Weighted Imaging sequences, High Resolution Computerized Tomography and Pulmonary Function Tests, including diffusing capacity factor for carbon monoxide. Images were scored using a modified version of the Bhalla scoring system.ResultsMagnetic Resonance Imaging was non-inferior to High Resolution Computerized Tomography in the capacity to identify bronchial and parenchymal abnormalities. HRCT had a higher capacity to identify peripheral airways abnormalities, defined as an involvement of bronchial generation up to the fifth and distal (scores 2–3). Bronchial scores negatively related to pulmonary function tests. One third of consolidations and nodules had Diffusion Weighted Imaging restrictions associated with systemic granulomatous disease and systemic lymphadenopathy. Lung Magnetic Resolution Imaging detected an improvement of bronchial and parenchymal abnormalities, in recently diagnosed patients soon after starting Ig replacement.ConclusionsMagnetic Resonance Imaging with Diffusion Weighted Imaging was a reliable technique to detect lung alterations in patients with Primary Antibody Deficiencies.

T-cell immune activation in children with vertically transmitted hepatitis C virus infection

Little is known concerning the clinical features, the histological outcome, and the effects on the maturation of immune system of children with vertically-transmitted hepatitis C virus (HCV) infection. Specifically, no data are available on the peripheral distribution of T-cell subsets. The frequency of naive and memory cells, activated T cells, and cytokine-producing T cells was analyzed in nine HCV-infected children born to HCV-positive mothers. In HCV-infected children, the distribution of naive and memory cells was not significantly altered in the CD4 subset whereas within the CD8 subset, an increase of memory and a decrease of naive cells was observed. The frequency of HLA-DR-positive and Fas-positive T cells was increased in HCV-infected children in both CD4 and CD8 subsets. The distribution of Fas-expressing T cells was directly related to that of HLA-DR cells and inversely related to the frequency of naive T cells. In regard with cytokine production we found increased levels of both CD4 and CD8 interferon-gamma (IFN-gamma)-producing cells whereas no difference in the percentage of interleukin-2 (IL-2)-producing T cells was observed. No meaningful correlation was observed between individual T cell subsets and ALT levels or HCV viral load. In conclusion, our results indicate an increased T-cell activation and a shift to a T(H)1 pattern of cytokine production in children with vertically transmitted HCV infection. The cause of this kind of immune response could reside in the persistent antigenic stimulation by chronic HCV infection.

Clinical use of polyvalent immunoglobulins.

Intravenous immunoglobulins (IVIG) and subcutaneous (SCIG) are used in treatment of a broad spectrum of diseases. Prepared from the collective plasma of several thousand people, therapeutic immunoglobulin consists mostly of human polyspecific IgG1–4. IgG replacement is the standard therapy for primary antibody deficiencies (PAD) aiming to replace the missing antibodies and thereby to prevent recurrent infections. Replacement therapy generally involves the use of 400–600 mg/kg administered every 3 or 4 weeks5–6. Debate continues regarding the exact timing and the optimal prophylaxis regimen, knowing that the system of care is itself an important determinant of patient outcomes7–8. The use of immunoglobulins as an immunomodulating therapy ranges from transplantation and treatment of autoimmune-haematological diseases to treatment of various neuroimmunological clinical entities9–10. Immunomodulating generally involves the use of 2 g/kg administered over either 2 or 5 consecutive days. US FDA approved IVIGs for the treatment of Primary Immune Deficiencies (PID), immune thrombocytopenic purpura, Kawasaki disease, bone marrow transplantation in patients aged over 20 years, chronic B-cell lymphocytic leukaemia, and paediatric AIDS (Table I). Table I FDA approved indications for the therapeutical usage of polyvalent human immunoglobulins. Similarly, in Italy, the indications for IVIGs treatment include Primary Immune Deficiencies, immune thrombocytopenic purpura, Kawasaki disease, bone marrow transplantation in patients aged over 20 years, chronic B-cell lymphocytic leukaemia and myeloma, paediatric AIDS and Guillain-Barre syndrome, and a new recently introduced indication (Table II). Table II Italian approved indications for the therapeutical usage of polyvalent human immunoglobulins. In addition to its use in primary and secondary immune deficiencies, many other clinical conditions might benefit from IVIGs therapy, all requiring documentation of contraindications to or a lack of response to conventional therapies according to US FDA (Table III). Some of these other conditions are extremely rare, making randomised controlled investigations difficult. Randomised clinical trials are warranted to support the evidence-based use of IVIg, and to identify the ideal administration protocols to maximise the benefits of what is a limited resource, knowing that many health care delivery systems are subjected to economic pressures and that individualised medicine and personalised health research presents methodological challenges11. Table III Clinical conditions that might benefit from immunoglobulin treatment according to Food and Drugs Administration additional approved indications with criteria. In this review we first discussed the issue of substitution treatment in primary antibody deficiencies, the choice of the immunoglobulin dosages, timing and the impact of therapy in survival. Then we discussed the immunoglobulin anti-inflammatory and immuno-modulating results in the treatment of immune-mediated demyelinating diseases, of rheumatological diseases (vasculitis and autoimmune connective tissue diseases), of haematological diseases (autoimmune cytopenias), of dermatological conditions (pemphigus and pemphigoid) and their usage in transplantation. Intentionally we did not address the issue of the off-label immunoglobulin treatments, despite their frequent usage carried on the basis of single case reports or uncontrolled studies.

AB0933 Endocarditis in Patients Under Immunosuppressive Treatment: Don't Stop Believin'

Background Patients with rheumatic disease under immunosuppressive treatment had an high risk of infection. For this subjects, infective disease could have unusual manifestation or could present as co-infection. Moreover, immunocompromised hosts could have untruthfully negative serological tests. For this reason clinicians have to search infections actively also by nested-PCR or microbial culture. Objectives Here we describe a case of endocarditis due to coinfection by Coxiella burnetii and Borrelia burgdorferi in a patients with Systemic Lupus Erythematosus and persistent fever and relapse of arthritis, not responding to immunosuppressive therapy. This case report emphasizes the importance of excluding an infection as a cause of unusual clinical manifestation in a patient under immunosuppressive treatment. Methods Case report. Data from medical files from a patient regularly followed up at the Immunology division of Umberto I Hospital of Rome were collected. Results A 70-year-old female with Systemic Lupus Erythematosus had fever and chills associated with arthritis, fatigue, lymphadenopathy, skin purple lesions and erythema nodosum. The patient was under therapy with methotrexate, adalimumab and methyl prednisone because of her rheumatic disease. Fever continued despite the increase of steroid therapy and antibiotics therapy. Patient underwent to laboratory tests showed pancytopenia and high erythrocyte sedimentation rate while other inflammatory markers were normal. A skin biopsy showed dermal perivascular inflammatory infiltrate with lymphohistiocytic cells and eosinophilic and neutrophilic granulocytes. An extensive infectious diseases laboratory workup, including sets of blood cultures and serological tests, was performed with a negative outcome. A trans-thoracic echocardiogram was performed and no vegetation was remarkable; a trans-esophageal echocardiogram showed a small posterior leaflet mitral valve vegetation. The patient was tested for the main etiologic agents of culture-negative endocarditis by PCR. Because of positivity of both Coxiella burnetii and Borrelia burgdorferi DNA, Chronic Q fever and Lyme disease were diagnosed. An association of doxycycline and hydroxychloroquine was started. After 10 days the fever disappeared and the patient had a progressive improvement of arthritis and skin lesions. Co-infection between C. burneti e B. burgorferi was rarely reported but pathogenically possible because these pathogens can be transmitted by the same species of arthropods. The negative outcome of serological tests for both B. burgdorferi and C. burnetii could be related to the condition of patients immunosoppression. Conclusions This case report emphasizes the importance of excluding an infection as a cause of unusual arthritis. The use of PCR is mandatory in patients under immunosuppressive therapy since serological response could be missing. Disclosure of Interest None declared