Cinzia Milito

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.

Longitudinal study on health-related quality of life in a cohort of 96 patients with common variable immune deficiencies.

Health-related quality of life (HRQoL) in common variable immunodeficiency diseases (CVID) was evaluated by different tools, which were mainly used to compare different schedules of immunoglobulins administration in cross-sectional or short-term longitudinal studies. We assessed the HRQoL and psychological status of CVID patients in a longitudinal study over a 6-year period by a generic, non-disease-specific instrument (SF-36), and by a General Health Questionnaire (GHQ-12) for the risk of depression/anxiety. At baseline, 96 patients were enrolled. After 1 year, a second assessment was performed on 92 patients and, after 6 years, a third assessment was performed on 66 patients. Eighteen patients died during the study time. HRQoL was low, with mental health scales less affected than physical scales. A decline in the score on SF-36 scales was observed between the first and the third assessment for the Physical Functioning, Body Pain, General Health, Social Functioning, and Role-Emotional scales. The General Health scale showed a lower score in these patients, when compared to patients with other chronic diseases. Approximately one-third of the patients were at risk of anxiety/depression at all observation times, a percentage that reached two thirds of the patients, considering only the group of females. Over the 6 years of the study, the health condition of 11/66 patients worsened, passing from “GHQ-negative” to “GHQ-positive”; their score on SF-36 scales also decreased. A decrement of one point in each of the Physical Functioning, Vitality, Social Functioning, and Mental Health SF-36 scales increased the risk of developing anxiety/depression from three to five percent. A negative variation of the Physical Functioning score increased the risk of psychological distress. In a survival analysis with dichotomized variables, Physical Functioning scores <50 were associated with a relative risk (RR) of 4.4, whereas Social Functioning scores <37.5 were associated with a RR of 10.0. In our study, it was the clinical condition, as opposed to the different treatment strategies with immunoglobulins, which had a major role on the deterioration of HRQoL. Moreover, in a quality-of-life evaluation, disorders such as anxiety/depression should be assessed, as they yet often go unrecognized. Our results might be helpful in the interpretation of currently available data on quality of life 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.

Shift from intravenous or 16% subcutaneous replacement therapy to 20% subcutaneous immunoglobulin in patients with primary antibody deficiencies.

In patients with primary antibody deficiencies, subcutaneous administration of IgG (SCIG) replacement is effective, safe, well-tolerated, and can be self-administered at home. A new SCIG replacement at 20% concentration (Hizentra®) has been developed and has replaced Vivaglobin® (SCIG 16%). An observational prospective multi-centric open-label study, with retrospective comparison was conducted in 15 Italian centers, in order to investigate whether and to what extent switching to Hizentra® would affect frequency of infusions, number of infusion sites, patients’ satisfaction, and tolerability in patients previously treated with Vivaglobin® or intravenous immunoglobulins (IVIG). Any variations of dosage, frequency and duration of the infusions, and of number of infusion sites induced by Hizentra® with respect to the former treatment were recorded. Practical advantages and disadvantages of Hizentra®, with respect to the medicinal product formerly used, and the variations in patients’ therapy-related satisfaction were monitored by means of the TSQM (Treatment Satisfaction Questionnaire for Medication); number, frequency, and duration of infectious events and adverse effects were recorded. Eighty-two patients switched to Hizentra®: 19 (23.2%) from IVIG and 63 (76.8%) from Vivaglobin®. The mean interval between infusions was not affected by the shift (7.0 ± 2.0 days with previous treatment versus 7.1 ± 1.2 during Hizentra®). A decrease in the number of infusion sites with Hizentra® was recorded in 12 out of 56 patients for whom these data were available. At 6 months, 89.7% of patients were satisfied with Hizentra®; no difference in terms of effectiveness, side effects, convenience, and global satisfaction was observed. No difference in the incidence of adverse events was reported.

Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes

We assessed the prevalence of TNFRSF13B mutations and the clinical correlates in an Italian cohort of 189 CVID, 67 IgAD patients, and 330 healthy controls to substantiate the role of TACI genetic testing in diagnostic workup. We found that 11% of CVID and 13% of IgAD carried at least one mutated TNFRSF13B allele. Seven per cent of CVID had monoallelic-mutations and 4% had biallelic-mutations. The frequency of C104R monoallelic-mutations was not higher than that found in healthy controls. Biallelic-mutations were exclusively found in CVID. CVID patients carrying monoallelic-mutations had an increased prevalence of lymphadenopathy, granulomata, and autoimmune cytopenias. CVID carrying biallelic-mutations had a low prevalence of autoimmunity in comparison with TACI wild-type CVID. Moreover, biallelic-mutated CVID had higher frequency of switched memory B-cells and higher IgM and IgA antibodies to polysaccharide antigens than TACI wild-type and monoallelic-mutated CVID. TACI-mutated IgAD patients had only monoallelic-mutations and did not display clinical difference from IgAD wild-type patients. In conclusion, TNFRSF13B genetic screening of antibody deficiencies may allow the identification of mutational patterns. However, as with counseling for risk assessment, geneticists should be aware that the interpretation of genetic testing for TACI mutations is difficult and the potential impact on clinical management is still limited.

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

Vaccination in immunocompromised host: Recommendations of Italian Primary Immunodeficiency Network Centers (IPINET)

Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient.