In the early decades since the introduction in the early '80s of immunoglobulin therapy many studies tried to identify which clinical indications might benefit from the therapy, which treatment’s schedules are effective and safe. It is universally accepted that immunoglobulin therapy is a life-saving treatment in patients with PID. The rise of new indications for further different clinical conditions resulted in a steady increase in demand for immunoglobulins. Currently the consumption of immunoglobulin for PID represents a small fraction of the market. In the recent past we have been observing: 1) An increase in the demand for plasma and in the consequent need to increase the number of donors; 2) Changes in methods to improve IgG recovery and to increase productivity as a response to growing clinical demand; 3) Introduction of immunoglobulin treatments with higher concentration; 4) Changes in the timing of administration with an increase in the rate of infusion; 5) Introduction of immunoglobulin treatment administered subcutaneously mainly confined initially to patients with PID and later extended to other clinical indications which often require higher volumes of infusion. Doctors following patients with PID were initially alarmed only to a possible risk of shortage. More relevant and less discussed appear the possible consequences of: 1) the risk of an improper transfer of information on treatments from a clinical indication to another. In particular, the idea of a mere replacement function in patients with PID might possibly be borrowed from the model of other clinical conditions requiring a replacement such as haemophilia. In PID, immunoglobulin treatment instead is obviously replacing a missing feature. However, other immune alterations are responsible for the large number of PID-associated diseases including inflammatory manifestations and tumors, common causes of morbidity and mortality. The immunomodulatory effects of immunoglobulin administered at replacement dosages on multiple cells and immune system functions are still largely to be checked in in vitro studies and in vivo. 2) the changes in the immunoglobulin production and schedules of administration. These should have been assessed in studies of drug surveillance, necessary in order to evaluate on large numbers of what it is initially reported on patients enrolled in the pivotal clinical trials, usually in the absence of most of the main disease-associated clinical conditions affecting pharmacokinetics, efficacy and tolerability. Severe side effects are now more frequently reported. This requires surveillance studies in order to verify the tolerability. Nowadays, personalized health research presents methodologic challenges, since emphasis is placed on the individual response rather than on the population. Even within a universally accepted indication, such as in PID, the identification of prognostic markers should guide the therapeutic intervention. 3) the risk of a decrease in the surveillance and monitoring of PID-associated clinical conditions. In fact, self- administration of immunoglobulins administered subcutaneously increased the independence of a number of patients. On the other hand, it led to the reduction in the number of contacts between specialized centers and patients who often require a close monitoring of disease-associated conditions. A wide debate between experts is necessary to afford the new challenge on immunoglobulin usage.

Abstract: Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking. Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up. Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS. Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up. Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients

Abstract: Background Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 105 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden). Results Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/105 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/105. With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/105 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p = 0.030, lymphoma: 5.48 (2.36; 12.71) p .0001 and granulomatous-lymphocytic interstitial lung disease: 4.85 (1.63; 14.39) p = 0.005. Diagnostic delay (median: 4 years) was associated with a higher risk of death: 1.04 (1.02; 1.06) p = .0003, bronchiectasis: 1.03 (1.01; 1.04) p = .0001, solid tumor: 1.08 (1.04; 1.11) p .0001 and enteropathy: 1.02 (1.00; 1.05) p = .0447 and stayed unchanged over four decades (p = .228).br

Abstract: Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients