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Hemolysis occurred in patients receiving immunoglobulin at replacement dosages. Polyvalent immunoglobulin preparations contained multiple clinically significant antibodies that could have unexpected hemolytic consequences, as anti-C whose research and titration are not required by the European Pharmacopoeia. The issue of hemolysis in long-term recipients of immunoglobulin treatment administered at replacement dosages should be more widely recognized.

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.

Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.

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