The prognosis and treatment of chronic lymphocytic leukemia (CLL) have improved significantly over the last years; however, CLL is still an incurable disease and infections are the major cause of morbidity and mortality, contributing to 25-50% of deaths. 1 Susceptibility to infections in CLL patients can be related to immunological defects associated with the disease (including hypogammaglobulinemia, T-cell, natural killercell and innate immunity dysfunctions) 2 and secondary to chemo-immunotherapy. Hypogammaglobulinemia and T-cell defects are quite common in these patients and become more pronounced with advanced-stage disease. 2 Interestingly, it has been described that even patients with monoclonal B-cell lymphocytosis have a higher risk of serious infection than do the general population. 3 Strategies to prevent bacterial infections in patients with symptomatic hypogammaglobulinemia include prophylactic antibiotics or immunoglobulin replacement therapy (IgRT). Although passive immunotherapy with immunoglobulins (Ig) can lower the risk of minor and major bacterial infections, several data suggest that IgRT does not result in a decrease of mortality, 4 and there are currently no clear indications for this treatment. As a consequence, IgRT is started in subjects with hypogammaglobulinemia complaining of serious or recurrent bacterial infections. 5, 6

The aim of this study was to identify the clinical and biochemical characteristics of subjects at higher risk of developing major infections; in particular, we focused on the role of hypogammaglobulinemia and the impact of IgRT. We retrospectively reviewed data from 706 patients with CLL referred to our Unit from 1983 to 2013. Major infections were defined as infective events that required inpatient management or intravenous antibiotics. Major infections associated with a concomitant neutropenia (white cell count< 1.0 x109/L) were excluded. Furthermore, the exclusion of non-serious events from our analysis lowered the risk of including other biases. We collected the closest clinical data preceding the onset of each major infection (mean time between measurement of Ig levels and major infections 2.5±1.3 months); Ig levels measured during major infections were not included in the analysis, because they could have been influenced by the infection. For patients who did not suffer any major infections, we considered the last available Ig level. Detailed information on prognostic markers, IgRT strategies and statistical methods are reported in the