There are few defects in the immunologic function of a transplant recipient that can be ameliorated without running the risk of causing rejection. Posttransplant hypogammaglobulinemia is one such condition. Over the past several decades, diverse centers throughout the world have noted that hypogammaglobulinemia in solid organ transplant recipients is more common than is generally recognized, and appears to be a risk factor for more frequent and severe posttransplant infections [1, 2]. Yet this potentially remediable condition remains under-recognized, and many transplant centers do not incorporate routine monitoring of IgG levels even when administering immunosuppressive therapies that affect B cell function. Although intravenous immunoglobulin (IVIg) preparations are often used in treatment of sensitized patients before and around the time of transplantation, and may be used to replete immunoglobulins after plasmapheresis and/or during treatment of antibody-mediated rejection, there is considerably more to be learned about the link between immunoglobulin levels and infection. The potential for immunoglobulin repletion as a means of infection prevention has yet to be fully explored.
In this issue, Florescu et al  present a meta-analysis of studies that have examined the impact of hypogammaglobulinemia on infections and survival in posttransplant recipients. This group, which has performed previous meta-analyses of other topics of importance in transplant infectious disease, is to be commended for addressing this topic. Their study reaches several notable conclusions. First, posttransplant hypogammaglobulinemia is indeed common, with mild hypogammaglobulinemia (IgG 400–700 mg/dL) occurring in 39% and severe hypogammaglobulinemia (IgG < 400 mg/dL) in 15% of transplant recipients in these studies. This latter category (<400 mg/dL) represents the highest risk, in pooled studies, for a variety of infections. It is not merely bacterial infections such as pneumonias and bacteremias, as might be expected from the involvement of the humoral immune system. In some studies, low IgG levels were also associated with higher risk of invasive fungal infections and with symptomatic CMV disease. In addition, in this meta-analysis, the all-cause mortality in the lowest IgG group was markedly higher than that in the other groups. It is not clear that this excess mortality is directly attributable to infection, however. For example, in the study of liver transplant recipients by Doron et al , hypogammaglobulinemia was associated with increased mortality at both 1 and 5 years, despite the finding that the infectious outcomes were not significantly different in the groups with and without hypogammaglobulinemia.
The difficulties in performing and interpreting the current analysis stem from the wide spectrum of studies in the literature, many of which are single-center, small to moderate in size and often focused on one type of organ transplant. These studies span over three decades and consequently reflect multiple disparate eras, protocols and immunosuppressive regimens. Not all studies examined the same types of infection outcomes, so for each infection that Florescu et al examined, there were sometimes few studies that had evaluable parameters for that particular infection. Moreover, the studies that have addressed the potential benefits of interventions such as immunoglobulin replacement are far fewer than those that describe hypogammaglobulinemia as a risk factor. Consequently, it is not clear whether repletion of the deficient immunoglobulins will improve outcomes, or if hypogammaglobulinemia is a key deficiency or simply a marker for other unidentified factors that increase the risk of infection. Nevertheless, the consistency of this finding over so many years and in unrelated groups of recipients may lend even greater support to this observation.
It is striking how consistently these studies have found that both mild and severe hypogammaglobulinemia are common, and that severe hypogammaglobulinemia appears to be associated with a variety of different infections in most studies, as well as all-cause mortality. While this meta-analysis cannot rule out the possibility that other aspects of immune function and/or comorbidities could have accounted for these outcomes, it still appears that the presence of low IgG levels identifies a patient population at higher risk.
Perhaps the most meaningful contribution of this meta-analysis is to draw attention to this potentially important and remediable risk factor that is worthy of further study, particularly in the era of newer immunosuppressive agents that have profound effects on B cell function. Larger prospective multicenter studies, incorporating periodic monitoring of immunoglobulin levels, should be considered to examine the association of hypogammaglobulinemia with particular immunosuppressive therapies, and with other aspects of immune function. This might help to discern the correlates of hypogammaglobulinemia and whether it is in fact an independent risk factor for infection and mortality that might be remediable with immunoglobulin repletion. Moreover, prospective trials could establish the optimal frequency of IgG level monitoring, something that is unknown. It may be more difficult to assess the impact of intervention with immunoglobulin replacement, as centers that are already convinced of the efficacy of immunoglobulin replacement may be reluctant to randomize patients in the lowest IgG group to receive or not receive IVIg, but there is room in this field for innovative study designs. It is hoped that this effort by Florescu et al will stimulate such studies and provide further insight into strategies for protecting our most fragile and vulnerable patients.