Solid organ transplantation: hypogammaglobulinaemia and infectious complications after solid organ transplantation

Hypogammaglobulinaemia (HGG), defined as a serum immunoglobulin G (IgG) level < 700 mg/dl, is a known complication of solid organ transplantation (SOT), with a high prevalence reported following heart, lung and kidney transplantation 1,2. HGG is associated with an increased risk of infection, which depends upon the degree of HGG, the type of allograft and the intensity of immunosuppression 1,2. Although all agents used for maintenance immunosuppression have a direct effect on T cell function and an indirect effect on B cell function and lymphokine production, some immunosuppressive agents (e.g. mycophenolate mofetil) have a more potent inhibitor effect on B lymphocyte proliferation and antibody production and may result in more pronounced HGG 1,3. HGG can occur following induction therapy, maintenance immunosuppressive regimens or treatment of rejection episodes 1. Monitoring serum IgG levels before and after SOT has been proposed as a tool to predict clinical outcomes; however, the conclusions of the published studies have been limited by the relatively small sample size. Therefore, our group from the University of Nebraska carried out a meta-analysis to evaluate the prevalence of HGG after SOT and its impact on the rate of opportunistic infections during the first year post-transplantation 1. This meta-analysis included 18 studies (1756 patients), with a mean age of 42 years [95% confidence interval (CI) = 30·9–53·1; Q-statistic = 8249·87; 15 studies, 1232 patients], 43% of whom were female (95% CI = 0·35–0·50; Q = 93·04; 14 studies, 1140 patients) 1. HGG (serum IgG < 700 mg/dl) was found to be highly prevalent, occurring in 45% of transplant recipients in the first year post-transplantation (95% CI = 0·34–0·55; Q = 329·63; P < 0·0001; 16 studies, 1482 patients), while severe HGG (defined as serum IgG < 400 mg/dl) was less common, occurring in only 15% of transplant recipients (95% CI = 0·08–0·22; Q statistic = 210·09, P < 0·0001; eight studies, 669 patients) 1. The heterogeneity of the studies included in the meta-analysis was high, most likely due to inherent differences in individual studies, such as the inclusion of both paediatric and adult studies, variation in study design and the inclusion of different allografts. Subset analysis showed a much higher rate of HGG in heart (49%), lung (63%) and kidney (40%) transplant recipients compared with liver transplant recipients (16%) 1.

No studies evaluating HGG after intestinal transplantation were included in the meta-analysis, and there are limited data available. A recent publication from Farmer et al. indicates that the rate of HGG may be high in these patients (59%) 4. This study retrospectively evaluated 34 intestinal transplant recipients, with a mean age of 12·4 years (standard deviation 17·2), 76% of whom were paediatric patients and 62% were male 4. Serum IgG levels were measured at the time of evaluation, at the time of transplantation and at weekly intervals for 2 months post-transplant 4. Serum IgG fell quickly in the first week after transplantation, most probably as a result of hypercatabolic state and protein-losing enteropathy 4. Following the first week, serum IgG levels did improve, but did not recover to pre-transplantation levels 4.

In our meta-analysis, we observed a 2·46-fold increased risk of overall infections in patients with severe HGG, compared with patients with serum IgG > 400 mg/dl (95% CI = 1·22–4·93; P = 0·01, two studies, 267 patients) and a 3·73-fold increased risk when compared with patients with normal levels of serum IgG (95% CI = 1·11–12·49; P = 0·03, two studies, 267 patients) 1. Studies in patients with primary immunodeficiency have demonstrated that respiratory infections are the most common infections in HGG patients. In SOT recipients, the odds of developing respiratory infections for patients with severe HGG were 4·83-fold higher than for recipients with serum IgG > 400 mg/dl (95% CI = 1·66–14·05; P = 0·004, two studies, 257 patients) 1. Cytomegalovirus (CMV) infections are the most common viral infections in the first year after transplantation. The rate of CMV infection in SOT with HGG was also evaluated in the meta-analysis 1. Recipients with severe HGG had a 2·4-fold increased risk of CMV infections compared with patients with serum IgG > 400 mg/dl (95% CI = 1·16–4·97; P = 0·02; four studies, 435 patients) and a 2·2-fold increased risk compared with patients with normal levels of serum IgG (95% CI = 0·96–4·91; P = 0·06, three studies, 378 patients) 1. Invasive aspergillosis is associated with severe morbidity and mortality, making it a priority for diagnosis and prevention. The subset analysis revealed 8·19-fold higher rates of Aspergillus infections in recipients with severe HGG when compared with patients with serum IgG > 400 mg/dl (95% CI = 2·38–28·1; P = 0·0009; two studies, 124 patients) 1. After we excluded patients with Aspergillus infections the results remained consistent; severe HGG patients were more likely to develop other invasive fungal infections than patients with serum IgG > 400 mg/dl (3·69-fold increased risk; 95% CI = 1·11–12·33; P = 0·03; two studies, 124 patients) 1.

Surprisingly, we found no impact of HGG on the rate of transplant rejection; we did observe a significant impact of HGG on 1-year all-cause mortality 1. Patients who developed HGG (IgG levels < 700 mg/dl) had a 2·71-fold increased risk of 1-year mortality than the group with normal IgG levels (95% CI = 1·05–6·99; P = 0·04; two studies, 179 patients), while the risk of death at 1 year was 21·91-fold higher for severe HGG patients than for patients with serum IgG > 400 mg/dl (95% CI = 2·49–192·55; P = 0·005; two studies, 124 patients).

It is important to consider whether treatment of HGG with intravenous immunoglobulins (IVIg) has an impact on the rate of infections, rejections and survival, as well as raising serum IgG levels. In order to evaluate this we identified five studies which included both a treatment arm [IVIg or CMV hyperimmunoglobulin (CMV-Ig)] and a control arm (in which the patients received placebo or no drug) 5–9. There was a wide variation between the studies, particularly in the cut-off of HGG definitions used (from <350 to <600 mg/dl) and the target IgG levels to be reached (from >350 to >700 mg/dl) (Table 1). Most of the studies included only heart transplant recipients 5,6,8,9, and one study 7 included heart–lung and lung transplant recipients, making it difficult to know how much of the data from these studies could be extrapolated to other allografts. Furthermore, in some of the studies 5,6 treatment arms included patients with more infections or more severe infections than the control arms, making results difficult to be interpreted. One of the studies included patients with HGG prior to transplant in the treatment arm 7 and patients with no HGG in the control arm 9. Three studies 5–7 administered IVIg and two studies 8,9 CMV-Ig as pre-emptive therapy.

Table 1.

Summary of key characteristics of studies investigating treatment of hypogammaglobulinaemia (HGG) with immunoglobulins versus comparator

Study	Design	Allograft	Cut-off HGG for the study	Goal IgG level to be reached	Patients with infections in the treatment arm	Patients with infections in the control arm	Type of immunoglobulin administered
Carbone, 2007 5	Retrospective	Heart	<600	>700	+*	+/–	IVIg
Carbone, 2012 6	Retrospective	Heart	<600	>750	+*	−	IVIg
Yamani, 2001 8	Prospective – historical control	Heart	<350	>350	+/–	+/–	CMV-Ig (pre-emptive)
Yamani, 2005 9	Prospective	Heart	350–500	>500	+/–	+/–	CMV-Ig (pre-emptive)
Nathan, 2005 7	Retrospective	Lung, heart/lung	n.a.	n.a.	+/–†	+/–	IVIg

^*Treatment arm included patients with severe infections, control arm included patients with no severe infections; ^†treatment arm included patients with bronchiectasis and hypogammaglobulinaemia (HGG) prior to transplantation; control arm included patients with bronchiectasis but no HGG. CMV = cytomegalovirus; HGG = hypogammaglobulinaemia; Ig = immunoglobulin; IVIg = intravenous immunoglobulin; CMV-Ig = CMV hyperimmunoglobulin; n.a. = not available.

Administration of immunoglobulins reduced the overall rate of infections 5–9, suggesting that IVIg administration might be associated with some reconstitution of the immune system. Additionally, when looking specifically at CMV infection, recipients who received immunoglobulins displayed a lower rate of infection 5,8,9. Two studies published by Carbone et al. found no impact of IVIg administration on rejection rate 5,6. However, the studies published by Yamani demonstrated a significant reduction in the occurrence of grade 2 and 3 rejection 8,9, and these results were supported by the results from Nathan et al. 7. Although three of the studies reported on mortality 5–7, the event rates in these studies were very low, making it difficult to draw valid conclusions. Nonetheless, as the main cause of mortality in SOT patients is infection, it can be expected that if the rate of infection is reduced, then mortality rates should also decrease.

Although studies to date have focused on IVIg replacement therapy, there are emerging data regarding subcutaneous immunoglobulin (SCIg). One recent study, a retrospective analysis of 10 lung transplant recipients with severe HGG, compared treatment with SCIg (six patients) with treatment with SCIg following a loading dose with IVIg (four patients) 10. IgG levels were increased in all 10 patients at 3 months, and this level was sustained at 6–12 months after SCIg administration. In addition, the majority of patients (70%) tolerated SCIg therapy without complications; the remainder of the patients experienced infusion site reactions which resolved within 24 h 10. These results indicate that SCIg may be a viable alternative to IVIg treatment for HGG.

A survey to assess practice variation in intestinal transplant programmes registered with the Intestinal Transplant Association found that 26·9% of the programmes surveyed perform screening for HGG during the first year following transplantation, including routine screening and screening in patients with severe infection 11. Once diagnosis has been made, IVIg is pre-emptively administered for mild HGG in only 7·7% of these programmes, while 53·9% will treat patients with severe HGG 11.

In conclusion, HGG is highly prevalent, and severe HGG is associated with a significantly increased risk of infection. It remains unclear whether there is a causal relationship between HGG and infections, or if HGG is just a marker of severe immunosuppression. HGG, and especially severe HGG, have a negative impact on mortality, but not on rejection rates. Treatment with immunoglobulins can reduce the incidence of infection; more studies are required to assess the impact of immunoglobulin treatment on mortality.

Disclosure

D. F. was a consultant for CSL Behring, received research grant from CSL Behring, Chimerix Inc., Viropharma and Cubist.