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Keywords:

  • Cytomegalovirus;
  • fungal;
  • hypogammaglobulinemia;
  • infection;
  • respiratory infections

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Hypogammaglobulinemia has been described after solid organ transplantation and has been associated with increased risk of infections. The aim of the study was to evaluate the rate of severe hypogammaglobulinemia and its relationship with the risk of infections during the first year posttransplantation. Eighteen studies (1756 patients) that evaluated hypogammaglobulinemia and posttransplant infections were included. The data were pooled using the DerSimonian and Laird random-effects model. Q statistic method was used to assess statistical heterogeneity. Within the first year posttransplantation, the rate of hypogammaglobulinemia (IgG < 700 mg/dL) was 45% (95% CI: 0.34–0.55; Q = 330.1, p < 0.0001), the rate of mild hypogammaglobulinemia (IgG = 400–700 mg/dL) was 39% (95% CI: 0.22–0.56; Q = 210.09, p < 0.0001) and the rate of severe hypogammaglobulinemia (IgG < 400 mg/dL) was 15% (95% CI: 0.08–0.22; Q = 50.15, p < 0.0001). The rate of hypogammaglobulinemia by allograft type: heart 49% (21%–78%; Q = 131.16, p < 0.0001); kidney 40% (30%–49%; Q = 24.55, p = 0.0002); liver 16% (0.001%–35%; Q = 14.31, p = 0.0002) and lung 63% (53%–74%; Q = 6.85, p = 0.08). The odds of respiratory infection (OR = 4.83; 95% CI: 1.66–14.05; p = 0.004; I2 = 0%), CMV (OR = 2.40; 95% CI: 1.16–4.96; p = 0.02; I2 = 26.66%), Aspergillus (OR = 8.19; 95% CI: 2.38–28.21; p = 0.0009; I2 = 17.02%) and other fungal infections (OR = 3.69; 95% CI: 1.11–12.33; p = 0.03; I2 = 0%) for patients with IgG <400 mg/dL were higher than the odds for patients with IgG >400 mg/dL. The odds for 1-year all-cause mortality for severe hypogammaglobulinemia group was 21.91 times higher than those for IgG >400 mg/dL group (95% CI: 2.49–192.55; p = 0.005; I2 = 0%). Severe hypogammaglobulinemia during the first year posttransplantation significantly increased the risk of CMV, fungal and respiratory infections, and was associated with higher 1-year all-cause mortality.


Abbreviations
CMV

cytomegalovirus

HGG

hypogammaglobulinemia

IgG

immunoglobulin

IVIG

intravenous immunoglobulins

MMF

mycophenolate mofetil

SOT

solid organ transplant

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Hypogammaglobulinemia (HGG), defined as serum immunoglobulin level <700 mg/dL, has been reported as a complication of solid organ transplantation (SOT) [1, 2]. Serum IgG has been reported to decrease after induction, immunosuppressive therapy or treatment of rejection episodes [1, 2]. Several studies have shown high prevalence of HGG after heart, lung and kidney transplantation with an associated increased risk for infections [3-6]. The risk of infection seems to depend on the degree of HGG, the type of allograft and the type and intensity of immunosuppression [1, 7, 8]. Further, HGG may be more pronounced with the use of maintenance immunosuppression with mycophenolate mophetil (MMF), which is known to affect both T cell and B cell lymphocyte function [8]. Monitoring immunoglobulin G (IgG) levels before and after organ transplantation was proposed as a potential tool to predict clinical outcomes [4, 7, 9-11]. A major limitation of previously published studies was the relatively small sample size. The aim of our meta-analysis was to determine the rate of overall HGG and, in particular, of severe HGG (IgG < 400 mg/dL) during the first year posttransplantation and its impact on the rate of opportunistic infections.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Literature search

PubMed (MEDLINE, PREMEDLINE and OLD MEDLINE), the Cochrane Library databases and EMBASE were searched from inception to October 2012. A combination of keyword- and subject heading-based search strategies was used in all databases and included HGG, hypogammaglobulinemia, agammaglobulinemia, immunoglobulin, IgG, IgM, IgA, transplant, organ transplant, organ transplantation, SOT, liver transplant, liver transplantation, lung transplant, lung transplantation, heart transplant, heart transplantation, small bowel transplant, small bowel transplantation, kidney transplant, kidney transplantation, pancreas transplant and pancreas transplantation. No language restrictions were applied. In addition, available abstracts from the American Transplantation Congress and the Infectious Disease Society of America from 2000 to 2012 were searched. Three authors performed the literature search (C.S, D.F. and U.S.). A total of 6182 records were retrieved by the searches—3633 PubMed records, 2477 EMBASE records and 72 Cochrane Library records. A total of 4288 records remained after duplicate records were removed; 419 of these records appeared potentially relevant after a topical review performed by C.S. and D.F. Two authors (D.F. and U.S.) performed the study selection independently. Any disagreement was resolved by review from a third author (A.K.) and a final consensus among all authors. All studies that evaluated HGG and posttransplant infections were included. Studies that did not report the rate of HGG or infection outcomes were excluded. We also excluded interventional studies that administered either intravenous immunoglobulin or cytomegalovirus immunoglobulin on both arms. However, we included interventional studies where the control arm received placebo or no drug, and had extractable data on the rate of HGG and infection outcomes from the control arm. We excluded studies in which immunoglobulins were administered because they might have an impact on the study outcomes (rate of infections, rejection and mortality). The PRISMA criteria were used for the search and flow of studies (Figure 1).

image

Figure 1. Selection of the studies included in the meta-analysis (PRISMA criteria).

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Data extraction

The following variables were collected from all studies: authors, publication year, study design; type of allograft; sample size; sex, age; induction, immunosuppressive therapy; total number of infections (reported as overall infections in the studies), including respiratory, urinary tract, cytomegalovirus (CMV), other viral infections, invasive aspergillosis and other fungal infections; length of follow-up; acute rejection rate; allograft survival; all-cause mortality at 1 year.

Definitions

Hypogammaglobulinemia: serum IgG <700 mg/dL; mild hypogammaglobulinemia: serum IgG = 400–700 mg/dL; severe hypogammaglobulinemia: serum IgG <400 mg/dL. All-cause mortality included all unexpected outcomes as reported by each study and it did not require assessment of the cause of death.

Statistical analysis

The meta-analysis was conducted using metafor package for R developed by Wolfgang Viechtbauer [12]. The data were pooled using the DerSimonian and Laird random-effects model for all studies [13]. The Q statistic method and I-squared method were used to assess statistical heterogeneity. For studies with no event of interest in a treatment group, 0.5 was added to all cells. For studies providing median and range only for continuous outcomes, mean value and variance were estimated using the median and range [14]. Binary outcomes results were expressed as odds ratios between two groups and continuous outcomes results were expressed as standardized mean difference between two groups. Egger regression and Begg and Mazumdar methods were used to evaluate publication bias.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Rate of HGG

The meta-analysis included 1756 patients (18 studies) [4-8, 10, 15-26]. Characteristics of the studies included in the analysis are presented in Table 1. The mean age of the patients (15 studies, 1232 patients) was 42 years (95% CI: 30.9–53.1; Q = 8249.87), of which 43% were female (95% CI: 0.35–0.50; Q = 93.04; 14 studies, 1140 patients). Within the first year posttransplantation the overall rate of HGG (16 studies, 1482 patients) was 45% (95% CI: 0.34–0.55; Q = 329.63, p < 0.0001), the rate of mild HGG (8 studies, 669 patients) was 39% (95% CI: 0.22–0.56; Q = 210.09, p < 0.0001) and the rate of severe HGG (8 studies, 669 patients) was 15% (95% CI: 0.08–0.22; Q = 50.15, p < 0.0001; Table 2). Children (two studies, 83 patients) had a lower overall HGG rate compared to adults (seven studies, 634 patients; 26% vs. 52%; p < 0.0001). The rate of HGG by the type of allograft is presented in Table 2. The rate of overall HGG was lower (p < 0.0001) for pediatric patients (two studies, 83 patients; 0.26; 95% CI: 0.001–0.66; Q = 18.95; p < 0.0001) than for adult patients (seven studies, 634 patients; 0.52; 95% CI: 0.43–0.62; Q = 30.42; p < 0.0001). When the data were analyzed by the study design, prospective studies versus retrospective studies, the overall rate of HGG was 35% (95% CI: 0.19–0.51; Q = 183.51) versus 52% (95% CI: 0.39–0.66; Q = 92.24; p < 0.0001), the rate of mild HGG was 24% (95% CI: 0.001–0.50; Q = 101.20) versus 47% (95% CI: 0.38–0.56; Q = 9.50; p < 0.0001) and the rate of severe HGG was 15% (95% CI: 0.03–0.28; Q = 26.38) versus 15% (95% CI: 0.06–0.25; Q = 23.48; p = 0.93).

Table 1. Characteristics of the studies included in the systematic review and meta-analysis
Refs.Dates of enrollmentType of studyAimsSample sizeAllograftImmune suppressionFollow-up (months)Cutoff IgG
  1. Ab, antibody; ALG, anti-lymphocyte globulin; Anti IL-2R, anti-interleukin 2 receptor monoclonal antibodies; ATG, anti thymocyte globulin; AZA, azathioprine, CsA, cyclosporine A, CMV, cytomegalovirus; EBV, Epstein–Barr virus; FK506, tacrolimus; IV, intravenous; Ig, immunoglobulin, IgA, IgG, IgM, immunoglobulin A, G and M; IVIG, intravenous immunoglobulin; HGG, hypogammaglobulinemia;; MBP, mannose binding protein; MMF, mycophenolate mofetil; NA, not available; OI, opportunistic infections; OKT3, muromonab; PTLD, posttransplant lymphoprolipherative disorder; UTI, urinary tract infection.

Kawut et al. [16]1/2002–9/2003Retrospective cohortDetermine prevalence and risk factors for HGG in patients after lung transplant57LungInduction: daclizumab; maintenance: MMF or AZA, CsA or FK506, steroids10<400, 400–700
Yip et al. [26]9/2003–12/2004Retrospective cohortAssess determinants of IgG levels and HGG before and early after lung transplant40LungInduction: daclizumab; maintenance: AZA or MMF, sirolimus, FK506 or CsA, steroids2.6400–700
Robertson et al. [20]10/2002–9/2006Retrospective cohortReport incidence, risk factors and outcomes of HG for IgG, IgM and IgA in pediatric lung transplant32LungInduction: basiliximab; maintenance: MMF, CsA, steroids3<641–425
Goldfarb et al. [4]10/1996–7/1999Retrospective cohortDefine the prevalence of HGG and correlate infectious disease outcomes and survival with Ig levels67LungInduction: NA; maintenance: MMF or AZA, CsA or FK506, steroids29.7<400, 400–600
Gregorek et al. [15]1/2004–12/2008Prospective cohortAssess simultaneous monitoring of EBV DNA, serum Ig and gammapathy in peripheral blood was useful to detect early changes before PTLD51LiverInduction: NA; maintenance: FK506, steroids47NA
Doron et al. [7]12/1987–6/1990Retrospective analysis of sera from a RCTAssess the incidence, timing, risk factors and outcome of HGG112LiverInduction: OKT3; maintenance: CsA, AZA, steroids70<560
Staak et al. [22]NAProspective randomized studyAnalyze the effect of IVIG induction therapy on Ig and regulatory antibody levels25KidneyInduction: Anti IL-2RA, ATG; maintenance: MMF or AZA, FK506, steroids3<600
Pollock et al. [19]NARetrospective analysisAssess Ig abnormalities after kidney transplant and correlate with UTI, viral infections, respiratory infections and skin infections110KidneyInduction: ATG, OKT3; maintenance: AZA, CsA, steroids78<700
Keven et al. [8]NAProspective randomized studyEvaluate serum Ig concentrations in patients receiving MMF vs. AZA, and evaluate the relationship of infectious complications and Ig deficiency41KidneyInduction: ATG; maintenance: AZA, FK506 or CsA, steroids1.5<650
Broeders et al. [6]1/1999–8/2002Prospective cohortEvaluate the kinetics of IgG, IgA and IgM and MBP in patients treated with MMF, CNI during the first year after kidney transplant. Also to evaluate association of low Ig and MBP with infections152KidneyInduction: anti IL-2RA, ATG, OKT3; maintenance: MMF, FK506 or CsA, steroids3<650
Vaughan et al. [23]11/1981–2/1983RetrospectiveCompare effects of CsA and thymoglobulin on humoral response against CMV in kidney transplant with regard to IgG levels, IgG subclass and anti-CMV titers29/23KidneyInduction: ALG; maintenance: AZA, CsA, steroids0.75/3<900
Ku et al. [17]1971–1973Retrospective cohortEvaluate pattern of change in Ig related to steroid and AZA use25KidneyInduction: NA; Maintenance: AZA, steroids17.4<700
Fernandez-Ruiz et al. [10]11/2008–10/2010Prospective cohortAssess the incidence, timing, predisposing factors and clinical significance of HGG in kidney transplant patients226KidneyInduction: basiliximab, ATG; maintenance: MMF or AZA, FK506, steroids16.8<700
Munoz et al. [18]1/1993–12/2005Prospective cohortAssess incidence, clinical presentation, risk factors, recurrence rate and outcome of C. difficile after heart transplant and potential impact of HGG on C. difficile associated diarrhea92HeartInduction: anti-IL-2RA, ATG; maintenance: MMF or AZA, CsA or FK50650<600
Sarmiento et al. [5]1998–2002Retrospective cohortAssociation between HGG and infections in heart transplant41HeartInduction: daclizumab, ATG; maintenance: MMF or AZA, CsA or FK506, steroids21.6<600
Sarmiento et al. [21]11/2002–9/2007Prospective cohortDetermine if quantitative assessment of anti-CMV Ab could be useful to identify patients at higher risk of CMV after heart transplant75HeartInduction: daclizumab; maintenance: MMF, CsA or FK506, steroids3<700
Yamani et al. [24]2/1997–1/1999Retrospective cohortDescribe relationship of HGG with rejection and infection111HeartInduction: OKT3; maintenance: AZA or MMF, CsA, FK50613.8501–700, 350–500, <350
Yamani et al. [25]1999–2004Prospective cohortEvaluate the use of CMV-IVIG in patients with moderate HGG (IgG 350-500) and the effect in prevention of CMV and OI300HeartInduction: yes; details: NA; maintenance: MMF or AZA, CsA or FK506, sirolimus, steroids3350–500
Table 2. Rates of overall, mild and severe hypogammaglobulinemia within the first post-transplant year, including subset analysis by the type of the allograft
Severity of hypogammaglobulinemiaType of allograftNumber of patients (number of articles)Rate (%)95% CITest of heterogeneity
Q statisticsp-Value
<700Overall1482 (16)450.34–0.55329.63<0.0001
Heart544 (4)490.21–0.78131.16<0.0001
Kidney579 (6)400.30–0.4924.550.0002
Liver163 (2)160.001–0.3514.310.0002
Lung196 (4)630.53–0.746.850.08
400–700Overall669 (8)390.22–0.56210.09<0.0001
Heart203 (2)420.32–0.522.050.15
Kidney251 (2)460.21–0.706.130.01
Lung164 (3)450.31–0.586.740.03
<400Overall669 (8)150.08–0.2250.15<0.0001
Heart203 (2)210.001–0.4316.140.0001
Kidney251 (2)80.01–0.162.830.09
Lung163 (3)220.08–0.3611.020.004

Number of infections

The mean number of all infections per patient in the study population (11 studies, 1067 patients) was 1.08 (95% CI: 1.02–1.13); for respiratory infections (7 studies, 534 patients) it was 0.29 (95% CI: 0.25–0.32) and for CMV infections (14 studies, 1144 patients) it was 0.37 (95% CI: 0.35–0.39). When only patients with HGG were analyzed, the mean number of infections per patient was the following: 1.49 (95% CI: 1.35–1.63) for all infections (eight studies, 321 patients); 0.55 (95% CI: 0.47–0.64) for respiratory infections (five studies, 207 patients) and 0.51 (95% CI: 0.47–0.56) for CMV infections (six studies, 266 patients).

Impact of severe HGG on the rate of different infections

The odds of developing infections for the group with IgG <700 mg/dL (OR = 1.93; 95% CI: 0.88–4.25; p = 0.10; Q = 16.17; I2 = 75.26%; five studies, 511 patients) and for the group with mild HGG (OR = 1.08; 95% CI: 0.29–4.03; p = 0.91; Q = 13.81; I2 = 85.51%; three studies, 378 patients) was not significantly different than the odds for the group with IgG >700 mg/dL. The odds of developing infections in the group with severe HGG was 2.46 times higher than the odds of infection for the group with IgG >400 mg/dL (95% CI: 1.22–4.93; p = 0.01; Q = 0.83; I2 = 0%; two studies, 267 patients) (Figure 2). The odds for all infections when comparing the severe HGG group with the IgG >700 mg/dL group (two studies, 267 patients) was increased by 3.73 times (95% CI: 1.11–12.49; p = 0.03, Q = 2.22; I2 = 55%) (Figure 3). We performed subset analyses by the types of infection: respiratory infections, urinary tract infections, CMV infections, invasive aspergillosis and other fungal infections:

  • The odds of respiratory infections for patients with IgG <700 mg/dL were not significantly different than the odds for patients with normal immunoglobulin levels (OR = 1.62; 95% CI: 0.20–13.13; p = 0.65; Q = 3.84; I2 = 73.94%; two studies, 292 patients). The odds of respiratory infections for patients with severe HGG was 4.83 times higher than the odds for patients with IgG > 400 mg/dL (95% CI: 1.66–14.05; p = 0.004; Q = 0.84; I2 = 0%; two studies, 257 patients).
  • The odds of CMV infections for IgG <700 mg/dL group (OR = 0.59; 95% CI: 0.18–1.96; p = 0.39; Q = 22.36; I2 = 87%; four studies, 490 patients) and the odds for mild HGG group (OR = 0.73; 95% CI = 0.33–1.59; p = 0.42; Q = 4.28; I2 = 53.26%; three studies, 378 patients) was not significantly different than the odds for the normal immunoglobulin group. The group with severe HGG had 2.4 times higher odds of CMV infections than the group with IgG >400 mg/dL (95% CI: 1.16–4.97; p = 0.02; Q = 4.09; I2 = 26.66%; four studies, 435 patients). The odds of CMV infections for severe HGG group was 2.89 times higher than the odds for mild HGG group (95% CI: 1.01–8.3; p = 0.05; Q = 4.64; I2 = 57%; three studies, 378 patients) and also was 2.2 times higher than the odds for the group with normal immunoglobulin levels (95% CI: 0.96–4.91; p = 0.06; Q = 0.24; I2 = 29.64%; three studies, 378 patients).
  • The odds of Aspergillus infections with severe HGG group was 8.19 times higher than the odds for the group with IgG >400 mg/dL (95% CI: 2.38–28.21; p = 0.0009; Q = 1.21; I2 = 17.02%; two studies, 124 patients).
  • The odds of other fungal infections for severe HGG group was 3.69 times higher than the odds for the group with IgG >400 mg/dL (95% CI: 1.11–12.33; p = 0.03; Q = 0.002; I2 = 0%; two studies, 124 patients).
image

Figure 2. Comparison between the group with severe hypogammaglobulinemia (<400 mg/dL) and the group with IgG >400 mg/dL regarding the risk of all infections.

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image

Figure 3. Comparison between the group with severe hypogammaglobulinemia (<400 mg/dL) and the group with IgG > 700 mg/dL regarding the risk of all infections.

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Impact of HGG on rejection rate

There was no evidence of a difference in the odds of rejection between the group with IgG <700 mg/dL and the group with normal immunoglobulin levels (OR = 1.14; 95% CI: 0.86–1.50; p = 0.38; I2 = 0%; two studies, 223 patients). The odds of rejection for severe HGG group was not different compared to the odds for group with IgG >400 mg/dL (OR = 1.43; 95% CI: 0.52–3.92; p = 0.48; I2 = 0%; two studies, 257 patients).

Impact of HGG on survival

The odds of 1-year all-cause mortality in the group with IgG <700 mg/dL was 2.71 times higher than the odds for the group with normal immunoglobulin levels (95% CI: 1.05–6.99; p = 0.04; Q = 0.01; I2 = 0%; two studies, 179 patients). The odds of death at 1 year for severe HGG was 21.91 times higher than the odds for IgG > 400 mg/dL (95% CI: 2.49–192.55; p = 0.005; Q = 0.23; I2 = 0%; two studies, 124 patients).

Publication bias

No significant publication bias was detected by Egger regression (t = 1.48, df = 3, p = 0.24) or Begg and Mazumdr rank correlation (Kendall's tau = 0.6, p = 0.23) for impact of hypogammaglobulinemia on overall infections.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Our study shows that overall HGG was highly prevalent (45%) during the first year posttransplantation, while severe HGG was diagnosed in fewer (15%) recipients. The rates of HGG were much higher in kidney (40%), heart (49%) and lung (63%) transplant recipients than in liver (16%) transplant recipients. The heterogeneity between studies was high when the rate of HGG was evaluated. This high heterogeneity could probably be explained by inherent differences in the individual studies such as inclusion of different subset of patients (different allografts and underlying diseases, pediatric and adult patients), variation in treatment regimens and study designs. The level of heterogeneity remained relatively constant for subset analyses. Differences in the prevalence of HGG among the allografts can probably be explained by different patient populations, and by different underlying diseases pretransplantation and the immunosuppressive regimens. Pretransplant HGG is less common in patients with chronic liver disease, who may actually have increased immunoglobulin levels, due to repeated antigenic stimulation as a consequence of shunting of the portal system [27, 28]. In contrast, patients with COPD seem to have more frequently low pretransplant HGG that would predict severe posttransplant HGG [26]. Patients on chronic pretransplant corticosteroids for asthma, chronic bronchitis and emphysema were reported to be at higher risk for HGG in comparison to patients with nonsteroid–dependent lung disease [29-31]. Steroids have lytic effect on lymphocyte populations and also affect leukocyte migration [32, 33]. The use of IL-2 receptor antagonists for induction therapy has been associated with significantly lower rate of bacterial and viral infections than polyclonal antibodies. All agents used for maintenance immunosuppression alter directly T cell function and lymphokine production and indirectly B cell function. Some immunosuppressive agents, such as mycophenolate mofetil, have more potent inhibitor-effect on B-lymphocyte proliferation and antibody production than others such as azathioprine, and the effect is independent of pretransplant IgG levels and patient diagnosis [8, 26].

The second important finding of our analysis is the significant increased risk of overall infections in patients with severe HGG. This risk remained consistently high in the subset analysis by the type of infection (CMV, Aspergillus, fungal and respiratory infections) for the severe HGG group. This finding was true only for patients with severe HGG, not for mild or overall HGG. We noticed a high statistical heterogeneity for studies that included mild HGG and overall HGG patients, while the heterogeneity was fairly low to null in most of the studies that evaluated infections in severe HGG group. For Aspergillus and other fungal infections, we could perform analysis only for patients with severe HGG. We also have to consider that for some of these infections, the sample that was analyzed was relatively small. These results might reflect local practices, since some of the studies have been published from the same centers. Our analysis showed an association between severe HGG and different infections, but not a cause–effect relationship. Bacterial infections have been traditionally associated with HGG, predominantly IgG2 subclass, while viral infections have been associated mainly with IgG1 and IgG3 [34-37]. The relationship between HGG and fungal infections is not completely elucidated, but it has been shown that phagocytosis of Aspergillus spp. is enhanced by immunoglobulins, complement and mannose-binding lectins [38], and that fungicidal response of PMN against A. fumigatus was associated with the degree of HGG [39]. It is unclear whether there is a causal relationship between HGG and CMV infections or if HGG is just a marker of severe immunosuppression. It is possible that IgG1 subclass deficiency plays an important role in HGG-associated CMV infections. IgG1 and IgG3 are the most active anti-CMV immunoglobulins and are detected in almost all patients who are CMV-seropositive or have sero–converted [23, 34, 40]. The absence of an association between severe HGG and urinary tract infections might be related to the small sample size and the low event rates reported in the studies. Also urinary tract infections are common infectious complications after any transplantation, most likely related to postoperative catheterization, urologic complications related to ureteral anastomosis and stent placement in kidney transplant recipients. Although the meta-analysis found a significant increased risk of infections in patients with severe HGG, it did not demonstrate causality with increased morbidity.

We did not find any association between HGG and rejection. The sample size we analyzed was relatively small (only two studies), but very homogeneous (I2 = 0%). Yamani et al. [24] found that replacement with CMV–IVIg in heart transplant recipients with severe HGG (<350 mg/dL) significantly decreased the number of rejection episodes compared with historical control group (grade ≥3, p = 0.03; grade ≥2, p = 0.02). This change in rejection rate could be explained by the decreased rate of infection with CMV–IVIG administration and by the immunomodulatory effects of the immunoglobulins [24]. More data would be needed to definitely state that HGG is or is not associated with rejection.

Another important finding from our study was the association between overall HGG, severe HGG and 1-year all-cause mortality. Only two studies were included in the survival analysis, but the heterogeneity of these studies was extremely low (I2 = 0%). Severe HGG seems to have a more significant impact on all-cause mortality compared with overall HGG; probably this could be explained by the increased risk of different infections with severe HGG. It has been previously reported that infections represent the number one cause of morbidity and mortality in SOT recipients [11, 17, 41]. HGG may indirectly raise mortality by increasing the risk of various infections. Goldfarb et al. [4] showed that mortality was the highest in the severe HGG group and intermediate in the mild HGG group of lung transplant recipients, most likely correlating with a higher rate of infections as shown in our study. Carbone et al. [3], in a retrospective study of heart transplant recipients, showed that patients who received IVIG for HGG (IgG < 600 mg/dL), or due to infections with goal to maintain IgG level >700 mg/dL, had a decreased risk of death (OR = 0.204, 95% CI: 0.04–0.92; p = 0.03). In Carbone et al. [3] study, the mortality rate of IVIG-treated versus nontreated patients was 20% versus 71% (OR = 0.06, 95% CI: 0.006–0.63; p = 0.01).

Several interventions might be effective in selected patients with severe HGG: changing immunosuppression (decreasing levels or changing to alternative drugs), administration of intravenous immunoglobulins (IVIG) and monitoring IgG levels on a monthly basis. From the data presented above, it would be expected that patients with severe HGG may benefit from IVIG treatment. Two studies showed that preemptive administration of IVIG to patients with severe HGG resulted in reduction of the number of opportunistic infections and rejection episodes [3, 24]. In secondary immunodeficiency after SOT, it remains unclear what threshold should be used to start treatment and what trough levels we should be aiming for. In nontransplant-associated primary immunodeficiencies, IVIG replacement is often successful in the goal of reducing the incidence of infections and associated complications (bronchiectasis, progressive lung disease). The goal for IgG trough depends on patients' comorbidities, yet a previous meta-analysis showed reduced incidence of pneumonia when the range of 650–1000 mg/dL was achieved [42]. We should have a better understanding of the cost-effectiveness of preemptive IVIG treatment in patients with severe HGG.

Our study has limitations and strengths. First, there was variability in the quality of the studies included in the meta-analysis, with inter-study heterogeneity. Second, there was no systematic collection and reporting of IgG levels at specific time points in most of the studies. Third, selection bias cannot be excluded since it is possible that patients with infections may have IgG levels drawn more frequently than patients without complications. This might also not reflect the true rate of HGG since these IgG levels were probably not at true steady state, knowing that the rate of IgG elimination would increase during a period of infection [43]. Fourth, besides HGG, defects in T cell responses, complement activating cascade and mannose binding protein levels have been associated with increased risk of infections and those were not investigated in this study. The strengths include the rigorous design, the sample size, the uniform definition of HGG used, relatively uniform length of follow-up and the homogeneity of population analyzed for risk of infections and all-cause mortality.

Several questions remain open for future studies: Can a population at risk for severe HGG after SOT be defined? Is there an optimal approach to IgG level monitoring? What should be the frequency of IgG level monitoring? Is the linkage between HGG and complicating clinical outcomes (i.e. infection, mortality) direct or indirect? Can a threshold IgG level be determined to start preemptive intravenous immunoglobulin treatment in SOT recipients? Would IVIG replacement impact all-cause mortality or infection–related mortality after SOT?

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Our meta-analysis, by pooling data from previously published studies, showed that HGG is a common complication during the first year posttransplantation. Severe posttransplant HGG is probably multifactorial, including pre- and posttransplant elements. Severe HGG might have an adverse impact on infections-related morbidity and mortality in the first year after transplantation. Our study suggests that monitoring IgG levels after SOT might identify a subgroup of patients at high risk for infections and increased mortality. These patients might potentially benefit from preemptive treatment with IVIG or reduction of immunosuppression. Future large prospective trials of SOT-associated HGG intervention would be valuable in light of the significant clinical infection impact seen in the data currently available.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

A research grant for this project was provided by CSL Behring (the makers of CytoGam). The authors are exclusively responsible for the preparation, writing and viewpoints expressed in the manuscript.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References

Dr. Kalil, Dr. Sandkovsky, Dr. Schmidt and Fang Qiu have no conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Florescu has the following conflicts of interest to disclose as described by the American Journal of Transplantation: received research grant and was consultant for CSL Behring.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Disclosure
  10. References
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