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Infection, Rejection, and Hypogammaglobulinemia: The Chicken or the Egg?


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Tam Khuu, PharmD, BCPS
UCLA Medical Center
Los Angeles, CA, USA
TKhuu@mednet.ucla.edu



Intravenous immune globulin (IVIG) products are derived from pooled human plasma from over tens of thousands of screened donors collected largely by private industry,[1] which contributes to its limited availability and high cost. Nevertheless, demand for IVIG continues to increase, with greatest use in North America, Australia/New Zealand and Europe.[2] Currently, the labelled indications for IVIG include treatment of primary immunodeficiency, acute/chronic immune thrombocytopenia (ITP), prevention of bacterial infection in chronic lymphocytic leukemia (CLL) patients with hypogammaglobulinemia (HGG), and provision of passive immunity for hepatitis A, measles, rubella, and varicella in specific patients.[3] The use of IVIG in the setting of thoracic transplantation, whether for treatment of rejection or provision of passive immunity, remains off-label.

Hypogammaglobulinemia (HGG) is common following transplantation, with a reported incidence of 34-70% for mild HGG (IgG<700mg/dL) and 10-37% for severe HGG (IgG<400mg/dL).[4-7] However, questions remain surrounding the clinical importance of these findings and whether treatment with IVIG will positively impact outcomes. Does HGG independently lead to poor outcomes or do patients with more severe disease have HGG? This question leads us into a "chicken versus the egg" paradox. The volume of evidence that links HGG with significant clinical implications, particularly infection, after transplantation is growing. A large meta-analysis of 1756 solid organ transplant recipients, including heart (OHT) and heart/kidney recipients, reported a 4.8-fold increase in respiratory infections, a 2.4-fold increase in the likelihood of CMV infections, a 8-fold increase in aspergillus infections (3.7-fold increase in other fungal infections), and a shocking 22-fold greater 1-year all-cause mortality rate in those with severe HGG (2.7-fold increase in mortality for those with mild HGG).[4] Two other groups have also reported an increased incidence of opportunistic infections in OHT with HGG, particularly CMV viremia.[8,9]

Many studies of HGG in lung transplant (LTx) have also found an increased incidence of fungal infections.[5,7,10] The incidence of CMV was found to be higher with HGG in two LTx studies,[10,7] but found to be similar in another.[5] Community-acquired respiratory viruses appeared not to be linked to low IGG[6,10] but possibly to low IGA.[10] Studies evaluating severe HGG also reported an increased incidence of bacterial infections, hospitalizations, and increased mortality.[5,7] There have not been any studies to date that link HGG with increased rejection risk or reduced lung function in the LTx population.[5,6,10]

Risk factors for development of severe HGG have currently been identified as OHT recipients with ≤ 3 episodes of rejection or those requiring intravenous methylprednisolone therapy,[8] and LTx recipients with emphysema, female gender, or presence of BOS.[5]

Given the mounting evidence linking morbidity and mortality with HGG, studies evaluating the treatment of HGG with IVIG are beginning to emerge. While one recent retrospective study of 37 SOT recipients did not find a patient or graft survival benefit when targeting IGG >400,[11] two smaller studies from one group found a reduced incidence of infection and mortality in IVIG-treated OHT recipients with infections or CMV disease when targeting IGG>700-750.[12,13] These two studies repleted IVIG at 200-400mg/kg . Published data regarding the benefits of IVIG for HGG in LTx is still materializing, as well. One small cross-over study of 11 patients found no difference in infection rate despite maintaining IGG>700 during the treatment phase.[14] Another recent retrospective found similar 5-year survival and 5-year chronic lung allograft dysfunction-free survival between patients who received IVIG and those who did not. Of note, this study used time-dependent exposure and was thus subject to immortal time bias in favor of treatment.[15] Immortal time bias is a time interval during the follow-up period in which the outcome(s) cannot occur by design. In this study, patients who received IVIG were alive until receiving IVIG; patients who had an event before treatment were automatically in the untreated group.

IVIG remains a costly and limited resource facing increasing demand. While current evidence likely supports a link between HGG, infection, and even mortality, there is much need for further evaluation of the effectiveness and optimal dosing strategy for IVIG repletion in this setting. As we delve deeper into this paradox, perhaps which comes first no longer matters. Whether we begin with HGG, infection or rejection, the result is the same: impaired outcomes. What is important for future pathways is the relationship between these characteristics. We may find that the benefits of IVIG in HGG are linked to target immunoglobulin levels, overall immunosuppression, or other patient-specific characteristics. On the other hand, we may find that HGG is a non-modifiable risk factor for inferior outcomes. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Kalorama Information. Blood: The Worldwide Market for Blood Products, Blood Testing, Blood Equipment, and Synthetic Blood Products. Oct 2014.
  2. Stonebraker JS, Farrugia A, Gathmann B; ESID Registry Working Party, Orange JS. Modeling primary immunodeficiency disease epidemiology and its treatment to estimate latent therapeutic demand for immunoglobulin. J Clin Immunol. 2014 Feb;34(2):233-44.
  3. Lexi-Comp, Inc. (Lexi-Drugs®). Lexi-Comp, Inc.; July 1, 2015.
  4. Florescu DF, Kalil AC, Qiu F, et al. What is the impact of hypogammaglobulinemia on the rate of infections and survival in solid organ transplantation? A meta-analysis. Am J Transplant. 2013 Oct;13(10):2601-10.
  5. Kawut SM, Shah L, Wilt JS, et al. Risk factors and outcomes of hypogammaglobulinemia after lung transplantation. Transplantation 2005;79:1723-6.
  6. Noell BC, Dawson KL, Seethamraju H. Effect of hypogammaglobulinemia on the incidence of community-acquired respiratory viral infections after lung transplantation. Transplant Proc. 2013 Jul-ug;45(6):2371-4.
  7. Goldfarb NS, Avery RK, Goormastic M, et al. Hypogammaglobulinemia in lung transplant recipients. Transplantation 2001;71:242-6.
  8. Yamani MH, Avery RK, Mawhorter SD, et al. Hypogammaglobulinemia Following Cardiac Transplantation: A Link Between Rejection and Infection. JHLT. 2001 Apr; 20(4): 425-430.
  9. Sarmiento E, Rodríguez-Molina J, Muñoz P, et al. Decreased levels of serum immunoglobulins as a risk factor for infection after heart transplantation. Transplant Proc. 2005 Nov;37(9):4046-9.
  10. Chambers DC, Davies B, Mathews A, et al. Bronchiolitis obliterans syndrome, hypogammaglobulinemia, and infectious complications of lung transplantation. J Heart Lung Transplant. 2013 Jan;32(1):36-43.
  11. Florescu DF, Kalil AC, Qiu F, et al. Does increasing immunoglobulin levels impact survival in solid organ transplant recipients with hypogammaglobulinemia? Clin Transplant. 2014 Nov;28(11):1249-55.
  12. Carbone J, Sarmiento E, Palomo J, et al. The potential impact of substitutive therapy with intravenous immunoglobulin on the outcome of heart transplant recipients with infections. Transplant Proc. 2007 Sep;39(7):2385-8.
  13. Sarmiento E, Arraya M, Jaramillo M, et al. Intravenous immunoglobulin as an intervention strategy of risk factor modification for prevention of severe infection in heart transplantation. Clin Exp Immunol. 2014 Dec;178 Suppl 1:156-8.
  14. Lederer DJ, Philip N, Rybak D, et al. Intravenous immunoglobulin for hypogammaglobulinemia after lung transplantation: a randomized crossover trial. PLoS One. 2014 Aug 4;9(8):e103908.
  15. Claustre J, Quétant S, Camara B, et al. Nonspecific immunoglobulin replacement in lung transplantation recipients with hypogammaglobulinemia: a cohort study taking into account propensity score and immortal time bias. Transplantation. 2015 Feb;99(2):444-50.



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