Immune Profiles to Detect Heart Recipients at Risk of Development of Severe Infection

Abstract

Introduction: Approaches that are able to quantify individual recipient risk for development of severe infections could allow us to make targeted adjustments to immunosuppressive and prophylactic strategies in solid organ transplantation. The aim of this study was the identification of immune profiles associated with elevated severe infection risk in heart recipients. Material and methods: Prospective single center study. Inclusion criteria: Adult heart recipients. Clinical follow-up: 6 months. Definition of severe infection: An event was defined as an infection requiring intravenous antimicrobial therapy, with positive cultures or antigenemia and having clinical compromise. Study points: pre-trasplant, day-7 and day-30 after transplant. The immunological study included humoral and cellular immunity markers of: adaptive and innate immunity: Serum IgG, IgA, IgM, IgG subclasses, C3, C4, factor B (Nephelometry), manose binding lectin (ELISA), specific antibodies after vaccination (anti-pneumococcal polysaccharide [anti-PPS], anti-HBs, [ELISA]), natural specific antibodies without vaccination (anti-cytomegalovirus, anti-haemophilus influenzae type B, anti-salmonella typhi, anti-varicella zoster [ELISA]) and T, B, NK lymphocyte subsets (flow-cytometry). Results: 154 patients were analysed. 59 (38.3%) developed severe infections during follow-up. Univariate single marker analysis: Patients who developed infections disclosed: Lower levels of IgG (day 7, p< 0.001), C4 (day 7, p=0.016), IgG (day 30, p=0.007), IgA (day 30, p=0.016), anti-PPS (day 30, p=0.003) and lower absolute counts of NK CD3-CD16/CD56+ (day 7, p=0.017), T-CD3+ (day 30, p=0.008), T-CD4+ (day 30, p=0.012) and T-CD8+ lymphocytes (day 30, p=0.003). Examples of immune profiles associated with severe infection risk: Day 7: IgG< 700 mg/dl + C4< 20 mg/dl + NK< 30 cells/uL (OR 3.327, p< 0.001, specificity 88.5%, PPV 72%); day 30: IgG< 700 mg/dl + anti-PPS< 10 mg/dl + CD8< 300 cells/uL (OR 4.521, p< 0.001, specificity 88.7%, PPV 77%). Specificity of combined markers was higher than that obtained with single markers. A substudy was also performed to identify CMV seropositive heart recipients at risk of CMV infection. The combination marker: low anti-CMV titer (< 16,100) and low CD8/IFNg+ IE1 percentages (< 0.40%), relative hazard, 6.07; p=0.019, was associated with risk of CMV infection. Conclusion: This novel approach of a simultaneous and combined assessment of humoral and cellular immunity markers might help identify heart transplant recipients with an increased risk of developing severe infections. Several of the tested parameters included are easily available and standardized. Using nephelometry, tests for IgG or C3 concentration normally requires from 1 to 2 hours before test results are available if done in hospital. The potential utility of the post transplant immunological evaluation might include the selection of candidates for long-term antimicrobial prophylaxis rather than universal administration of prolonged prophylaxis (i.e. anti-CMV prophylaxis). Immune monitoring could also aid in the identification of cutoff values for immunological variables that confer risk of development of severe infection for starting antimicrobial prophylaxis or immunebased therapies (i.e. intravenous immunoglobulin in patients with IgG hypogammaglobulinemia). A multicenter prospective study is on going with larger patient populations to validate the predictive value of some of these markers for development of severe infections after heart and lung transplantation.