ImmuKnow as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: A systematic review and meta-analysis
2012; Lippincott Williams & Wilkins; Volume: 18; Issue: 10 Linguagem: Inglês
10.1002/lt.23497
ISSN1527-6473
AutoresEmilio Rodrigo, Marcos López‐Hoyos, M T García del Corral, Emilio Fábrega, Gema Fernández‐Fresnedo, David San Segundo, Celestino Piñera, Manuel Arias,
Tópico(s)Cytomegalovirus and herpesvirus research
ResumoLiver TransplantationVolume 18, Issue 10 p. 1244-1252 Original ArticleFree Access ImmuKnow as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: A systematic review and meta-analysis† Emilio Rodrigo, Corresponding Author Emilio Rodrigo nefrce@humv.es Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, Spain Telephone: +34 942202738; FAX: +34 942315101Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Avenida Valdecilla sn., Santander, Spain 39008Search for more papers by this authorMarcos López-Hoyos, Marcos López-Hoyos Immunology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorMario Corral, Mario Corral Marquesa de Pelayo Library, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorEmilio Fábrega, Emilio Fábrega Gastroenterology and Hepatology Unit, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorGema Fernández-Fresnedo, Gema Fernández-Fresnedo Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorDavid San Segundo, David San Segundo Immunology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorCelestino Piñera, Celestino Piñera Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorManuel Arias, Manuel Arias Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this author Emilio Rodrigo, Corresponding Author Emilio Rodrigo nefrce@humv.es Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, Spain Telephone: +34 942202738; FAX: +34 942315101Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Avenida Valdecilla sn., Santander, Spain 39008Search for more papers by this authorMarcos López-Hoyos, Marcos López-Hoyos Immunology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorMario Corral, Mario Corral Marquesa de Pelayo Library, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorEmilio Fábrega, Emilio Fábrega Gastroenterology and Hepatology Unit, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorGema Fernández-Fresnedo, Gema Fernández-Fresnedo Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorDavid San Segundo, David San Segundo Immunology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorCelestino Piñera, Celestino Piñera Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this authorManuel Arias, Manuel Arias Nephrology Service, Marqués de Valdecilla University Hospital, University of Cantabria, Institute for Training and Research of the Marqués de Valdecilla Foundation, Santander, SpainSearch for more papers by this author First published: 27 June 2012 https://doi.org/10.1002/lt.23497Citations: 61 † This work was supported by the Carlos III Institute of Health (REDINREN 06/16) and by the Institute for Training and Research of the Marqués de Valdecilla Foundation. Emilio Rodrigo was supported by grants from the Institute for Training and Research of the Marqués de Valdecilla Foundation and the Spanish Society of Nephrology. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Immune status monitoring of transplant recipients could identify patients at risk of acute rejection, infection, and cancer, which are important sources of morbidity and mortality in these patients. The ImmuKnow assay provides an objective assessment of the cellular immune function of immunosuppressed patients. Inconclusive results concerning the ability of the ImmuKnow test to predict acute rejection and infection have raised concerns about the predictive value of ImmuKnow in liver transplant recipients. We conducted a systematic literature review to identify studies published up to March 2012 that documented the use of ImmuKnow for monitoring immune function in liver transplant recipients. The study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 score. We identified 5 studies analyzing ImmuKnow performance for infection and 5 studies analyzing ImmuKnow performance for acute rejection. The pooled sensitivity, specificity, positive likelihood ratio, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 83.8% [95% confidence interval (CI) = 78.5%-88.3%], 75.3% (95% CI = 70.9%-79.4%), 3.3 (95% CI = 2.8-4.0), 14.6 (95% CI = 9.6-22.3), and 0.824 ± 0.034, respectively, for infection and 65.6% (95% CI = 55.0%-75.1%), 80.4% (95% CI = 76.4%-83.9%), 3.4 (95% CI = 2.4-4.7), 8.8 (95% CI = 3.1-24.8), and 0.835 ± 0.060, respectively, for acute rejection. Heterogeneity was low for infection studies and high for acute rejection studies. In conclusion, the ImmuKnow test is a valid tool for determining the risk of further infection in adult liver transplant recipients. Significant heterogeneity across studies precludes the conclusion that ImmuKnow identifies liver transplant patients at risk for rejection. Liver Transpl 18:1245–1253, 2012. © 2012 AASLD. In the field of solid organ transplantation, the maintenance of an adequate level of immunosuppression is of the greatest importance. On the one hand, overimmunosuppression can promote the appearance of infection, cancer, and other undesirable secondary effects. Infectious diseases remain an important source of morbidity and mortality for all types of transplant patients.1 Up to two-thirds of all liver transplant patients have at least 1 infectious episode during their follow-up, infection being one of the most frequent causes of death after liver transplantation.2, 3 On the other hand, underimmunosuppression leads to acute rejection and a chronic allograft immune response, which shorten graft survival and function and patient survival. For liver transplant recipients who suffer severe acute rejection, the time to death or retransplantation is shorter.4, 5 Although acute rejection rates have declined for most types of organs in recent years, acute rejection continues to be an important problem that promotes early and late graft loss. The most widely accepted practice for monitoring solid organ transplants involves the estimation of graft function and the measurement of the blood levels of immunosuppressive drugs,6, 7 although it is known that neither method is sensitive or specific for determining the current immunosuppressive status. In recent years, several tests have been developed for monitoring the immune status of transplant patients. Some tests have focused on detecting the risk of acute rejection, and some have focused on predicting the risk of infection; however, few have been used to estimate both risks at the same time.8-12 For example, the expression of 3 calcineurin-dependent, nuclear factor of activated T cells–regulated genes (interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor) in whole-blood samples has been related to the development of infection, cancer, and acute rejection, but this method has not been standardized for use in clinical practice.13, 14 In 2002, the Food and Drug Administration approved an in vitro assay, ImmuKnow (Cylex), which was designed to measure increases in intracellular adenosine triphosphate (iATP) after CD4 cell activation. This assay allows the assessment of cellular immune function and the monitoring of the immune status of transplant recipients. A meta-analysis using individual data prospectively collected from 504 solid organ transplant recipients during several observational studies carried out at 10 transplant centers throughout the United States confirmed the utility of the ImmuKnow assay in identifying levels of immune function. Recipients with an iATP immune response value of 25 ng/mL were 12 times more likely to develop an infection than recipients with stronger immune responses. On the other hand, a recipient with a response value of 700 ng/mL was 30 times more likely to develop rejection than a recipient with a lower immune response value.15 Despite this, several more studies of liver transplant patients have reported inconclusive results for the performance of the ImmuKnow test in predicting acute rejection and infection, and this has precluded the generalization of its use.16-25 Thus, we performed a systemic review and meta-analysis to investigate the diagnostic accuracy of the ImmuKnow test for the risk of infection and acute rejection in liver transplant recipients. Although the ImmuKnow test was not developed as a diagnostic test for infection or acute rejection, it was developed to estimate the risk of both. PATIENTS AND METHODS Search Strategy A comprehensive literature search was performed for studies documenting the use of ImmuKnow for monitoring immune function in liver transplant recipients. The key search terms were transplantation, ImmuKnow, Cylex, and intracellular ATP. The search was limited to human studies but was not restricted to studies published in English. The MEDLINE (January 1996 to March 2012) and Embase databases (January 1988 to March 2012) were searched. Abstracts from American Transplant Congress annual meetings were also evaluated. In addition, reference lists of identified articles were reviewed manually to identify additional articles. Eligibility Titles and abstracts were independently evaluated by 2 authors (E.R. and M.L.-H.) for eligibility. Studies were eligible if they seemed to include information about the relationship of ImmuKnow with infection or acute rejection in adult liver transplant recipients. Prospective and retrospective studies were eligible, and reviews were excluded. Inclusion and Exclusion Criteria Full reports for all eligible studies were independently evaluated by E.R. and M.L.-H. Disagreement was resolved by consensus. Studies were included if they reported extractable data on the performance of ImmuKnow for predicting acute rejection or infection in adult liver transplant recipients. Case reports were excluded. Acute rejection was considered according to the authors' diagnosis, and both biopsy-proven acute rejection and non–biopsy-proven acute rejection were included. Infections were defined in accordance with the different criteria adopted by the authors and included the following: opportunistic and nonopportunistic infections; viral, fungal, bacterial, and parasitic infections; and clinical, histological, and microbiological diagnoses. Eligible studies were included when accuracy data could be extracted in the form required for the analysis (true positives, false positives, false negatives, and true negatives) or when this information could be inferred from the sensitivity, specificity, and number of included cases. Data Extraction Data extraction was performed by E.R. and M.L.-H. with a standard data extraction form. The following variables were recorded for each study: true positives, false positives, false negatives, true negatives, study type, mean age, sex, mean time of transplant follow-up, maximum time from the ImmuKnow test to the diagnosis, cutoffs, and areas under the receiver operating characteristic curve (AUC-ROCs). Moreover, infection diagnoses (clinical, histological, and microbiological) and infection types (opportunistic and nonopportunistic infections and viral, fungal, bacterial, and parasitic infections) were included in the infection meta-analysis; the meta-analysis of acute rejection included whether or not acute rejection was biopsy-proven. Study Quality The methodological quality of all included studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) score, which was used to analyze the risk of bias and concerns regarding the applicability of the following domains: the patient selection, the index test, the reference standard, and the flow of patients through the study/timing of the index test and reference standard.26 Statistical Analysis The computation was performed with freely available software (Meta-DiSc 1.4).27 We carried out the meta-analysis by pooling sensitivities, specificities, positive likelihood ratios, and diagnostic odds ratios (DORs) with random effects models and by using a summary receiver operating characteristic (SROC) curve analysis. Heterogeneity was quantitatively assessed with the I2 statistic and was explored further with a subgroup analysis restricted to different clinical settings. Abbreviations: AUC, area under the curve; AUC-ROC, area under the receiver operating characteristic curve; CI, confidence interval; df, degrees of freedom; DOR, diagnostic odds ratio; HCV, hepatitis C virus; iATP, intracellular adenosine triphosphate; QUADAS-2, Quality Assessment of Diagnostic Accuracy Studies 2; SE, standard error; SROC, summary receiver operating characteristic. RESULTS Search Results and Study Characteristics The search initially yielded 172 reports, and 166 were excluded for the following reasons: they were reviews, repeated studies, nonhuman studies, nontransplant studies, non–solid organ transplant studies, nonliver solid organ transplant studies, or pediatric studies; they did not report data about infection or acute rejection; or they provided information that was inadequate for calculating true positives, true negatives, false positives, and false negatives. As a result, 6 studies were included: 5 for analyzing the relationship between infection and ImmuKnow and 5 for determining the performance of ImmuKnow for acute rejection (Fig. 1). The studies included 651 cases for the infection meta-analysis and 543 for the acute rejection meta-analysis. Figure 1Open in figure viewerPowerPoint Flow chart of the study selection process. The characteristics of the studies included for the infection and acute rejection meta-analyses are listed in Tables 1 and 2, respectively. All included studies were published in English. The mean posttransplant follow-up ranged from less than 1 to 50.7 months. The mean time from ImmuKnow testing to the infection diagnosis ranged from 0 to 7 days, although this was not clearly stated in several reports. Infection was defined as any kind of infection according to positive microbiological or serological tests and imaging studies in 3 reports17, 19, 21 and as biopsy-defined recurrent hepatitis C virus (HCV) in 2 studies.16, 18 Acute rejection was clearly reported to be biopsy-proven in 4 of the 5 reports. Table 1. Characteristics of the Studies Included in the Infection Meta-Analysis Study Country Study Type Mean Age (Years) Male Sex (%) Mean Posttransplant Follow-Up (Months) Maximum Time from ImmuKnow Testing to Diagnosis (Days) Cutoff (μg/L) True Positives (n) False Positives (n) False Negatives (n) True Negatives (n) AUC-ROC Cheng et al.21 (2011) China Retrospective 48 86 3 0 200 84 59 22 177 0.842 Mizuno et al.19 (2011) Japan Not reported 50 73 50.7 Not reported 225 6 7 0 27 Not reported Hashimoto et al.18 (2010) United States Retrospective 52 76 7.9 0 225 23 7 3 16 0.930 Xue et al.17 (2010) China Retrospective 49 78 Not reported Not reported 126 69 23 12 74 Not reported Cabrera et al.16 (2009) United States Prospective 51 71 Not reported 0 225 15 7 0 20 Not reported Table 2. Characteristics of the Studies Included in the Acute Rejection Meta-Analysis Study Country Study Type Mean Age (Years) Male Sex (%) Mean Posttransplant Follow-Up (Months) Maximum Time from ImmuKnow Testing to Diagnosis (Days) Cutoff (ng/mL) True Positives (n) False Positives (n) False Negatives (n) True Negatives (n) AUC-ROC Cheng et al.21 (2011) China Retrospective 48 86 3 0 304 43 68 11 220 0.806 Mizuno et al.19 (2011) Japan Not reported 50 73 50.7 Not reported 525 1 2 1 36 Not reported Dong et al.20 (2011) China Not reported 43 64 <1 Not reported 407 12 11 2 45 0.869 Hashimoto et al.18 (2010) United States Retrospective 52 76 7.9 0 525 1 0 10 38 0.930 Cabrera et al.16 (2009) United States Prospective 51 71 Not reported 0 325 4 7 8 23 Not reported Quality Assessment The assessment of the methodological quality of the included studies was completed independently by 2 authors (E.R. and M.L.-H.) with the QUADAS-2 score. The QUADAS-2 results for the infection meta-analysis are displayed in Fig. 2.26 Discrepancies were discussed until a consensus was reached, although the initial level of agreement was high. As shown in the graph, most of the studies showed a low risk of bias with respect to the index test, reference standard, and flow of patients through the study/timing of the index test and reference standard. Only for patient selection was the number of studies with a low risk of bias lower than the number of studies with an unclear risk of bias. There were low levels of concern regarding applicability for most of the studies included in the infection meta-analysis. Figure 2Open in figure viewerPowerPoint Graphical display of the QUADAS-2 results of infection studies. In the infection meta-analysis, both prospective and retrospective studies were included. Three of the studies did not clearly specify the selection method, but there were no major concerns regarding the applicability of the domain of patient selection. In 2 studies, the time gap between ImmuKnow testing and the infection diagnosis was not reported.17, 19 Although this could have led to a timing bias, the interval seemed short enough, as in most of the other studies. The reference standard was evaluated in different ways. Three studies included any kind of infection during the follow-up time.17, 19, 21 Although in these studies only patients with infections received the reference standard test, there were low levels of concern with respect to applicability because infections were not assessed in transplant patients unless they developed special signs or symptoms. Partial verification bias was avoided in 2 studies because HCV recurrence was diagnosed by biopsy in all patients.16, 18 The index test performance was generally well described. In 4 studies,17-19, 21 it was not reported whether the index test was interpreted without knowledge of the reference standard; however, ImmuKnow testing has not yet been added to routine clinical practice at most centers, and the possibility of bias is low. In 3 studies,16, 18, 19 patients with a conventional cutoff of 225 μg/L were placed in the low immune response group with a higher risk of infection. Studies included in the acute rejection meta-analysis were evaluated in a similar way with the QUADAS-2 score (Fig. 3). Both prospective and retrospective studies were included. The risk of bias and concerns about applicability for all the domains were mostly low. In 2 studies, the time between ImmuKnow testing and the infection diagnosis was not reported.19, 20 In 2 studies, all included patients were biopsied, and there was no risk of partial verification bias.16, 18 In the other studies, patients were biopsied because of graft dysfunction, and although partial verification bias was possible, there were no major concerns regarding their applicability because it was the current clinical practice.19-21 The index test was performed according to the manufacturer's instructions in all studies. The cutoff defining a strong immune response was the recommended value of 525 ng/mL in 2 studies18, 19; it was not predefined in the other 3 studies.16, 20, 21 Figure 3Open in figure viewerPowerPoint Graphical display of the QUADAS-2 results of acute rejection studies. ImmuKnow Value in Predicting Infection Five studies provided complete data for investigating the diagnostic value of ImmuKnow in predicting infection in adult liver transplant recipients. Infections were defined by clinical and microbiological criteria in 3 studies and by exclusively histological criteria in only 2 reports. The pooled sensitivity, specificity, positive likelihood ratio, DOR, and SROC curve values are shown in Table 3. For the ability of the ImmuKnow test to predict infection, we found a DOR of 14.7 with a sensitivity of 83.8% and a specificity of 75.3% (Fig. 4). Figure 4Open in figure viewerPowerPoint Forest plot of individual and pooled estimate DORs for the relationship between ImmuKnow and the risk of infection. Table 3. Pooled Results for the Diagnostic Role of ImmuKnow in Predicting Infection or Acute Rejection in Adult Solid Organ Recipients Sensitivity** The 95% CIs and I2 values are presented in parentheses. Specificity** The 95% CIs and I2 values are presented in parentheses. DOR** The 95% CIs and I2 values are presented in parentheses. Summary Positive Likelihood Ratio** The 95% CIs and I2 values are presented in parentheses. SROC†† The data are presented as means and SEs. Infection 83.8% (78.5%-88.3%, 23.1%) 75.3% (70.9%-79.4%, 0.0%) 14.6 (9.6-22.3, 0.0%) 3.3 (2.8-4.0, 0.0%) 0.824 ± 0.034 Acute Rejection 65.6% (55.0%-75.1%, 86.2%) 80.4% (76.4%-83.9%, 82.2%) 8.8 (3.1-24.8, 47%) 3.4 (2.4-4.7, 16.5%) 0.835 ± 0.060 * The 95% CIs and I2 values are presented in parentheses. † The data are presented as means and SEs. Among the studies, the sensitivity and the specificity ranged from 79.2% to 96.8% and from 69.6% to 79.4%, respectively. The DOR values varied from 11.4 to 85.7. The SROC curve value for the ability of ImmuKnow to discriminate patients with further infection was 0.824 ± 0.034 (Fig. 5). The I2 values were 23.1%, 0.0%, 0.0%, and 0.0% for the sensitivity, specificity, positive likelihood ratio, and DOR, respectively, and indicated a lack of heterogeneity across all these studies. Figure 5Open in figure viewerPowerPoint SROC curve based on all studies included in the systematic review of ImmuKnow for the prediction of infection in liver transplant recipients. ImmuKnow Value in Predicting Rejection Five studies provided complete data for investigating the diagnostic value of ImmuKnow in predicting acute rejection. The pooled sensitivity, specificity, positive likelihood ratio, DOR, and SROC curve values are shown in Table 3. For the ability of the ImmuKnow test to predict rejection, we found a DOR of 8.8 with a sensitivity of 65.6% and a specificity of 80.4%. The sensitivity, specificity, and DOR ranges (9.1%-85.7%, 76.4%-98.7%, and 1.6-24.5, respectively) were wider than those for the infection studies. The SROC curve value for the ability of ImmuKnow to discriminate patients with further rejection was 0.835 ± 0.060 with a lower confidence interval (CI) limit near 0.5. The I2 values and the wide range of values indicated significant heterogeneity (Table 3). No study characteristic was related to the lack of homogeneity in the relationship between acute rejection and the ImmuKnow test. The Spearman correlation coefficient (0.500, P = 0.39) suggested that there were no threshold effects.24 DISCUSSION The main finding of our study is that the ImmuKnow test is clearly related to the further development of infection in liver transplant recipients. The overall accuracy of ImmuKnow for predicting infection is good with a sensitivity of 83.8% and a specificity of 75.3%. According to the DOR, transplant recipients with a positive ImmuKnow result have 14.6 greater odds of having an infection than patients with a negative test result. Similarly, a positive likelihood ratio of 3.3 suggests that a positive ImmuKnow result significantly increases the posttest probability of infection, and the area under the SROC curve shows the good diagnostic performance of this test for infection after liver transplantation. These results are more remarkable when we take into account that ImmuKnow was designed not as a diagnostic test for infection but as a way of monitoring the global immunosuppressive status. As in clinical practice, infections were defined with different methods and included different types of pathogens, and the studies were conducted at different institutions. Despite this, there was no heterogeneity among the included studies. In contrast, the performance of the ImmuKnow test for acute rejection was not fully demonstrated. The moderate I2 value for the DOR and the high I2 values for sensitivity and specificity indicated that there was a high degree of heterogeneity attributable to real differences among the studies rather than chance.28 Because heterogeneity due to a threshold effect was not detected and there was no other source of heterogeneity, the pooled data must be interpreted with caution. Despite the lack of homogeneity, the significant sensitivity, specificity, and DOR values suggest a possible role for the ImmuKnow test in predicting the development of acute rejection. Studies of nonliver solid organ transplant recipients have also reported that ImmuKnow is better for predicting infection than acute rejection.29-31 The ImmuKnow test provides information about the global immunosuppressive status that is not provided by any other test. Moreover, it has been shown to be related to infections in kidney transplant patients independently of other risk factors such as age, leukocyte counts, immunosuppressive therapy, and immunosuppressor blood levels30 and in lung transplant recipients independently of age, sex, race, single transplantation (versus double transplantation), cystic fibrosis, primary cytomegalovirus mismatching, and tacrolimus blood levels.32 iATP production by CD4 lymphocytes predicts infections in heart transplant patients better than soluble CD30 and various interleukin concentrations.33 In liver transplant patients, the ImmuKnow assay has also been shown to have an independent relationship with the development of invasive fungal infections (odds ratio = 3.44, 95% CI = 1.07-11.02), whereas immunosuppressive trough levels were not related.23 Our study does not rule out that the ImmuKnow test is related to further acute rejection; it shows only that it is not possible to conclude this issue because of the significant heterogeneity of the included studies. The clear relationship with infections in liver transplant recipients and the possible relationship with acute rejection suggest that the ImmuKnow test could be a useful tool for determining the immunological status of these patients. A recently published meta-analysis34 reported that ImmuKnow could not be used to identify individuals at risk of infection or rejection among solid organ transplant recipients. Because of significant heterogeneity, the authors conducted a subgroup analysis of liver transplant recipients, and they found sensitivity (85%), specificity (61%), positive likelihood ratio (2.72), and DOR values (10.22) for infection similar to ours. In contrast, the SROC value was strikingly low (0.0026). This liver transplant subgroup included only 3 studies with substantial heterogeneity, and this precluded the drawing of a definitive conclusion concerning the role of ImmuKnow in identifying patients at risk of infection or rejection. On the other hand, we included 5 studies with high heterogeneity for acute rejection prediction but with adequate homogeneity for infection prediction, and our results support the relationship between the ImmuKnow test and further infection risk in liver transplant recipients. In addition to a role in monitoring the risks of infection and acute rejection, recent reports have demonstrated a possible role for ImmuKnow in surveying different complications in the field of liver transplantation. On the one hand, the utilization of the ImmuKnow assay helped to manage immunosuppression in a group of 13 kidney or liver transplant patients with de novo malignancies.35 Cheng et al.21 reported that ImmuKnow has the potential to predict posttransplant tumor recurrence in liver transplant recipients with hepatocellular carcinoma. On the other hand, a greater suppression of cellular immunity, as measured by the ImmuKnow assay, has been associated with more rapid progression of HCV allograft fibrosis in patients with recurrent HCV after liver transplantation. For each 25-U increase in iATP levels 12 months after transplantation, the hazard of fibrosis progression decreased by 12% (P = 0.015). The monitoring of CD4-iATP activity after liver transplantation may identify a subset of patients at greatest risk for early fibrosis progression.36, 37 A prospective randomized trial is currently being conducted in liver transplant recipients: in the study group, the immunosuppression is being modulated according to ImmuKnow results, and the control group is undergoing standard monitoring. The results of this trial will clarify the role of immune monitoring by ImmuKnow in preventing infection, acute rejection, HCV-related fibrosis, and hepatocellular carcinoma after liver transplantation.38 In conclusion, we performed a systematic review and meta-analysis focusing on whether the ImmuKnow test could be used as a diagnostic tool to predict the risk of infection and acute rejection in adult liver transplant recipients. Stringent criteria for a rigorous, systematic review and a broad search strategy were applied. The study quality was evaluated with the standardized QUADAS-2 score. We summarized the evidence when heterogeneity was avoided. On the basis of our results, we conclude that the ImmuKnow test should be added to current clinical practice because it is a valid tool for determining the risk of infection in adult liver transplant recipients. 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