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Absolute Lymphocyte Count Thresholds: A Simple, Readily Available Tool to Predict the Risk of Cytomegalovirus Infection After Transplantation

Absolute Lymphocyte Count Thresholds: A Simple, Readily Available Tool to Predict the Risk of... Downloaded from https://academic.oup.com/ofid/article-abstract/5/10/ofy230/5094812 by Ed 'DeepDyve' Gillespie user on 16 October 2018 Open Forum Infectious Diseases BRIEF REPORT Board approval, we enrolled 43 consecutive patients with CMV Absolute Lymphocyte Count DNA detected in peripheral blood (COBAS Ampliprep/Taqman Thresholds: A Simple, Readily CMV Monitor, Roche Diagnostics). In parallel, we randomly Available Tool to Predict the Risk selected 21 transplant patients undergoing CMV surveillance who did not develop CMV infection. of Cytomegalovirus Infection Aer ft CMV-seropositive (CMV R+) HSCT recipients underwent Transplantation weekly CMV surveillance, and any quantifiable CMV (>137 1,2, 1,3 Atibordee Meesing and Raymund R. Razonable IU/mL of plasma) was treated with intravenous ganciclovir or Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota; oral valganciclovir. Valganciclovir prophylaxis was given for Division of Infectious Disease and Tropical Medicine, Department of Medicine, Khon Kaen 3 3  months to moderate-risk CMV R+ kidney, pancreas, and University, Khonkean, Thailand; William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine and Science, Rochester, Minnesota heart recipients; 6  months to high-risk CMV D+/R- kidney, liver, heart, and pancreas recipients and CMV R+ lung recipi- This study of 64 solid organ and hematopoietic stem cell trans- ents; and 12 months for CMV D+/R- lung recipients. CMV R+ plant recipients found that peripheral blood absolute lympho- liver recipients underwent CMV surveillance, and preemptive cyte count of <610 and <830/µL, respectively, correlated with valganciclovir therapy was initiated when a viral load of 1000 cytomegalovirus infection. In an era when sophisticated meas- IU/mL of plasma was reached. All D+/R- SOT patients under- ures of CMV-specific T cells are emerging, we emphasize the went CMV surveillance for 3 months aer ft completing antiviral utility of the inexpensive and readily-available absolute lym- prophylaxis [7]. phocyte count. Clinical and laboratory data were recorded, including viral load Keywords. infection; cytomegalovirus; lymphocyte. and PBALC (differential count). PBALC values were collected from pretransplant, pre-CMV (2–4 weeks before CMV infection or testing), time of CMV infection (or CMV PCR testing), and Effective control of cytomegalovirus (CMV), a common infec- virologic clearance (for those with CMV). PBALC was correlated tion aer s ft olid organ transplantation (SOT) and hematopoie- with CMV infection, which was defined as detection of CMV by tic stem cell transplantation (HSCT) [1, 2], requires functional nucleic acid testing of blood (CMV DNAemia) or other speci- CMV-specific T cells [3–5]. There is increasing interest in utilizing mens, or demonstration of CMV-associated cytopathic changes sophisticated CMV-specific T-cell assays for CMV prognostication on histopathology [8]. CMV nucleic acid testing was performed aer t ft ransplantation, but these are expensive and are not readily using COBAS Ampliprep/Taqman (Roche Diagnostics), as pre- available. Based on observations that the risk of CMV infection viously described [9]. If accompanied by symptoms and signs, and relapse is associated with lymphopenia [6], we aimed to define CMV infection was further categorized as a CMV syndrome (for the peripheral blood absolute lymphocyte count (PBALC) thresh- SOT) or tissue-invasive CMV disease [10]. Patients without signs old that correlates with CMV infection in SOT and HSCT patients. and symptoms were categorized simply as having CMV infection. Statistical Analysis METHODS The chi-square test or Fisher exact test was used to compare Study Population categorical variables. Both CMV infection and disease were This observational study was conducted between July 1, 2017, considered outcome variables of the study. Bivariate correlation and March 31, 2018. After Mayo Clinic Institutional Review analyses were performed using the Pearson or Spearman test for nonparametric variables. The 2-tailed statistical significance level was P < .05. Receiver operating characteristic curve ana- lysis was used to determine the PBALC cutoff associated with Received 29 June 2018; editorial decision 5 September 2018; accepted 7 September 2018. Correspondence: R. R. Razonable, MD, Division of Infectious Diseases, Mayo Clinic, 200 First CMV infection and disease. Associations were expressed as Street SW, Rochester, MN 55905 (razonable.raymund@mayo.edu). hazard ratio (HR) and 95% confidence interval (CI). All analy- Open Forum Infectious Diseases ses were performed with JMP software. © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ RESULTS by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work Sixty-four SOT (56%) and HSCT (44%) patients were enrolled; is properly cited. For commercial re-use, please contact journals.permissions@oup.com 43 (67.2%) had CMV infection or disease. Before transplant, the DOI: 10.1093/ofid/ofy230 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/10/ofy230/5094812 by Ed 'DeepDyve' Gillespie user on 16 October 2018 median PBALC for all 64 patients (interquartile range [IQR]) Twenty-five of 36 patients developed CMV (infection, 72%; was 965/µL (750–1515). Among 43 patients who developed disease, 28%) at a median (IQR) of 7 (2.4–9.3) months aer ft CMV infection or disease, the median PBALC (IQR) declined transplantation. Among SOT recipients, a PBALC <610/µL cor- from a pretransplant value of 1050/µL (810–1520) to 450/µL related with CMV infection and disease (sensitivity, 80%; spec- (330–640; P < .0001) at onset of infection; the median PBALC ificity, 73%). Patients with a PBALC <610/µL had a higher risk (IQR) 2–4 weeks before onset of CMV infection was 490/µL of CMV compared with those with a PBALC ≥610/µL (HR, 2.2; (170–950). The 10 patients with CMV disease had a signifi- 95% CI, 0.91–6.97; P = .08). The median PBALC of SOT patients cantly lower median PBALC (315/µL; IQR, 155–520) than the 33 with CMV infection or disease was lower than patients without patients with CMV infection (450/µL; IQR, 365–670; P  = .03). CMV, whereas the median PBALC was lower among patients In contrast, the median PBALC of 21 transplant recipients who with CMV disease than those with CMV infection (Table 2). did not develop CMV infection or disease increased from a PBALC and Risk of CMV in HSCT Patients pretransplant baseline (IQR) of 870/µL (635–1430) to 1060/µL The 28 HSCT recipients had a median age (IQR) of 60 (37– (630–2215; P = .07). Overall, a PBALC <830/µL after transplan- 66) years, with equal gender distribution. The majority were tation correlated with the development of CMV infection or CMV-seropositive (D+/R+, 36%; D-/R+, 43%) and recipients disease (sensitivity, 95%; specificity, 71%). A  PBALC <830/µL of matched unrelated transplants (57%) (Table  1). Eighteen of conferred a higher risk of CMV infection or disease compared 28 patients developed CMV (infection, 83%; pneumonia or with ≥830/µL (HR, 7.5; 95% CI, 2.69–31.03; P < .0001). enterocolitis, 17%) at a median (IQR) of 1.6 (1.4–6.1) months PBALC and Risk of CMV in SOT Patients after transplantation. A PBALC <830/µL correlated with CMV The SOT cohort had a median age (IQR) of 52 (40–62) years (sensitivity, 100%; specificity, 80%). Patients with a PBALC and was mostly male (72%) (Table  1). CMV risk statuses were <830/µL had a higher risk of CMV compared with a PBALC D+/R- (58%), D+/R+ (30%), and D-/R+ (11%). The most com- ≥830/µL (HR, 10.1; 95% CI, 2.05–181.88; P = .002). The median mon types of organ transplant were liver (47%), kidney with or PBALC of HSCT patients with CMV infection or disease was without pancreas (22%), and lung or heart-lung (14%). significantly lower than in patients without CMV, but there was no difference in median PBALC between patients with CMV infection and disease (Table 2). PBALC and the Duration of CMV DNAemia and Risk of Relapse Table  1. Baseline Characteristics of 64 Solid Organ and Hematopoietic Stem Cell Transplant Recipients The median duration of CMV DNAemia (IQR) was 19 (14– 32) days and was similar between patients with CMV disease   SOT (n = 36) HSCT (n = 28) (22 days; IQR, 14–45) and CMV infection (19 days; IQR, 14–33; Age (IQR), y 52 (40–62) 60 (37–66) P  =  .86), and those with a PBALC ≥830/µL (22  days; IQR, Male, No. (%) 26 (72.2) 15 (53.4) 14–28) and <830/µL (19 days; IQR, 14–34; P = .92). White, No. (%) 33 (91.7) 28 (100) Recurrent CMV infection (11.6%; 3 SOT and 2 HSCT) CMV status, No. (%) occurred at median (IQR) of 3.6 (2.8–4.1) months aer ini ft - D+R+ 11 (30.6) 10 (35.7) tial infection. A PBALC <390/µL at the time of viral clearance D+R- 21 (58.3) 2 (7.1) D-R+ 4 (11.1) 12 (42.9) correlated with CMV recurrence (sensitivity, 80%; specificity, Type of transplant (SOT), No. (%) 90%). Patients with a PBALC <390/µL upon viral clearance Lung 2 (5.6) had a higher risk of recurrence than those with a PBALC ≥390/ Heart/lung 3 (8.3) µL (HR, 6.4; 95% CI, 1.05–49.49; P  =  .04). Notably, 5 patients Kidney 5 (13.9) with recurrence had a nonsignificant decline in median PBALC Kidney/pancreas 3 (8.3) during antiviral treatment (450; IQR, 215–575; to 220/µL; IQR, Liver 17 (47.2) Liver/heart 1 (2.8) 7–390). In contrast, the median PBALC in 38 patients without Pancreas 2 (5.6) CMV recurrence significantly increased from a pretreatment Heart 1 (2.8) value (IQR) of 445/µL (328–663) to 985/µL (675–1365; P < Heart/kidney 2 (5.6) .0001) at the time of viral clearance. Type of transplant (HSCT), No. (%) Matched related 9 (32.1) DISCUSSION Matched unrelated 16 (57.1) Haploidentical 1 (3.6) Lymphocytopenia is a major risk factor for CMV after transplan- Autologous 2 (7.1) tation [6, 11]. The PBALC was low among transplant recipients Onset to CMV infection and disease (IQR), mo 7 (2.4–9.3) 1.6 (1.4–6.1) who developed CMV infection, especially transplant recipients Abbreviations, CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; with CMV disease, and those patients who had recurrent CMV IQR, interquartile range; PBALC, peripheral blood absolute lymphocyte count; SOT, solid organ transplantation. infection. Herein, we propose PBALC values of <830/µL for 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/10/ofy230/5094812 by Ed 'DeepDyve' Gillespie user on 16 October 2018 Table  2. Peripheral Blood Lymphocyte Subsets Among Transplant Patients With CMV Disease, CMV Infection, and Those Who Did Not Develop CMV Infection CMV Disease CMV Infection No CMV Infection P Value SOT (n = 36) n = 7 n = 18 n = 11 1140 1260 890 .55 Pretransplant median PBALC (IQR), /µL (800–1790) (855–1595) (660–1590) 270 450 1120 .001 Median PBALC at 1st CMV (IQR), /µL (140–460) (388–675) (590–1400) HSCT (n = 28) n = 3 n = 15 n = 10 560 970 780 .39 Pretransplant median PBALC (IQR), /µL (16–1060) (730–1080) (483–1355) 520 510 1020 .03 Median PBALC at 1st CMV (IQR), /µL (300–560) (330–670) (795–3308) Abbreviations, CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; IQR, interquartile range; PBALC, peripheral blood absolute lymphocyte count; SOT, solid organ transplantation. Use PBALC on the first day of CMV virological testing. emerging, our study emphasizes the clinical utility of an inex- HSCT and <610/µL for SOT as clinically relevant thresholds for pensive, commonly ordered, and readily available PBALC—a predicting the risk of CMV infection and disease after trans- component of routine differential of a complete blood count. plantation. Moreover, we also observed that a PBALC of <390/ µL (and lack of lymphocyte recovery) at the time of virologic Acknowledgments clearance correlated with subsequent CMV recurrence. Financial support. This study did not have any financial support. Lymphocyte depletion during the post-transplant period is a Potential conifl cts of interest. All authors: no reported conflicts of recognized risk factor for CMV infection or disease, although interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the magnitude of clinically relevant decline is not fully defined. the content of the manuscript have been disclosed. We observed that SOT and HSCT recipients who developed CMV infection had a significant decline in PBALC during the References post-transplant period to a level <830/µL for HSCT and <610/ 1. Harvala H, Stewart C, Muller K, et  al. High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy. J Med Virol µL for SOT. In contrast, the PBALC among patients who did not 2013; 85:893–8. develop CMV infection increased. Moreover, we also observed 2. Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection fol- that further decline (or lack of significant recovery) in lympho- lowing hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther 2017; 10:233–8. cyte count during antiviral treatment of CMV infection and dis- 3. Roddie C, Peggs KS. Immunotherapy for transplantation-associated viral infec- ease may predict risk of relapse. In our cohort, a declining trend tions. J Clin Invest 2017; 127:2513–22. 4. van Rhee F, Barrett J. Adoptive transfer of Ag-specific T cells to prevent CMV in PBALC during antiviral treatment correlated with CMV disease after allogeneic stem-cell transplantation. Cytotherapy 2002; 4:3–10. relapse, whereas recovery of lymphocyte count during antiviral 5. Mui TS, Kapp M, Einsele H, Grigoleit GU. T-cell therapy for cytomegalovirus infection. Curr Opin Organ Transplant 2010; 15:744–50. treatment correlated with lack of recurrence. 6. Gardiner BJ, Nierenberg NE, Chow JK, et al. Absolute lymphocyte count: a pre- e r Th esults of our study are limited by the relatively small size dictor of recurrent cytomegalovirus disease in solid organ transplant recipients. Clin Infect Dis. In press. of a heterogenous cohort of SOT and HSCT recipients, and thus, 7. Arthurs SK, Eid AJ, Deziel PJ, et  al. The impact of invasive fungal diseases on we were unable to perform multivariate analysis. Accordingly, we survival after lung transplantation. Clin Transplant 2010; 24:341–8. encourage other clinician-scientists to perform similar studies to 8. Razonable RR, Humar A; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13(Suppl confirm our findings. In another study of a larger cohort of 130 4):93–106. SOT recipients, we also found a similar value: A PBALC of <630/ 9. Razonable RR, Åsberg A, Rollag H, et  al. Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization µL was significantly correlated with CMV infection or disease international standard is predictive of CMV disease resolution in transplant [12]. Hence, we believe that our observations may be reproducible. recipients. Clin Infect Dis 2013; 56:1546–53. 10. Ljungman P, Boeckh M, Hirsch HH, et al; Disease Definitions Working Group of In conclusion, we highlight the importance of the simple, the Cytomegalovirus Drug Development Forum. Definitions of cytomegalovirus readily available PBALC as a prognostic indicator of CMV infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 2017; 64:87–91. risk and outcome aer t ft ransplantation. Specifically, a PBALC 11. Nierenberg NE, Poutsiaka DD, Chow JK, et  al. Pretransplant lymphopenia is a <830/µL in HSCT and <610/µL in SOT can serve as a marker novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive of a transplant patient’s heightened risk for CMV. Moreover, infections after liver transplantation. Liver Transpl 2014; 20:1497–507. 12. Meesing A, Abraham R, Razonable RR. CMV-specific CD8+ T-cell immune com- a declining trend over time may also serve a similar prognos- petence score as predictor of outcome for CMV infection after transplantation. tic role. In an era when measuring CMV-specific T cells is Am J Transplant 2018; 18(Suppl 4):877–877. BRIEF REPORT • OFID • 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Absolute Lymphocyte Count Thresholds: A Simple, Readily Available Tool to Predict the Risk of Cytomegalovirus Infection After Transplantation

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© The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
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Abstract

Downloaded from https://academic.oup.com/ofid/article-abstract/5/10/ofy230/5094812 by Ed 'DeepDyve' Gillespie user on 16 October 2018 Open Forum Infectious Diseases BRIEF REPORT Board approval, we enrolled 43 consecutive patients with CMV Absolute Lymphocyte Count DNA detected in peripheral blood (COBAS Ampliprep/Taqman Thresholds: A Simple, Readily CMV Monitor, Roche Diagnostics). In parallel, we randomly Available Tool to Predict the Risk selected 21 transplant patients undergoing CMV surveillance who did not develop CMV infection. of Cytomegalovirus Infection Aer ft CMV-seropositive (CMV R+) HSCT recipients underwent Transplantation weekly CMV surveillance, and any quantifiable CMV (>137 1,2, 1,3 Atibordee Meesing and Raymund R. Razonable IU/mL of plasma) was treated with intravenous ganciclovir or Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota; oral valganciclovir. Valganciclovir prophylaxis was given for Division of Infectious Disease and Tropical Medicine, Department of Medicine, Khon Kaen 3 3  months to moderate-risk CMV R+ kidney, pancreas, and University, Khonkean, Thailand; William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine and Science, Rochester, Minnesota heart recipients; 6  months to high-risk CMV D+/R- kidney, liver, heart, and pancreas recipients and CMV R+ lung recipi- This study of 64 solid organ and hematopoietic stem cell trans- ents; and 12 months for CMV D+/R- lung recipients. CMV R+ plant recipients found that peripheral blood absolute lympho- liver recipients underwent CMV surveillance, and preemptive cyte count of <610 and <830/µL, respectively, correlated with valganciclovir therapy was initiated when a viral load of 1000 cytomegalovirus infection. In an era when sophisticated meas- IU/mL of plasma was reached. All D+/R- SOT patients under- ures of CMV-specific T cells are emerging, we emphasize the went CMV surveillance for 3 months aer ft completing antiviral utility of the inexpensive and readily-available absolute lym- prophylaxis [7]. phocyte count. Clinical and laboratory data were recorded, including viral load Keywords. infection; cytomegalovirus; lymphocyte. and PBALC (differential count). PBALC values were collected from pretransplant, pre-CMV (2–4 weeks before CMV infection or testing), time of CMV infection (or CMV PCR testing), and Effective control of cytomegalovirus (CMV), a common infec- virologic clearance (for those with CMV). PBALC was correlated tion aer s ft olid organ transplantation (SOT) and hematopoie- with CMV infection, which was defined as detection of CMV by tic stem cell transplantation (HSCT) [1, 2], requires functional nucleic acid testing of blood (CMV DNAemia) or other speci- CMV-specific T cells [3–5]. There is increasing interest in utilizing mens, or demonstration of CMV-associated cytopathic changes sophisticated CMV-specific T-cell assays for CMV prognostication on histopathology [8]. CMV nucleic acid testing was performed aer t ft ransplantation, but these are expensive and are not readily using COBAS Ampliprep/Taqman (Roche Diagnostics), as pre- available. Based on observations that the risk of CMV infection viously described [9]. If accompanied by symptoms and signs, and relapse is associated with lymphopenia [6], we aimed to define CMV infection was further categorized as a CMV syndrome (for the peripheral blood absolute lymphocyte count (PBALC) thresh- SOT) or tissue-invasive CMV disease [10]. Patients without signs old that correlates with CMV infection in SOT and HSCT patients. and symptoms were categorized simply as having CMV infection. Statistical Analysis METHODS The chi-square test or Fisher exact test was used to compare Study Population categorical variables. Both CMV infection and disease were This observational study was conducted between July 1, 2017, considered outcome variables of the study. Bivariate correlation and March 31, 2018. After Mayo Clinic Institutional Review analyses were performed using the Pearson or Spearman test for nonparametric variables. The 2-tailed statistical significance level was P < .05. Receiver operating characteristic curve ana- lysis was used to determine the PBALC cutoff associated with Received 29 June 2018; editorial decision 5 September 2018; accepted 7 September 2018. Correspondence: R. R. Razonable, MD, Division of Infectious Diseases, Mayo Clinic, 200 First CMV infection and disease. Associations were expressed as Street SW, Rochester, MN 55905 (razonable.raymund@mayo.edu). hazard ratio (HR) and 95% confidence interval (CI). All analy- Open Forum Infectious Diseases ses were performed with JMP software. © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ RESULTS by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work Sixty-four SOT (56%) and HSCT (44%) patients were enrolled; is properly cited. For commercial re-use, please contact journals.permissions@oup.com 43 (67.2%) had CMV infection or disease. Before transplant, the DOI: 10.1093/ofid/ofy230 BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/10/ofy230/5094812 by Ed 'DeepDyve' Gillespie user on 16 October 2018 median PBALC for all 64 patients (interquartile range [IQR]) Twenty-five of 36 patients developed CMV (infection, 72%; was 965/µL (750–1515). Among 43 patients who developed disease, 28%) at a median (IQR) of 7 (2.4–9.3) months aer ft CMV infection or disease, the median PBALC (IQR) declined transplantation. Among SOT recipients, a PBALC <610/µL cor- from a pretransplant value of 1050/µL (810–1520) to 450/µL related with CMV infection and disease (sensitivity, 80%; spec- (330–640; P < .0001) at onset of infection; the median PBALC ificity, 73%). Patients with a PBALC <610/µL had a higher risk (IQR) 2–4 weeks before onset of CMV infection was 490/µL of CMV compared with those with a PBALC ≥610/µL (HR, 2.2; (170–950). The 10 patients with CMV disease had a signifi- 95% CI, 0.91–6.97; P = .08). The median PBALC of SOT patients cantly lower median PBALC (315/µL; IQR, 155–520) than the 33 with CMV infection or disease was lower than patients without patients with CMV infection (450/µL; IQR, 365–670; P  = .03). CMV, whereas the median PBALC was lower among patients In contrast, the median PBALC of 21 transplant recipients who with CMV disease than those with CMV infection (Table 2). did not develop CMV infection or disease increased from a PBALC and Risk of CMV in HSCT Patients pretransplant baseline (IQR) of 870/µL (635–1430) to 1060/µL The 28 HSCT recipients had a median age (IQR) of 60 (37– (630–2215; P = .07). Overall, a PBALC <830/µL after transplan- 66) years, with equal gender distribution. The majority were tation correlated with the development of CMV infection or CMV-seropositive (D+/R+, 36%; D-/R+, 43%) and recipients disease (sensitivity, 95%; specificity, 71%). A  PBALC <830/µL of matched unrelated transplants (57%) (Table  1). Eighteen of conferred a higher risk of CMV infection or disease compared 28 patients developed CMV (infection, 83%; pneumonia or with ≥830/µL (HR, 7.5; 95% CI, 2.69–31.03; P < .0001). enterocolitis, 17%) at a median (IQR) of 1.6 (1.4–6.1) months PBALC and Risk of CMV in SOT Patients after transplantation. A PBALC <830/µL correlated with CMV The SOT cohort had a median age (IQR) of 52 (40–62) years (sensitivity, 100%; specificity, 80%). Patients with a PBALC and was mostly male (72%) (Table  1). CMV risk statuses were <830/µL had a higher risk of CMV compared with a PBALC D+/R- (58%), D+/R+ (30%), and D-/R+ (11%). The most com- ≥830/µL (HR, 10.1; 95% CI, 2.05–181.88; P = .002). The median mon types of organ transplant were liver (47%), kidney with or PBALC of HSCT patients with CMV infection or disease was without pancreas (22%), and lung or heart-lung (14%). significantly lower than in patients without CMV, but there was no difference in median PBALC between patients with CMV infection and disease (Table 2). PBALC and the Duration of CMV DNAemia and Risk of Relapse Table  1. Baseline Characteristics of 64 Solid Organ and Hematopoietic Stem Cell Transplant Recipients The median duration of CMV DNAemia (IQR) was 19 (14– 32) days and was similar between patients with CMV disease   SOT (n = 36) HSCT (n = 28) (22 days; IQR, 14–45) and CMV infection (19 days; IQR, 14–33; Age (IQR), y 52 (40–62) 60 (37–66) P  =  .86), and those with a PBALC ≥830/µL (22  days; IQR, Male, No. (%) 26 (72.2) 15 (53.4) 14–28) and <830/µL (19 days; IQR, 14–34; P = .92). White, No. (%) 33 (91.7) 28 (100) Recurrent CMV infection (11.6%; 3 SOT and 2 HSCT) CMV status, No. (%) occurred at median (IQR) of 3.6 (2.8–4.1) months aer ini ft - D+R+ 11 (30.6) 10 (35.7) tial infection. A PBALC <390/µL at the time of viral clearance D+R- 21 (58.3) 2 (7.1) D-R+ 4 (11.1) 12 (42.9) correlated with CMV recurrence (sensitivity, 80%; specificity, Type of transplant (SOT), No. (%) 90%). Patients with a PBALC <390/µL upon viral clearance Lung 2 (5.6) had a higher risk of recurrence than those with a PBALC ≥390/ Heart/lung 3 (8.3) µL (HR, 6.4; 95% CI, 1.05–49.49; P  =  .04). Notably, 5 patients Kidney 5 (13.9) with recurrence had a nonsignificant decline in median PBALC Kidney/pancreas 3 (8.3) during antiviral treatment (450; IQR, 215–575; to 220/µL; IQR, Liver 17 (47.2) Liver/heart 1 (2.8) 7–390). In contrast, the median PBALC in 38 patients without Pancreas 2 (5.6) CMV recurrence significantly increased from a pretreatment Heart 1 (2.8) value (IQR) of 445/µL (328–663) to 985/µL (675–1365; P < Heart/kidney 2 (5.6) .0001) at the time of viral clearance. Type of transplant (HSCT), No. (%) Matched related 9 (32.1) DISCUSSION Matched unrelated 16 (57.1) Haploidentical 1 (3.6) Lymphocytopenia is a major risk factor for CMV after transplan- Autologous 2 (7.1) tation [6, 11]. The PBALC was low among transplant recipients Onset to CMV infection and disease (IQR), mo 7 (2.4–9.3) 1.6 (1.4–6.1) who developed CMV infection, especially transplant recipients Abbreviations, CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; with CMV disease, and those patients who had recurrent CMV IQR, interquartile range; PBALC, peripheral blood absolute lymphocyte count; SOT, solid organ transplantation. infection. Herein, we propose PBALC values of <830/µL for 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/10/ofy230/5094812 by Ed 'DeepDyve' Gillespie user on 16 October 2018 Table  2. Peripheral Blood Lymphocyte Subsets Among Transplant Patients With CMV Disease, CMV Infection, and Those Who Did Not Develop CMV Infection CMV Disease CMV Infection No CMV Infection P Value SOT (n = 36) n = 7 n = 18 n = 11 1140 1260 890 .55 Pretransplant median PBALC (IQR), /µL (800–1790) (855–1595) (660–1590) 270 450 1120 .001 Median PBALC at 1st CMV (IQR), /µL (140–460) (388–675) (590–1400) HSCT (n = 28) n = 3 n = 15 n = 10 560 970 780 .39 Pretransplant median PBALC (IQR), /µL (16–1060) (730–1080) (483–1355) 520 510 1020 .03 Median PBALC at 1st CMV (IQR), /µL (300–560) (330–670) (795–3308) Abbreviations, CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; IQR, interquartile range; PBALC, peripheral blood absolute lymphocyte count; SOT, solid organ transplantation. Use PBALC on the first day of CMV virological testing. emerging, our study emphasizes the clinical utility of an inex- HSCT and <610/µL for SOT as clinically relevant thresholds for pensive, commonly ordered, and readily available PBALC—a predicting the risk of CMV infection and disease after trans- component of routine differential of a complete blood count. plantation. Moreover, we also observed that a PBALC of <390/ µL (and lack of lymphocyte recovery) at the time of virologic Acknowledgments clearance correlated with subsequent CMV recurrence. Financial support. This study did not have any financial support. Lymphocyte depletion during the post-transplant period is a Potential conifl cts of interest. All authors: no reported conflicts of recognized risk factor for CMV infection or disease, although interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the magnitude of clinically relevant decline is not fully defined. the content of the manuscript have been disclosed. We observed that SOT and HSCT recipients who developed CMV infection had a significant decline in PBALC during the References post-transplant period to a level <830/µL for HSCT and <610/ 1. Harvala H, Stewart C, Muller K, et  al. High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy. J Med Virol µL for SOT. In contrast, the PBALC among patients who did not 2013; 85:893–8. develop CMV infection increased. Moreover, we also observed 2. Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection fol- that further decline (or lack of significant recovery) in lympho- lowing hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther 2017; 10:233–8. cyte count during antiviral treatment of CMV infection and dis- 3. Roddie C, Peggs KS. Immunotherapy for transplantation-associated viral infec- ease may predict risk of relapse. In our cohort, a declining trend tions. J Clin Invest 2017; 127:2513–22. 4. van Rhee F, Barrett J. Adoptive transfer of Ag-specific T cells to prevent CMV in PBALC during antiviral treatment correlated with CMV disease after allogeneic stem-cell transplantation. Cytotherapy 2002; 4:3–10. relapse, whereas recovery of lymphocyte count during antiviral 5. Mui TS, Kapp M, Einsele H, Grigoleit GU. T-cell therapy for cytomegalovirus infection. Curr Opin Organ Transplant 2010; 15:744–50. treatment correlated with lack of recurrence. 6. Gardiner BJ, Nierenberg NE, Chow JK, et al. Absolute lymphocyte count: a pre- e r Th esults of our study are limited by the relatively small size dictor of recurrent cytomegalovirus disease in solid organ transplant recipients. Clin Infect Dis. In press. of a heterogenous cohort of SOT and HSCT recipients, and thus, 7. Arthurs SK, Eid AJ, Deziel PJ, et  al. The impact of invasive fungal diseases on we were unable to perform multivariate analysis. Accordingly, we survival after lung transplantation. Clin Transplant 2010; 24:341–8. encourage other clinician-scientists to perform similar studies to 8. Razonable RR, Humar A; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13(Suppl confirm our findings. In another study of a larger cohort of 130 4):93–106. SOT recipients, we also found a similar value: A PBALC of <630/ 9. Razonable RR, Åsberg A, Rollag H, et  al. Virologic suppression measured by a cytomegalovirus (CMV) DNA test calibrated to the World Health Organization µL was significantly correlated with CMV infection or disease international standard is predictive of CMV disease resolution in transplant [12]. Hence, we believe that our observations may be reproducible. recipients. Clin Infect Dis 2013; 56:1546–53. 10. Ljungman P, Boeckh M, Hirsch HH, et al; Disease Definitions Working Group of In conclusion, we highlight the importance of the simple, the Cytomegalovirus Drug Development Forum. Definitions of cytomegalovirus readily available PBALC as a prognostic indicator of CMV infection and disease in transplant patients for use in clinical trials. Clin Infect Dis 2017; 64:87–91. risk and outcome aer t ft ransplantation. Specifically, a PBALC 11. Nierenberg NE, Poutsiaka DD, Chow JK, et  al. Pretransplant lymphopenia is a <830/µL in HSCT and <610/µL in SOT can serve as a marker novel prognostic factor in cytomegalovirus and noncytomegalovirus invasive of a transplant patient’s heightened risk for CMV. Moreover, infections after liver transplantation. Liver Transpl 2014; 20:1497–507. 12. Meesing A, Abraham R, Razonable RR. CMV-specific CD8+ T-cell immune com- a declining trend over time may also serve a similar prognos- petence score as predictor of outcome for CMV infection after transplantation. tic role. In an era when measuring CMV-specific T cells is Am J Transplant 2018; 18(Suppl 4):877–877. BRIEF REPORT • OFID • 3

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Open Forum Infectious DiseasesOxford University Press

Published: Oct 1, 2018

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