Diagnostic Test Accuracy of Antigenemiafor Cytomegalovirus Infection

Diagnostic test accuracy of antigenemiafor cytomegalovirus infection

[Supplement file]

Authors

Hisashi Eguchi, Nobuyuki Horita, Ryota Ushio, Ikuma Kato, Yuki Nakajima, Erika Ota,Takeshi Kaneko.

Supplement Text 1. Search formulas.

PubMed

(((cytomegalovirus OR CMV OR HCMV OR cytomegaloviral OR (cytomeg virus) OR HHV-5 OR HHV5 OR "human herpesvirus 5" OR "human herpesvirus-5" OR betaherpesvirinae) AND (antigenemia OR antigenaemia OR (antigen blood))) OR pp65 OR pp65emia) AND (PCR OR (polymerase chain reaction) OR (polymerase-chain-reaction)) AND (sensitivity OR specificity OR "predictive value" OR "likelihood" OR "true positive" OR "true negative" OR "false positive" OR "false negative" OR "diagnostic odds ratio").

Web Ob Science Core Collection Advanced Search

#1: TS=((cytomegalovirus OR CMV OR HCMV OR cytomegaloviral OR (cytomeg virus) OR HHV-5 OR HHV5 OR "human herpesvirus 5"OR "human herpesvirus-5"OR betaherpesvirinae) AND (antigenemia OR antigenaemia OR (antigen blood))

#2: TS=(pp65 OR pp65emia)

#3: TS=(PCR OR (polymerase chain reaction) OR (polymerase-chain-reaction))

#4: TS=(sensitivity OR specificity OR "predictive value" OR "likelihood" OR "true positive" OR "true negative" OR "false positive" OR "false negative" OR "diagnostic odds ratio")

(#1 OR #2) AND #3 AND #4 258

Cochrane Library hosts the Central Register of Controlled Trials

Embase

('cytomegalovirus'/exp OR cytomegalovirus OR cmv OR 'hcmv'/exp OR hcmv OR cytomegaloviral OR 'hhv 5'/exp OR 'hhv 5' OR hhv5 OR 'human herpesvirus 5'/exp OR 'human herpesvirus 5' OR 'human herpesvirus-5'/exp OR 'human herpesvirus-5' OR 'betaherpesvirinae'/exp OR betaherpesvirinae OR pp65 OR pp65emia) AND (antigenemia OR antigenaemia OR pp65 OR pp65emia) AND (pcr OR (polymerase AND chain AND reaction) OR 'polymerase chain reaction'/exp OR 'polymerase chain reaction') AND (sensitivity OR specificity OR 'predictive value'/exp OR 'predictive value' OR 'likelihood' OR 'true positive' OR 'true negative' OR 'false positive' OR 'false negative' OR 'diagnostic odds ratio')

Supplement text 2. List of included studies.

1. Allice T, Cerutti F, Pittaluga F, et al. Evaluation of a novel real-time PCR system for cytomegalovirus DNA quantitation on whole blood and correlation with pp65-antigen test in guiding pre-emptive antiviral treatment. J Virol Methods 2008;148(1-2):9-16. doi: 10.1016/j.jviromet.2007.10.006

2. Ashokkumar, C. Ningappa, M. Mazariegos, G. Soltys, K. Bond, G. Trautz, C. Green, M. Michaels, M. Sindhi, R. TCMV-specific CD154+T-cells and CMV disease status after liver or intestine transplantation (LTX, ITX). Am J Transplant. 2016;15.

3. Beckmann C, Dumoulin A, Rinaldo CH, et al. Comparison of a UL111a real-time PCR and pp65 antigenemia for the detection of cytomegalovirus. J Med Virol 2011;83(12):2143-50. doi: 10.1002/jmv.22232

4. Bergallo M, Costa C, Terlizzi ME, et al. Evaluation of two set of primers for detection of immediate early gene UL123 of human cytomegalovirus (HCMV). Mol Biotechnol 2008;38(1):65-70. doi: 10.1007/s12033-007-0074-5

5. Boaretti M, Sorrentino A, Zantedeschi C, et al. Quantification of cytomegalovirus DNA by a fully automated real-time PCR for early diagnosis and monitoring of active viral infection in solid organ transplant recipients. J Clin Virol 2013;56(2):124-8. doi: 10.1016/j.jcv.2012.10.015

6. Boeckh M, Gallez-Hawkins GM, Myerson D, et al. Plasma polymerase chain reaction for cytomegalovirus DNA after allogeneic marrow transplantation: comparison with polymerase chain reaction using peripheral blood leukocytes, pp65 antigenemia, and viral culture. Transplantation 1997;64(1):108-13.

7. Boeckh M, Huang M, Ferrenberg J, et al. Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR. J Clin Microbiol 2004;42(3):1142-8.

8. Boivin G, Handfield J, Toma E, et al. Evaluation of the AMPLICOR cytomegalovirus test with specimens from human immunodeficiency virus-infected subjects. J Clin Microbiol 1998;36(9):2509-13.

9. Boland GJ, de Weger RA, Tilanus MG, et al. Detection of cytomegalovirus (CMV) in granulocytes by polymerase chain reaction compared with the CMV antigen test. J Clin Microbiol 1992;30(7):1763-7.

10. Bonon SH, Rossi CL, de Souza CA, et al. Comparison of serology, antigenemia assay and the polymerase chain reaction for monitoring active cytomegalovirus infections in hematopoietic stem cell transplantation patients. Rev Inst Med Trop Sao Paulo 2006;48(5):275-8.

11. Breda G, Almeida B, Carstensen S, et al. Human cytomegalovirus detection by real-time PCR and pp65-antigen test in hematopoietic stem cell transplant recipients: a challenge in low and middle-income countries. Pathog Glob Health 2013;107(6):312-9. doi: 10.1179/2047773213Y.0000000114

12. Camargo LF, Uip DE, Simpson AA, et al. Comparison between antigenemia and a quantitative-competitive polymerase chain reaction for the diagnosis of cytomegalovirus infection after heart transplantation. Transplantation 2001;71(3):412-7.

13. Cardeñoso L, Pinsky BA, Lautenschlager I, et al. CMV antigenemia and quantitative viral load assessments in hematopoietic stem cell transplant recipients. J Clin Virol 2013;56(2):108-12. doi: 10.1016/j.jcv.2012.10.001

14. Cathomas G, Tamm M, Bock A, et al. [Early diagnosis of cytomegalovirus infection and disease in patients following kidney transplantation]. Schweiz Med Wochenschr 1994;124(45):2042-5.

15. Choi SM, Lee DG, Lim J, et al. Comparison of quantitative cytomegalovirus real-time PCR in whole blood and pp65 antigenemia assay: clinical utility of CMV real-time PCR in hematopoietic stem cell transplant recipients. J Korean Med Sci 2009;24(4):571-8. doi: 10.3346/jkms.2009.24.4.571

16. Martín-Dávila P, Fortún J, Gutiérrez C, et al. Analysis of a quantitative PCR assay for CMV infection in liver transplant recipients: an intent to find the optimal cut-off value. J Clin Virol 2005;33(2):138-44. doi: 10.1016/j.jcv.2004.09.032

17. Deback C, Fillet AM, Dhedin N, et al. Monitoring of human cytomegalovirus infection in immunosuppressed patients using real-time PCR on whole blood. J Clin Virol 2007;40(3):173-9. doi: 10.1016/j.jcv.2007.08.014

18. Eckart P, Brouard J, Legoff C, et al. Virological diagnosis of cytomegalovirus in renal transplantation: comparison of three diagnostic methods: DNA in plasma by PCR, PP65 leukocytic antigenemia, and viremia. Transplant Proc 1996;28(5):2806-7.

19. Flexman J, Kay I, Fonte R, et al. Differences between the quantitative antigenemia assay and the cobas amplicor monitor quantitative PCR assay for detecting CMV viraemia in bone marrow and solid organ transplant patients. J Med Virol 2001;64(3):275-82.

20. Garrigue I, Boucher S, Couzi L, et al. Whole blood real-time quantitative PCR for cytomegalovirus infection follow-up in transplant recipients. J Clin Virol 2006;36(1):72-5. doi: 10.1016/j.jcv.2006.01.002

21. Guiver M, Fox AJ, Mutton K, et al. Evaluation of CMV viral load using TaqMan CMV quantitative PCR and comparison with CMV antigenemia in heart and lung transplant recipients. Transplantation 2001;71(11):1609-15.

22. Hadaya K, Wunderli W, Deffernez C, et al. Monitoring of cytomegalovirus infection in solid-organ transplant recipients by an ultrasensitive plasma PCR assay. J Clin Microbiol 2003;41(8):3757-64.

23. Halfon P, Berger P, Khiri H, et al. Algorithm based on CMV kinetics DNA viral load for preemptive therapy initiation after hematopoietic cell transplantation. J Med Virol 2011;83(3):490-5. doi: 10.1002/jmv.21996

24. Hebart H, Müller C, Löffler J, et al. Monitoring of CMV infection: a comparison of PCR from whole blood, plasma-PCR, pp65-antigenemia and virus culture in patients after bone marrow transplantation. Bone Marrow Transplant 1996;17(5):861-8.

25. Heo WB, Won DI, Kim YL, et al. [Evaluation of Biosewoom Real-Q Cytomegalovirus Quantification kit for Cytomegalovirus viral load measure]. Korean J Lab Med 2007;27(4):298-304.

26. Marque-Juillet S, Touzard A, Monnier S, et al. [Evaluation of cytomegalovirus quantification in blood by the R-gene real-time PCR test]. Pathol Biol (Paris) 2010;58(2):162-5. doi: 10.1016/j.patbio.2009.07.029

27. Khansarinejad B, Soleimanjahi H, Mirab Samiee S, et al. Monitoring human cytomegalovirus infection in pediatric hematopoietic stem cell transplant recipients: using an affordable in-house qPCR assay for management of HCMV infection under limited resources. Transpl Int 2015;28(5):594-603. doi: 10.1111/tri.12545

28. Kidd IM, Fox JC, Pillay D, et al. Provision of prognostic information in immunocompromised patients by routine application of the polymerase chain reaction for cytomegalovirus. Transplantation 1993;56(4):867-71.

29. Ksouri H, Eljed H, Greco A, et al. Analysis of cytomegalovirus (CMV) viremia using the pp65 antigenemia assay, the amplicor CMV test, and a semi-quantitative polymerase chain reaction test after allogeneic marrow transplantation. Transpl Infect Dis 2007;9(1):16-21. doi: 10.1111/j.1399-3062.2006.00171.x

30. Landini MP, Lazzarotto T, Maine GT, et al. Recombinant mono- and polyantigens to detect cytomegalovirus-specific immunoglobulin M in human sera by enzyme immunoassay. J Clin Microbiol 1995;33(10):2535-42.

31. Lazzarotto T, Campisi T, Dal Monte P, et al. A quantitative test (HCMV-hybrid-capture(TM)) to detect human cytomegalovirus DNA in the blood of immunocompromised patients compared with antigenemia and polymerase chain reaction. New Microbiol 1996;19(3):193-201.

32. Li H, Dummer JS, Estes WR, et al. Measurement of human cytomegalovirus loads by quantitative real-time PCR for monitoring clinical intervention in transplant recipients. J Clin Microbiol 2003;41(1):187-91.

33. Lo CY, Ho KN, Yuen KY, et al. Diagnosing cytomegalovirus disease in CMV seropositive renal allograft recipients: a comparison between the detection of CMV DNAemia by polymerase chain reaction and antigenemia by CMV pp65 assay. Clin Transplant 1997;11(4):286-93.

34. García de Lomas J, Gimeno C, Artero A, et al. [Use of DNA amplification to diagnose cytomegalovirus in HIV seropositive patients]. Med Clin (Barc) 1992;99(7):249-52.

35. Luchsinger V, Vásquez P, Silva M, et al. [Antigenemia and real time polymerase chain reaction for diagnosis of cytomegalovirus disease in HIV infected adults]. Rev Chilena Infectol 2015;32(6):664-71. doi: 10.4067/S0716-10182015000700008

36. Madhavan HN, Sowmya P, Therese KL, et al. Development and application of a novel multiplex polymerase chain reaction for semi-quantitation of human Cytomegalovirus in clinical specimens. J Virol Methods 2007;141(2):166-72. doi: 10.1016/j.jviromet.2006.12.003

37. Mansy F, Brancart F, Liesnard C, et al. A PCR based DNA hybridisation capture system for the detection of human cytomegalovirus. A comparative study with other identification methods. J Virol Methods 1999;80(2):113-22.

38. Marenzi R, Cinque P, Ceresa D, et al. Serum polymerase chain reaction for cytomegalovirus DNA for monitoring ganciclovir treatment in AIDS patients. Scand J Infect Dis 1996;28(4):347-51.

39. Martiny PB, de-Paris F, Machado AB, et al. Comparison of the performance of polymerase chain reaction and pp65 antigenemia for the detection of human cytomegalovirus in immunosuppressed patients. Rev Soc Bras Med Trop 2011;44(3):286-9.

40. Masaoka T, Hiraoka A, Ohta K, et al. Evaluation of the AMPLICOR CMV, COBAS AMPLICOR CMV monitor and antigenemia assay for cytomegalovirus disease. Jpn J Infect Dis 2001;54(1):12-6.

41. Matsunaga T, Sakamaki S, Ishigaki S, et al. Use of PCR serum in diagnosing and monitoring cytomegalovirus reactivation in bone marrow transplant recipients. Int J Hematol 1999;69(2):105-11.

42. Farfán U MJ, Torres T JP, Vergara A A, et al. [Comparison of real-time polymerase chain reaction and antigenemia assay to detect cytomegalovirus in pediatric transplants]. Rev Chilena Infectol 2011;28(2):113-7. doi: /S0716-10182011000200002

43. Milan A, Sampaio AM, Guardia AC, et al. Monitoring and detection of cytomegalovirus in liver transplant recipients. Transplant Proc 2011;43(4):1360-1. doi: 10.1016/j.transproceed.2011.02.031

44. Miller S, Seet H, Khan Y, et al. Comparison of QIAGEN automated nucleic acid extraction methods for CMV quantitative PCR testing. Am J Clin Pathol 2010;133(4):558-63. doi: 10.1309/AJCPE5VZL1ONZHFJ

45. Mori T, Kato J, Yamane A, et al. [Comparison of the results of quantitative polymerase chain reaction for cytomegalovirus among laboratories]. Rinsho Ketsueki 2011;52(4):204-9.

46. von Müller L, Hinz J, Bommer M, et al. CMV monitoring using blood cells and plasma: a comparison of apples with oranges? Bone Marrow Transplant 2007;39(6):353-7. doi: 10.1038/sj.bmt.1705593

47. Nitsche A, Oswald O, Steuer N, et al. Quantitative real-time PCR compared with pp65 antigen detection for cytomegalovirus (CMV) in 1122 blood specimens from 77 patients after allogeneic stem cell transplantation: which test better predicts CMV disease development? Clin Chem 2003;49(10):1683-5.

48. Pang XL, Chui L, Fenton J, et al. Comparison of LightCycler-based PCR, COBAS amplicor CMV monitor, and pp65 antigenemia assays for quantitative measurement of cytomegalovirus viral load in peripheral blood specimens from patients after solid organ transplantation. J Clin Microbiol 2003;41(7):3167-74.

49. Pellegrin I, Garrigue I, Ekouevi D, et al. New molecular assays to predict occurrence of cytomegalovirus disease in renal transplant recipients. J Infect Dis 2000;182(1):36-42. doi: 10.1086/315688

50. Peres RM, Costa CR, Andrade PD, et al. Surveillance of active human cytomegalovirus infection in hematopoietic stem cell transplantation (HLA sibling identical donor): search for optimal cutoff value by real-time PCR. BMC Infect Dis 2010;10:147. doi: 10.1186/1471-2334-10-147

51. Piiparinen H, Höckerstedt K, Grönhagen-Riska C, et al. Comparison of plasma polymerase chain reaction and pp65-antigenemia assay in the quantification of cytomegalovirus in liver and kidney transplant patients. J Clin Virol 2001;22(1):111-6.

52. Rautenberg P, Lübbert C, Weers W, et al. Evaluation of the AmpliSensor PCR and the SHARP signal detection system for the early prediction of symptomatic CMV infection in solid transplant recipients. J Clin Virol 1999;13(1-2):81-94.

53. Rayes N, Seehofer D, Lullius SG, et al. Monitoring of human cytomegalovirus, HHV-6 and HHV-7 infection in kidney transplant recipients by molecular methods to predict HCMV disease after transplantation: a prospective study. Ann Transplant 2005;10(2):23-8.

54. Rhee JY, Peck KR, Lee NY, et al. Clinical usefulness of plasma quantitative polymerase chain reaction assay: diagnosis of cytomegalovirus infection in kidney transplant recipients. Transplant Proc 2011;43(7):2624-9. doi: 10.1016/j.transproceed.2011.05.054

55. Sakamaki H, Yuasa K, Goto H, et al. Comparison of cytomegalovirus (CMV) antigenemia and CMV in bronchoalveolar lavage fluid for diagnosis of CMV pulmonary infection after bone marrow transplantation. Bone Marrow Transplant 1997;20(2):143-7. doi: 10.1038/sj.bmt.1700856

56. Sanghavi SK, Abu-Elmagd K, Keightley MC, et al. Relationship of cytomegalovirus load assessed by real-time PCR to pp65 antigenemia in organ transplant recipients. J Clin Virol 2008;42(4):335-42. doi: 10.1016/j.jcv.2008.03.031

57. Schirm J, Kooistra A, van Son WJ, et al. Comparison of the Murex Hybrid Capture CMV DNA (v2.0) assay and the pp65 CMV antigenemia test for the detection and quantitation of CMV in blood samples from immunocompromised patients. J Clin Virol 1999;14(3):153-65.

58. Schmidt CA, Oettle H, Wilborn F, et al. Demonstration of cytomegalovirus after bone marrow transplantation by polymerase chain reaction, virus culture and antigen detection in buffy coat leukocytes. Bone Marrow Transplant 1994;13(1):71-5.

59. Schmidt CA, Oettle H, Peng R, et al. Comparison of polymerase chain reaction from plasma and buffy coat with antigen detection and occurrence of immunoglobulin M for the demonstration of cytomegalovirus infection after liver transplantation. Transplantation 1995;59(8):1133-8.

60. Schvoerer E, Henriot S, Zachary P, et al. Monitoring low cytomegalovirus viremia in transplanted patients by a real-time PCR on plasma. J Med Virol 2005;76(1):76-81. doi: 10.1002/jmv.20326

61. Seehofer D, Meisel H, Rayes N, et al. Prospective evaluation of the clinical utility of different methods for the detection of human cytomegalovirus disease after liver transplantation. Am J Transplant 2004;4(8):1331-7. doi: 10.1111/j.1600-6143.2004.00510.x

62. Solano C, Muñoz I, Gutiérrez A, et al. Qualitative plasma PCR assay (AMPLICOR CMV test) versus pp65 antigenemia assay for monitoring cytomegalovirus viremia and guiding preemptive ganciclovir therapy in allogeneic stem cell transplantation. J Clin Microbiol 2001;39(11):3938-41. doi: 10.1128/JCM.39.11.3938-3941.2001

63. Sowmya P, Madhavan HN, Therese KL. Evaluation of three polymerase chain reaction tests targeting morphological transforming region II, UL-83 gene and glycoprotein O gene for the detection of human cytomegalovirus genome in clinical specimens of immunocompromised patients in Chennai, India. Virol J 2006;3:20. doi: 10.1186/1743-422X-3-20

64. Sun Z, Ceng X, Mao Z, et al. Diagnostic value of HCMV pp65 antigen detection by FCA for symptomatic and asymptomatic infection: compared to quantification of HCMV DNA and detection of IgM antibody in infants. Med Microbiol Immunol 2009;198(2):107-12. doi: 10.1007/s00430-009-0112-y

65. Tantivanich S, Sawatmongkonkun W, Balachandra K, et al. Rapid diagnosis of cytomegalovirus in Thai pediatric AIDS patients. Southeast Asian J Trop Med Public Health 2002;33(2):306-11.

66. Thorne LB, Civalier C, Booker J, et al. Analytic validation of a quantitative real-time PCR assay to measure CMV viral load in whole blood. Diagn Mol Pathol 2007;16(2):73-80. doi: 10.1097/PDM.0b013e318033ab9e

67. Poirier-Toulemonde AS, Milpied N, Cantarovich D, et al. Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients. J Clin Microbiol 2000;38(9):3143-9.

68. Velzing J, Rothbarth PH, Kroes AC, et al. Detection of cytomegalovirus mRNA and DNA encoding the immediate early gene in peripheral blood leukocytes from immunocompromised patients. J Med Virol 1994;42(2):164-9.

69. Vlieger AM, Boland GJ, Jiwa NM, et al. Cytomegalovirus antigenemia assay or PCR can be used to monitor ganciclovir treatment in bone marrow transplant recipients. Bone Marrow Transplant 1992;9(4):247-53.

70. Wang XT, Dong ZB, Luo LM, et al. [Application of throat swab nested PCR in the diagnosis of congenital human cytomegalovirus infection in neonates]. Zhongguo Dang Dai Er Ke Za Zhi 2013;15(12):1086-8.

71. Weber B, Nestler U, Ernst W, et al. Low correlation of human cytomegalovirus DNA amplification by polymerase chain reaction with cytomegalovirus disease in organ transplant recipients. J Med Virol 1994;43(2):187-93.

72. Wie SH, Song HC, Kim YR, et al. Immunocytochemical assay for cytomegalovirus detection in peripheral blood for renal transplant patients in clinical practice. Transplant Proc 1996;28(3):1505-6.

73. Wirgart BZ, Claesson K, Eriksson BM, et al. Cytomegalovirus (CMV) DNA amplification from plasma compared with CMV pp65 antigen (ppUL83) detection in leukocytes for early diagnosis of symptomatic CMV infection in kidney transplant patients. Clin Diagn Virol 1996;7(2):99-110.

74. Xue W, Liu H, Yan H, et al. Methodology for monitoring cytomegalovirus infection after renal transplantation. Clin Chem Lab Med 2009;47(2):177-81. doi: 10.1515/CCLM.2009.033

75. Yakushiji K, Gondo H, Kamezaki K, et al. Monitoring of cytomegalovirus reactivation after allogeneic stem cell transplantation: comparison of an antigenemia assay and quantitative real-time polymerase chain reaction. Bone Marrow Transplant 2002;29(7):599-606. doi: 10.1038/sj.bmt.1703513

SupplementTable 1. Sensitivity and subgroup analyses of diagnostic test accuracy.

Not high risk study / qrtPCR / PCR/Blood specimen / Pediatric
Studies / 10 / 29 / 71 / 6
PCR positive / 241 / 3711 / 8892 / 369
PCR negative / 386 / 10914 / 22086 / 1345
DOR / 23 (8-68)
I2 = 3% / 30 (21-43)
I2 = 9% / 30 (23-38)
I2 = 26% / 44 (23-84)
I2 = 4%
AUC / 0.86 (0.78-0.96) / 0.84 (0.82-0.87) / 0.86 (0.83-0.88) / 0.87 (0.82-0.93)
Sensitivity / 0.68 (0.50-0.83) / 0.61 (0.52-0.70) / 0.64 (0.58-0.70) / 0.65 (0.43-0.82)
Specificity / 0.90 (0.83-0.95) / 0.95 (0.93-0.96) / 0.94 (0.92-0.95) / 0.97 (0.96-0.98)
PLR / 7.1 (3.7-13.3) / 12.0 (8.4-16.9) / 10.9 (8.4-14.0) / 21.7 (12.7-33.2)
NLR / 0.35 (0.20-0.56) / 0.41 (0.32-0.51) / 0.38 (0.32-0.45) / 0.36 (0.19-0.59)

PCR positive/negative: a number of subjects allowing repeated evaluation of same subjects.

DOR: diagnostic odds ratio.

AUC: area under hierarchical summary receiver operating characteristics curve.

PLR:Positive likelihood ratio.

NLR:Negative likelihood ratio.

qrtPCT: quantitative real-time PCR.

PCR/Blood specimen: Only blood specimen was used for PCR

Supplement Figure 1. Summary of the Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies.

Supplement Figure 2. Funnel plot.

Kendall's rank correlation test: P-value = 0.051

Supplement Figure 3. Positive and negative predictive values.