Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M
Centre for Health Services Studies, University of Warwick, UK.
Health Technol Assess. 2006 Apr;10(10):1-176. doi: 10.3310/hta10100.
To evaluate selected molecular tests in diagnosis and screening of cytomegalovirus (CMV) infection in immunosuppressed patients.
Clinical and cost-effectiveness were assessed through a prospective two-stage trial of CMV screening regimes in a routine service setting. Different molecular test results were fed back to clinicians in each stage, plus antigenaemia results. The technical performance of the molecular methods was assessed through an independent masked comparison of each molecular test against the established (antigenaemia) test. Scientists performing a particular test were blind to the other test results for that sample. Diagnostic and therapeutic impact were recorded prospectively for all tests, to include any effect on diagnostic certainty, changes to CMV therapy and any other reported impact on patient management. The cost of each test was estimated under different laboratory conditions. Prospective patients undergoing CMV screening were compared with consecutive historical controls in the same unit. Towards the end of the study, a survey of all UK virology laboratories was undertaken to identify current CMV screening practice and test preferences. In addition, all UK renal transplant surgeons and haematology transplant centres were surveyed in order to identify current clinical practice and perceptions of the benefits of CMV screening.
Study patients were recruited from University Hospital Wales (UHW), Cardiff. Staff in the Cardiff Public Health Laboratory Service virology laboratory performed the tests.
A consecutive series of transplant patients was recruited to the prospective study over a 42-month period, totalling 98 renal and 140 haematology patients. A consecutive series of historical controls was identified, with 199 renal and 136 haematology patients who underwent transplants in the UHW during the 29 months prior to the prospective CMV screening trial.
A predefined CMV screening protocol was applied to all patients in the prospective trial. Renal patients were tested every 4 weeks until 16 weeks post-transplant (five tests in total). Haematology patients were tested every 2 weeks until 12 weeks post-transplant, and then every 4 weeks until 24 weeks (10 tests in total). The assays used for CMV screening were as follows: non-molecular test, (1) pp65 antigenaemia assay; molecular tests, semi-quantitative in-house polymerase chain reaction (PCR), (2) single-round (PCR1) and (3) two-round, nested (PCR2); and qualitative commercial tests, (4) Roche Amplicor Assay (Amplicor) and (5) pp67 NASBA assay (NASBA).
Test failure rates, sensitivity/specificity values and positive predictive value (PPV) and negative predictive value (NPV) were measured for each assay. The laboratory cost of undertaking various CMV tests was measured and other NHS costs associated with false-positive or false-negative test results were estimated. The likelihood of CMV disease and the likely impact of positive or negative test result on therapy and further investigations were recorded. On receipt of the test result, interim outcome measures were recorded to include the impact of test result on diagnostic certainty, changes to planned patient management (e.g. therapy, investigations) and perceived benefit. All definitive diagnoses of CMV disease, prescribing of CMV therapy and interim patient outcome at the end of the screening period were recorded.
In haematology and renal transplant patients, all tests had a similar NPV (0.976--0.997 and 0.935--0.995, respectively) when used in CMV screening. PCR1 is the least expensive molecular test (7.80-13.70 UK pounds). Commercial tests, NASBA and Amplicor, are both more expensive (22.50-34.70 UK pounds NASBA; 23.20-29.20 UK pounds Amplicor). Antigenaemia costs 12.50-27.40 pounds depending on staff grade and batch size. Quantitative PCR (COBAS) is the most expensive at around 50 UK pounds per sample. No clear link between screening test results and CMV prescribing was detected; clinicians appear to consider screening results in the context of other factors. There was no evidence that the introduction of CMV screening led to reductions in CMV deaths or improved transplant success rates. For cost per positive test result, PCR1 was the most cost-effective screening test on this indicator (renal patients 116 UK pounds per true positive, haematology patients 518 pounds). Antigenaemia was the least cost-effective screening test (renal patients 643 UK pounds per true positive, haematology patients 2475 pounds). Cost-effectiveness analysis and cost per "beneficial result" (as judged by clinicians) confirmed that PCR1 remained the most cost-effective test. Modelling outputs for targeted screening protocols also supported this.
The study findings offer some evidence that a CMV screening regime is more cost-effective than diagnostic testing alone, based on the cost per true positive detected and interim outcome such as changes in patient management. However, the study was unable to demonstrate any benefits in terms of longer term patient outcomes. If CMV screening is introduced, the use of antigenaemia pp65 is clearly less cost-effective than the use of molecular tests. The study identified the optimum test for CMV screening as an in-house molecular test (single-round PCR test). This test was less costly to perform and also resulted in lower costs linked to false positives and negatives than other tests. The in-house, semi-quantitative test was two to three times more cost-effective than the commercial molecular tests assessed; however changes to European Union legislation may mean that it may not be feasible to use in-house tests. The use of targeted screening (limiting CMV screening to high-risk transplants) as opposed to universal screening offers a significant improvement in the cost-effectiveness ratio for haematology transplant patients, but has limited impact in the case of renal transplants. Economic analyses could be expanded to model the cost-effectiveness of more frequent screening tests (as reported nationally), and screening in other "at risk" groups. Subgroup specific disease groups should be investigated across a larger population to allow more accurate modelling of the impact of CMV screening on disease progression. Further studies of CMV screening programmes should address a range of outcome measures, including patient outcomes.
评估特定分子检测在免疫抑制患者巨细胞病毒（CMV）感染诊断和筛查中的作用。
通过在常规服务环境中对CMV筛查方案进行前瞻性两阶段试验，评估临床效果和成本效益。在每个阶段，将不同的分子检测结果反馈给临床医生，同时反馈抗原血症检测结果。通过将每种分子检测与既定的（抗原血症）检测进行独立的盲法比较，评估分子方法的技术性能。进行特定检测的科学家对该样本的其他检测结果不知情。前瞻性记录所有检测的诊断和治疗影响，包括对诊断确定性的任何影响、CMV治疗的变化以及对患者管理的任何其他报告影响。在不同实验室条件下估计每项检测的成本。将接受CMV筛查的前瞻性患者与同一单位的连续历史对照进行比较。在研究接近尾声时，对英国所有病毒学实验室进行了一项调查，以确定当前的CMV筛查实践和检测偏好。此外，对英国所有肾移植外科医生和血液学移植中心进行了调查，以确定当前的临床实践以及对CMV筛查益处的看法。
研究患者招募自威尔士大学医院（UHW），位于加的夫。加的夫公共卫生实验室服务病毒学实验室的工作人员进行检测。
在42个月期间，连续招募了一系列移植患者进入前瞻性研究，共有98例肾移植患者和140例血液学患者。确定了一系列连续的历史对照，包括在进行前瞻性CMV筛查试验前的29个月内在UHW接受移植的199例肾移植患者和136例血液学患者。
对前瞻性试验中的所有患者应用预先定义的CMV筛查方案。肾移植患者在移植后每4周检测一次，直至移植后16周（共检测5次）。血液学患者在移植后每2周检测一次，直至移植后12周，然后每4周检测一次，直至移植后24周（共检测10次）。用于CMV筛查的检测方法如下：非分子检测，（1）pp65抗原血症检测；分子检测，半定量内部聚合酶链反应（PCR），（2）单轮（PCR1）和（3）两轮巢式（PCR2）；以及定性商业检测，（4）罗氏Amplicor检测（Amplicor）和（5）pp67核酸序列扩增检测（NASBA）。
测量每种检测方法的检测失败率、敏感性/特异性值以及阳性预测值（PPV）和阴性预测值（NPV）。测量进行各种CMV检测的实验室成本，并估计与假阳性或假阴性检测结果相关的其他国民保健制度（NHS）成本。记录CMV疾病的可能性以及阳性或阴性检测结果对治疗和进一步检查的可能影响。收到检测结果后，记录中期观察指标，包括检测结果对诊断确定性的影响、对计划中的患者管理（如治疗、检查）的改变以及感知到的益处。记录筛查期结束时所有CMV疾病的确诊、CMV治疗的开具情况以及患者的中期结局。
在血液学和肾移植患者中，所有检测方法用于CMV筛查时NPV相似（血液学患者分别为0.976 - 0.997，肾移植患者分别为0.935 - 0.995）。PCR1是最便宜的分子检测方法（7.80 - 13.70英镑）。商业检测方法NASBA和Amplicor都更昂贵（NASBA为22.50 - 34.70英镑；Amplicor为23.20 - 29.20英镑）。抗原血症检测根据工作人员级别和批次大小，成本为12.50 - 27.40英镑。定量PCR（COBAS）最昂贵，每个样本约50英镑。未检测到筛查检测结果与CMV治疗开具之间存在明确关联；临床医生似乎在考虑其他因素的背景下看待筛查结果。没有证据表明引入CMV筛查可降低CMV死亡人数或提高移植成功率。就每个阳性检测结果的成本而言，PCR1在此指标上是最具成本效益的筛查检测方法（肾移植患者每个真阳性为116英镑，血液学患者为518英镑）。抗原血症检测是最不具成本效益的筛查检测方法（肾移植患者每个真阳性为643英镑，血液学患者为2475英镑）。成本效益分析和每个“有益结果”（由临床医生判断）的成本证实，PCR1仍然是最具成本效益的检测方法。针对目标筛查方案的建模输出也支持这一点。
研究结果提供了一些证据，表明基于每检测到一个真阳性的成本以及诸如患者管理变化等中期结局，CMV筛查方案比单独的诊断检测更具成本效益。然而，该研究未能证明在长期患者结局方面有任何益处。如果引入CMV筛查，使用pp65抗原血症检测显然不如使用分子检测具成本效益。该研究确定CMV筛查的最佳检测方法为内部分子检测（单轮PCR检测）。该检测方法执行成本较低，与其他检测相比，与假阳性和假阴性相关的成本也较低。内部半定量检测的成本效益比评估的商业分子检测高两到三倍；然而，欧盟立法的变化可能意味着使用内部检测不可行。与普遍筛查相比，使用目标筛查（将CMV筛查限于高风险移植）可显著提高血液学移植患者的成本效益比，但对肾移植患者影响有限。经济分析可扩展以模拟更频繁筛查检测（如全国报告的那样）以及在其他“风险”群体中进行筛查的成本效益。应在更大规模人群中对特定亚组疾病群体进行调查，以便更准确地模拟CMV筛查对疾病进展的影响。CMV筛查项目的进一步研究应涉及一系列结局指标，包括患者结局。
