Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Care Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this diagnostics guidance and prepare a Diagnostics Assessment Report (DAR). The DAR for this diagnostic guidance was prepared by Kleijnen Systematic Reviews Ltd in collaboration with Erasmus University Rotterdam and Maastricht University (see the "Availability of Companion Documents" field).
Assessment of Clinical Effectiveness
Development of search strategies followed the recommendations of the Centre for Reviews and Dissemination guidance for undertaking reviews in health care and the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Strategies were based on procalcitonin (PCT) assays and target conditions (sepsis or bacterial infection); initial searches included a sensitive filter for randomised controlled trials (RCTs). Because initial searches identified no RCTs for the paediatric intensive care unit (ICU) population and only one RCT for the paediatric emergency department (ED) population, searches were re-run without a study design filter and limited to the paediatric population.
Candidate search terms were identified from target references, browsing database thesauri (e.g., MEDLINE, Medical Subject Headings [MeSH] and EMBASE Emtree), existing reviews identified during the rapid appraisal process and initial scoping searches. These scoping searches were used to generate test sets of target references, which informed text mining analysis of high-frequency subject indexing terms using EndNote reference management software. Strategy development involved an iterative approach testing candidate text and indexing terms across a sample of bibliographic databases, aiming to reach a satisfactory balance of sensitivity and specificity.
No restrictions on language or publication status were applied. Date restrictions were determined in consultation with clinical specialist members of the Assessment Subgroup, based on expert advice on the earliest appearance of literature of PCT diagnostic testing. Searches took into account generic and other product names for the intervention. The main EMBASE strategy for each set of searches was independently peer reviewed by a second Information Specialist, using the Canadian Agency for Drugs and Technologies in Health (CADTH) Peer Review Checklist. Search strategies were developed specifically for each database and keywords were adapted according to the configuration of each database.
See Appendix 1 of the Assessment Report (see the "Availability of Companion Documents" field) for full search strategies.
Rapid Appraisal Searches
To assess the scope and scale of the literature, and to identify candidate search terms, a rapid appraisal of the literature was conducted.
The following databases were searched for relevant studies from database inception date to June 2014:
See the Assessment Report for information on RCT searches, paediatric population searches, searches for abstracts and poster presentations, and searches for completed and on-going trials.
Inclusion and Exclusion Criteria
- Adults and children with confirmed or highly suspected sepsis, in whom antibiotic therapy is indicated, who are being treated in ICUs
- Adults and children presenting to the ED with suspected bacterial infection
Studies of neonates or immunosuppressed neutropenic patients on chemotherapy, immunosuppressant drugs or transplant programmes were excluded.
Treatment decisions based on laboratory-based PCT testing, using any of the tests currently available to the UK National Health Service (NHS) as described in Section 2.2 of the Assessment Report, in addition to standard practice (as reported in individual studies).
Point-of-care tests, which do not provide a quantitative estimate of PCT levels, were excluded.
Treatment decisions based on standard practice (as reported in individual studies), without PCT testing.
Antibiotic exposure (initiation/duration of antibiotic therapy), resource use (number of hospital admissions, length of hospital/ICU stay, costs), adverse clinical outcomes (e.g., Sequential Organ Failure Assessment [SOFA] scores, in-hospital mortality, condition-specific outcomes), antibiotic-related adverse events.
RCTs, or controlled clinical trials (CCTs) where no RCTs were available. Where no controlled trials (RCTs or CCTs) were available for a specified population, studies assessing the change in diagnostic accuracy associated with the addition of PCT testing to standard diagnostic work-up were sought. On the advice of clinical specialist members of the Assessment Subgroup, such studies were required to use adjudication of infection by independent panel as the reference standard; microbiological testing alone was not considered adequate. Studies that assessed the diagnostic accuracy of PCT testing alone, or that used culture alone as the reference standard, were excluded.
Two reviewers independently screened the titles and abstracts of all reports identified by searches and any discrepancies were discussed and resolved by consensus. Full copies of all studies deemed potentially relevant were obtained and the same two reviewers independently assessed these for inclusion; any disagreements were resolved by consensus. Details of studies excluded at the full paper screening stage are presented in Appendix 5 of the Assessment Report (see the "Availability of Companion Documents" field).
The principal investigators of completed trials (identified through searches of clinical trials registries) that appeared to meet the inclusion criteria but for which no publication was identified, were contacted and asked to provide publication details or un-published data. Details of ongoing trials and trials for which data were requested are reported in Appendix 2 of the Assessment Report.
Results of the Clinical Effectiveness Assessment
The initial literature searches of bibliographic databases for RCTs identified 2,919 references. After initial screening of titles and abstracts, 146 were considered to be potentially relevant and ordered for full paper screening; of these 35 were included in the review. Additional searches of bibliographic databases for non-RCTs conducted in paediatric populations yielded an additional 515 references. After initial screening of titles and abstracts, 14 were considered to be potentially relevant and ordered for full paper screening; none of these met the criteria for inclusion in the review (see Appendix 5 of the Assessment Report). All potentially relevant studies cited in documents supplied by the test manufacturers had already been identified by bibliographic database searches. One additional publication was obtained through contact with the authors, after searches had identified the study protocol. Figure 1 in the Assessment Report shows the flow of studies through the review process, and Appendix 4 in the Assessment Report provides details, with reasons for exclusions, of all publications excluded at the full paper screening stage.
Assessment of Cost-effectiveness
Review of Economic Analyses of Procalcitonin (PCT) Assays
Searches were undertaken to locate relevant economic evaluations on adults and children presenting to or being treated at EDs and ICUs with sepsis or bacterial infection.
The following databases were searched for relevant studies from 2005 to August 2014:
Studies reporting a full economic analysis, with (at least) one of the comparators including PCT testing and with survival and/or quality-adjusted life years (QALYs) as an outcome measure, were eligible for inclusion.
The literature search identified 221 records from bibliographic database searches and supplementary searching (e.g., reference/citation checking, additional database searches including the database search for the assessment of clinical effectiveness). The studies identified through supplementary searching also included one potentially relevant unpublished paper sent by bioMérieux. After title and abstract screening, 21 records were considered to be potentially relevant and after full text screening two studies (three publications) were considered eligible for inclusion (see Figure 21 of the Assessment Report for the flow of studies for the review of economic analyses). One study considered PCT testing for adult patients with acute respiratory tract infections (outpatient setting) and one considered PCT testing for adult patients with community-acquired pneumonia (in-hospital setting). These studies are summarised in Table 8 of the Assessment Report.
Review of Health-related Quality of Life (HRQoL) Studies
Searches were undertaken to locate relevant utility value studies on adults and children presenting to or being treated at EDs and ICUs with sepsis or bacterial infection.
The following databases were searched for relevant studies from database inception date to September 2014:
- MEDLINE (OvidSP): 1946 - August Week 3 2014
- MEDLINE In-Process Citations and Daily Update (OvidSP): up to 2 September 2014
- EMBASE (OvidSP): 1974 to 2 September 2014
- Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley): up to Issue 8 of 12, August 2014
- Health Technology Assessment (HTA) Database (Wiley): up to Issue 3 of 4, July 2014
- PubMed (http://www.ncbi.nlm.nih.gov/pubmed ): up to 3 September 2014
- PROQOLID (Internet) (http://www.proqolid.org/ ): up to 3 September 2014
Studies reporting on HRQoL, in terms of utility scores, for patients with confirmed/highly suspected sepsis in intensive care settings or patients presenting to the ED with suspected bacterial infection were eligible for inclusion.
The literature search identified 476 records (472 through database searches and four through supplementary searching). After title and abstract screening, 82 potentially relevant records were identified and after full text screening nine studies (10 papers) were considered eligible for inclusion (see Figure 22 of the Assessment Report). The HRQoL studies are summarised in Appendix 6 of the Assessment Report.