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Meta-Analysis
. 2019 Sep 3;9(9):CD009551.
doi: 10.1002/14651858.CD009551.pub4.

Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people

Mario Cruciani  1 , Carlo Mengoli, Rosemary Barnes, J Peter Donnelly, Juergen Loeffler, Brian L Jones, Lena Klingspor, Johan Maertens, Charles O Morton, Lewis P White
Affiliations
Meta-Analysis

Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people

Mario Cruciani et al. Cochrane Database Syst Rev. .

Abstract

Background: This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 10, 2015.Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently, there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Increasingly, newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are being investigated.

Objectives: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people.

Search methods: We searched MEDLINE (1946 to June 2015) and Embase (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. For this review update we updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3) in the Cochrane Library; MEDLINE via Ovid (June 2015 to March week 2 2018); and Embase via Ovid (June 2015 to 2018 week 12).

Selection criteria: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control and retrospective studies were excluded from the analysis.

Data collection and analysis: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity.

Main results: We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results.

Authors' conclusions: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.

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Conflict of interest statement

RAB has been a consultant to Astellas Pharma, Gilead Sciences, Merck, Sharpe & Dohme, Pfizer and Schering‐Plough, has received a research grant from Pfizer, has been a member of a speakers' bureau for Astellas Pharma, Gilead Sciences, Merck, Sharpe & Dohme, Pfizer and Schering‐Plough, and has received travel grants from Astellas Pharma, Gilead Sciences, Merck, Sharpe & Dohme, Pfizer and Schering‐Plough.

JL has received research grants from Novartis and travel grants from Pfizer and Cephalon.

PD has been a consultant to Gilead Sciences, Ipsat Therapies and Pfizer, has received research grants from AM‐Pharma, Basilea Pharmaceutica and Schering‐Plough, has been a member of a speakers' bureau for Gilead Sciences, Janssen Pharmaceuticals, Pfizer, Schering‐Plough, and Xian‐Janssen and has received travel grants from Merck, Sharpe & Dohme and UCB Pharma.

LK has been an adviser to Astellas, Gilead, Schering‐Plough, has received research grants from Gilead, Merck, Sharpe & Dohme, Schering‐Plough and has received honoraria for educational lectures from Gilead, Pfizer, Merck, Sharpe & Dohme, Schering‐Plough and Janssen.

BLJ has been an advisor to Gilead, MSD, Astellas and Pfizer; has received research grants from Gilead, Astellas, Pfizer, Janssen and MSD; has received honoraria for educational lectures from Gilead, MSD and Pfizer; and owns stock in Gilead, MSD and Pfizer.

JM has served as consultant to Schering‐Plough, Gilead Sciences, Merck, Sharp & Dohme, Pfizer, Bio‐Rad, Fujisawa healthcare, Astellas, Nextar and Zeneus (Cephalon), has received research funding from Bio‐Rad, Merck, Sharp & Dohme, and Pfizer, and has been on the speakers' bureau for Schering‐Plough, Gilead Sciences, Merck, Sharp & Dohme, Pfizer, Bio‐Rad, Fujisawa healthcare, Astellas and Zeneus (Cephalon).

MC, CM, OM: no conflicts of interest to declare with regard to the content of the article.

LW has received research funding from Bruker, Luminex and Renishaw Diagnostics, provided consultancy for Gilead Sciences, has been a member of a speakers' bureau for Gilead Sciences, Merck, Sharpe and Dohme, Bruker and Dynamiker Ltd, and received travels funding from Gilead Sciences, Launch Diagnostics, Bruker and Renishaw Diagnostics.

RAB, JL and PD are founder members of the European Aspergillus PCR Initiative Working Group of the International Society for Human and Animal Mycology, and board members of the EAPCRI, which is registered with the Dutch Chamber of Commerce, number 09165918

None of the authors has any interests, financial or otherwise, in any of the companies involved in the diagnosis of IFD. The authors' disclosures are on public record to ensure their independence and integrity and to help avoid potential conflicts of interest.

Figures

1
1
Study flow diagram.
2
2
Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies
3
3
Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study
4
4
Forest plot of PCR: one (single) positive requirement.
5
5
Forest plot of PCR: two positive requirement.
6
6
Summary ROC Plot. Bivariate analysis of the sensitivity and specificity of the PCR as a diagnostic tool for Aspergillus invasive infection. One single positive PCR result is required to define the test as positive
7
7
Summary ROC Plot. Bivariate analysis of the sensitivity and specificity of the PCR as a diagnostic tool for Aspergillus invasive infection. Two or more consecutive positive PCR result are required to define the test as positive.
8
8
Predictive values. Positive and negative predictive value (PPV and NPV, respectively) of the Aspergillus PCR detection test (y‐axis) as a function of the prevalence of the disease, invasive aspergillosis (x‐axis). The curves are related to the diagnostic criterion (a single positive result or two consecutive positive PCR results). The PVs were calculated by applying the Bayes rule. The mean prevalence of invasive aspergillosis (16.3%) is indicated by the vertical dashed line. It corresponds to PPV1 = 42%, NPV1 = 95%, PPV2 = 70%, NPV2 = 92%.
1
1. Test
PCR: single positive requirement.
2
2. Test
PCR: two positive requirement.
3
3. Test
no anti‐mould prophylaxis.
4
4. Test
antimould prophylaxis.
5
5. Test
in‐house qPCR.
6
6. Test
qPCR kit.
7
7. Test
PCR on whole blood.
8
8. Test
PCR on serum.
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