Syndromic platforms in the management of infection in the critically ill patient: test indication and diagnostic interpretation

Introduction

The prompt initiation of appropriate antibiotic therapy is a critical determinant of survival in the critically ill patient. Each hour of delay in administration is associated with an approximate 8% decrease in survival [1]. The emergence of multidrug-resistant (MDR) bacteria poses a further challenge to the selection of appropriate antibiotic therapy and contributes to increased mortality. This phenomenon is particularly evident in conditions prevalent in critically ill patients, such as ventilator-associated pneumonia (VAP), which accounts for 36.5% of infections acquired in the ICU, and bacteremia from various sources (including catheter-associated infections, other foci or unknown origin), which accounts for 34.3% [2]. This clinical landscape has driven the development and adoption of a series of diagnostic tools: syndromic panels. A syndromic panel is defined as a test that uses molecular techniques to simultaneously detect a broad spectrum of relevant pathogens, including viruses, bacteria, fungi and parasites, commonly associated with specific clinical syndromes, such as meningitis/encephalitis, respiratory infections, gastrointestinal infections or bone and joint infections. A salient feature of syndromic panels is their substantially reduced turnaround time, which typically yields results within a span of less than three hours. Furthermore, some panels include the detection of genotypic markers associated with antibiotic resistance mechanisms. The aim of these techniques is to clarify the aetiological diagnosis by facilitating early identification of the causative organism, improving the choice of initial antibiotic therapy and the discontinuation of antibiotics, in certain circumstances. Several commercial syndromic panels are currently approved and available, each designed to detect a specific set of targets relevant to the specimen type being processed and the suspected diagnosis. Examples of syndromic panels used in clinical practice at our hospital include the BioFire^® FilmArray^® Pneumonia (PN) Panel, BioFire^® Joint Infection (JI) Panel, BioFire^® Blood Culture Identification 2 (BCID2) Panel, QIAstat-Dx^® Meningitis/Encephalitis (ME) Panel and QIAstat-Dx^® Respiratory SARS-CoV-2 Panel. The implementation of these syndromic panels in microbiological diagnostics offers several advantages [3]. Primarily, these panels are characterised by their expeditious result generation and their generally high sensitivity and specificity, which enables the detection of microorganisms at low concentrations. Furthermore, the multiplexing capability of these panels facilitates the simultaneous identification of multiple pathogens in a single assay. Automation is also an advantage, reducing hands-on time and sample manipulation, and some platforms show potential for point-of-care testing. However, it should be noted that there are disadvantages to using these tools [3]. These include the significant financial cost when compared to conventional diagnostic methods, and the technical complexity, which often requires specialised equipment and trained laboratory staff. The limited scope of the assays, as indicated by the number of targets included in a given panel, poses a risk of missing relevant pathogens not covered by the assay. Furthermore, the interpretation of results can present a challenge in certain cases. In light of these considerations, the present review has been undertaken with the objective of addressing fundamental questions surrounding the utilisation of these tools in daily clinical practice, with a specific focus on the BioFire^® FilmArray^® Pneumonia (PN) Panel. The application of this panel in high-utilisation settings, such as the Intensive Care Unit (ICU), will be highlighted.

Can these panels be used on all types of respiratory specimens?

The PN panel has been approved for use with various respiratory specimen types, including sputum, endotracheal aspirates and bronchoalveolar lavage (BAL). It is widely accepted that the most suitable respiratory specimen for the microbiological diagnosis of lower respiratory tract infections is BAL fluid [4], and that this is the preferred sample type for the PN panel. Utilising BAL fluid reduces the likelihood of detecting commensal microorganisms not involved in the infectious process, thus reducing the risk of erroneous interpretations. However, it is acknowledged that obtaining BAL fluid is not always feasible, necessitating the analysis of other specimen types, such as sputum or endotracheal aspirates, in certain situations. Consequently, for accurate interpretation of results derived from both the PN panel and conventional culture, it is crucial to consider the quantification and specimen quality relative to the specific respiratory sample type being processed [3]. 

What is the significance of the detected microorganisms?

In order to accurately interpret the obtained results, it is essential to comprehend the fundamental distinctions between diagnostic panels and microbiological culture, whilst acknowledging the limitations inherent to each method. Molecular techniques detect nucleic acid sequences (in this case, reported as copies/mL), whereas culture isolates viable microorganisms (reported as Colony Forming Units, CFU/mL). The following reasons have been posited to explain why molecular techniques might detect a microorganism that is not recovered by conventional culture: • Detection of labile, fastidious, or non-culturable microorganisms. • Administration of antibiotic therapy prior to specimen collection. • Inadequate specimen transport conditions (e.g., incorrect transport medium, delays in processing). • Host immune factors affecting microbial viability. • Variability in the definition and characterisation of normal oral microbiota. Conversely, there are reasons why molecular techniques may fail to detect microorganisms isolated by microbiological culture: • The target microorganism may not be included in the syndromic panel’s target list. • The bacterial load is below the limit of detection of the panel. • The specimen transport conditions or inhibitory factors interfere with the molecular assay. The PN panel detects 33 targets, including 8 viruses, 18 bacteria, and seven resistance genes, providing semi-quantitative results for 15 bacterial species, helping differentiate between colonisation and infection. Some studies have analysed the correlation between results obtained via the PN panel and conventional microbiological culture. Murphy et al. [5] conducted a multicentre study in which they observed concordance rates exceeding 90% when the bacterial load, as determined by culture, was high (i.e. ≥10⁶ CFU/mL). The PN panel demonstrated a 63% increase in pathogen detection in the studied bronchoalveolar lavage (BAL) specimens compared to microbiological culture, exhibiting sensitivities ranging from 85.7% to 100% and specificities from 88.9% to 99.5%. However, when the bacterial load is low, the correlation between the PN panel and culture decreases. False positive results were observed in 25% of cases where the PN panel was positive, but the corresponding microorganism was isolated by culture but below the established cut-off for significance. Consequently, the interpretation of results from these techniques necessitates careful consideration within the patient’s overall clinical context. Another study by Rand et al. [6] established that a bacterial load of 10⁶–10⁷ copies/mL generally correlates well with causality identified through traditional culture. However, at lower bacterial loads (10⁴ – 10⁵ copies/mL), causality was more strongly associated when specific pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, were detected.

How should resistance genes be interpreted?

A resistance marker detected by the diagnostic panel should be reported if a microorganism potentially harbouring that gene is also detected concurrently. Conversely, the absence of detection of a specific genetic resistance marker does not confirm susceptibility to the associated antibiotic classes, as other resistance mechanisms not targeted by the panel may be present [7]. The presence of non-pathogenic, environmental or colonising Pseudomonas spp. could lead to the detection of carbapenemase genes, even if this organism is not the cause of the infection. This possibility underscores the critical importance of appropriate specimen collection techniques to avoid erroneous interpretations and their potential impact on antimicrobial treatment decisions.

How can the clinical utility of syndromic panels be measured?

In the study conducted by Monard et al. [8], the findings suggested that the early use of the PN panel in patients with pneumonia can facilitate the optimisation of antimicrobial therapy, reducing the administration of inappropriate or unnecessary treatments without compromising therapeutic adequacy. The study revealed that the PN panel identified a greater number of pathogens compared to conventional microbiological culture methods. The most prevalent microorganisms identified by the molecular panel in the absence of growth on culture were S. aureus, Haemophilus influenzae and Streptococcus pneumoniae. Of particular note, the results obtained from the PN panel led to a change in the antibiotic regimen for 87% of the patients. A retrospective study by Buchan et al. [9] demonstrated that the syndromic panel enabled antibiotic de-escalation and cessation, thereby supporting its impact on antibiotic management. This resulted in a reduction of unnecessary antibiotic duration totalling 18,000 cumulative hours across 122 patients, representing an average of six fewer treatment days per patient. A notable decline in the utilisation of vancomycin (38%) and piperacillin/tazobactam (23%) was also observed. In the field of medical diagnostics, the employment of syndromic panels has emerged as a notable advancement in the diagnosis of bacteraemia and sepsis. The BioFire^® Blood Culture Identification 2 (BCID2) Panel, which has been validated for use directly from positive blood culture bottles, offers high sensitivity and a rapid time to result when compared to conventional culture and identification methods. It is particularly useful for the identification of slow-growing or fastidious microorganisms. However, it is important to note that the implementation of this technology is not without certain limitations. One such limitation is the potential for an increase in false positives, which may be attributable to the detection of non-viable genetic material or contaminants. Furthermore, pathogen coverage is not universal, meaning certain pathogenic microorganisms not included on the panel may be missed [3]. Studies such as that by Chen HY et al. [10] support the impact of using these panels. This work evaluated the impact of the BCID2 panel on the management of bacteraemias in the ICU, demonstrating rapid identification of pathogens and resistance genes with high concordance to traditional methods. The use of this technique was associated with a decreased time from blood culture collection to result availability compared to conventional microbiology, facilitating timely adjustments to antimicrobial therapy and contributing to treatment optimisation in critically ill patients. When applying syndromic panels to diagnose meningitis/encephalitis, it is crucial to interpret results in correlation with the patient’s clinical context. It is important to rationalise the use of these panels, particularly in immunocompetent patients. Overutilisation can be as problematic as underutilisation, potentially generating clinically irrelevant or confusing results, leading to increased costs [3]. At present, a variety of diagnostic and clinical management algorithms are being developed to promote the most efficient and effective use of these syndromic panels. The aim of these algorithms [11] is to standardise test ordering practices, guide result interpretation, and establish protocols for therapeutic actions based on the obtained results. In conclusion, the implementation of syndromic panels necessitates a well-defined strategy. Their deployment should be prioritised in scenarios where the swiftness of diagnosis offers the most significant potential benefit, particularly in cases of critically ill patients with severe pathologies. It is imperative that testing is requested at the earliest opportunity, in collaboration with the Microbiology Department, given the importance of high-quality specimen collection and the value of performing parallel microbiological culture for comprehensive diagnosis. A meticulous evaluation of the results is imperative for informed therapeutic decision-making. While cost savings alone should not dictate the use of these tools, ongoing monitoring of the cost-benefit relationship and utilisation patterns is important to ensure the rational and sustainable application of these diagnostic techniques. Funding  None to declare.  Conflict of interest  The author declares that they have no conflicts of interest.   Author contributions  Sara Sanz and Natalia Burillo writing—original draft preparation; Juan M. García-Lechuz; writing—review and editing. All authors have read and agreed to the published version of the manuscript.

References

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