Point-of-Care Testing in Children With Respiratory Tract Infections and Its Impact on Management and Patient Flow : The Pediatric Infectious Disease Journal

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Point-of-Care Testing in Children With Respiratory Tract Infections and Its Impact on Management and Patient Flow

Tegethoff, Sina A.*; Fröhlich, Franziska*,†; Papan, Cihan MD*

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The Pediatric Infectious Disease Journal: November 2022 - Volume 41 - Issue 11 - p e475-e477
doi: 10.1097/INF.0000000000003615
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Infectious diseases are the most frequent cause for medical consultations in children, contributing to morbidity and mortality worldwide. However, securing an accurate infectious disease diagnosis is a major challenge with immediate impact on the quality of patient care. This is particularly the case for respiratory tract infections, which can be of viral and/or bacterial origin, often clinically indistinguishable from each other. Clinicians tend to over-diagnose bacterial infections, resulting in unnecessary “just-in-case” prescriptions of antibiotics,1 which is not only an established driver of antimicrobial resistance, but can also have negative effects on an individual level as well. Furthermore, a diagnosis solely on clinical grounds is often hampered by the nonspecificity of clinical symptoms, highlighting the need for accurate, objective diagnostic tools. Since the majority of children are seen in ambulatory care, point-of-care testing (POCT), that is, tests with an actionable turn-around time that can be run within an emergency department (ED) or a pediatrician’s office without the need for a laboratory or dedicated staff, is of particular importance.

In general, there are 2 different angles on infectious diseases diagnostics. While measuring host-response biomarkers can give a first impression on whether an infection is present and if it is more likely to be of bacterial or of viral etiology, microbiological testing enables the identification of a defined pathogen. However, both have their pertinent limitations. Many host-response biomarkers can be induced by noninfectious states, for example, trauma, tumors, autoimmune diseases, or surgery, hence, reducing specificity. Pathogen testing, in turn, suffers from other constraints, such as long turn-around times (laboratory-based tests), low sensitivity (antigen-based POCT), or the inaccessibility of the infected site, for example, in lower respiratory tract infection. In addition, not every detected microorganism is necessarily a causative pathogen, since some bacteria can be part of the “normal” microbiome and viral shedding can occur as a result of past infection (eg, adenovirus).

In the following, we discuss existing and novel tools for POCT with the potential to accelerate patient flow, facilitate appropriate management, and ultimately improve patient outcomes.

PATHOGEN DETECTION: HOW MANY BIRDS WITH HOW MANY STONES?

Here, we focus on pathogen-specific POCTs detecting influenza virus, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2, and Group A streptococci (GAS).

Rapid Antigen Detection Tests (RADTs), which are mostly lateral flow assays, are frequently used in ED settings to quickly identify single pathogens. Their power lies in simple handling, little material being required, and short turn-around times. However, performance characteristics vary greatly between different target pathogens and test manufacturers. A large systematic review yielded an impact of influenza POCT on increased antiviral prescribing and a reduction in subsequent blood test and chest radiographies. However, no effect could be demonstrated on hospital admission, antibiotic prescribing, or time spent in the ED.2

Nevertheless, a positive rapid test result for influenza or respiratory syncytial virus was associated with reduced antibiotic prescriptions in a different study regarding febrile children with respiratory symptoms (adjusted odds ratio, 0.6; 95% confidence interval [CI], 0.5–0.8).3

Data on severe acute respiratory syndrome coronavirus 2 POCT in children are mainly limited to diagnostic accuracy. A recent systematic review reported a sensitivity of 64.2% (95% CI, 57.4%–70.5%) and a high specificity of 99.1% (95% CI, 98.2%–99.5%), despite large inter-study and inter-test variability.4 Of note, sensitivity was higher in symptomatic compared with asymptomatic children (71.8% vs. 56.2%).

An alternative way to detect pathogens at the point of care are nucleic acid amplification tests (NAATs) (also called molecular POCT) that can be operated in a similarly rapid way. Dubois et al5 systematically reviewed NAATs for GAS, showing that overall, they provide higher sensitivities compared with RADTs (96.8% vs. 82.3%). Of note, most of the included studies reported to conduct NAATs in laboratory settings, thereby not meeting the criteria for POCT. Furthermore, the higher costs of NAATs make them less suitable for resource-limited settings. Rao et al6 reported in a single-center study that NAAT led to a higher rate of appropriate antibiotic use (97.1% vs. 87.5%) than RADT in children with GAS.

In the past years, several companies have developed and introduced multiplex polymerase chain reaction (PCR) assays into the market. These are designed to detect around 20 different pathogens, mostly viruses, and to a lesser extent, bacteria and fungi.7 With a turn-around time of under an hour, the assays are more appealing than conventional laboratory-based methods.

Compared with standard of care, their use was associated with a shorter duration of intravenous antibiotic treatment in a single-center study performed in children with signs of a respiratory tract infection.7 A subgroup analysis of children with comorbidities that were tested with a multiplex PCR assay showed a reduction in antibiotic treatment duration and hospitalization costs.7 Limitations of this technology are its higher costs, varying sensitivity for particular target pathogens (eg, herpes simplex virus), the sometimes difficult-to-interpret result constellations with co-detections, and the difficulties of switching to a different manufacturer once one specific platform has been implemented. Table 1 provides an overview on study results regarding the impact of different POCTs on clinical outcomes.

TABLE 1. - Summary of Studies Investigating the Clinical Impact of Point-of-Care Tests in Pediatric Cohorts
Target Test Type Impact on Antibiotic Use Impact on LOS Other Outcomes
GAS POC NAAT +
Adequate prescription of antibiotics in 97.1% (vs. 87.5% RADT plus culture) 6 No impact on follow-up visits 6
Influenza virus POCT +
More antivirals prescribed 2 * No impact on ED LOS 2 * No impact on returning for further care 2 *
No significant results on antibiotic prescribing in RCTs (RR, 0.97; 95% CI, 0.82–1.15) 2 *
RSV + influenza virus POCT +
Positive test result led to reduced antibiotic prescriptions (OR, 0.7; 95% CI, 0.6–0.9) 3
No significant impact on antibiotic prescriptions (OR, 1.2; 95% CI, 1.0–1.4) 3
Respiratory pathogens Multiplex PCR panel + +
Higher rate of appropriate antibiotic therapy compared with antigen tests (93.6% vs. 87.9%) 7 Positive test result associated with slightly shorter appointment duration (48.0 vs. 54.9 min) 7
Host-response Biomarkers CRP + +
Reduction of antibiotic treatment by 11.6% (631/1685 vs. 785/1599) 8 * Reduction of ED consultation time by an average of 120 min (60, IQR 33–125 vs. 180, IQR 158–208) 9 Increase in hospitalizations 8 *
No reduction of antibiotic prescribing (risk difference, –3%; 95% CI, –14% to 8%) 10
PCT
No impact on ED LOS in infants 29–60 d old (OR, 1.08; 95% CI, 0.92–1.28) 11 No impact on admission rates in infants 29–60 d old (OR, 1.07; 95% CI, 0.59–1.96) 11
*Study population includes adults.
IQR indicates interquartile range; LOS, length of stay; OR, odds ratio; POC NAAT, point-of-care nucleic acid amplification test; RCTs, randomized controlled trials; RR, relative risk; RSV, respiratory syncytial virus.

MEASURING HOST-RESPONSE BIOMARKERS: MAKING DO WITH THE BODY’S OWN

Since the natural immune response uses differing pathways in the defense against bacterial and viral pathogens, it appears reasonable to leverage these differences by measuring host-response biomarkers to approximate the true infectious etiology. Biomarkers can be increased in viral infections and suppressed in bacterial infections, such as tumor necrosis factor-related apoptosis-inducing ligand, and vice versa, as is the case, at least theoretically, for procalcitonin (PCT). C-reactive protein (CRP) has been widely used in many European countries with measurable clinical impact,8 despite its weaknesses. PCT is another inflammatory marker that has been consistently used as a discriminator between viral and bacterial etiology. The use of the aforementioned bi-directional kinetics of PCT is limited as very low values can often not be displayed for technical reasons due to the lower limit of detection employed in most assays. Even though clinical utility in intensive care settings for both, adults and neonates has been shown,12 there is a lack of high-quality data showing benefit of PCT in the pediatric ED setting (Table 1).

Apart from CRP and PCT, there is an increasing list of biomarkers, but real clinical impact remains to be demonstrated for most of these. A host signature based on TRAIL, interferon-γ-induced protein-10, and CRP reached a sensitivity of 93.7% and a specificity of 94.2% in differentiating between bacterial and viral illnesses in a large prospective multicenter study. Combined with the reported negative predictive value of 98.9%, it results in a high potential to cut down on antibiotic overuse.13 A different test combines in a semi-quantitative assay CRP and Myxovirus resistance protein A, a virally-induced protein similar to TRAIL, in finger prick blood samples, making it feasible especially in less well-equipped settings.14

Transcriptomics have been another exciting technology, which offers the opportunity to measure different gene transcripts at once. Recent efforts demonstrated suitability of this technology to be implemented into a POCT platform.15 However, their utility and cost-effectiveness on a larger scale still need to be demonstrated.

COMBINED PATHOGEN AND HOST TESTING: THE BEST OF BOTH WORLDS

Although both approaches have been investigated on their own, the combination of both has been studied only rarely. A more comprehensive approach to unbiased pathogen detection is metagenomic next generation sequencing. It enables a hypothesis-free testing for nearly any organism’s DNA or RNA and, depending on the technology used, offers coverage of host genes as well.16 This approach could also help to unravel cases in which carriage microorganisms are found by simultaneously probing the host response. Nevertheless, applicability in the real-world clinical setting has not been studied sufficiently, and the question of causality of detected sequences remains.

Fueled by the coronavirus disease 2019 pandemic, the market for POCT has rapidly expanded during the last 2 years. Other high-end technologies not described in detail here can be expected to be more readily available in the future for POCT, for example, clustered regularly interspaced short palindromic repeats-based diagnostics.

Notably, the implementation success of a test or a test bundle is highly dependent on simultaneous educational efforts addressing the practitioners who are expected to order and ultimately interpret test results, including, for example, the use of algorithms. Other potential barriers may be inherent to the very setting itself on both, micro and macro levels, including technical feasibility or reimbursement policies.

There are other factors that may influence how testing approaches may change over time, such as seasonality and, related to this, prevalence. In settings and times of high prevalence of a given infectious disease, RADTs may offer a very reasonable and cost-effective approach to POCT. In contrast, multiplex PCR arrays may be reserved for more difficult-to-diagnose, hospitalized cases. An ideal biomarker in turn should assist in informing whether an antibiotic is necessary in the first place, whereas using specific biomarker cutoffs to guide antibiotic treatment duration is another potential use, albeit less important for ED settings.

Ultimately, diagnostic equity should be aimed for by stakeholders, since access to modern diagnostics with real impact on clinical outcomes is also a matter of justice and should not be contingent on a patient’s or their family’s income, or societal, religious, ethnic, or geographic background.

In conclusion, POCT can be integrated into routine diagnostics in pediatric EDs, where rapid clinical decisions must be undertaken. However, performing diagnostic procedures that ultimately do not influence clinical decision-making should be avoided. Besides their impact in terms of diagnostic accuracy, both pathogen tests and biomarkers have the potential to positively affect outcomes such as length of stay or antibiotic treatment, thereby contributing to antimicrobial stewardship efforts. There remains a substantial need for further prospective, controlled studies especially on host biomarkers and their impact on clinically relevant outcomes in pediatric EDs in both high- and low-resource settings.

REFERENCES

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Keywords:

biomarker; children; nucleic acid amplification techniques; point-of-care testing; respiratory tract infection

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