In-vitro diagnostic point-of-care tests in paediatric ambulatory care: A systematic review and meta-analysis.

INTRODUCTION: Paediatric consultations form a significant proportion of all consultations in ambulatory care. Point-of-care tests (POCTs) may offer a potential solution to improve clinical outcomes for children by reducing diagnostic uncertainty in acute illness, and streamlining management of chronic diseases. However, their clinical impact in paediatric ambulatory care is unknown. We aimed to describe the clinical impact of all in-vitro diagnostic POCTs on patient outcomes and healthcare processes in paediatric ambulatory care.
METHODS: We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from inception to 29 January 2020 without language restrictions. We included studies of children presenting to ambulatory care settings (general practice, hospital outpatient clinics, or emergency departments, walk-in centres, registered drug shops delivering healthcare) where in-vitro diagnostic POCTs were compared to usual care. We included all quantitative clinical outcome data across all conditions or infection syndromes reporting on the impact of POCTs on clinical care and healthcare processes. Where feasible, we calculated risk ratios (RR) with 95% confidence intervals (CI) by performing meta-analysis using random effects models.
RESULTS: We included 35 studies. Data relating to at least one outcome were available for 89,439 children of whom 45,283 had a POCT across six conditions or infection syndromes: malaria (n = 14); non-specific acute fever 'illness' (n = 7); sore throat (n = 5); acute respiratory tract infections (n = 5); HIV (n = 3); and diabetes (n = 1). Outcomes centred around decision-making such as prescription of medications or hospital referral. Pooled estimates showed that malarial-POCTs (Plasmodium falciparum) better targeted antimalarial treatment by reducing over-treatment by a third compared to usual care (RR 0.67; 95% CI [0.58 to 0.77], n = 36,949). HIV-POCTs improved initiating earlier antiretroviral therapy compared to usual care (RR, 3.11; 95% CI [1.55 to 6.25], n = 912). Across the other four conditions, there was limited evidence for the benefit of POCTs in paediatric ambulatory care except for acute respiratory tract infections (RTI) in low-and-middle-income countries (LMICs), where POCT C-Reactive Protein (CRP) may reduce immediate antibiotic prescribing by a third (risk difference, -0.29 [-0.47, -0.11], n = 2,747). This difference was shown in randomised controlled trials in LMICs which included guidance on interpretation of POCT-CRP, specific training or employed a diagnostic algorithm prior to POC testing.
CONCLUSION: Overall, there is a paucity of evidence for the use of POCTs in paediatric ambulatory care. POCTs help to target prescribing for children with malaria and HIV. There is emerging evidence that POCT-CRP may better target antibiotic prescribing for children with acute RTIs in LMIC, but not in high-income countries. Research is urgently needed to understand where POCTs are likely to improve clinical outcomes in paediatric settings worldwide.

Introduction

Point-of-care tests (POCTs) promise to revolutionise the amount and quality of care that we can deliver in the community [1]. There has been laudable progress in developing tests that are fast and simple enough to support clinical decision-making [2, 3]. These fall into two main areas: acute presentations in which a decision needs to be taken within the time frame of the consultation; and monitoring of chronic conditions, allowing advice and medication adjustments to made without the need for additional healthcare contacts. Research on the benefits of POCT has focussed on improvement of care and clinical pathways for adults [2, 4–9]. These include POCTs for cardiovascular diseases (cholesterol, NT-pro-BNP), diabetes mellitus (HbA1c and glucose), kidney disease (microalbuminuria), blood coagulation (INR and D-dimers for deep vein thrombosis and pulmonary embolism), myocardial damage (heart-type fatty acid binding protein (H-FABP), troponin, CK-MB). Here, for example, immediate POCT results are associated with the same or better medication adherence in adults compared with a laboratory-based test result [10]. However, in high-income countries (HICs), a substantial proportion (25%) of consultations in ambulatory care are for children and in particular, children with acute illness [11-13]. In low and middle-income countries (LMICs), the proportion of consultations for children with acute illness is likely to be at least this high, compounded by the disproportionate burden and mortality of infectious disease dominated by malaria, tuberculosis and HIV.

Both HIC and LMIC settings pose diagnostic challenges. The diagnostic process of acute illness and monitoring of chronic disease in children is mostly based on clinical assessment. Globally, very few children will have a serious condition requiring urgent care [14, 15], but the non-specific nature of early symptoms makes it difficult to detect those children who will progress to more serious infections and require secondary care management. This diagnostic uncertainty often leads to inappropriate prescribing, unnecessary referrals to hospital, needless additional testing [16], and a 10–20% trend increase in potentially avoidable, short stay hospital admissions of children since 1997–2012 [17-19].

In LMICs, these factors exist alongside the risk of serious communicable diseases and high childhood mortality rates. Population-level interventions, for example, like the mass roll-out of antibiotics may reduce mortality, but remains controversial and is likely unsustainable in resource-poor settings [20-22]. One factor which could help reduce this diagnostic uncertainty is POC technology. POCTs may help to improve diagnostic precision, optimise prescribing and improve the quality of care for children, and, indirectly, relieve pressure on healthcare systems [17-19]. Likewise, the benefit of POCTs for long-term conditions shorten the feedback loop by providing an immediate result that allows timely adaptation of treatment [10]. This mitigates against the impact of tardy laboratory results, or results only being actioned at the next consultation. Therefore, when treatment decisions lag behind “real-time”, they often become empirical.

Yet, we should be mindful that the complexity of clinical decision-making in children is not the same as in adults. Although the analytical and clinical diagnostic accuracy of POCTs may be broadly similar in adults and children, the clinical effectiveness of using a POCT within a clinical pathway cannot be generalised from adults to children. The clinical needs are distinct. Factors such as parental concern and the potential for rapid clinical deterioration may alter the test’s clinical effectiveness and diagnostic value in paediatric populations.

Currently, we do not know the existing evidence base for in-vitro POCTs in children and the clinical impact of this technology on patient outcomes and healthcare processes in paediatric ambulatory care. We therefore performed a systematic review to describe this.

Methods

Search strategy and inclusion criteria

The study protocol was published prospectively [23]. This review is a sub-study and evaluates the clinical impact of any in-vitro diagnostic point-of-care test (POCT) in paediatric populations in ambulatory care.

We systematically searched the six main electronic databases (MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science) from database inception to 29 January 2020. With the help of an Information specialist, we used validated search filters for “primary care/ambulatory care”, “point of care/rapid test", and “adolescent/child/infant” (example of search strategy S8 Appendix in S1 File).

We included randomised controlled trials (RCTs) and non-randomised studies of children presenting first to ambulatory care settings (general practice, hospital outpatient clinics, or emergency departments, walk-in centres, registered drug shops) where healthcare is delivered and/or POCTs are used. Children were defined by the authors of included studies.

Where studies involved both adults and children, we included studies where we were able to distinguish outcomes of children from adults. We only included studies that examined in-vitro POCTs that were defined as in-vitro i.e. tests involving blood or other bodily fluid or excreta that have been taken from the human body. Diagnostic POCTs that were not in-vitro (e.g. POC ultrasound) were excluded. Studies were eligible if they compared the POCT with usual care. Usual care could include no testing or central laboratory tests, but not another novel test or diagnostic strategy. We included and distinguished studies where POCTs were used in conjunction with another training or communication strategy.

We included all quantitative clinical outcome data across all conditions or infection syndromes reporting on the impact of POCTs on clinical care and healthcare processes. Outcome data could include: patient outcomes (e.g. mortality; morbidity); decision-making/clinical management decisions (e.g. hospital attendance/referral); medication prescribing (e.g. antibiotic prescribing); and additional diagnostic testing.

We compared studies according to similar condition as stated by authors, study design, and outcomes. Data had to be reported in sufficient detail to compare relevant outcomes between children with similar conditions/illnesses, and a POCT versus usual care.

We excluded health economic outcomes, qualitative studies, diagnostic accuracy studies, studies solely conducted in hospital inpatient settings and hospital-acquired infections. We excluded study designs that precluded comparisons between tested and non-tested participants (case studies, case series, and studies without a suitable control).

Analyses

Two reviewers (OVH, MR) independently screened articles in duplicate at title and abstract, and full-text levels. A third reviewer (GH) resolved any disagreement. The team (MR, GH, JJL, AvB, JV, PT, CRG) extracted data on the characteristics of included studies and assessed quality of included studies based on their respective risk-of bias tool. We used the Cochrane Risk of Bias tool for RCTs [24]. This was extended to accommodate non-randomised studies by including additional parameters such as reporting of baseline characteristics; whether intervention and control groups were similar; and whether there was a detailed description of the usual care pathway [7]. OVH checked data extraction and quality assessment. We contacted corresponding authors for clarification.

We used random effects meta-analyses (where possible) to generate pooled estimates with 95% confidence intervals (CI) for the same condition or infection syndrome. Heterogeneity was assessed using the χ2 test and I statistic. We calculated risk ratios (RR) for dichotomous outcomes and mean differences for continuous outcomes. Subgroup analyses were performed according to study design (RCTs vs non-randomised studies). We used sensitivity analyses, excluding studies to explore heterogeneity. Results were summarised narratively where data were not sufficient to perform meta-analysis. We used Covidence software [25] for citation management. Meta-analysis was performed with Revman [26] and STATA 14 SE [27].

Results

The searches resulted in 6,860 unique records, of which 163 full-text articles were eligible for inclusion after selection on title and abstract (Fig 1). We excluded 114 studies at the full text stage. The two most common reasons for exclusion after assessing the full text were that studies were conducted in adult populations (n = 30/114) or that clinical outcomes were not reported separately for adult and paediatric populations (n = 26/114). Finally, 49 studies satisfied our selection criteria. A systematic review on the clinical impact of influenza POCTs has been published in 2019 by our research group which included 11 studies (seven RCTs, four non-randomised studies) [6]. We found three further observational influenza studies [28-30] which do not change the overall findings of the original influenza review. As a result, we excluded the 14 influenza studies leaving 35 studies for this review.

Fig 1

PRISMA flowchart of included and excluded studies.

Abbreviations: POCTs, point-of-care tests; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, randomised controlled trials.

Characteristics of included studies

We included 35 included studies (Table 1, Fig 1).

Table 1

Characteristics of included studies.

Study	Design	Setting	Number of children	Point-of-care test	Role in clinical pathway	Comparator (description)	Outcomes
Malaria (Pf) a
Ansah et al. (2010)	RCT	Primary healthcare clinics, Ghana	3,957 (data from children 0–15 years old)	OptiMAL-IT rapid diagnostic test	Replacement	Two arms:(a) Microscopy (b) Clinical diagnosis	i Antimalarial treatment ii Antibiotic prescribing in malaria iii Safety
Ansah et al. (2015)	Cluster RCT	Registered drug shops, Ghana	2,101	CareStart Malaria HRP2	Triage	Shops in communities were expected to dispense medicines without malarial POCT as per current practice	i Safety
Baiden et al. (2016)	Cluster RCT	Primary healthcare clinics, Ghana	3,046	CareStart Malaria First Response	Add-on	Usual care (clinical judgment)	i Mortality ii Antimalarial treatment iii Antibiotic prescribing
Chandler et al. (2017)	Cluster RCT	Primary healthcare clinics, Uganda	1,336	Not reported	Add-on	Usual care(Standard care includes services typically provided by public health centres)	i Antimalarial treatment ii Antibiotic prescribing in malaria iii Safety
Hopkins et al. (2017)	Observational pre- and post-implementation [Tanz-1-pub study only] b	Primary healthcare clinics, Tanzania	3,454 (paediatric data from Tanz-1-pub study)	SD Bioline Pf Standard Diagnostics	Add-on/Replacement	Period before implementation (not reported)	i Antibiotic prescribing in malaria
Lal et al. (2016)	Cluster RCT	Primary healthcare clinics, Uganda	23,104	First Response Malaria HRP2	Add-on	Usual care (Presumptive diagnosis for malaria based on clinical symptoms)	i Referral
Mbonye et al. (2015)	Cluster RCT	Registered drug shops, Ghana	8,781	Not reported	Add-on	Usual care (Presumptive diagnosis for malaria based on clinical symptoms)	i Antimalarial treatment ii Prompt antimalarial treatment within 24 hrs
Msellum et al. (2009)	Non-randomised crossover study	Primary healthcare clinics, Tanzania	1,453	Paracheck Pf	Add-on	Usual care (symptom-based clinical diagnosis)	i Antimalarial treatment ii Antibiotic prescribing in malaria
Mubi et al. (2011)	Cross-over RCT	Primary healthcare clinics, Tanzania	1,505	Paracheck Pf	Add-on	Usual care (Clinical diagnosis)	i Antimalarial treatment ii Referral iii Mortality iv Patient recovery
Mukanga et al. (2012)	Cluster RCT	Primary healthcare clinics, Burkina Faso, Ghana, Uganda	4,216	Multiple (First Sign Malaria Pf Card Test; Paracheck Pf; ICT Malaria Pf)	Add-on	Usual care (presumptive treatment) (presumptive diagnosis for malaria based on clinical symptoms	i Antimalarial treatment ii Antibiotic prescribing in malaria iii Patient recovery iv Safety
Ndyomugyenyi et al. (2016)	Cluster RCT	Primary healthcare clinics, Uganda	2,575	First Response Malaria HRP2	Add-on	Usual care (presumptive treatment)	i Antimalarial treatment ii Prompt antimalarial treatment within 24 hrs iii Safety
Sayang et al. (2009)	Non-randomised parallel group trial	One primary healthcare clinic, Cameroon	312	Diaspot Malaria RDT cassette	Add-on	Usual care (presumptive treatment)	i Antimalarial treatment ii Patient recovery
Ukwaja et al. (2010)	Quasi-experimental	One primary healthcare clinic, Nigeria	100	Paracheck Pf	Add-on	Usual care (all children received oral antimalarial treatment in control group)	i Antimalarial treatment ii Early clinic reattendance iii Patient recovery
Yeboah-Antwi et al. (2010)	Cluster RCT	Primary healthcare clinics, Zambia	3,047	ICT Malaria Pf	Add-on	Usual care (presumptive treatment)	i Antimalarial treatment ii Hospitalisation iii Additional antibiotics iv Mortality
Non-specific fever ‘illness’
Althaus et al. (2019)	3-arm RCT	Primary healthcare clinics, and one outpatient department in Thailand, Myanmar	1,201	Nyocard II Reader (Axis Shield)	Triage (Two pre-defined CRP-POCT thresholds before medical examination	Usual care (described as “standard prescribing practice”)	i Immediate antibiotic prescribing ii Additional antibiotic prescription within 14 days
Cohen et al. (2008)	Non-randomised parallel group trial	Ambulatory paediatric private practice, France	227	Nyocard CRP analyser	Replacement	Usual care (laboratory CRP testing)	iii Immediate antibiotic prescribing iv Hospital attendance c v Additional test use
Lemiengre et al. (2018)	Cluster RCT	General practice, Belgium	2,227	Afinion AS 100 CRP analyser	Add-on	Usual care (not reported)	i Immediate antibiotic prescribing ii Hospital attendance
Nijman et al. (2015)	Observational pre- and post-implementation	Single ED, The Netherlands	1,939	Afinion AS 100 CRP analyser	Triage	Period before implementation (laboratory CRP at the discretion of the ED clinician)	i Immediate antibiotic prescribing ii Hospital attendance iii Additional test use
Rebnord et al. (2017)	RCT	Out-of-hours general practice Norway	397	QuikRead Go CRP (Orion Diagnostica)	Add-on	Usual care (POC CRP at clinician’s discretion)	i Immediate antibiotic prescribing ii Hospital attendance
Van den Bruel et al. (2016)	RCT	Out-of-hours general practice, UK	54	Afinion AS 100 CRP analyser	Triage	Usual Care (usual practice)	i Immediate antibiotic prescribing
Verbakel et al. (2016)	Cluster RCT	General practices, Belgium	3,147	Afinion AS 100 CRP analyser	Triage	Usual Care (clinically-guided CRP testing)	i Hospital attendance
Acute RTIs
Diederichsen et al. (2000)	RCT	General practices, Denmark	139	Nycocard CRP II (Axis Shield)	Add-on	Usual Care (clinical assessment only)	i Immediate antibiotic prescribing
Do et al. (2016)	RCT	Primary healthcare clinics, Vietnam	1,028	Nyocard CRP analyser	Add-on	Usual care (treated according to routine practice and local treatment guidelines)	ii Immediate antibiotic prescribing iii Subsequent antibiotic at re-consultation iv Change in antibiotic regime
Doan et al. (2009)	RCT	ED in tertiary hospital, Canada	199	Viral panel test for Adenovirus, Influenza A/B, parainfluenza 1/2/3, RSV	Triage	Usual Care (POC swab at discretion of clinician)	i Immediate antibiotic prescribing ii Subsequent antibiotic at re-consultation iii Length of stay in ED iv Additional test use v Reattendance vi Ancillary tests at re-consultation
Keitel et al. (2019)	Subgroup analysis of RCT*febrile patients with non-severe respiratory symptoms	Public outpatient clinics, Tanzania	1,726	Two-step diagnostic algorithm (ePOCT) followed by an POCT- CRP (BioNexia CRPplus)	Add-on	Decision algorithm (ALMANACH) control arm (New Algorithm for Managing Childhood Illness Using Mobile Technology (ALMANACH)	i Immediate antibiotic prescribing ii Hospital attendance iii Subsequent antibiotic at re-consultation iv Patient recovery v Mortality
Schot et al. (2018)	RCT	General practices, The Netherlands	309	Afinion POC CRP (Alere Technologies AS, Oslo, Norway),	Add-on	Usual care: (GPs were advised not to use POC CRP, and treatment decisions were based on clinical assessment as usual.)	i Immediate antibiotic prescribing ii Subsequent antibiotic at re-consultation within same illness period iii Subsequent antibiotic at re-consultation within 3 months
Acute sore throat
Ayanruoh et al. (2009)	Retrospective record review	Paediatric ED, USA	8,280	Rapid streptococcal test	Replacement	Period before implementation(clinical assessment only)	i Immediate antibiotic prescribing
Bird et al. (2018)	Observational pre- and post-implementation	ED in tertiary hospital, UK	605	Diagnostic algorithm, clinical scoring system, bionexia rapid streptococcal test	Add-on	Period before implementation(clinical assessment only)	i Immediate antibiotic prescribing
Malecki et al. (2017)	RCT	Primary healthcare clinics, Poland	1,307	OSOM Strep A test		Usual care (decision to prescribe an antibiotic was based on history and physical examination)	i Immediate antibiotic prescribing ii Re-consultation
Maltezou et al. (2008)	Quasi RCT	Ambulatory paediatric private clinics, Greece	820	BD Link 2 Strep A Rapid antigen test	Add-on	Usual care (evaluation of children and decision to prescribe antibiotics by clinical criteria only, as in their usual everyday clinical practice)	i Immediate antibiotic prescribing
Meier et al. (1990)	Retrospective record review	Single community health centre, USA	176	Latex agglutination antigen detection method(Culturette, Marion Laboratories)	Replacement	Period before implementation (usual care not reported)	i Immediate antibiotic prescribing
HIV
Bianchi et al. (2019)	Observational pre- and post-implementation	Cameroon, Côte d’Ivoire, Kenya, Lesotho, Mozambique, Rwanda, Swaziland, and Zimbabwe	792 HIV positive infants (cohort of 20,865)	m-PIMA HIV-1/2 Detect (Abbott Laboratories; Lake Forest, IL, USA) or Xpert HIV-1 Qual (Cepheid; Sunnyvale, CA, USA)	Replacement	Period before implementation with conventional EID tests	i Initiating antiretroviral (ARV) therapy within 60 days
Jani et al. (2018)	Cluster RCT	Rural and urban primary healthcare clinics, Mozambique	277 HIV positive children (cohort of 3,910)	Alere q HIV 1/2 Detect System	Replacement	Usual care (all HIV-exposed infants who presented at regular consultation visits) and existing laboratory testing	i Initiating antiretroviral (ARV) therapy within 60 days ii Retention of patients remaining on ARV
Mwenda et al. (2018)	Observational study	Ambulatory healthcare facilities, Malawi	76 HIV positive children (cohort of 1,762)	Alere q HIV 1/2 Detect System	Replacement	Usual care and existing laboratory testing	i Initiating antiretroviral (ARV) therapy within 60 days
Insulin-dependent diabetes mellitus
Agus et al. (2010)	RCT	Paediatric outpatients, USA	215	POCT Hba1C, DCA2000+ Analyser	Replacement	Usual care (laboratory Hba1c available several days after clinic visit)	i Change in Hba1c from baseline ii Patient communication between clinic visits

a Pf: Plasmodium Falciparum;

b In Tanz1-pub, microscopy was available in some higher-level facilities but was not frequently use;

c Hospital attendance includes referral to hospital and hospital admission.

There were 24 RCTs of which 11 were cluster RCTs [31-41], one a quasi-randomised trial (term used by study authors) [42], and the remaining 12 studies were individually randomised RCTs [5, 43–53]. Two RCTs had a 90% overlap in the population [31, 32]. In Lemiengre et al., children with episodes at a high risk of serious infection were excluded from the analysis [31]. In Verbakel et al., CRP in all children was compared to CRP only in high-risk children [32]. We were careful to only evaluate data from either the Verbakel or Lemiengre study. There were 11 non-randomised studies. Of these, six studies compared records before and after the introduction of POCTs [54-59], three were non-randomised parallel group trials [60-62], one an observational study [63], and one a quasi-experimental study [64].

There were six conditions or infection syndromes (number of studies): malaria (n = 14); non-specific acute fever ‘illness’ (n = 7); sore throat (n = 5); acute respiratory tract infections (n = 5); HIV (n = 3); and diabetes (n = 1). Data relating to at least one outcome were available for 89,439 children of whom 45,283 had a POCT. Two thirds of these data (66%, 58,987/89,439) related to suspected malaria.

We have summarised a brief description of usual care as comparator in Table 1 (extracted from the original text). This was often not clearly defined and, in most cases, this was taken to be a clinical diagnosis with no POCT used. For example, in malarial studies set in LMICs, usual care involved children prescribed antimalarials based on clinical symptoms in outpatient clinics and cared for at home. In the usual care arm, around 90% of children were prescribed antimalarials. In non-clinical settings e.g. registered drug shops, usual care was a presumptive diagnosis of malaria. Three studies used existing laboratory-based testing as comparator as part of usual care [33, 62, 63]. In other studies, e.g. acute fever ‘illness’, antibiotic prescribing in usual care was around 28% and based on clinical assessment (see Fig 8) [31, 50, 51, 57, 62]. In one study, usual care was a decision algorithm modelled on a set of important paediatric signs and symptoms [52].

Fig 8

Immediate antibiotic prescribing for non-specific acute fever illness.

Forest plot of meta-analyses of randomised trials and non-randomised studies reporting immediate antibiotic prescribing comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

Locations

Overall, 33 studies were conducted in ambulatory care settings and two malaria studies were conducted in registered drug shops where medicines are dispensed [34, 38]. Twenty studies were in LMICs in Africa focussing mainly on malaria or HIV, and the remaining 15 studies in mainly high-income European countries (Table 1).

Of the 20 studies conducted in LMICs, 18 studies were conducted in primary healthcare clinics and two studies in registered drug shops.

Of the 15 studies conducted in HICs, six studies were conducted in general practice [31, 32, 45, 48, 53, 56], four studies in emergency departments [47, 54, 57, 59], two studies in private paediatric practice [42, 62], two studies in an out-of-hours community setting [50, 51], and one study in paediatric outpatients [43].

Principle method and target analytes of POCTs

A summary and description of each POCT and target analyte is given in S1 Appendix in S1 File. All point-of-care malaria devices used an immunochromatographic assay to either detect histidine-rich protein (HRP-2) produced by Plasmodium falciparum, or parasite lactate dehydrogenase (pLDH, panmalarial antigen). The three HIV studies used the same nucleic acid-based HIV POCT [33, 58, 63]. All studies using POCT-CRP employed a quantitative immunochemical assay for C-reactive protein. Five studies used a rapid antigen test for Strep A [42, 48, 54, 56, 59].

POCTs and their intended role in clinical pathway and associated training

We examined the intended role of POCTs in the clinical pathway (S2 Appendix in S1 File) [65]. The majority of POCTs were defined as ‘add-on’ (n = 20) in which the new test is performed at the end of a clinical pathway to decide on appropriate treatment; nine studies used POCTs as ‘replacement’, in which the new test replaces an existing test, either as a faster equivalent test or to replace a non-point-of-care laboratory test, and six studies used POCTs as ‘triage’, in which the new test is used at the start of the clinical pathway excluding patients from further testing.

We tabulated any associated educational component in addition to POCT training offered (S2 Appendix in S1 File). Nine studies did not report any educational or training component, five studies focussed only on POC training for clinicians, and the remaining studies included a package of POC training, clinical training and guideline update, and/or interpretation of POCT.

Risk of bias assessment

Randomised trials were of moderate risk of bias (Fig 2); non-randomised studies had a higher risk (Fig 3). As we anticipated, none of the studies were able to blind participants and personnel to testing or test results. There were two cluster RCTs [32, 46]. that were able to conduct blind outcome assessment (one reported in two separate papers) [31, 32]. The non-randomised and before–after studies suffered from a high risk of selection, performance and detection bias and an unclear risk of reporting bias, as there was no protocol available.

Fig 2

Risk of bias summary for 24 randomised controlled trials across all conditions.

Fig 3

Risk of bias summary for 11 non-randomised studies across all conditions.

We have categorised relevant outcome data according to four groups:

Patient outcomes (mortality; morbidity; patient recovery)

Decision-making/management decisions (hospital attendance/referral; early clinic reattendance/re-consultation i.e. the decision of the parent/carer to re-consult); length of stay; initiating therapy within time period; patient retention on therapy; Hba1c monitoring)

Prescribing (antimalarial treatment; antibiotic prescribing in malaria; initiating immediate antibiotic prescribing; subsequent antibiotic prescriptions; change in antibiotic regime)

Additional diagnostic testing (additional test use; ancillary tests at re-consultation)

As there were so few studies that evaluated the impact of POCT on patient outcomes, we have grouped these results together. The remaining outcomes are described per condition.

Patient outcomes

Across all conditions, six studies specifically reported mortality and morbidity measures such as illness course [31, 35, 41, 44, 49, 52], of which one study for non-specific acute fever illness in Belgium reported no deaths during the study using POCT-CRP [31], and one study for acute RTIs in Tanzania, found there were two fewer deaths in the POCT-CRP arm than usual care (0/865 vs 2/854) [52]. This latter study, using a two-step intervention (diagnostic algorithm followed by POCT-CRP), also found that the difference for patient recovery within one week was clinically negligible between intervention and control arms respectively, 97.1% (840/865) vs 95.2% (813/854).

The other four studies (two RCTs, two non-randomised studies) all relating to malaria studies in LMICs, found no difference in deaths between POCT and usual care (S3 Appendix in S1 File) [35, 41, 44, 49]. There was no difference in patient recovery between malarial POCTs and usual care 3 to 7 days after treatment in four malaria studies (Fig 4) [39, 49, 61, 64]. The definition of patient recovery varied between studies, from self-reported full recovery [49], afebrile and negative blood smear [61], resolution of fever [39], or the absence of symptoms [64].

Fig 4

Recovery between day 3 to 7.

Forest plot of meta-analyses of randomised trials and non-randomised studies reporting recovery after antimalarial treatment comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

(A) Malaria

Decision-making

The proportion of children referred to the next level of care was significantly greater in children receiving a malarial-POCT than those in usual care based on two randomised studies (RR, 7.10 95% CI [2.3 to 21.92], I2 = 95%) [37, 49]. One cluster RCT evaluating hospitalisation rate in children with malaria and pneumonia found no difference between POCTs 0.4% (4/1,017) and usual care 0.7% (14/2,108) [41].

Prescribing

Antimalarial treatmen. There were 11 studies (8 RCTs and 3 non-randomised studies) evaluating the use of malarial-POCTS in endemic malaria areas [35, 36, 38–41, 44, 49, 60, 61, 64]. One RCT had two usual care arms (microscopy vs usual care; POCTs vs usual care) in which the two comparison arms were analysed separately in the meta-analysis [44]. Pooled estimates of RCTs showed that the use of malarial-POCTs better targeted antimalarial treatment by reducing over-treatment by a third in comparison to usual care (RR, 0.67; 95% CI [0.58 to 0.77], I2 = 99%) (Fig 5).

Fig 5

Effect of malaria-POCT on antimalarial prescriptions in suspected malaria.

Forest plot of meta-analyses of randomised trials and non-randomised studies reporting a reduction in antimalarial treatment comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

There were two RCTs which had a marked effect on the pooled estimate [40, 41]. In these two studies, almost all children in the usual care arm received antimalarials (97–99%). In addition, community health workers in the intervention arm of one of these two RCTs received additional refresher training six months after initial training [41]. Sensitivity analysis excluding these two studies showed that the effect remains significant (RR, 0.86; 95% CI [0.79 to 0.93], I2 = 98%).

Based on two cluster RCTs [38, 40], the proportion of children with malaria receiving prompt and targeted antimalarial treatment within 24 hours was significantly greater with rapid diagnostic tests compared to usual care, whether that care was delivered by community health workers or registered drug shops (RR 2.72, 95% CI [1.15 to 6.43], n = 11,304, S4 Appendix in S1 File). We also summarised safety aspects of malarial-POCT interpretation and antimalarial treatment in comparison to usual care (S5 Appendix in S1 File).

Antibiotic prescribing in suspected malaria. There was no significant difference in antibiotic prescribing in suspected malaria cases between POCTs and usual care, based on three cluster RCTs (RR 1.04, 95% CI [0.88 to 1.22], n = 8,403, Fig 6) [35, 36, 44]. In contrast, antibiotic prescribing was more likely in usual care in two non-randomised studies [55, 60].

Fig 6

Antibiotic prescribing in suspected malaria.

Forest plot of meta-analyses of randomised trials and non-randomised studies of the likelihood of antibiotic treatment in malaria comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

Based on one RCT, there was no statistically significant difference in the proportion of children who received additional antibiotics between days 5 to 7, POCTs 13/975 (1.3%) versus usual care 25/2,054 (1.2%) [41].

(B) HIV

Three studies evaluated the use of HIV-POCT in children: one cluster RCT in Mozambique [33] and two observational studies [58, 63] set in Malawi and multiple African countries respectively.

Initiating antiretroviral (ARV) therapy within 60 days in newly-diagnosed HIV children was almost 3-fold higher in those children that had an HIV-POCT compared to usual care in three studies (RR, 3.11; 95% CI [1.55 to 6.25], p<0.001; n = 912) [33, 58, 63].

HIV-positive children who initiated ARV therapy based on HIV-POCT were also more likely to be retained in care at 90 days follow-up compared to usual care (adjusted RR, 1.40; 95% CI [1.1–1.9], p<0.027; n = 213) [33].

(C) Non-specific acute fever ‘illness’

There were seven studies that addressed non-specific acute fever ‘illness’ in children: one cluster RCT reported in two papers with slightly different included populations [31, 32]; three RCTs [5, 50, 51]; and two non-randomised studies [57, 66]. Studies were set in general practice (2 studies), out-of-hours setting (2 studies), primary care clinics in Thailand and Myanmar (1 study), ambulatory paediatric private practice (1 study), and the emergency department (1 study) (Table 1).

All studies used POCT-CRP (S1 Appendix in S1 File). Guidance on the interpretation of CRP results was given/available in one study [51]; intentionally not provided to clinicians in one cluster RCT (citing that safe cut-off levels in primary care are unknown) [31, 32]; subdivided into groups greater or less than CRP 60mg/L with no threshold justification [62]; subdivided into two pre-defined CRP-POCT thresholds (CRP 20mg/L and CRP 40mg/L) before medical examination [5], and not reported in two studies [50, 57]. In the one UK study, clinicians were informed that a CRP level <20 mg/L suggested a serious infection was less likely compared to a value of >80 mg/L where serious infection was more likely [51]. Additional information about CRP values can be found in S6 Appendix in S1 File.

Five studies evaluated decisions related to hospital attendance or hospital admission for non-specific acute fever illness [32, 50, 51, 57, 62]. Pooled estimates of either randomised (RR, 0.93; 95% CI [0.49 to 1.77], I2 = 49%) [32, 50, 51] or non-randomised studies (RR, 0.40; 95% CI [0.12 to 1.36], I2 = 81%) [57, 62] did not show a statistically significant effect on hospital attendance or admission rates (Fig 7).

Fig 7

POCT impact on reducing hospital attendance for non-specific acute illness.

Forest plot of meta-analyses of randomised trials and non-randomised studies reporting hospital attendance (immediate hospital assessment and/or admission) comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

Immediate antibiotic prescribing

Six studies reported antibiotic prescribing [5, 31, 50, 51, 57, 62]. using POCT-CRP. Neither RCTs (RR, 0.93; 95% CI [0.84 to 1.03], I2 = 0%) nor non-randomised studies (OR, 0.95; 95% CI [0.83 to 1.10], I2 = 0%) showed an effect of the use of POCT-CRP on antibiotic prescribing (Fig 8).

Further analysis of the Althaus study [5],where the researchers used two pre-defined POCT-CRP thresholds (CRP 20mg/L and CRP 40mg/L) before medical examination, showed that the effect on immediate prescribing was not significant for the POCT-CRP group (133/400) which used thresholds of 20mg/L (RR, 0.94; 95% CI [0.78 to 1.14]), but had an effect on immediate prescribing for the POCT-CRP group (114/399) which used thresholds of 40mg/L (RR, 0.73; 95% CI [0.54 to 0.99], p = 0.04) compared with the control group (142/402). The risk of additional antibiotic prescriptions between day 0 and day 14 in the POCT-CRP groups versus control groups was not statistically significant for either intervention group compared to the control group (CRP20 group RR, 0.94; 95% CI [0.46 to 1.92], n = 14; CRP40 group RR, 1.36; 95% CI [0.69 to 2.70], n = 20; control group n = 15).

Test use

Two non-randomised studies [57, 62] reported the impact of POCT-CRP on additional tests: urinalysis, blood culture, routine bloodwork, lumbar puncture and radiological imaging (Table 2).

Table 2

Impact of POCTs on additional tests.

Outcome	Studies (n)	(Pooled) Effect estimate
Urinalysis	1 (n = 227) [62]	RR, 0.29 [95% CI, 0.20 to 0. 41]
Blood Culture	1 (n = 1,939) [57]	RR, 1.33 [95% CI, 0.92 to 1.94]
Additional blood work	2 (n = 2,166) [57, 62]	RR, 0.21 [95% CI, 0.01 to 5.37], I2 = 98%
Lumbar puncture	1 (n = 1,939) [57]	RR, 0.74 [95% CI, 0.37 to 1.47]
Imaging (chest radiography or MRI)	2 (n = 2,166) [57, 62]	RR, 1.25 [95% CI, 0.76 to 2.07], I2 = 0%

(D) Acute respiratory tract infections

Five RCTs focussed on acute RTIs [45–47, 52, 53]. Three studies used POCT-CRP in primary care settings in Denmark, Vietnam and The Netherlands [45, 46, 53]. One hybrid study used a two-step diagnostic algorithm (ePOCT) followed by an POCT-CRP in primary care clinics in Tanzania [52]. One study used a viral panel POCT in a Canadian emergency department [47].

The viral panel POCT showed no effect on re-consulting within a 7–10 day time period, and found no effect (RR, 0.88; 95% CI [0.61 to 1.27]) [47]. The duration of patient visits was not found to be different when using the viral panel POCT in the emergency department (POCT 105.7min vs usual care 156.1min; mean difference -50.4min, 95% CI [-104.6 to 3.7] [47].

The Tanzanian hybrid study (diagnostic algorithm and POCT-CRP) found that the risk of hospital admissions within thirty days was lower in the intervention arm than in the usual care arm, 0.5% (4/865) vs 1.5% (13/854), respectively (RR, 0.30; 95% CI, [0.10–0.93] [52].

Antibiotic prescribing

There were four RCTs using POCT-CRP to guide immediate antibiotic prescribing for acute RTIs in children (Fig 9) [45, 46, 52, 53]. These studies were conducted in four different clinical settings (Vietnam; Denmark, Tanzania, The Netherlands) including POCT-CRP guidance and interpretation (Table 3).

Fig 9

Immediate antibiotic prescribing for acute respiratory tract infections.

Forest plot of meta-analyses of randomised trials and non-randomised studies reporting immediate antibiotic prescribing comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

Table 3

POCT-CRP guidance and interpretation for antibiotic prescribing (acute RTIs).

Study	POCT-CRP guidance and interpretation for acute RTIs
Do et al. (2016) [46]	Clinicians trained to use specific CRP cut-offs: no antibiotics when the CRP level was ≤20 mg/L for patients aged ≥6 years old, and ≤ 10 mg/L for patients aged 1–5 years; referral or antibiotics when the CRP level was ≥50 mg/L. Between these thresholds no specific recommendation was given and clinicians were advised to use their clinical discretion.
Diederichsen et al. (2000) [45]	Clinicians informed of the normal value of CRP (<10 mg/l) and that CRP values <50 mg/l were seldom the result of bacterial infection. No strict guidelines for the use of antibiotics in relation to the CRP value were given.
Keitel et al. (2019) [52]	Two-step intervention, diagnostic algorithm (ePOCT) followed by POCT-CRP to inform antibiotic prescribing (combination of CRP ≥80 mg/L plus age/temperature-corrected tachypneoa and/or chest indrawing).
Schot et al. (2018) [53]	GPs were given the following guidance: POCT-CRP levels should be interpreted in combination with symptoms and signs; POCT-CRP levels <10mg/L make pneumonia less likely, but should not be used to exclude pneumonia when the GP finds the child ill, or when duration of symptoms is <6 hours; POCT-CRP levels >100mg/L make pneumonia much more likely, however, such levels can also be caused by viral infections; between 10mg/L and 100mg/L, the likelihood of pneumonia increases with increasing CRP levels.

In the Vietnam study [46], where CRP data for children only were available (n = 81), a third of children younger than 6 years old (n = 28) received immediate antibiotic prescription when the CRP value at enrolment was 10 mg/L or less. However, this is substantially less than in the control group of children of all ages receiving an immediate antibiotic prescription (333/518, 64·3%). In the Danish study [45], where there was no significant effect [45], there was a small sample size (n = 139), and the baseline antibiotic prescribing was almost half of that of the Vietnamese study (34%). The authors infer that the clinicians may have ignored low CRP values for prescribing antibiotics. For example, at CRP values of less than 11 mg/l, antibiotics were prescribed to 25% of patients, and at values of between 11 mg/l and 25 mg/l they were prescribed to 51% of patients. The hybrid study in Tanzania [52] children with a POCT-CRP <80 mg/L were prescribed salbutamol as a home treatment in 17% (136/780) of patients in the ePOCT arm (based on a respiratory rate decrease after a salbutamol trial) and for 2% (17/769) of patients in the usual care arm. In the Dutch study [53], GPs were not provided with strict decision rules based on POCT-CRP levels, but were given guidance (Table 3). However, a relatively sample size (n = 309), protocol violations in the control group, and risk that clinicians were unblinded to the CRP level before noting a final diagnosis, which may have influenced their diagnostic labelling, limit the conclusions of this study.

There is substantial heterogeneity between the four studies described. When the Danish and Dutch studies are excluded, the findings suggest that well conducted RCTs in LMICs which include guidance on interpretation of POCT-CRP, specific training or employ a diagnostic algorithm prior to POCT-CRP testing, may reduce antibiotic prescribing by around a third (risk difference, -0.29 [-0.47, -0.11], n = 2,747) [46, 52].

There was no effect on the frequency of subsequent antibiotic prescriptions at re-consultation (day 3–5) when POCT-CRP was compared with usual care in the Vietnam study (RR, 1.16; 95% CI [0.83 to 1.61]) [46] or in the Dutch study (specified as same illness period), (RR, 0.92; 95% CI [0.33 to 2.53]) [53]. The Dutch study also assessed the effect on future consultations within the next three months, and found that 16% (13/81) of children in the POCT-CRP group consulted their GP for a new respiratory tract illness, compared to 29% (29/99) in the control group (OR 0.61; 95% CI = 0.32–1.17) [53].

In the context of the hybrid Tanzanian study, POCT-CRP underpinned by a diagnostic algorithm, led to less subsequent antibiotic prescriptions at day 7 than usual care employing another decision algorithm (RR, 0.16; 95% CI [0.12 to 0.20]) [52].

Do et al. (2016) also evaluated the effect of POCTs on subsequent antibiotic regime change but there was no statistically significant effect (RR, 1.33; 95% CI [0.41 to 4.36]) [46].

A viral panel POCT in Canada did not influence the immediate prescription of antibiotics when compared to usual care (RR, 0.86; 95% CI [0.48 to 1.53], p<0.61), but did find that fewer antibiotic prescriptions were prescribed at re-consultation within 1 week (RR, 0.36; 95% CI [0.14 to 0.95], p<0.04) [47].

One study (n = 199) evaluated the effect of POCTs to detect multiple viral pathogens in acute RTIs and showed no statistically significant effect on the frequency of other test investigations (Table 4) [47]

Table 4

Additional test investigations.

Outcome	(Pooled) Effect estimate
Urinalysis	RR, 1.12; 95% CI [0.73 to 1.71]
Additional blood work	RR, 0.59; 95% CI [0.28 to 1.23]
Imaging (chest radiography or MRI)	RR, 0.70; 95% CI [0.44 to 1.11]
Ancillary testing after re-consultation	RR, 0.24; 95% CI [0.03 to 1.88]**

**Based on n = 73 children re-consulting within 7-10-day window.

(E) Sore throat

Five studies focussed on POCT in paediatric sore throat: one RCT [48]; one quasi-randomised trial [42]; one pre-/post-implementation observational study [59]; and two retrospective chart review studies [54, 56]. Three studies were set in primary care and two studies in a paediatric emergency department [54, 59]. All studies used a rapid Strep A POCT.

One RCT evaluated the effects of a Strep A test POCTs on re-consultation events [48] and found a statistically significant effect for decreasing subsequent visits when compared to usual care (RR, 4.70; 95% CI [2.94 to 7.51]; n = 1307). However, the time interval between visits was not reported.

Use of the Strep A POCT did not have an impact on immediate antibiotic prescribing in randomised studies (n = 2,127) [42, 48], but did show an effect in non-randomised studies (RR, 0.48; 95% CI [0.33 to 0.69], p <0.001 n = 8,717) (Fig 10) [54, 56, 59].

Fig 10

Immediate antibiotic prescribing in sore throat.

Forest plot of meta-analyses of randomised trials and non-randomised studies reporting immediate antibiotic prescribing comparing POCT vs usual care. Abbreviations: CI, confidence interval; POCT, point-of-care test; RCT, randomised controlled trial.

(F) Diabetes Mellitus

There was one study (n = 215) involving children with insulin-dependent diabetes mellitus which evaluated POCT for glycated haemoglobin (HbA1c) on laboratory HBA1c concentrations [43].

Over a period of 12 months, HbA1c concentrations in children with a POCT-HbA1c were initially lower when compared to the usual care group; however, at 12 months there was no significant difference. POCT-HbA1c concentrations initially decreased from baseline at 3 months (−0.20 ± 0.66%, p = 0.005) and then returned to baseline after 6 months (−0.03 ± 0.86%, p = 0.72), 9 months (+0.14 ± 0.98%, p = 0.21), and 12 months (+0.16 ± 0.81%, p = 0.08) (S7 Appendix in S1 File). POCT-HbA1c use resulted in less frequent patient-clinician communication between visits compared to usual care (0.29 ± 0.48 vs. 0.38 ± 0.49 contacts/visit, p = 0.043).

Discussion

Summary of main findings

The range of conditions or illnesses for which in-vitro diagnostic POCTs have been evaluated in paediatric ambulatory care is very limited. Of the 35 studies we identified, 14 studies focused on malarial-POCTs. Only three studies focused on POCTs in other acute paediatric illness in LMICs [5, 46, 52]. Most outcomes centred around decision-making such as hospital referral or prescription of medications; mortality data and other safety data were generally not reported.

Pooled estimates from eight RCTs showed that the use of malarial-POCTs better targeted antimalarial treatment by reducing over-treatment by a third. This is not surprising as almost all children (90%) in the usual care arm were prescribed antimalarials. However, there was no significant difference in antibiotic prescribing between children who had a malarial-POCT and those that did not for malaria cases with a suspected bacterial co-infection [35, 36, 44]. HIV-POCTs helped initiate ARV therapy early in HIV-positive children and kept them in care. This suggests that POCT can also indirectly improve access to healthcare.

POCT-CRP in undifferentiated acute fever illness did not reduce hospital attendance or admission or immediate antibiotic prescribing. Likewise, pooled estimates for Strep A POCT in sore throat did not reduce immediate antibiotic prescribing. In acute RTIs, there is some evidence that POCT-CRP may reduce immediate antibiotic prescribing in LMICs, but only in well conducted RCTs which include guidance on interpretation of POCT-CRP, specific training or employ a diagnostic algorithm prior to POC testing [46, 52].

Interpretation of results

There are a number of factors to consider when interpreting our findings. Diagnostics are complex interventions where clinical context, patient flow, and timing affect their impact. In addition, study variability (different setting, participants, intervention design) also needs to be considered when interpreting study findings and assessing the value of a POCT.

For example, POCT-CRP in acute fever illness did not affect hospital attendance or admission. However, most studies did not offer clear guidance on the interpretation of POCT-CRP in children leaving room for variation in practice and subsequent adherence to established practice.

In acute RTI, POCT-CRP studies were conducted in very different clinical settings (Vietnam; Denmark, Tanzania, The Netherlands), using different methodology. For example, the Danish study [45], found no effect on antibiotic prescribing likely because the baseline prescription rate was so low (half that of the Vietnamese study [46]). Most outcomes did not meet the accepted threshold of statistical significance. Many studies were underpowered to detect clinically relevant effects, or focussed on a selected population at low risk of serious infection. Other studies employed POCT-CRP in different roles in the clinical pathway in acute fever illness (e.g. triage or add-on).

These are problems that have been widely recognised as being major hurdles for diagnostic randomised controlled trials [67]. There are also likely to be important social determinants of prescribing that may override POCT-driven prescribing e.g. parental concern, the potential of rapid deterioration, and especially in LMICs, access to care [31, 68, 69]. Our data were not able to evaluate if and how parents or carers of children might influence prescribing decisions despite a ‘normal’ POC result.

Comparison with existing literature

Existing literature on POCTs has focused on adult populations or mixed populations of adults and children. Our findings concur with a 2011 Cochrane meta-analysis evaluating POCTs versus clinical diagnosis of malaria in febrile mixed populations in African malaria endemic regions, where malarial-POCTs reduced antimalarial prescribing by over 50% based on four RCTs [70]. This reduction in antimalarial prescribing was more modest in our systematic review in children only (33%). One reason for this difference, might be that clinicians are more risk averse in children in LMICs where the prevalence of infectious disease, malnutrition and risk of death are greater [68]. Other reasons include perceptions that the risk of taking antimalarials is negligible for individual patients or that in high prevalence areas of malaria transmission, there is a significant false-positive malarial-POCT rate (i.e. slide negative) influencing a clinician’s trust in the POCT result (due to persistent antigenaemia in individuals recently infected by malaria in hyperendemic areas [71]). Although other systematic reviews have found a reduction in antibiotic prescribing when POCT-CRP was used in adult-only and mixed populations [7, 72], we found that when POCT-CRP are evaluated in children only, there is limited evidence of benefit for their use in undifferentiated acute illness.

Strengths and limitations

Our search strategy was comprehensive using validated search filters, and we included both RCTs and non-randomised studies conducted in ambulatory healthcare settings. We focussed on paediatric populations, an under-researched group and specifically focused on the impact of in-vitro POCTs in clinical care as opposed to diagnostic accuracy studies.

There are also important limitations. We accept that many studies showed high risk-of-bias. We had to exclude some mixed population studies where data for adults and children were inseparable and not suitable for meta-analysis. We also recognise that the distinction between acute fever illness, acute RTIs and sore throat is somewhat arbitrary, and does not necessarily reflect routine practice where infection syndromes are not always clear-cut. The data available did not allow us to sufficiently compare studies in terms of POCT-CRP thresholds. Although consultations in ambulatory care have a dual purpose—to rule out serious infections and make antibiotic prescribing decisions–the interpretation of POCT results also needs to be seen in this heterogenous context as explained above.

Implications for clinical practice and future research

Children represent a significant proportion of consultations in ambulatory care. Yet, unlike the growing evidence in adult populations, there is a clear evidence gap for the use of POCTs to improve clinical outcomes in children worldwide. There is some evidence for POCTs in a few well-defined areas in specific settings e.g. HIV in LMICs. Yet for many other areas, mainly in HICs, the evidence for POCTs is scarce and often at high risk of bias. Therefore, because the impact of POCTs is so context-specific, we would recommend that any implementation of POCT be closely monitored to investigate their clinical effectiveness including monitoring of any unintended consequences of testing. Failure to heed these caveats, will mean that many new tests are not routinely taken up into routine care, or are implemented despite skipping essential stages such as clinical effectiveness, and waste resources [73].

Secondly, fit-for-purpose POCTs need to be accompanied by clear guidelines on their interpretation e.g. POCT-CRP cut-off values for children. Strategies are needed to help clinicians deal with inconclusive or dubious results e.g. to aid decisions in malarial POCT-negative children who are prescribed antimalarials, or where children with acute RTIs receive antibiotics when the CRP value ≤ 10 mg/L. Likewise, the role of POCTs in paediatric ambulatory care will differ between LMICs and HICs in helping to guide treatment decisions in acute illness and chronic disease monitoring. For example, in LMICs, where the prevalence of serious infections is high, the role of POCTs will be to exclude serious infection. In HICs, this role may be to make antibiotic prescribing decisions based on prognosis of common (self-limiting) infections. For LMICs in particular, POCTs ought to be incorporated into existing clinical pathways e.g. the World Health Organization (WHO) Integrated Management of Childhood Illnesses (IMCI) guidelines, to ensure that there is a seamless transition [52].

Finally, this review is important to provide direction and design of future studies. Studies should expand their remit beyond malaria and HIV in LMICs and incorporate POCTs for common infection syndromes. The impact of POCTs requires careful evaluation in well-designed RCTs or other controlled study designs, taking into account that the introduction of a new diagnostic test is a complex intervention. This will require mapping the patient pathway to understand all steps from patient presentation, selection for testing, interpretation of the test result, to integration of the result in clinical decision-making. For this to be possible, qualitative and quantitative contextual information needs to be embedded in to future clinical trials. Producing studies that are too small do not guide clinicians in their interpretation and clinical decision-making, or are at high risk of bias because of methodological shortcomings, or may even lead to wrongly rejecting a valuable tool for clinical practice.

Conclusion

There are clear evidence gaps for the use of POCTs in paediatric ambulatory care. Research has focussed on malaria- and HIV-POCTs in LMICs where they have shown benefits. There is emerging evidence that POCT-CRP may better target antibiotic prescribing for children with acute RTIs in LMICs but not in HICs. More paediatric-focussed research is urgently needed to understand where POCTs are likely to improve clinical outcomes in paediatric ambulatory settings worldwide.

(DOCX)

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28 Jan 2020

PONE-D-19-31785

In-vitro diagnostic point-of-care tests in paediatric ambulatory care: a systematic review and meta-analysis

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Reviewer #1: This is a very well written and important manuscript. With the emergence of AMR across the world and the reduction of malaria cases in many previously highly endemic areas have put a new focus on diagnostics to guide appropriate care. Many clinical decisions are currently guided purely by clinical decision making and little is known how the right POCT at the appropriate time in the care cascade could influence outcomes and prescribing. This systematic review nicely highlights the available data but also identifies a gap in quality data, particularly for LMICs.

While this paper is well written and the analysis is presented in a very compelling way, it could benefit from some improvments:

- Abstract: While the main body of the paper is written well, the abstract needs revision. It is lacking data and clarity.

o Delete the sentence about the influenza study, not relevant in abstract

o Provide more specificity and actual data for the statements that are provided. Reduce text if needed but currently it reads like a laundry list without evidence.

o ARV: spell out in abstract

o RTIs: spell out

- Introduction:

o Rephrase the first sentence it is unusual to put so much emphasize on the In-Vitro.

o Line 88/89 and also 92: provide a reference

o Line 102: not clear why this only applies to HIC a lot of evidence suggests that this is also relevant for LMICs. See for example McDonald et al. 2018

o Line 110: why “novel” wouldn’t it be better to say “available and emerging POCTs”?

o Line 116: I don’t quite understand what the authors are saying here? Can you rephrase this for clarity? Why does treatment lag behind?

o Fig1: appears very blurry on my screen

- Results:

o What are Quasi-randomised trials? Is this a technical term? Could you define it?

o Line 229: add reference for the 28%

o Line 235: Could you provide at least the most frequent countries?

o Table 1: in the “POCT” column, could you please add the target analyte for consistency? For example: Paracheck=hrp2? QuikRead Go=?? CRP? NycoCard II… many tests exists please add CRP; latex agglutination? For what?

- Discussion:

o In the third paragraph (no line numbers…): care vs car

o 3rd paragraph in “implication” section: please add a reference or reflection on the use of clinical treatment guidelines and how POCTs should be integrated into those with clear guidance. Particularly for LMICs where IMCI guidelines exist this is relevant for uptake and use.

- Financial discloser statement includes a “?”, I suspect this is a typo?

Reviewer #2: Summary

The authors present a systematic review of studies that evaluate the impact point-of-care tests (POCT) on clinical practice, in paediatric ambulatory care. They find 30 studies, of which half evaluate the impact of malaria POCT, and other often studied conditions are non-specific fever, sore throat and acute respiratory infections. Use of malaria POCT reduced antimalarial treatment, HIV POCT increased start and retention of HIV treatment; one study in a low or middle income country (LMIC) shows a reduction of antibiotics after implementation of CRP POCT, this is not evident in high-income countries. The authors conclude there is an evidence gap for the use of POCT in ambulatory paediatric care, and that more research is needed.

The topic of evaluating impact of POCT is very relevant. A lot of research is performed to develop new diagnostic tests for infectious diseases, but it is crucial to not only show their diagnostic accuracy, but also their impact on clinical care. The authors did a good job in giving an overview on a very broad and important topic. However, I have some major concerns that have to be addressed before the study can be published.

Main concerns.

1. The literature search has been performed 1.5 years ago, which is a long time, given the fast developments in the field of POCT. Therefore, some important recent studies are missing in this review, for example studies in the impact of CRP POCT on antibiotic prescription by Keitel et al (CID 2019), Schot et al (BJGP Open, 2018) and Althaus et al (Lancet Glob Health, 2019). The last study is cited by the authors in the introduction, but not included in the review. These recent developments will influence the conclusions of the review, so the search has to be updated to be accurate and relevant.

2. The aim of the study is to review POCT and their impact on paediatric clinical care, but the results are grouped by medical conditions instead of POCTs. This reduces the clarity of the manuscript, since it is often unclear which POCT is meant. The authors already mention in the discussion that the distinction between acute illness, acute respiratory infection and sore throat is arbitrary, and in my opinion not necessary for this study. For example, CRP POCT is now covered in acute illness and in RTIs, but then also one study on a viral panel is included in RTIs. In addition, under the heading ‘malaria’ the impact of POCTs on antimalarial treatment and antibiotics is presented, which is confusing, because multiple POCTs could be used for this purpose (malaria and CRP). I suggest to restructure the manuscript and present the results by POCT instead of medical condition. In general, the manuscript often lacks precision, affecting the readability and clarity of the paper. Specific comments are provided below.

3. It is insufficiently clear in the manuscript how exactly the POCTs were used in practice in the various included studies of the review, and how the authors decided to pool the results or not. Especially the CRP studies are highly variable in how they used the test in clinical practice. Information on exact use of POCTs in the different studies needs to be added to Table 1. Then, how did the authors decide to pool these results? Did they specify criteria in terms of intended use, cut-offs or outcomes to justify the of pooling results? This is currently unclear in the methods, and not discussed in the Discussion section.

Other major issues.

Abstract

4. Please clearly state the aim in the introduction

5. Results: see main comment 2: be more specific on which POCT is meant, in line 69, 71, 73.

Introduction

6. Be more specific in what the exact evidence in adult studies is. How have POCTs impacted adult clinical care? Especially because this comes back in the conclusion ‘not show the benefits previously demonstrated in adults’. And in line 118 ‘Yet, (…) not the same as in adults’: this implies a contrast to the previous section, but the previous section does not seem to talk about adults.

7. Line 100-104: be more specific. To what does ‘both’ refer? High and low income settings? Acute and chronic diseases? ‘Few children will have a serious condition …’: in general? In acute and chronic care? This statements needs a reference.

8. Line 110-116: add references

Methods

9. Search strategy needs an update (see main comment). Moreover, please provide the exact search strategy, so that the search can be reproduced or updated by other researchers.

10. POCTs with or without training or communication strategy were not distinguished. This is a pity, since it likely makes a big difference in impact. Moreover, why did the authors then not include POCTs as part of prediction models?

11. Economic outcomes were excluded: why? Especially since the overall conclusion of the article calls for cost-effectiveness studies.

12. Hospital-acquired infections were excluded: why? Studies on inpatients were excluded already, and if children present to ambulatory care after hospitalization, the use of POCT may still be relevant.

13. Line 172 refers to another review. Is the same extended bias tool used in this study?

14. Subgroup analyses: the study protocol on PROSPERO mentions cardiac conditions, acute kidney injury, confusion, influenza, PE/DVT. This is not in line with the subgroup analysis mentioned in the manuscript. If this is because the current study is a sub-study, this needs to be explained in more detail. Also, explain why studies on influenza were published separately.

Results

15. The text mentions 6204 unique records, but figure 1 mentions 223 additional records from updates, this would be in total 6427 unique records?

16. Please add all reasons for exclusion of articles in the full text phase, also in Figure 1.

17. Refer earlier in the text to Table 1, as this is providing the overview of studies. Now the first referral to the details of POCTs is to appendix S1.

18. Line 220: influenza studies were not included at all in this review, right? Why is this mentioned explicitly here?

19. Line 223-229: description of usual care is very important in order to compare the different studies, especially since this is so variable. Please add a short description of usual care to Table 1, also if ‘not specified’ in the original study.

20. Line 228 on antibiotic prescription of 28%: to which studies does this refer?

21. line 247: ‘principle method’, unclear terminology, be more precise. Then the immunological details are not needed in the main body of the text.

22. Intended use: this is also very important when comparing POCTs. Please add a column in Table 1, describing shortly what the exact decision advice was in the included studies. Which cut-off was used? What was the advised action? Also if ‘not specified’. The current categories replacement, triage etc, do not provide enough detail.

23. Risk of bias assessment. ‘there were two cluster RCTs’; this is in contradiction with page 6 that there were 11 cluster RCTs, referring to references 23-33? At page 14 the authors refer to refs 24, 44 and 49? Then also the study of Do et al was blinded to the outcome (fig 2), so the statement that ‘one reported in two separate papers that (they?) were able to blind outcomes’ is confusing and not necessary.

24. Description of the outcome. See main comment 2: the way the results are presented is very confusing. First patient outcomes are reported (apparently defined as morbidity, mortality and recovery). Then under that heading other measures of impact were described as decision-making, prescribing and other testing. However, prescribing and doing other tests are also decision-making? To which decisions do the authors refer exactly? For malaria this is referral, for HIV it is initiating treatment, for fever hospital admission, for RTIs re-consultation? I suggest that the authors clearly specify in the Methods section which outcome measures of impact they have reviewed (it is currently not mentioned in the methods at all). It may be more clear to distinguish an impact on 1) diagnostics, 2) treatment and 3) disposition. This should be clear in Table 1 as well, as suggested in the previous comment 22.

25. Page 15 ‘in the context of safety…’ This sentence is vague, what do the authors mean hear? And why are the 3 RCTs on microscopy-positive and negative children of Table 2 not visualised in a forest plot, while their results are pooled? Other forest plots contain even fewer studies? And what is the reference standard for the effect estimate? Also after reading appendix 4 this is confusing to me. Based on the table I assume ‘microscopy results’ are the usual care? Then what is the reference standard? But in the figure of Appendix 4 the forest plot mentions POCT, when describing 3 studies on microscopy-positive children? This whole malaria treatment section needs to be revised thoroughly to improve clarity. Be consistent and specific in the terminology (POCT, usual care, rapid diagnostic tests etc)

26. Page 16 – HIV section. Confusing to mention the (absent) patient outcomes reported here again, while this topic was reported on page 14. Same holds for acute RTIs at page 18.

27. Page 17 – non-specific acute illness. See main comment 2. All studies evaluate the CRP-POCT, so I think it makes more sense to describe the CRP POCT here.

28. Page 17 – decision making. ‘(…) did not show a benefit on hospital attendance or admission’. What would be the benefit: increase or reduce? Use more neutral language, since the appropriateness of the admissions cannot be judged (like ‘there was no effect on …’). This sentence reports no effect, but then the next sentence starts with ‘However…’. This implies a contradiction, please revise.

29. Page 17 ‘We attribute the differences…’ This is for the Discussion, not results section. It does raise the question whether it makes sense at all to pool the results of such variable studies? See main comment 3.

30. Page 17 – immediate antibiotic prescribing. First sentence is unclear.

31. Page 19. The Danish study showed no effect on antibiotic prescribing, maybe because they had a lower baseline prescription rate? This is an important topic, please comment on this in the Discussion.

32. Page 19 – what do the authors mean with subsequent antibiotic prescriptions? What timeframe?

33. Page 19 ‘there was no effect on the frequency (…), however fewer antibiotics’. To what study does the second part of the sentence refer? Another than ref 44? In its current form it suggests that this was studied in the same population.

34. Page 20. How is the effect of strep A POCT on re-consultation a decision-making outcome? Whose decision? What was the advice of the POCT? In addition: how does the clinical protocol of making cultures in POCT negative children explain a rise in throat cultures? What was the usual care protocol then?

35. Page 20. Diabetes. This topic is very different from all the other POCTs that focus on infectious diseases. The authors may consider removing this topic from the review, so that it has more focus. If they decide to keep it, this sections needs to be clarified: Only the trends in HbA1c levels are provided of children who used the POCT? What was the difference with usual care? Which decision was influenced by the POCT?

Discussion

36. Summary of findings is very long, please summarize.

37. Page 21 bottom: to which figures to the authors refer? Are these new results?

38. Please include a section ‘interpretation of results’, in which the authors can discuss for example: how did the variability in studies influence the pooled results? What are reasons for finding a limited impact? It is mentioned a bit in the ‘comparison to the literature’ and ‘strengths and limitations’, but would be more clear if after the summary of findings the findings are shortly interpreted.

39. Page 22 line ‘one explanation for this difference is that…’: logic is unclear: how can a negative test result carry a high false-positive rate? And then influence the clinicians trust? (not trusting a false-positive test would then lead to less prescriptions?)

40. Page 22 ‘Another reason might be…’ this section needs a reference.

41. Page 22 ‘Strengths and limitations’ ‘Our data were not able to evaluate if and how’ This refers to the discussion of confounders in general, that might explain the lack of evidence for impact of POCT. Not only parental concern, but also clinician’s concern etc. The section where that is described (just above strengths and limitations’ is important for the interpretation of findings, and needs more references to existing literature.

42. Page 23 first line ‘dual purpose’: this is not a dual purpose, but refers to the same decision, right? By identifying serious infections you make the prescription decision.

43. Page 23 Implications. The fact that there are many children in ambulatory care does not directly justify a call for more evidence for POCTs. The fact that adult studies have proven an impact does provide more justification for that call (see also comment in introduction).

44. Page 23 ‘POCT-negative children’. Be more specific, which POCT?

45. Page 23 ‘The role of POCTs in paediatric care will differ between LMICs and HICs’. Fair point, comment on how this will be different.

Conclusion

46. The conclusion is to broad and not supported by the rest of the manuscript. It refers to benefits in adults, that has not been clearly demonstrated in the introduction or the discussion. Moreover, it calls for cost effectiveness studies, while economic outcomes were excluded from this review.

Minor issues.

- Abstract – methods: line 54 ‘compared this…’: this suggests that the authors themselves compared the POCTs to usual care, whereas they included studies that did so. Please rephrase.

- Introduction, line 96 ‘, this is likely’. To what does ‘this’ refer? The proportion of children? Acute illness?

- Line 106: 20% increase in short stay. Compared to what?

- Line 111: optimise prescribing. Of antibiotics? Please add.

- Line 206: add references of the remaining nine studies

- Line 242-244: this does not describe locations, and is already mentioned earlier, please remove.

- Line 251 POCT test, remove ‘test’.

- Table 1: there is an asterisk (*) in the row of the Nijman study that is not explained in the footnote.

- After Table 1, line numbers are missing.

- Figure 5 legend: please remove ‘inappropriate’, since this cannot be judged based on these data

- Page 16 ‘the effect of HIV-POCTs (…)’. Unclear sentence. Do the authors mean that in POCT care 4 times more children initiated ARV treatment than in usual care?

- Page 18, acute RTIs. Add reference of the Canadian ED study.

- Table 4 lacks a title.

- Page 20 – antibiotic prescribing. Be more specific. ‘Use of the Strep A POCT did not have an impact on immediate antibiotic prescribing.’

- There are no references in the manuscript to Appendices 5 and 7.

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Reviewer #1: Yes: Sabine Dittrich

Reviewer #2: No

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6 May 2020

17 April 2020

Editor,

PLoS One

Dear Editor

Revision PONE-D-19-31785

In-vitro diagnostic point-of-care tests in paediatric ambulatory care: a systematic review and meta-analysis

Thank you for providing us the opportunity to improve this manuscript albeit slightly later than planned because of the current COVID pandemic. We respond to reviewer comments point by point below. Where feasible, we have incorporated the suggestions to improve the manuscript. Changes are highlighted in the revised manuscript using tracked changes.

Reviewer #1:

This is a very well written and important manuscript. With the emergence of AMR across the world and the reduction of malaria cases in many previously highly endemic areas have put a new focus on diagnostics to guide appropriate care. Many clinical decisions are currently guided purely by clinical decision making and little is known how the right POCT at the appropriate time in the care cascade could influence outcomes and prescribing. This systematic review nicely highlights the available data but also identifies a gap in quality data, particularly for LMICs.

Thank you.

While this paper is well written and the analysis is presented in a very compelling way, it could benefit from some improvements:

- Abstract: While the main body of the paper is written well, the abstract needs revision. It is lacking data and clarity.

We have rewritten the abstract and included specific findings which were lacking in the original submission.

o Delete the sentence about the influenza study, not relevant in abstract

We have deleted this sentence in the abstract.

o Provide more specificity and actual data for the statements that are provided. Reduce text if needed but currently it reads like a laundry list without evidence.

We have added more clarity to the abstract highlighting the main findings with relevant data.

o ARV: spell out in abstract. Done

o RTIs: spell out. Done

- Introduction:

o Rephrase the first sentence it is unusual to put so much emphasize on the In-Vitro.

We have deleted the word ‘in-vitro’.

o Line 88/89 and also 92: provide a reference

We have provided references for the statements as an example of the progress that has been made with POCTs in ambulatory care.

o Line 102: not clear why this only applies to HIC a lot of evidence suggests that this is also relevant for LMICs. See for example McDonald et al. 2018

Thank you for the useful reference. We agree that, for example, in the majority of paediatric febrile illnesses, these illnesses will be uncomplicated and self-limiting and have changed the sentence to reflect this.

o Line 110: why “novel” wouldn’t it be better to say “available and emerging POCTs”?

Thank you. We have changed the wording as per your suggestion.

o Line 116: I don’t quite understand what the authors are saying here? Can you rephrase this for clarity? Why does treatment lag behind?

By “treatment lagging behind”, we mean that treatment decisions are made empirically after the patient has left the consultation while waiting for laboratory test to come back. We have reworded this sentence to avoid confusion.

o Fig1: appears very blurry on my screen

We have updated a new version of Fig 1.

- Results:

o What are Quasi-randomised trials? Is this a technical term? Could you define it?

A quasi-randomised trial is one in which participants are allocated to different arms of the trial using a method of allocation that is not truly random. This is a known methodological term, quasi meaning ‘partly’ or ‘seemingly’. We have used this term as per the original description that the authors used to describe their study and have included this in the text.

o Line 229: add reference for the 28%

This is based on included studies involving children with acute fever ‘illness’ (5 studies). We have added the references and signposted readers to Figure 8.

o Line 235: Could you provide at least the most frequent countries?

Table 1 provides the reader with the most frequent high-income countries. However, we feel that adding this detailed information in the text is perhaps less informative. However, we have amended the sentence to read that the most frequent HICs were European. For information only, the number of studies conducted in HIC were: USA (3); Belgium (2); The Netherlands (2); UK (2); France (1); Denmark (1); Norway (1); Poland (1); Greece (1).

o Table 1: in the “POCT” column, could you please add the target analyte for consistency? For example: Paracheck=hrp2? QuikRead Go=?? CRP? NycoCard II… many tests exists please add CRP; latex agglutination? For what?

The names of POCT listed in Table 1 are as described by the authors of included studies. Detailed description of POCT was often not consistent or unavailable. We have tried to homogenous these for consistency. As space is limited within Table 1, and Reviewer 2 has also suggested we include a description of ‘usual care’, we have decided to rather include a description of the target analyte for each POCT in Appendix S1.

- Discussion:

o In the third paragraph (no line numbers…): care vs car

Thank you. We have corrected this typo. It should read ‘care’.

o 3rd paragraph in “implication” section: please add a reference or reflection on the use of clinical treatment guidelines and how POCTs should be integrated into those with clear guidance. Particularly for LMICs where IMCI guidelines exist this is relevant for uptake and use.

Thank you for highlighting this important point. We have incorporated this and reworded the sentence.

- Financial discloser statement includes a “?”, I suspect this is a typo? Thank you for spotting this.

Reviewer #2: Summary

The authors present a systematic review of studies that evaluate the impact point-of-care tests (POCT) on clinical practice, in paediatric ambulatory care. They find 30 studies, of which half evaluate the impact of malaria POCT, and other often studied conditions are non-specific fever, sore throat and acute respiratory infections. Use of malaria POCT reduced antimalarial treatment, HIV POCT increased start and retention of HIV treatment; one study in a low- or middle-income country (LMIC) shows a reduction of antibiotics after implementation of CRP POCT, this is not evident in high-income countries. The authors conclude there is an evidence gap for the use of POCT in ambulatory paediatric care, and that more research is needed.

The topic of evaluating impact of POCT is very relevant. A lot of research is performed to develop new diagnostic tests for infectious diseases, but it is crucial to not only show their diagnostic accuracy, but also their impact on clinical care. The authors did a good job in giving an overview on a very broad and important topic. However, I have some major concerns that have to be addressed before the study can be published.

Thank you. This review is a bit of a behemoth and we appreciate the time you have taken to improve our manuscript.

Main concerns.

1. The literature search has been performed 1.5 years ago, which is a long time, given the fast developments in the field of POCT. Therefore, some important recent studies are missing in this review, for example studies in the impact of CRP POCT on antibiotic prescription by Keitel et al (CID 2019), Schot et al (BJGP Open, 2018) and Althaus et al (Lancet Glob Health, 2019). The last study is cited by the authors in the introduction, but not included in the review. These recent developments will influence the conclusions of the review, so the search has to be updated to be accurate and relevant.

We agree, the field is rapidly progressing. We have therefore updated the search as planned up to 29 January 2020 and included 5 new studies: Althaus et al. 2019 (Fever); Keitel et al. 2019, Schot et al. 2018 (acute RTIs); Bird et al. 2018 (sore throat); Bianchi et al. 2019 (HIV).

2. The aim of the study is to review POCT and their impact on paediatric clinical care, but the results are grouped by medical conditions instead of POCTs. This reduces the clarity of the manuscript, since it is often unclear which POCT is meant. The authors already mention in the discussion that the distinction between acute illness, acute respiratory infection and sore throat is arbitrary, and in my opinion not necessary for this study. For example, CRP POCT is now covered in acute illness and in RTIs, but then also one study on a viral panel is included in RTIs. In addition, under the heading ‘malaria’ the impact of POCTs on antimalarial treatment and antibiotics is presented, which is confusing, because multiple POCTs could be used for this purpose (malaria and CRP). I suggest to restructure the manuscript and present the results by POCT instead of medical condition. In general, the manuscript often lacks precision, affecting the readability and clarity of the paper. Specific comments are provided below.

We have given these suggestions some thought however restructuring the manuscript according to POCT presents its own problems. Firstly, we would prefer to keep this review clinically-focussed, and therefore structuring this according to disease/condition would be more relevant for clinicians. Secondly, as you mention in point 3 (below), even if the same POCTs are used in different studies, how these POCTs are used by health professionals also varies from study to study, and where they slot into the clinical pathway varies. Lastly, by presenting the results per POCT we assume that the tests have the same diagnostic accuracy. Therefore, presenting the results per POCT has its own limitations.

We mention the ‘arbitrary’ distinction between acute illness, acute respiratory infection etc. because paediatric illness is sometimes undifferentiated at first, however from a clinical point of view, it is sensible to describe the value of POCTs according to condition. We have taken the condition at face value as presented in the original studies and where this was described.

We agree that more clarity is needed about which POCTs we are referring to in the Results sections e.g. malaria and CRP, and have tried to be more specific throughout the manuscript e.g. POCT-CRP.

3. It is insufficiently clear in the manuscript how exactly the POCTs were used in practice in the various included studies of the review, and how the authors decided to pool the results or not. Especially the CRP studies are highly variable in how they used the test in clinical practice. Information on exact use of POCTs in the different studies needs to be added to Table 1. Then, how did the authors decide to pool these results? Did they specify criteria in terms of intended use, cut-offs or outcomes to justify the of pooling results? This is currently unclear in the methods, and not discussed in the Discussion section.

We agree that the studies involving POCT-CRP were highly variable and were acutely aware that simply combining these may lead to misinterpretation. We compared studies according to similar condition as stated by authors, study design, and outcomes. Data had to be reported in sufficient detail to assess relevant outcomes between patients with similar POC test and usual care. The data available did not allow us to sufficiently compare studies in terms of CRP cut-offs. The description of the exact use of POCTs in included studies was very limited or not available at all.

However, as per your suggestion, we felt it was important to highlight the role of the POCT in the clinical pathway and have now expanded on the description of these roles (where possible) in Appendix S2.

Other major issues.

Abstract

4. Please clearly state the aim in the introduction

We have added the aim in the abstract introduction.

5. Results: see main comment 2: be more specific on which POCT is meant, in line 69, 71, 73.

We have clarified which POCT is meant.

Introduction

6. Be more specific in what the exact evidence in adult studies is. How have POCTs impacted adult clinical care? Especially because this comes back in the conclusion ‘not show the benefits previously demonstrated in adults’. And in line 118 ‘Yet, (…) not the same as in adults’: this implies a contrast to the previous section, but the previous section does not seem to talk about adults.

Thank you for pointing this out. We have now included some examples where POCTs have transformed clinical care in adults for comparison.

7. Line 100-104: be more specific. To what does ‘both’ refer? High and low income settings? Acute and chronic diseases? ‘Few children will have a serious condition …’: in general? In acute and chronic care? This statements needs a reference.

We have clarified this sentence to refer to both high-income and low-income settings. We have also added references to explain the relatively low incidence of serious conditions in children.

8. Line 110-116: add references

We have now added references to support these statements.

Methods

9. Search strategy needs an update (see main comment). Moreover, please provide the exact search strategy, so that the search can be reproduced or updated by other researchers.

We have updated the search and included an example of the search strategy in Appendix S8 which can be modified across search platforms.

10. POCTs with or without training or communication strategy were not distinguished. This is a pity, since it likely makes a big difference in impact. Moreover, why did the authors then not include POCTs as part of prediction models?

We have taken this suggestion onboard. We agree that most POCTs would have required some sort of training before using the POC equipment, however we are mainly interested in whether there were specific educational and communications packages that were expressly incorporated with the POCT, as opposed to the complex intervention of prediction models incorporating POCT. This is a different research question as we would be evaluating the effect of a POCT test on its own. We have reviewed all included studies again and added a detailed description of any educational and/or training packages where these data were available (Appendix S2).

11. Economic outcomes were excluded: why? Especially since the overall conclusion of the article calls for cost-effectiveness studies.

This is important to address for future studies but falls beyond the scope of the review. We focussed on patient relevant clinical outcomes. Economic outcomes of course are also relevant to patients, but more at a policy level.

12. Hospital-acquired infections were excluded: why? Studies on inpatients were excluded already, and if children present to ambulatory care after hospitalization, the use of POCT may still be relevant.

The latter point is valid but again this is a different research question and falls beyond the scope of this review. Our review focusses on the use of POCTs where children presented first in ambulatory care.

13. Line 172 refers to another review. Is the same extended bias tool used in this study?

Yes, the same risk-of-bias tool was used.

14. Subgroup analyses: the study protocol on PROSPERO mentions cardiac conditions, acute kidney injury, confusion, influenza, PE/DVT. This is not in line with the subgroup analysis mentioned in the manuscript. If this is because the current study is a sub-study, this needs to be explained in more detail. Also, explain why studies on influenza were published separately.

Our group has now published a number of systematic reviews assessing the impact of point-of-care tests on patients and healthcare processes. The conditions listed on Prospero are potential examples of where the group thought POCTs were use, however this review in not limited to these conditions. For sake of ease, we have subdivided these. The recently published influenza review includes adults and paediatric populations.

Results

15. The text mentions 6204 unique records, but figure 1 mentions 223 additional records from updates, this would be in total 6427 unique records?

We have updated the PRISMA flow diagram to reflect the updated search. The 223 additional records have been de-duplicated against existing Endnote libraries including the 6,860 unique records.

16. Please add all reasons for exclusion of articles in the full text phase, also in Figure 1.

We have added all reasons for exclusion for Figure 1.

17. Refer earlier in the text to Table 1, as this is providing the overview of studies. Now the first referral to the details of POCTs is to appendix S1.

Thank you. We refer to Table 1 now much earlier under Characteristics of included studies.

18. Line 220: influenza studies were not included at all in this review, right? Why is this mentioned explicitly here?

We have deleted reference to influenza studies as this is not relevant here.

19. Line 223-229: description of usual care is very important in order to compare the different studies, especially since this is so variable. Please add a short description of usual care to Table 1, also if ‘not specified’ in the original study.

We agree. We have now included a description of ‘usual care’ where available in Table 1 as per the description in the original text . However, we must add that in many studies ‘usual care’ was not well described and we took this to be a clinical diagnosis where no POCT was used.

20. Line 228 on antibiotic prescription of 28%: to which studies does this refer?

This is based on included studies involving children with acute fever ‘illness’ (5 studies). We have added the references and signposted readers to Figure 8.

21. line 247: ‘principle method’, unclear terminology, be more precise. Then the immunological details are not needed in the main body of the text.

We have changed this to read ‘target analyte’ and signposted the reader to Appendix for further details.

22. Intended use: this is also very important when comparing POCTs. Please add a column in Table 1, describing shortly what the exact decision advice was in the included studies. Which cut-off was used? What was the advised action? Also if ‘not specified’. The current categories replacement, triage etc, do not provide enough detail.

As explained above, available data did not allow us to compare studies in terms of CRP cut-offs. The description on the exact use of POCTs in included studies was either very sketchy or not available at all. However, we agree that it is important to highlight the role of the POCT in the clinical pathway (Table 1) and have now expanded on the description of these roles in the main text and more detailed in Appendix S2.

23. Risk of bias assessment. ‘there were two cluster RCTs’; this is in contradiction with page 6 that there were 11 cluster RCTs, referring to references 23-33? At page 14 the authors refer to refs 24, 44 and 49? Then also the study of Do et al was blinded to the outcome (fig 2), so the statement that ‘one reported in two separate papers that (they?) were able to blind outcomes’ is confusing and not necessary.

There were two cluster RCTs that were able to blind outcome assessment. We have rearranged this sentence and references for clarity.

24. Description of the outcome. See main comment 2: the way the results are presented is very confusing. First patient outcomes are reported (apparently defined as morbidity, mortality and recovery). Then under that heading other measures of impact were described as decision-making, prescribing and other testing. However, prescribing and doing other tests are also decision-making? To which decisions do the authors refer exactly? For malaria this is referral, for HIV it is initiating treatment, for fever hospital admission, for RTIs re-consultation? I suggest that the authors clearly specify in the Methods section which outcome measures of impact they have reviewed (it is currently not mentioned in the methods at all). It may be more clear to distinguish an impact on 1) diagnostics, 2) treatment and 3) disposition. This should be clear in Table 1 as well, as suggested in the previous comment 22.

Thank you for highlighting this potential ambiguity. In the Methods section, we state that we will include all quantitative clinical outcome data reporting on the impact of POCTs on clinical care and healthcare processes. We did not want to pre-empt what we were likely to find but have now outlined examples of relevant outcomes data in the Methods. We accept that there is some overlap however there is also a clear distinction between prescribing treatment and decision-making (which also includes the decision of the patient/parent to re-consult). We have now provided a more detailed description of the four distinct categories in the Method section before discussing them in detail per condition in the Results section (with the exception of patient-relevant outcomes (mortality, time to recovery) as there were so few studies. We have now clearly indicated this for the reader.

25. Page 15 ‘in the context of safety…’ This sentence is vague, what do the authors mean hear? And why are the 3 RCTs on microscopy-positive and negative children of Table 2 not visualised in a forest plot, while their results are pooled? Other forest plots contain even fewer studies? And what is the reference standard for the effect estimate? Also after reading appendix 4 this is confusing to me. Based on the table I assume ‘microscopy results’ are the usual care? Then what is the reference standard? But in the figure of Appendix 4 the forest plot mentions POCT, when describing 3 studies on microscopy-positive children? This whole malaria treatment section needs to be revised thoroughly to improve clarity. Be consistent and specific in the terminology (POCT, usual care, rapid diagnostic tests etc)

This section is slightly complicated but is detailed in the Cochrane review of Odaga 2014 et al. examining the safety profile of POCTs versus clinical diagnosis for managing people with fever in malaria endemic settings i.e. the impact of false-negatives and positives, human error, overprescribing or clinician distrust of result. However, we agree with you that perhaps this section might detract from the overall theme and have therefore moved this entire section to Appendix S5. For clarification, we have added in a description of these to each of the four outcomes in Appendix S5. Forest plots and a detailed description are given explaining the reference standard.

26. Page 16 – HIV section. Confusing to mention the (absent) patient outcomes reported here again, while this topic was reported on page 14. Same holds for acute RTIs at page 18.

Thanks for pointing this out. We have deleted these sentences.

27. Page 17 – non-specific acute illness. See main comment 2. All studies evaluate the CRP-POCT, so I think it makes more sense to describe the CRP POCT here.

Please see our response above.

28. Page 17 – decision making. ‘(…) did not show a benefit on hospital attendance or admission’. What would be the benefit: increase or reduce? Use more neutral language, since the appropriateness of the admissions cannot be judged (like ‘there was no effect on …’). This sentence reports no effect, but then the next sentence starts with ‘However…’. This implies a contradiction, please revise.

We have corrected this ambiguity by explaining the effect differences between RCTs and observational studies.

29. Page 17 ‘We attribute the differences…’ This is for the Discussion, not results section. It does raise the question whether it makes sense at all to pool the results of such variable studies? See main comment 3.

We were careful to meta-analyse RCTs or observational studies separately. We have shifted this sentence to the Discussion section outlining the potential reasons for the effect differences as this was specific to POCT-CRP in non-specific acute illness (Interpretation of results).

30. Page 17 – immediate antibiotic prescribing. First sentence is unclear.

We have edited this to read; “Five studies reported antibiotic prescribing.(27, 42, 45, 48, 49) using CRP-POCT. Neither RCTs (RR, 0.96; 95% CI [0.85 to 1.09], I2=0%) nor non-randomised studies (OR, 0.95; 95% CI [0.83 to 1.10], I2=0%) showed an effect on antibiotic prescribing (Fig 8).”

31. Page 19. The Danish study showed no effect on antibiotic prescribing, maybe because they had a lower baseline prescription rate? This is an important topic, please comment on this in the Discussion.

We have added this comment to the Discussion section.

32. Page 19 – what do the authors mean with subsequent antibiotic prescriptions? What timeframe?

By subsequent antibiotic prescriptions, we mean prescriptions at re-consultation between day 3 to 5 after the initial consultation. We have clarified this in the text.

33. Page 19 ‘there was no effect on the frequency (…), however fewer antibiotics’. To what study does the second part of the sentence refer? Another than ref 44? In its current form it suggests that this was studied in the same population.

Thanks for spotting this ambiguity. This second half of the sentence refers to Doan et al. We have re-written the sentence to clarify this.

34. Page 20. How is the effect of strep A POCT on re-consultation a decision-making outcome? Whose decision? What was the advice of the POCT? In addition: how does the clinical protocol of making cultures in POCT negative children explain a rise in throat cultures? What was the usual care protocol then?

Here, the decision-making outcome reflects the decision of parents/carers of children to re-consult. We have clarified this in the text. In relation to throat cultures and the pre/post-implementation study by Aynaroah et al. 2009, we agree with you that this finding may not be relevant (protocol-driven). We have removed this outcome.

35. Page 20. Diabetes. This topic is very different from all the other POCTs that focus on infectious diseases. The authors may consider removing this topic from the review, so that it has more focus. If they decide to keep it, this sections needs to be clarified: Only the trends in HbA1c levels are provided of children who used the POCT? What was the difference with usual care? Which decision was influenced by the POCT?

We agree this topic is very different from other POCTs. However, it is important to illustrate that this was the only study retrieved from our extensive search that focussed on chronic disease monitoring in children. To exclude it would detract from our aim to describe the current evidence base for POCT in children across all conditions and countries. With this in mind, we think it is important to show there is a clear evidence gap here. Readers are signposted to Appendix S7 for HbA1c levels in the usual care group. The decision influenced by the POCT relates to the clinician initiating communication with the patient between clinic visits. We have added a sentence to clarify this here and also in Table 1.

Discussion

36. Summary of findings is very long, please summarize.

We have shortened the main findings.

37. Page 21 bottom: to which figures to the authors refer? Are these new results?

This is an error and refers to Figures from an earlier draft. We have deleted this.

38. Please include a section ‘interpretation of results’, in which the authors can discuss for example: how did the variability in studies influence the pooled results? What are reasons for finding a limited impact? It is mentioned a bit in the ‘comparison to the literature’ and ‘strengths and limitations’, but would be more clear if after the summary of findings the findings are shortly interpreted.

Thank you for this useful suggestion. We agree context is so important in interpreting these findings. We have included a new section “Interpretation of results”.

39. Page 22 line ‘one explanation for this difference is that…’: logic is unclear: how can a negative test result carry a high false-positive rate? And then influence the clinicians trust? (not trusting a false-positive test would then lead to less prescriptions?)

Thank you for pointing out this ambiguous sentence. We have restructured this sentence.

40. Page 22 ‘Another reason might be…’ this section needs a reference.

We have added a reference.

41. Page 22 ‘Strengths and limitations’ ‘Our data were not able to evaluate if and how’ This refers to the discussion of confounders in general, that might explain the lack of evidence for impact of POCT. Not only parental concern, but also clinician’s concern etc. The section where that is described (just above strengths and limitations’ is important for the interpretation of findings, and needs more references to existing literature.

We have added moved this section to the new section “Interpretation of results” and added more references here.

42. Page 23 first line ‘dual purpose’: this is not a dual purpose, but refers to the same decision, right? By identifying serious infections you make the prescription decision.

Not necessarily. Identifying a serious infection in ambulatory care means unscheduled hospital admission in the majority of cases. We agree that once hospitalised, a prescribing decision is also made.

43. Page 23 Implications. The fact that there are many children in ambulatory care does not directly justify a call for more evidence for POCTs. The fact that adult studies have proven an impact does provide more justification for that call (see also comment in introduction).

Agree. We have restructured this sentence to incorporate your suggestion.

44. Page 23 ‘POCT-negative children’. Be more specific, which POCT?

We mean malarial POCT-negative.

45. Page 23 ‘The role of POCTs in paediatric care will differ between LMICs and HICs’. Fair point, comment on how this will be different.

We have illustrated this with two examples. These of course are not exclusive to either LMIC or HIC but in are listed in terms of priority.

Conclusion

46. The conclusion is to broad and not supported by the rest of the manuscript. It refers to benefits in adults, that has not been clearly demonstrated in the introduction or the discussion. Moreover, it calls for cost effectiveness studies, while economic outcomes were excluded from this review.

We have rewritten the Conclusion reflecting your suggestions.

Minor issues.

- Abstract – methods: line 54 ‘compared this…’: this suggests that the authors themselves compared the POCTs to usual care, whereas they included studies that did so. Please rephrase.

Agree. We have rephrased this sentence.

- Introduction, line 96 ‘, this is likely’. To what does ‘this’ refer? The proportion of children? Acute illness?

This refers to the proportion of consultations. We have corrected this sentence.

- Line 106: 20% increase in short stay. Compared to what?

We have redrafted the sentence to reflect the comparison relating to a time trend.

- Line 111: optimise prescribing. Of antibiotics? Please add.

Added.

- Line 206: add references of the remaining nine studies

Done.

- Line 242-244: this does not describe locations, and is already mentioned earlier, please remove.

We have removed this sentence.

- Line 251 POCT test, remove ‘test’.

Done.

- Table 1: there is an asterisk (*) in the row of the Nijman study that is not explained in the footnote.

Thanks for spotting this. This has been corrected.

- After Table 1, line numbers are missing.

These are added now.

- Figure 5 legend: please remove ‘inappropriate’, since this cannot be judged based on these data

We have removed this word.

- Page 16 ‘the effect of HIV-POCTs (…)’. Unclear sentence. Do the authors mean that in POCT care 4 times more children initiated ARV treatment than in usual care?

We have rephrased this sentence to read “Initiating antiretroviral (ARV) therapy within 60 days in newly-diagnosed HIV children was almost 4-fold higher in those children that had an HIV-POCT compared to usual care in two studies…”.

- Page 18, acute RTIs. Add reference of the Canadian ED study.

Done.

- Table 4 lacks a title.

We have added the following title “Table 4. Additional test investigations”.

- Page 20 – antibiotic prescribing. Be more specific. ‘Use of the Strep A POCT did not have an impact on immediate antibiotic prescribing.’

We have redrafted this sentence to be more specific.

- There are no references in the manuscript to Appendices 5 and 7.

We have now signposted readers to these appendices.

Yours sincerely,

*Oliver van Hecke (University of Oxford ) on behalf of co-authors.

*corresponding author

19 Jun 2020

In-vitro diagnostic point-of-care tests in paediatric ambulatory care: a systematic review and meta-analysis

PONE-D-19-31785R1

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24 Jun 2020

PONE-D-19-31785R1

In-vitro diagnostic point-of-care tests in paediatric ambulatory care: a systematic review and meta-analysis

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