BRIEF RESEARCH REPORT published: 08 October 2020 doi: 10.3389/fped.2020.00565 The Importance of Rapid Influenza Testing in Pediatric Primary Care: Experience During Three Consecutive Influenza Seasons (2016–2019) in Barcelona (Catalonia, Spain) Diego van Esso 1*, Monica Vilà 2 , Cristina Andrés 3 , Sheila Iglesias 4 , Josep Ferrer 5 , Edited by: Lucia Losada 6 , Gemma Ricos 6 , Lorena Sanchez 7 , Patricia Morera 8 , Mar Pérez 8 , Robert Cohen, Mª Angeles Ferrandez 9 , Esther Hernando 10 , Carlos Rodrigo 11,12 , Tomàs Pumarola 3 and Independent Researcher, France Andrés Antón 3 Reviewed by: 1 Antonio Arbo, Primary Care Health Service SAP Muntanya, Catalan Institute of Health, Barcelona, Spain, 2 Primary Care Carmel, Catalan Institute of Tropical Institute of Health, Barcelona, Spain, 3 Respiratory Virus Unit, Microbiology Department, Vall d’Hebron Research Institute, Vall Medicine, Paraguay d’Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain, 4 Primary Care CAPI Casernes, Hervé Haas, Catalan Institute of Health, Barcelona, Spain, 5 Primary Care Roquetes-Canteres, Catalan Institute of Health, Barcelona, Princess Grace Hospital Spain, 6 Primary Care LP Drassanes, Catalan Institute of Health, Barcelona, Spain, 7 Primary Care LP La Marina, Catalan Centre, Monaco Institute of Health, Barcelona, Spain, 8 Primary Care LP Pare Claret, Catalan Institute of Health, Barcelona, Spain, 9 Primary Care Ciutat Meridiana, Catalan Institute of Health, Barcelona, Spain, 10 Primary Care LP Rio de Janeiro, Catalan Institute of *Correspondence: Health, Barcelona, Spain, 11 Department of Paediatrics, Vall d’Hebron University Hospital, Barcelona, Spain, 12 School of Diego van Esso Medicine Germans Trias i Pujol University Hospital, Autonomous University of Barcelona, Barcelona, Spain diegovanesso@gmail.com Specialty section: Clinical diagnosis of influenza has low sensitivity in infants and children. Signs and This article was submitted to symptoms are non-specific and similar to those of other respiratory viruses. Rapid Pediatric Infectious Diseases, a section of the journal influenza diagnostic tests (RIDTs) with adequate sensitivity and specificity used at the Frontiers in Pediatrics point of care can be useful for an etiologic diagnosis of influenza in primary care. This Received: 18 January 2020 should have an impact on better management of these patients. We conducted a study Accepted: 03 August 2020 Published: 08 October 2020 during three consecutive influenza seasons (2016–2017, 2017–2018, and 2018–2019) Citation: in pediatric primary care settings collecting data from influenza point-of-care tests van Esso D, Vilá M, Andrés C, (POCTs)-confirmed ≤6-year-old patients. During the first two influenza seasons, antibiotic Iglesias S, Ferrer J, Losada L, prescriptions and additional visits from influenza POCT-confirmed patients (Group_1) Ricos G, Sanchez L, Morera P, Pérez M, Ferrandez MªA, Hernando E, were compared to patients with influenza-like illness (ILI) (Group_2), or fever (2016 ICD-10 Rodrigo C, Pumarola T and Antón A code R50) with no other signs of influenza (Group_3). Group_1 had 0.19 (2016–2017) and (2020) The Importance of Rapid Influenza Testing in Pediatric Primary 0.23 (2017–2018) additional visits compared to 0.48 (2016–2017) and 0.49 (2017–2018) Care: Experience During Three Group_2 p < 0.001 and 1.01 (2016–2017) and 0.80 (2017–2018) Group_3 p < 0.001. Consecutive Influenza Seasons Antibiotic prescription was lower in Group_1 (10.2%) vs. Group_3 (17.2%) p < 0.002, (2016–2019) in Barcelona (Catalonia, Spain). Front. Pediatr. 8:565. difference statistically significant only for the 2017–2018 season. During the third season doi: 10.3389/fped.2020.00565 (2018–2019), RIDTs results were transmitted in real time to the reference laboratory Frontiers in Pediatrics | www.frontiersin.org 1 October 2020 | Volume 8 | Article 565 van Esso et al. Rapid Influenza Testing Primary Care ia the cloud, which strengthens the monitoring of circulating influenza viruses in the community. In our experience, the use of POCTs has a great potential in primary care specially in infants and young children in which the diagnosis maybe missed due to non-specific signs and symptoms. Keywords: influenza, primary care, children, rapid influenza diagnostic test (RIDT), point of care test (POCT), pediatrics, respiratory viral infection INTRODUCTION reassessed if the symptoms persist, increasing the burden on the healthcare system. Influenza virus is an important cause of respiratory illness The primary objectives of this study, during the first two among infants and children. The burden of influenza in consecutive influenza seasons (2016–2017 and 2017–2018), were pediatric primary care is not well-known as patients are seldom the comparison of antibiotic prescriptions and the number investigated for virologic evidence of influenza. Morbidity is of additional consultations to healthcare centers 10 days after highest in children with attack rates of 30% or more (1, 2). diagnosis between children with POCT-confirmed influenza In day care attendees rates up to 50% have been reported (1). in the primary care office with those diagnosed of influenza Cromer et al. (3) estimated the burden of influenza in England like illness (ILI) or fever when no other signs of influenza and reported that the highest influenza admission rates are found were apparent. During the third consecutive season (2018– in children <5 years (1.9/1,000) and that infants <6 months 2019), weekly results of RIDTs in children ≤6 years reported had the highest consultation rates. Poehling et al. (4) reported in from primary care were compared with influenza cases of the USA a rate of influenza hospitalization of 0.4 per 1,000 children reference hospital and the sentinel influenza surveillance system and 50 clinic visits attributable to influenza per 1,000 children of Catalonia (Spain). Our secondary objectives were to (i) during the 2002–2003 season, and 1,5 hospitalizations and 97 describe and compare the clinical signs and symptoms between clinic visits per 1,000 children during the 2003–2004 season positive and negative influenza patients, as well as between showing a great variability of the burden of disease between influenza A (IAV) and B (IBV) virus infections, (ii) compare the seasons, a fact that may be partially attributed to the specific performance of the Sofia test to a real-time reverse transcription circulating viruses in each season (1, 2). Neuzil et al. (5), in polymerase chain reaction (RT-PCR) analysis, which is the a 25-year-prospective study also confirmed that influenza is a current gold standard. common infection in healthy children <5 years with a high burden of influenza related consultations. Mortality rates caused by seasonal influenza are generally low in children (<1/100,000 MATERIALS AND METHODS people per year) (1). Children play a key role in the transmission of influenza as they act spreading the disease in the community. We conducted a descriptive, prospective, longitudinal study Morbidity in this age group is higher than in adults due to limited during three consecutive influenza seasons (2016–2017, 2017– pre-existing immunity, close contact in schools or day care, 2018, and 2018–2019) in four (first season) and seven (second hygienic habits and due to their higher viral load and persistent and third seasons) primary care centers of Barcelona, involving a shedding (6). total of 22 pediatricians. This study was reviewed and approved Clinical diagnosis of influenza is difficult in infants and by the ethics committee of IDIAP Jordi Gol (P16/135) and young children because of non-specific signs and symptoms. conducted in compliance with the Declaration of Helsinki and Fever, cough and nasal congestion are symptoms of most the principles of Good Clinical Practices. viral respiratory infections. In their study, Peltola et al. (7) During the first two seasons, eligible participants included reported that both sensitivity and positive predictive value of children ≤6 years presenting either (i) axillary temperature clinical diagnosis were low (38 and 32%, respectively). Myalgia, ≥38◦ C or (ii) axillary temperature between 37.2 and 38.0◦ C headache, and malaise, useful features for a clinical diagnosis in with rhinorrhoea, nasal congestion, or cough within 72 h older children and adults, are not useful in infants and young from symptom onset. No exclusion criteria were established. children unable to reliably describe them (8). Nasopharyngeal swabs from enrolled patients were collected In the absence of a confirmed influenza microbiologic in a tube with viral transport medium. Patients were asked diagnosis using point-of-care tests (POCTs) in primary care to complete a diary for 10 days to assess clinical symptoms, settings, infants and young children are more frequently antibiotic treatment taken during this period, and the additional attended in hospitals, submitted to laboratory tests, and receive visits at any healthcare service. This information was collected by unnecessary antibiotics (9). The percentage of patients with an a phone call, maximum 3 attempts, starting the first working day unspecific diagnosis of viral infection who receive antibiotic after the 10-days period. treatment is high but varies widely depending on the country’s Before enrolment in the study for the first two seasons, antibiotic policy and the site in which the patient is diagnosed written and informed consent was obtained from parents or (emergencies, primary care, or hospital). The consequence legal guardians concerning sample collection and follow-up. of an unspecific diagnosis is that patients often need to be Eligible patients who were not willing to sign informed consent Frontiers in Pediatrics | www.frontiersin.org 2 October 2020 | Volume 8 | Article 565 van Esso et al. Rapid Influenza Testing Primary Care were not tested. During the third season, no clinical data were cio-de-les-infeccions-respiratories-agudes-a-catalunya-pidirac/i collected, and no follow-up or microbiological comparison with ndex.html#googtrans(ca|en) were compared with data collected a molecular assay were done. Therefore, informed consent was in the present study from primary care centers and data collected not required. Data of the third season were collected in the seven from the reference hospital. primary care centers and transmitted in real time through a cloud system to the microbiology laboratory and were compared weekly with data of hospital patients and cases reported by the RESULTS sentinel respiratory virus surveillance system of Catalonia. During the first season (2016–2017), respiratory specimens During the first season, a total of 189 nasopharyngeal samples were tested in parallel using two rapid tests: Sofia R Influenza were collected, of which 93 (49%) were positive for influenza A+B (Quidel, US), which is an immunofluorescence virus. Some data of this first season have been previously nucleoprotein antigen detection-based test, and Cobas R published (10) and are included in this three-season comparison Liat R (Roche Diagnostics, Spain), an automated multiplex of clinical data, antibiotic use and additional visits. During the RT-PCR based assay, as described previously (10). Both assays first season only influenza A circulated, and a small number were used according to the user’s manual to give results of tests was performed in comparison to the following season. concerning influenza infection within 15 (Sofia R ) and 20 min During the second and third seasons, both influenza A and B (Cobas R Liat R ). Residual volume of all respiratory specimens circulated, and the number of nasopharyngeal tests was much were kept frozen at primary care centers until they were sent higher, 610 tests with 391 (64%) positive and 856 with 443 (52%) to the laboratory for the definitive influenza confirmation at positive, respectively. the end of the season by a commercial, one-step, multiplex, Study demographics and clinical signs and symptoms during RT-PCR assay (AllplexTM , Respiratory Panel Assay, Seegene, the 2016–2017 and 2017–2018 seasons are summarized in South Korea), which is the current routine respiratory virus Table 1. The mean age of children with POCT-confirmed confirmation technique in the hospital’s reference laboratory. influenza virus infection was 31 months for the 2016–2017 season Since Sofia R and Cobas R Liat R showed similar and adequate and 37 months for the 2017–2018 season. Patients presented sensitivities and specificities in this patient cohort during the long-lasting clinical signs and symptoms: mean duration of fever first season (2016–2017) (10), Sofia R was the only test used >5, cough >8, and rhinorrhoea >8 days. Duration of fever (5 during the second season and after running the test in primary vs. 4 days, P < 0.01), cough (8 vs. 7 days, P = 0.045), and care, residual volume of specimens was kept frozen and were feeding difficulties (i.e., anorexia; 5 vs. 4 days; P = 0.036) were used for definitive influenza confirmation using the same significantly longer in influenza-positive patients during the first procedure as the first season. During the third season, Sofia R season. The same trend was also observed in the second season, tests further provided real time results through a cloud system to in which rhinorrhoea also lasted significantly longer (9 vs. 7 days, the reference laboratory. No clinical data were collected during P < 0.001). During the 2016–2017 season, differences between the third season and no confirmation RT-PCR was performed. symptoms and clinical signs from patients with confirmed IAV Regarding the statistical analysis, antibiotic treatment and or IBV could not be calculated because IBV did not circulate. use of primary care healthcare services for enrolled patients However, during the 2017–2018 season, when both influenza with a confirmed influenza diagnosis (Group 1), which were viruses circulated, no clinical differences were observed. obtained through 10 days follow up, were compared with data Antibiotic consumption data and additional reassessment collected from electronic health records of patients with similar visits during the 2016–2017 season have already been published age, geographic area, time period, an attended in other primary (10), except that in this analysis Group 3 only includes patients care centers. For comparison, 2 groups were established: patients having a diagnosis of fever (R50) without any microbiologic coded J11 (ILI with no influenza virus confirmation; Group 2) confirmation (Table 2). For both seasons, influenza-confirmed and patients coded R50 (fever of other or unknown origin; Group patients (i.e., Group 1) received fewer antibiotics during the 10 3). All these codes are included in the ICD-10 2016 classification. days after influenza diagnosis compared with Group 3 (2016– Univariate methods were used to describe the sampling. 2017: 4.4% vs. 11.5; 2017–2018: 10.2 vs. 17.2%), but this difference Comparison of antibiotic consumption and frequency of was only statistically significant during the 2017–2018 season (P consultations at the healthcare center was performed by = 0.002). Influenza-confirmed patients in both seasons showed comparative statistics using bivariate analysis (χ2 and Student’s significant lower additional visit rate (2016–2017: 0.19 additional t-test). A P < 0.05 was considered to be significant. visits per patient; 2017–2018: 0.23) compared to Group 2 (2016– The sensitivity, specificity, positive (PPV) and negative (NPV) 2017:0.48, P = 0.001; 2017–2018: 0.49, P < 0.001) and Group 3 predictive values, and inter-rate agreement (Cohen’s kappa, (2016–2017: 1.01, P = 0.001; 2017-2018: 0.80, P < 0.001). k) for both RIDTs in comparison with routine PCR assay Both RIDTs used in our study showed high sensitivities were determined using MedCalc R Statistical Software v18.9.1 and specificities (Table 3), with excellent agreement with (MedCalc R bvba, Belgium). definitive results provided by routine PCR-based assay (gold Weekly data provided by the sentinel surveillance network standard), which is in line with previous manuscripts in for acute respiratory infections coordinated by the Public Health pediatric population (11, 12). Sofia R showed high sensitivity and Agency of Catalonia (Spain), available at: https://canalsalut.gen specificity for IAV, particularly for A(H1)pdm09 strains but also cat.cat/ca/professionals/vigilancia-epidemiologica/pla-dinforma for A(H3), specificity for IBV was excellent, but its sensitivity Frontiers in Pediatrics | www.frontiersin.org 3 October 2020 | Volume 8 | Article 565 van Esso et al. Rapid Influenza Testing Primary Care TABLE 1 | Study demographics and clinical signs & symptoms of included patients. Season 2016–2017 (N = 189)* Season 2017–2018 (N = 610) IAV Influenza PU Influenza Influenza P IAV IBV P (N = 91) negative positive (A negative (N = 207)** (N = 181)** (N = 93) or B; (N = 219) N = 391) Age, months: 31.2 25 0.05 36.9 26 <0.001 33.9 40.4 0.47 mean, (SD; range) (16.5; 4–60) (14–60) (18.7; 2–72) (18.8; 3–72) (18.8; 2–72) (17.9; 3–72) Sex: male/female 43/48 41/52 0.61 179/212 128/91 0.003 99/108 80/101 0.001 Mean duration of symptoms: days (SD) Fever 5.36 (2.16) 4.02 (2.07) < 0.01 5.62 (2.02) 4.37 (2.12) <0.001 5.63 (2.02) 5.60 (2.04) 0.90 Max. temperature 38.9 (0.52) 38.7 (1.14) 0.28 38.8 (0.54) 38.8 (0.59) 0.126 38.9 (0.51) 38.8 (0.57) 0.158 ◦ C Rhinorrhoea 8.73 (3.74) 7.68 (4.20) 0.79 8.52 (4.07) 7.47 (4.48) 0.005 8.58 (4.23) 8.42 (3.89) 0.713 Cough 8.23 (3.71) 6.99 (4.50) 0.045 7.70 (4.28) 5.94 (4.25) <0.001 8.05 (4.25) 7.26 (4.30) 0.077 Irritability 3.81 (3.66) 3.20 (2.98) 0.20 3.11 (3.33) 2.71 (3.04) 0.160 3.30 (3.23) 2.90 (3.45) 0.249 Anorexia 5.06 (2.97) 4.12 (3.04) 0.036 4.44 (3.90) 3.40 (3.55) 0.002 4.42 (3.82) 4.48 (4.00) 0.892 Vomiting 0.73 (1.50) 0.73 (1.84) 0.99 0.80 (1.51) 0.69 (1.43) 0.387 0.87 (1.53) 0.71 (1.45) 0.281 Diarrhea 1.02 (2.01) 0.73 (1.81) 0.30 0.76 (1.81) 1.20 (2.65) 0.02 0.79 (1.87) 0.73 (1.74) 0.734 Headache 0.98 (2.00) 0.46 (1.25) 0.037 0.83 (1.75) 0.43 (1.36) 0.005 0.75 (1.61) 0.90 (1.86) 0.428 Myalgia 0.86 (1.73) 0.40 (1.34) 0.046 1.10 (1.96) 0.46 (1.45) <0.001 1.08 (1.84) 1.12 (2.70) 0.822 *IBV did not circulate during the 2016–2017 season **3 patients had a combined A+B infection (not included in this analysis); U P < 0.05 is significant. IAV, influenza A virus; IBV, influenza B virus; N, number of patients. was slightly lower than what has been previously reported in the the immunofluorescent assay (Sofia R ), and thus the overall literature (11). accuracy of diagnosis improved, although the difference was During the third season (2018–2019), weekly distribution of not statistically significant. On this basis we considered that primary care positive RIDTs results were compared to those the immunofluorescence, nucleoprotein, antigen detection-based obtained from (i) the reference hospital and (ii) the Catalan test (Sofia R ), was adequate for pediatric primary care patients sentinel influenza surveillance system. The first influenza- because their viral load is very high in nasopharynx, especially confirmed cases from both primary care and reference hospital at the onset of the symptoms and therefore we used it as the only were detected between 1 and 2 weeks earlier than those of test during the following two seasons. the surveillance system during the initial steps of the seasonal Based on our experience, RIDTs are an excellent tool influenza epidemic (Figure 1). for primary care pediatricians to correctly confirm influenza infection in infants and young children presenting non-specific DISCUSSION symptoms. In the US, RIDTs aim to identify patients who can benefit of oseltamivir treatment started within the first 48 h Influenza in healthy children can be associated with severe after the onset of symptoms. However, in other countries, where morbidity and mortality (6) although in most cases it is antiviral treatment is not an usual option in primary care, the use a self-limited and usually uncomplicated disease that needs of RIDTs have other purposes such as: (i) minimizing the use of only symptomatic treatment. Hence, it is crucial to have antibiotics, (ii) making an aetiological diagnosis that reassures the a microbiological diagnosis in few minutes to confirm the patient, and (iii) explaining the possible evolution of the disease, respiratory infection due to influenza virus in the primary care thus enhancing the trust of families in their healthcare provider. setting, in those cases in which the clinician cannot make an In our study, as shown in Table 2, patients with a clinical accurate clinical diagnosis, usually infants and young children diagnosis of influenza-like illness (Group 2) or diagnosed which may present with high fever as the only symptom, initially as fever (Group 3) doubled or tripled the number of or when pre-existing health condition may warrant antiviral additional consultations in comparison with RIDT-confirmed treatment. In recent years, sensitive and specific RIDTs have patients (Group 1). Prolonged symptoms and uncertainty about been commercialized for such purpose, either based on antigen their cause are often the reasons for families to revisit their (Sofia R ) or nucleic acid detection (Cobas R Liat R ) (12–14). The pediatrician or attend the emergency room. On the other hand, latter is often more sensitive, but its higher cost can represent an influenza-confirmed patients had less additional visits in primary economic burden to the healthcare system in many countries, care because the expected evolution of disease can be better a fact that may hinder its use in daily clinical practice. In explained to the family based on the certainty of an objective test. our previous manuscript of the first season (10), the molecular The additional visits for the same process make an important RIDT (Cobas R Liat R ) showed a slightly higher sensitivity than difference as the healthcare system is usually under pressure Frontiers in Pediatrics | www.frontiersin.org 4 October 2020 | Volume 8 | Article 565 van Esso et al. Rapid Influenza Testing Primary Care TABLE 2 | Comparison of antibiotic treatment and additional visits in primary care in the different influenza diagnosis groups. Group 1* Group 2U Group 3§ Pγ Pγ Group 1 vs. Group 1 vs. Group 2 Group 3 2016–2017 2017–2018 2016–2017 2017–2018 2016–2017 2017–2018 2016–2017 2017–2018 2016–2017 2017–2018 No subjects 91 343 166 769 253 1029 Age, months: 31.2 35.9 34.0 39.8 27.3 32.1 0.23 0.002 0.07 0.002 mean, (SD; range) (16.5; 4–60) (18.6; 2–72) (16.7; 6–60) (19.1; 1–72) (17.4; 6–60) (20.4; 0–72) Antibiotic 4 (4.4) 35 (10.2) 12 (7.2) 62 (8.1) 29 (11.5) 177 (17.2) 0.38 0.24 0.052 0.002 treatment n◦ (%) Additional visits in 0.19 (0.45) 0.23 (0.47) 0.48 (0.98) 0.49 (1.05) 1.01 (1.57) 0.80 (1.25) 0.001 <0.001 <0.001 <0.001 primary care (SD) *Group 1: Influenza according to results of RT-PCR confirmation after RIDT. U Control group 2: Influenza clinical diagnosis (J11). § Control group 3: Diagnosis of fever (R50). γ P < 0.05 is significant. ICD10 2016 coding: J11: Influenza, virus, not identified; R50: Fever of other and unknown origin. Results of first season (N = 91) are based on final PCR, while results of second season (N = 343) are based on Sofia® test. TABLE 3 | Sofia® vs. Allplex® , sensitivity, specificity, PPV, NPV, diagnostic accuracy, and Kappa values. Targets No positive Sensitivity Specificity PPV % NPV % Diagnostic Kappa % Agreement specimens % (95% CI) % (95% CI) (95% CI) (95% CI) accuracy % (95% CI) (95% CI) Influenza A 191 91.0 (86.2–94.5) 97.0 (94.8–98.4) 94.1 (90.1–96.5) 95.2 (93.0–96.9) 94.9 (92.9–96.5) 0.887 (0.848–0.925) Excellent H1pdm09 123 93.2 (87.5–96.8) 83.3 (79.6–86.5) 60.6 (55.6–65.4) 97.8 (95.9–98.8) 85.4 (82.4–88.1) 0.640 (0.574–0.706) Good H3 68 87.2 (77.7–93.7) 74.6 (70.7–78.3) 33.5 (29.9–37.4) 97.5 (95.7–98.6) 76.2 (72.7–79.6) 0.367 (0.293–0.441) Moderate Influenza B 137 74.4 (67.5–80.6) 98.6 (97.0–99.5) 95.8 (91.1–98.1) 89.9 (87.5–92.0) 91.3 (88.8–93.4) 0.780 (0.724–0.836) Good CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value. due to the high number of consultations during the influenza most of the published data come from emergency services or season (15, 16). hospitalized patient cohorts (19). A limitation of our study was Antibiotic prescriptions were also reduced when patients had that the data from clinically diagnosed patients without influenza a confirmed RIDT confirmation of influenza, compared to those confirmation or patients with fever (Groups 2 and 3) were having a clinical diagnosis without microbiologic confirmation, extracted from the EHR of similar patients visited at other health although the differences were statistically significant only for the care centers within the same geographical area, and although 2017–2018 season. Our results are in line with data published the system is capable of detecting any antibiotic prescription by other groups, like Tillekeratne et al. (17), who showed a or visit to the primary health care system, these data could be 20% decrease in the antibiotic prescription with the use of higher due to over-the-counter purchased antibiotics or health an POCT for influenza confirmation, and Jennings et al. (18), care visits at private pediatricians or other health care providers. who showed a five-fold increase of antibiotic prescriptions Data collected during the 10-days follow-up of RIDT-confirmed in clinical diagnosed patients. Egilmezer et al. (19) recently patients (Group 1) are more exact as they included any antibiotic published a systematic review of the impact of diagnosing prescription and health care visit. The differences between groups influenza with a POCT in patients with acute respiratory mentioned in this paper are therefore a bottom line and could tract infection. The main findings were that a positive POCT be higher. significantly increased the proper use of antivirals and decreased One of the results to be highlighted of this study is the antibiotic prescriptions. Unfortunately, the number of papers value of real-time transmission of RIDTs results from pediatric addressing prospectively the impact of influenza POCTs on primary care patients for the surveillance of influenza viruses antibiotic treatment in pediatric primary care were only two for the whole community, as this system may detect early out of the 30 papers included in this systematic review circulating strains. Still more, sentinel surveillance system (19). These papers confirm that decision-making process of data need usually a week from collection to publication whilst an antibiotic prescription is vastly influenced by an accurate RIDTs and hospital results are daily real-time reported without diagnosis (17, 20). any delay. Therefore, RIDTs data may be complementary One of the strengths of our study is that our data are to data collected traditionally through the sentinel based on the use of a POCT in pediatric primary care, while surveillance systems. Frontiers in Pediatrics | www.frontiersin.org 5 October 2020 | Volume 8 | Article 565 van Esso et al. Rapid Influenza Testing Primary Care FIGURE 1 | Weekly distribution of positive rate (%) of tested samples (n) during the season 2018–2019 collected at the primary care settings, the reference hospital, and sentinel influenza surveillance system. The period of influenza epidemics (more than 110.7 infuenza-like illness cases per 100,000 inhabitants) in Catalonia according to Catalan Public Health Agency is highlighted in blue. In summary, the use of RIDTs has a great potential in confirmation test at the reference hospital. DE, CA, and AA primary care specially in infants and young children, allowing a analyzed and discussed results, drafted the manuscript, tables, better management of these patients, less additional consultations and figures. CR and TP aided in interpreting the results. DE in primary care reducing therefore the burden of disease on coordinated the execution of this study. All authors discussed the the health care system. The results of the RIDTs done in results and commented on the manuscript. primary care provide a good source of real-time surveillance data when a cloud system connected to the reference hospital FUNDING is available. This study was partially financed by an unrestricted grant from DATA AVAILABILITY STATEMENT AstraZeneca Pharmaceutical Spain. The funders had no role in the study design, data collection and analysis, decision to publish, The datasets generated for this study will not be made publicly or preparation of the manuscript. Roche Diagnostics (Spain) available. Confidentiality of patient data. and Werfen (Spain) provided reagents and equipment for the study. This study was also supported by the Spanish Ministry of ETHICS STATEMENT Economy and Competitiveness, Instituto de Salud Carlos III, co- financed by the European Development Regional Fund (ERDF) The studies involving human participants were reviewed and A way to achieve Europe, Spanish Network for Research in approved by Idiap Jordi Gol. Evaluated 28/09/2016 and approved Infectious Diseases (REIPI RD16/0016/0003). CA was a recipient code number P16/135. Written informed consent to participate of a predoctoral fellowship from the Vall d’Hebron Research in this study was provided by the participants’ legal guardian/next Institute, PRED-VHIR-2013. of kin. ACKNOWLEDGMENTS AUTHOR CONTRIBUTIONS We thank Irene Farré (IF Medical Writing) for providing medical DE, MV, CR, TP, and AA conceived and designed the study. writing support, Francesc Orfila for his statistical analysis, and MV, SI, JF, LL, GR, LS, PM, MP, Ma F, and EH recruited the Miguel Angel Muñoz for his help as head of the Primary Care patients performed point-of-care tests, preserved respiratory Research Unit of the Catalan Institute of Health. We are indebted samples prior to the shipment to the reference hospital, and to the other members of the BCN_FLU study group; study collected the clinical data. CA performed the laboratory influenza physicians: Josep Ma Casanovas, Anna Bosch, Ingrid Subirana, Frontiers in Pediatrics | www.frontiersin.org 6 October 2020 | Volume 8 | Article 565 van Esso et al. 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Diagnostic accuracy of novel and traditional rapid tests for influenza infection compared Copyright © 2020 van Esso, Vilà, Andrés, Iglesias, Ferrer, Losada, Ricos, Sanchez, with reverse transcriptase polymerase chain reaction: a systematic review Morera, Pérez, Ferrandez, Hernando, Rodrigo, Pumarola and Antón. This is an and meta-analysis. Ann Internal Med. (2017) 167:394–409. doi: 10.7326/ open-access article distributed under the terms of the Creative Commons Attribution M17-0848 License (CC BY). The use, distribution or reproduction in other forums is permitted, 12. Nitsch-Osuch A, Wozniak-Kosek A, Korzeniewski K, Zycinska K, Wardyn K, provided the original author(s) and the copyright owner(s) are credited and that the Brydak LB. Accuracy of rapid influenza detection test in diagnosis of influenza original publication in this journal is cited, in accordance with accepted academic A and B viruses in children less than 59 months old. Adv Exp Med Biol. (2013) practice. No use, distribution or reproduction is permitted which does not comply 788:71–6. doi: 10.1007/978-94-007-6627-3_11 with these terms. Frontiers in Pediatrics | www.frontiersin.org 7 October 2020 | Volume 8 | Article 565