Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antigen detection in the Emergency Department: data from a pediatric cohort during the fourth COVID-19 wave in Italy

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has been challenging health care systems worldwide in multiple ways, one of which has been the increasing necessity of rapid, cost-effective and largely available testing methods, particularly in Emergency Department (ED) settings [1]. It is widely known that Reverse Transcription-Polymerase Chain Reaction (RT-PCR) performed on nasopharyngeal samples is the gold standard to detect the presence of SARS-CoV-2 infection [2].

Rapid Antigen Diagnostic Tests (RADTs), however, have been shown to be a valid alternative to RT-PCR, even in pediatric populations, proving adequate sensibility and specificity [3, 4]. Furthermore, RADT immunoassay’s sensibility increases when conducted on symptomatic children, up to a 80–90% rate [5, 6].

Among the pediatric population, SARS-CoV-2 infection appears to be milder. In comparison to adults, in fact, asymptomatic cases are more frequent and hospitalization and mortality rates are substantially lower. COronaVIrus Disease-19 (COVID-19) symptoms in children are mainly aspecific and often overlap with symptoms of other seasonal respiratory viruses, consisting in fever, upper respiratory tract’s mucositis, fatigue, migraine, dry cough, muscle pain, abdominal pain, diarrhea, nausea and vomit. Moderate cases of pneumonia are rare, even though radiological features suggesting pneumonia were found in asymptomatic patients too [7]. Nevertheless, the spread of new viral variants and the rise of vaccination rates represent new possible variables that can influence COVID-19 presentation in children, so further research is needed in this field.

Taking that into account, this retrospective observational study has been conducted on a pediatric cohort afferent to the ED of the San Giovanni di Dio and Ruggi d’Aragona University Hospital in Salerno, tested at Point of Care with RADT Panbio® (Abbott), from September 1^st, 2021 to February 28^th, 2022. This paper aims to analyze the positivity rate and clinical features of this pediatric cohort, considering the rise of positive cases observed in the aforementioned period, and the introduction in Italy of COVID-19 vaccination for children and teens on December 16^th, 2021.

During the observation period (September 1^st, 2021 - February 28^th, 2022), 1904 pediatric patients (age 0–14 years) were admitted to the ED of the San Giovanni di Dio and Ruggi d’Aragona University Hospital in Salerno and 1890 (1040 males) were tested for the presence of SARS-CoV-2 with RADT (14 patients did not perform the test because left the ED before visiting and were therefore excluded from the study). The total cost for antigen swabs was about 2500 euros.

The 2.7% of children (n = 51, median age 43 months, 28 males) tested positive, with a peak in January 2022. Hospitalization was required in 6 positive children (11.8%; median age 19 months) and 376 negative ones (20.4%; median age 43.5 months): the 6 patients tested positive for RADT were confirmed positive for the RT-PCR test; however, among the 376 negative ones, 3 patients were actually positive for the RT-PCR test (false negative). The specificity of RAD testing was 100% and the sensitivity was 94% (3 false negative patients, 51 true positives ones). Main characteristics of the study cohort are summarized in Table 1.

The main symptoms in positive patients were: fever (n = 34; 66.7%), cough (n = 11; 21.5%), headache (n = 4; 7.8%), chest pain (n = 2; 3.9%) and abdominal pain (n = 1; 2%). Seven patients reported respiratory distress among the presenting symptoms; however, only in one child it was actually confirmed by physical examination (tachypnea, nasal flaring, use of accessory muscles).

Fourteen positive patients (27.4%) were admitted to the ED in January for other medical problems (seizures, lipothymia, accidental ingestion of toxic substances, etc).

Patients were divided into three different age groups basing on the different access timing to vaccination:

The distribution of positivity in these three groups showed no statistically significant differences (p > 0.05). Related to the expansion of the nation’s vaccination campaign to children as young as 6–11 (16^th December 2021), we observed in groups A and C a number of accesses pre-expansion of vaccination campaign significantly greater (p < 0.01) (Fig. 2) and a non significant (p > 0.05) difference in the number of positives pre / post expansion of the vaccination campaign (Fig. 3). The number of positive patients in group A was greater in the post-vaccine group. Our data are concordant with the national trend of the pandemic showing a fourth wave peak in January 2022 (Fig. 4) [8]. Literature research on this topic was carried out on PubMed database using the following key words: pediatric, children, emergency department, antigen, COVID-19, SARS-CoV-2 (Fig. 5). A total of 93 articles was retrieved from PubMed database; 84 were excluded as they were guidelines, adult studies (> 18 years), letters, commentaries, studies concerning the use of RADTs in a setting other than ED. A final set of 9 articles (2 retrospectives and 7 prospectives) was suitable for the scope of our review as they described the use of RADTs in a pediatric emergency department setting (Table 2). These papers compared the performance of RADTs with PCR test as the gold standard. As shown in the table, RADTs showed a wide range of sensitivity (45.4–94.1%) though all of them presented a good specificity (range 91.9–100%).

From 2019, SARS-CoV-2 was recognized as the etiological agent of COVID-19 [14], making necessary rapid detection of infected patients.

PCR- RT is the gold standard for diagnosing SARS-CoV-2 infection. However, especially in the ED, it is important the use of rapid screening methods to limit viral transmission and prevent COVID-19 spreading in hospital settings [15].

RADTs represent an efficient alternative as a first-line diagnostic method combining both advantages: low price and quick results. As the detected antigens are expressed during viral active replication, RADT accuracy is closely linked to the viral load and it can be used to identify acute infection [16].

The guidance released on 11^th September by the World Health Organization (WHO) [17] recommended use of RADTs for diagnosis of COVID-19 when the RT-PCR test is not available underlying that it must have a sensitivity of at least 80%.

Many studies are available in literature about the use of RADTs in the pediatric ED, mainly focused on comparison with the gold standard RT-PCR.

Carbonell- Sahuquillo et al. [3] evaluated the Panbio™ COVID-19 Ag Rapid Test Device as a point-of-care diagnostic tool for COVID-19 at a pediatric ED. The authors underline that, even if the assay did not meet one of the criteria (at least 80% sensitivity) recommended by WHO interim guidance for RADT diagnosis of SARS-CoV-2 infection, its performance in identifying children with high SARS-CoV-2 RiboNucleic Acid loads in the upper respiratory tract, which associate with contagiousness, makes it a valuable tool for the management of children with suspected COVID-19 at the ED.

Ollier et al. [6] found that sensitivity of RADTs increased from 69.6 to 82.9% when performed on symptomatic children suggesting that RADTs sensitivity depends on the entity of nasal viral load at testing time, which is higher in the first few days of infection when patients are most likely to be symptomatic. Their results are in line with what has been observed by Mockel et al. [13]: false negatives obtained with RADTs coincide with low viral load confirmed by RT-PCR.

The Panbio™ rapid antigen test kit for SARS-CoV-2 (Abbott Diagnostic GmbH, Jena, Germany) is a qualitative test using specimens from nasopharyngeal swabs. The manufacturer declared in patients with symptoms a sensitivity of 93.3% overall and 98.2% in those RT-PCR cycle threshold ≤33, and a specificity of 99.4% [18]. These data agree with the findings in our cohort of hospitalized, and therefore symptomatic patients: the Panbio™ rapid antigen test showed a sensitivity of 94% and a specificity of 100%.

It is interesting to note that, in the period before vaccine implementation among children, the number of accesses to the ED was significantly higher for groups A and C than in the subsequent period, probably due to the pandemic curve with a peak of the “fourth wave” in January 2022. However, group B did not show this trend. Furthermore, epidemiological context must be considered: by the start of the study period, the 7-day Italian incidence rate was 54 per 100,000 on September 6–12, 2021 and the peak of the fourth wave was reached in the week 10–16 January 2022 with an incidence rate of 2021 per 100,000. At the end of the observational period a 7-day incidence rate of 433 per 100,000 was recorded in Italy [8].

According to our knowledge, this is the first study describing the clinical characteristics of a pediatric cohort afferent to the ED who tested positive for a rapid antigen test also referring to the progress of the vaccination campaign in children and the national trend of the pandemic.

It is not possible to express an absolute opinion about the vaccination campaign’s impact because the effects are to be sought after the observation period of this study.

Our study has some limitations: first, no data about time of onset of symptoms have been collected and all patients were subjected to RADT indifferently; furthermore, the most important limitations of this study are its retrospective design and the lack of RT-PCR data for all patients because this test, as per our protocol, is performed only in children requiring hospitalization. However, we have tried to limit the effects of these by opting to adopt a descriptive rather than an analytical approach, and by making within-group comparisons.

In conclusion, the use of rapid antigen test as a first point-of-care screening, later integrated with molecular test, may be helpful, time-saving and cost-sparing, and could reduce the time children stay in the waiting room and reducing the hospital infection with SARS-CoV-2 or other pathogens. Clearly it must be designed in synergy with other containment measures, such as the use of masks and frequent ventilation of the rooms. Our data suggest that, during the observation period, most children admitted to the ED for fever actually tested positive for SARS-CoV-2 with a statistically greater difference than negative children.

Instead, number of patients admitted for cough was statistically higher among negative than positive ones, probably due to the circulation of other respiratory viruses in children. In fact, the highest number of positivity was observed in children under the age of 5 who had not been involved in the vaccination campaign and were not required to wear personal protection. Learning also from this experience and the diagnostic yield of RADTs, we encourage health care systems to move toward more integrated models between hospitals and community services, perhaps with safer rapid swab hubs benefitting both ED and primary care.