ABSTRACT
This study aims to assess COVID-19 and other respiratory viruses in pediatric patients. Between April 17 and September 30, 2020, we collected 1,566 respiratory samples from 1,044 symptomatic patients who were younger than 18 years old to assess SARS-CoV-2 infection. Of these, 919 were analyzed for other respiratory pathogens (ORP). Patients with laboratory-confirmed COVID-19 or ORP were included. We evaluated 76 pediatric COVID-19 infections and 157 other respiratory virus infections. Rhinovirus occurred in 132/157 (84%). COVID-19 patients who were significantly older, had more fevers, headaches and pneumonia than those with ORP. The median white blood cell count was lower in patients with SARS-CoV-2 than in those with ORP (6,470 versus 8,170; p=0.02). COVID-19 patients had significantly worse symptoms than those with ORP.
Child; COVID-19; SARS-CoV-2; Rhinovirus
BACKGROUND
The impacts of SARS-CoV-2 and other respiratory viral infections on adults have been widely studied, but pediatric data are scarce. This may be due to broad social distancing as a result of school closures during the coronavirus pandemic in 2019 (COVID-19).
Trenholme et al .1 from New Zealand demonstrated a reduction in hospitalization rates in infants under 2 years old with lower respiratory tract virus infections in 2020 compared to the 6 years prior, except for rhinovirus, which remained stable. According to Zhang et al .2, the influenza virus decreased from 14.9% in March 2020 to 1.86% in April 2020. Studies show pediatric coinfection rates of SARS-CoV-2 and other respiratory pathogens (ORP) ranging from 13.2% to 51.4%2 , 3 .
Therefore, the objective of the present study was to compare the SARS-CoV-2 infection and other respiratory tract virus infections in the pediatric population, assessing demographics, laboratory data, comorbidities, clinical features, treatment and outcomes.
MATERIALS AND METHODS
Study design
A single-center prospective study was conducted from April 17, 2020 to September 30, 2020. Visits occurred at the Hospital das Clinicas da Faculdade de Medicina da USP (HCFMUSP) in Sao Paulo, Brazil. The Ethics Committee of our institution approved this study (CAAE 30344420.6.0000.0008). Informed consent was obtained from the parents or legal guardians of the patients. Regarding children over seven years old or adolescents, a consent term was provided in addition to the consent obtained from the parents.
We collected 1,566 respiratory samples from 1,044 patients younger than 18 years old to assess the SARS-CoV-2 infection. Of these, 919 were analyzed further in search of other respiratory pathogens (ORP). The samples were collected from pediatric patients with the following clinical findings: a flu-like syndrome in high-risk children (under 5 years old or with underlying conditions), fever with no source, severe acute respiratory syndrome (SARS), complete or incomplete Kawasaki Disease (KD), KD shock syndrome, MAS (macrophage activation syndrome), and gastrointestinal or neurological signs/symptoms4.
We included only patients with laboratory-confirmed COVID-19 or ORP. In patients with a high suspicion of COVID-19 but a negative RT-PCR (real-time reverse transcription-polymerase chain reaction), serology was collected within 14 days of symptom onset. We excluded pre-surgical screenings or the presence of bacterial coinfections.
Patients were divided into two groups: (a) Group 1 – laboratory-confirmed pediatric COVID-19 patients without coinfection of ORP; and (b) Group 2 – other respiratory virus infections, excluding SARS-CoV-2.
Data collection
Data were systematically reviewed through patients’ medical records: (a) demographics: age, gender and duration of signs/symptoms prior to diagnosis; (b) chronic conditions: pulmonary, neuropathies, cardiopathies, diabetes mellitus, systemic arterial hypertension, immunocompromising diseases (primary immunodeficiency, solid organ transplantation, hematopoietic stem cell transplant (HSCT), malignancies, chronic kidney disease, autoimmune diseases), and use of immunosuppressive agents; (c) clinical features: fever, fever duration, nasal discharge, sneezing, coughing, dyspnea, anosmia, pneumonia, myalgia, headache, conjunctivitis, rash, diarrhea, vomiting, abdominal, pain, neurological symptoms, seizure, SARS, hypoxemia, and arterial hypotension; (d) laboratory parameters: hemoglobin concentration, leucocyte, lymphocyte and thrombocyte counts, C-reactive protein, fibrinogen, D-dimer, ferritin, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, blood urea, serum creatinine, triglycerides, creatine kinase, and troponin T; (e) radiological exams: thoracic radiography and computer tomography; (f) treatments: supplemental oxygen, antibiotics, oseltamivir, intravenous immunoglobulin, enoxaparin, aspirin, systemic glucocorticoids, and dialysis; (g) and outcomes: hospitalization, admission to a pediatric intensive care unit (PICU), duration of hospitalization and PICU, mechanical ventilation, vasoactive agents, shock, cardiac abnormalities and death.
Laboratory methods
Respiratory samples (nasopharynx swab and/or tracheal aspirates) were submitted for molecular analysis at the Molecular Biology Laboratory HCFMUSP: the Fast-track Diagnostics Respiratory Pathogens 21 Assay® (Siemens Healthineers, Erlangen, Germany) detects 21 respiratory pathogens: adenovirus, bocavirus, coronavirus (229E; HKU1; NL63; OC43), human rhinovirus/enterovirus, influenza virus A (H1N1, H3N2, Influenza A H1N1/2009), influenza virus B, Influenza virus C, metapneumovirus A e B, Mycoplasma pneumoniae, parainfluenza virus (1–4), parechovirus, respiratory syncytial virus (RSV) A, and B5. RT-PCR for SARS-CoV-2 analysis was performed according to the Charité University protocol6.
Serology was performed at the HCFMUSP Immunology Laboratory by immunochromatographic test, Wondfo SARS-CoV-2 antibody test® (Wondfo Biotech, Guangzhou, China), or by anti-SARS-CoV-2 enzyme-linked immunosorbent assay, LIAISON®SARS-CoV-2 IgG kit (DiaSorin, Saluggia, Italy)7 , 8 .
Statistical analysis
For continuous variables, Mann-Whitney’s test and Student’s t-test were applied and results were presented by median (minimum and maximum values) or mean ± standard deviation, as appropriate. For categorical variables, the Chi-square test and Fisher’s exact test were used. We considered statistical significance to be p <0.05. The IBM-SPSS statistical software (version 22, IBM Corporation, Armonk, NY, USA) was applied in the statistical analyses.
RESULTS
SARS-CoV-2 infection was detected in 91 patients (77 detected by RT-PCR and 14 by serology). Eight pediatric COVID-19 cases were excluded for bacterial coinfection. Panel 21 was performed on 56 laboratory-confirmed COVID-19 patients. Seven patients had coinfection with rhinovirus. Respiratory viruses were detected in 195 patients, and 31 were excluded for bacterial coinfection. Therefore, 76 patients were included in Group 1 and 157 in Group 2 ( Figure 1 ).
Description of the samples from pediatric patients with clinical findings (Groups 1 and 2) from April 17 to September 30, 2020. ORP = other respiratory pathogens.
In Group 1, nine patients had multisystem inflammatory syndrome in children (MIS-C), of which none presented viral coinfection; 50% of all deaths (4/8) occurred in MIS-C patients.
The ORP identified in Group 2 were: human rhinovirus/enterovirus, n = 132/157 (84.0%); adenovirus, n = 18/157 (11.5%); bocavirus, n = 8/157 (5%); RSV, n = 6/157 (3.8%); other coronavirus n = 3/157 (1.9%); influenza, parainfluenza, and parechovirus, n = 2/157 (1.3%) each; 17/157 (10.8%) had viral coinfections, of which 94.1% (16/17) were attributed to rhinovirus/enterovirus. Table 1 presents the demographic features, clinical presentation and underlying conditions of patients in Groups 1 and 2. Laboratory tests, radiographic abnormalities, treatment and outcomes of patients in Groups 1 and 2 are described in Table 2 .
Further analysis between SARS CoV-2 infection compared to rhinovirus showed that the last group was significantly younger [135 (1–215) months vs. 63 (2–216 months of age); p = 0.001]; presented a higher frequency of coughing [30/74 (41%) vs. 73/123 (59%); p = 0.01]; lower frequency of fever [52/76 (69%) vs. 62/130 (48%); p = 0.01] and shorter duration of fever [median of 2 (0-15) vs. 1 (0-12) days; p = 0.02] compared to the former group. On the other hand, the SARS-CoV-2 group presented the following signs/symptoms more frequently: anosmia [7/48 (15%) vs. 2/85 (2%); p = 0.01]; pneumonia [17/76 (22%) vs. 6/130 (5%); p < 0.001]; myalgia [18/62 (29%) vs. 7/88 (8%); p = 0.001]; headache [18/58 (31%) vs. 14/91 (15%); p = 0.03] and rash [7/74 (10%) vs. 2/120 (2%); p = 0.03]. SARS-CoV-2 group also presented with higher ferritin levels [median 201 (15–35,976) vs. 85 (18–3,837); p = 0.002] and lower leucocyte count [median 6,470 (430-25,890) vs. 8,630 (170–21,120); p = 0.01]. Radiographic abnormalities were found more frequently in the SARS-CoV-2 group [25/49 (51%) vs. 20/67 (30%); p = 0.03]. Use of antibiotics [40/76 (53%) vs. 49/131 (38%); p = 0.04], oseltamivir [20/76 (26%) vs. 13/131 (10%); p = 0.003], intravenous immunoglobulin [7/75 (9%) vs. 2/131 (2%); p = 0.01] and enoxaparin [7/76 (9%) vs. 1/130 (1%); p = 0.004] were more frequent in SARS-CoV-2 group. Furthermore, SARS-CoV-2 group presented poorer outcomes: higher rates of hospitalization [51/76 (67%) vs. 58/131 (44%); p = 0.002], PICU admission [18/76 (24%) vs. 5/130 (4%); p < 0,001], need of oxygen [23/76 (30%) vs. 19/131 (15%); p = 0.01], shock [8/76 (11%) vs. 3/131 (2%); p = 0.02], mechanical ventilation [9/76 (12%) vs. 3/131 (2%); p = 0.01], use of vasoactive agents [5/76 (7%) vs. 1/131 (1%); p = 0.03] and cardiac abnormalities [10/76 (13%) vs. 1/130 (1%); p < 0.001].
There were no statistically significant differences between the seven cases of rhinovirus/enterovirus and SARS-CoV-2 coinfected patients and those in Group 1 (p>0.05).
DISCUSSION
During the COVID-19 pandemic in 2020, rates of viral infections in the pediatric population were low worldwide1 , 2 . The same pattern was observed in our study. Despite the SARS-CoV-2 outbreak, rhinovirus was the most frequently detected respiratory virus in the studied population. In this specific clinical scenario, we will mainly discuss some striking differences between SARS-CoV-2 and rhinovirus infections. Due to differences in management, the distinction between rhinovirus and SARS-CoV-2 is of clinical importance.
In our study, patients with COVID-19 were older than those with ORP infections. This finding was similar to the results of Melé et al .9: the median age was 16.9 years old for SARS-CoV-2 versus 3.5 years for non-SARS-CoV-2 (p = 0.004). We also demonstrated that fever, headache, anosmia, dysgeusia, myalgia, and rash were more common in the SARS-CoV-2 group, while cough was more frequent in Group 2. On the other hand, Melé et al .9 indicated similar clinical findings between the groups.
Considering the outcomes and the greater demand for clinical support, we found that pediatric COVID-19 was more severe when compared to other respiratory virus infections. In the Spanish study, COVID-19 patients also needed more cardiovascular support9. In our study, radiographic examinations were more often altered in the SARS-CoV-2 group, which contradicted the findings of the Spanish team, whose radiographic results were similar between the groups9.
Trenholme et al .1 reported stable rhinovirus infection rates in 2020, as opposed to reduced RSV and influenza infection rates. Accordingly, we showed that the rhinovirus seems to be the main circulating virus in 2020, besides SARS-CoV-2, to such a degree that the rhinovirus was the only virus to be present as a coinfection with SARS-CoV-2. According to Zhang et al .2 the rate of rhinovirus/SARS-CoV-2 coinfection was 23.3%.
Rhinovirus comprises 84% of all respiratory viruses, excluding SARS-CoV-2 in our study. Due to this selection bias inherent to the world’s epidemiological status, we are unable to suggest that these differences apply to other respiratory viruses such as influenza or RSV.
Comparing SARS-CoV-2 and influenza infection, Piroth et al .10 observed that in the pediatric population: (a) influenza infection was more significantly frequent than COVID-19, (b) COVID-19 patients had worse outcomes (higher PICU admission and in-hospital mortality), which was confirmed by our findings; and (c) COVID-19 patients had more underlying conditions (hypertension, respiratory disease, heart failure, and obesity) than patients with influenza.
Alvares11 compared children with solely SARS-CoV-2 infection versus SARS-CoV-2/RSV coinfection and demonstrated longer hospitalizations in the coinfection group. Here, coinfection rates of SARS-CoV-2 were low, as reported in other studies2 , 9 , 12 .
The limitations of our study were selection bias and the fact that we only evaluated patients from a single high-complexity center, primarily for pediatric chronic conditions, over a short time.
Our data reinforce the differences in clinical presentation, laboratory abnormalities, and outcomes between pediatric COVID-19 and rhinovirus infections. Further studies are required to better understand SARS-CoV-2 and its role in the myriad of pediatric respiratory infections.
ACKNOWLEDGMENTS
We thank Lucas Ruiter Kanamori, Lucia Maria Mattei de Arruda Campos, Nadia E. Aikawa, Mayra de Barros Dorna, Ana Paula Beltran Moschione, Antonio Carlos Pastorino, Ana Cristina Aoun Tannuri, Uenis Tannuri, Ricardo Katsuya Toma, Andreia Watanabi, Aurora Rosaria Pagliara Waetge, Sonia Regina Testa da Silva Ramos, Mariana Nutti de Almeida Cordon, Vera Aparecida dos Santos, Werther Brunow de Carvalho and Magda Carneiro-Sampaio.
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Publication Dates
-
Publication in this collection
25 May 2022 -
Date of issue
2022
History
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Received
26 Nov 2021 -
Accepted
12 Apr 2022