Distinguishing coronavirus disease 2019 from influenza in children remains challenging.

Clinical descriptions about influenza-like illness in children seem non-specific during the co-circulation of SARS-CoV-2 and influenza. This paper aimed to summarize recent studies comparing clinical features and outcome, laboratory and radiological findings of COVID-19 patients with influenza patients in the paediatric population.

To the Editor,

Coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in December 2019 in Wuhan in the province of Hubei in China. Since then, it has evolved into a worldwide pandemic and became one of the world's toughest health problems, especially in adult patients but also in pediatric population [1–[2], [3]]. Influenza A and B affect 20%–30% of children annually with most cases occurring during the winter season [4,5]. The 2019–2020 influenza season had a lower than expected burden, especially in children. This decrease was probably the result of a behavioural or ecological interaction with COVID-19. The occurrence of a syndemic episode with co-circulating influenza virus and SARS-CoV-2 is still an unknown hypothesis. SARS-CoV-2 and influenza virus share similarities, such as viral shedding, route of transmission and clinical presentation in adults and children presenting with influenza-like illness. In October 2020, we published a paper in Microbes and Infection describing an observational study of 124 adults comparing clinical features and outcome between COVID-19 and influenza [6]. We showed that regarding demographic characteristics such as age, sex and co-morbidities no differences were found between the two groups. Neurological symptoms (facial headache, anosmia and dysgeusia) and diarrhoea were statistically more frequent in COVID-19 patients. Respiratory symptoms (productive cough and dyspnoea), ocular symptoms (conjunctival hyperhaemia and tearing) and vomiting were more frequent with influenza infection [6].

Until now, there have been few studies comparing COVID-19 with influenza in paediatric populations [[7], [8], [9], [10]]. The current paper compares the clinical features and outcomes, and laboratory and radiological findings of children with COVID-19 and those with influenza. In these four studies, all patients were hospitalized. One study compared hospitalized COVID-19 patients with outpatients with influenza [8]. Table 1 summarizes studies of children comparing significant clinical features, and laboratory and radiological findings in COVID-19 and influenza paediatric populations with a value of p < 0.05. In the study by Song et al., the median age was 8.4 years for COVID-19 patients and 3.9 years for influenza patients. The hospitalization rate was 17.1% for COVID-19 patients and 20.8% for influenza patients [7]. The mean age in the Zhao et al. paediatric population was 5.7 ± 3.8 years in 23 hospitalized children with COVID-19, whereas in Li et al. the mean age was 21.8 ± 16.7 months in 59 patients infected with influenza A virus [8,10]. Hospitalized children infected with SARS-CoV-2 were older, and had a lower body temperature than those with influenza; however, fever and gastrointestinal symptoms such as vomiting and diarrhoea were more often described (in two of three studies) in influenza patients, and this difference was significant [8,10]. Song et al. reported that 65% of children hospitalized with COVID-19 had at least one underlying medical condition versus 42% in those hospitalized with influenza (OR 2.6; 95% CI 1.4–4.7, p 0.002). Neurological issues were the most often identified underlying condition and were present in 20% of patients hospitalized with COVID-19 compared with 8% of patients hospitalized with influenza (OR 2.8; 95% CI 1.3–6.2, p 0.002) [7]. In the paediatric population, symptoms such as fever, diarrhoea or vomiting, were more often described in hospitalized patients with seasonal influenza than in those with COVID-19 [8,10]. However, Song et al. concluded that fever and gastrointestinal symptoms were more often described in children hospitalized with COVID-19. This can be explained by the demographic characteristics of the included patients; 37% were adolescents over 15 years old, who have results similar to those of adults [6]. Currently, it is known that neurological symptoms such as the association of anosmia and dysgeusia can lead to the diagnosis of SARS-CoV-2 infection in patients presenting with influenza-like illness [11]. This is not possible with children who are not going to express their subjective olfactory and gustatory dysfunctions; however, it is necessary to look for new loss of smell and taste in children from a certain age range. Concerning the outcome, no statistically significant difference was found in hospitalization rate, intensive care unit admission rate and use of mechanical ventilator support between the two groups [7]. These observations were habitually reported in adult studies [6]; however, SARS-CoV-2 and influenza virus affect children less severely than adults [3]. Zhao et al. concluded that children with COVID-19 were associated with a higher ratio of in-home infection than influenza inpatients (95.6% versus 21.7%, p < 0.001). Milder COVID-19 symptoms in children could be explained by the lower intracellular response induced by angiotensin-converting enzyme 2 in alveolar epithelial cells [8]. Concerning laboratory investigations, three studies of four concluded that children with COVID-19 had higher levels of lymphocytes, creatine kinase, aspartate aminotransferase (AST) and cholinesterase than children with influenza [8,10]. However, Liu et al. concluded in a recent paper that children with COVID-19 had statistically lower levels of procalcitonin, AST and lactate dehydrogenase on univariate analysis; only AST was found to be statistically significant after multivariate analysis [9]. Since the identification of SARS-CoV-2 in children, a European systematic review of 655 children with mild to moderate clinical manifestations of COVID-19 noted lymphopenia or neutropenia in 13% and elevated inflammatory markers in 31% [3]. Laboratory results were comparable to those found in adult patients; COVID-19 patients showed significantly lower levels of leucocytes (especially of neutrophils) and inflammatory markers such as C-reactive protein and procalcitonin, whereas lymphocyte levels were significantly higher compared with influenza patients [10]. In children, imaging results more commonly presented as ground-glass opacities (GGO) in children with COVID-19 under 5 years of age; however, consolidation was more common in influenza patients [10]. In terms of imaging characteristics, only one study compared chest CT scans in this population and reported that GGO were significantly more common in children with COVID-19 than children with influenza [10]. Radiological data showed that GGO, interlobular septal thickening and a peripheral distribution were more common in adult patients with COVID-19 than in patients with influenza. However, consolidation, nodules and linear opacities and pulmonary complications such as pneumomediastinum and pneumothorax were more common in patients with influenza than those with COVID-19 [5]. The scarcity of moderate to severe respiratory forms in children makes the amount of radiological data limited in this population [3].

Table 1

Significant clinical features, and laboratory and radiological findings in COVID-19 and influenza paediatric populations

Reference (number of COVID-19/influenza patients)	Findings type	Significant findings	Hospitalized with COVID-19 (%)	Hospitalized with influenza (%)	OR (95% CI)	p value
Song et al. [7](315/1402)	Clinical	Age >15 years	37	6	25.8 (14.2–48.5)	<0.001
		Fever	76	55	2.6 (1.4–5.1)	0.01
		Diarrhoea/vomiting	26	12	2.5 (1.2–5.0)	0.01
		Myalgia	22	7	3.9 (1.8–8.5)	0.001
		Headache	11	3	3.9 (1.3–11.5)	0.01
		Chest pain	11	3	3.9 (1.3–11.5)	0.01
Yang et al. [8](23/138)			Hospitalized COVID-19 (%)	Influenza (%)		Both p∗
				Inpatients	Outpatients
	Clinical	Cough duration (days)	2.0 ± 5.2	2.4 ± 3.2	3.8 ± 2.3	<0.05
		Body temperature (°C)	37.4 ± 1.2	38.3 ± 1.5	39.3 ± 0.9	<0.05
		Fever duration (days)	1.0 ± 1.4	2.4 ± 3.0	4.0 ± 1.5	<0.05
		Fever >39.0°C	8.7	37.7	60.9	<0.05
		Nasal congestion	4.3	31.9	30.4	<0.05
		Rhinorrhoea	4.3	29.0	27.5	<0.05
		Sore throat	0.0	37.8	23.2	<0.05
		Vomiting	0.0	27.5	24.6	<0.05
	Laboratory	Aspartate aminotransferase (U/L)	37.5 ± 56.1	35.5 ± 72.8	28.6 ± 11.1	<0.001
		Alanine aminotransferase (U/L)	36.3 ± 37.1	46.0 ± 83.7	24.8 ± 9.4	<0.001
		Cholinesterase (U/L)	9477.2 ± 2414.1	6512.7 ± 2085.7	7391.4 ± 1193.5	<0.001
		CRP (mg/L)	2.2 ± 4.4	48.0 ± 74.8	7.9 ± 9.0	<0.001
		ESR (mm/h)	9.6 ± 9.8	21.2 ± 18.5	22.2 ± 7.0	0.019
Liu et al. [9](24/67)	Laboratory	Aspartate aminotransferase (U/L, extr)	31.5 (20.35–40.0)	46.5 (36–59.3)		<0.001
		Procalcitonin (ng/l, extr)	0.07 (0.05–0.1)	0.31 (0.09–0.63)		0.001
		Lactate dehydrogenase (U/L)	300.5 (206.0–394.0)	369 (319–467)		0.036
Li et al. [10](57/59)	Clinical	Cough	70.2	98.3	—	<0.001
		Fever	54.4	84.7	—	<0.001
		GI symptoms	14.1	35.7	—	0.007
		Severe pneumonia	3.5	18.6	—	0.016
	Laboratory	Lymphocyte (× 109/L)	4.58 ± 2.06	3.56 ± 2.01	—	0.006
		Leucocytes (× 109/L)	7.87 ± 2.87	9.89 ± 4.84	—	0.027
		Neutrophils (× 109/L)	2.43 ± 1.92	5.16 ± 4.46	—	<0.001
		CRP (mg/L)	3.7 ± 6.85	15.1 ± 32.2	—	0.001
		Procalcitonin (mm/h)	0.09 ± 0.09	0.68 ± 1.82	—	<0.001
		Creatine kinase (U/L)	147 ± 89	130 ± 121	—	0.042
		D-dimer (ng/mL)	0.34 ± 0.29	1.94 ± 2.88	—	<0.001
		Prothrombin time (mm/h)	10.8 ± 0.7	11.2 ± 0.8	—	0.014
		Potassium (mmol/L)	5.14	7.07	—	0.001
	Radiological	GGO	42.1	15.0	—	0.032
		Consolidation	5.2	25.0	—	0.025

Abbreviations: COVID-19, coronavirus disease 2019; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; extr, extremes; GI, gastrointestinal; GGO, ground-glass opacity.

∗p values for both COVID-19 versus influenza inpatients and COVID-19 versus influenza outpatients.

Bold type indicates illness (COVID-19 or influenza) with significant difference.

There are some limitations to our review. COVID-19 is relatively novel with a limited number of patients and studies. In most articles, the clinical features, laboratory data and CT findings reported about influenza dated before the onset of COVID-19. A meta-analysis is recommended to further define the differences and the similarities between COVID-19 and influenza.

This paper provides a comprehensive comparison between children with SARS-CoV-2 and influenza infections, regarding co-morbidities, clinical and paraclinical features and outcome. Clinical manifestations of COVID-19 and influenza seem to be similar with few differences; fever and gastrointestinal symptoms were more often described in children aged <15 years with COVID-19 than in children with influenza. The two viruses seem to provide laboratory abnormalities with no specifics for either of them (only AST level seems to be more elevated in COVID-19 than influenza). Radiological findings showed that GGO were usually more frequent and peripherally located in COVID-19 compared with influenza. All these findings can help paediatric infectious diseases clinicians when dealing with cases of influenza-like illness during the period of possible co-circulation of influenza and SARS-CoV-2.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions

SZ and MO collected the epidemiological and clinical data, and drafted the manuscript. TK, NU, NB and VG revised the final manuscript.

Conflict of interest

None.