Epidemiological characteristics and clinical manifestations of pediatric patients with COVID-19 in China: A multicenter retrospective study

2.1 Ethical approval

The study design was in accordance with the Helsinki Declaration and was approved by the Beijing Children’s Hospital Ethics Committee (Approval number 2020-K-20). Because this was a retrospective study and data were analyzed anonymously, informed consent was waived.

2.2 Study design and participants

This multicenter study included pediatric inpatients (≤ 18 years old) with confirmed COVID-19 diagnosis, from 46 hospitals in China—12 provinces [Hubei except Wuhan (51), Guangdong (46), Hunan (37), Anhui (25), Guizhou (18), Shandong (9), Henan (5), Guangxi (4), Hainan (3), Hebei (3), Heilongjiang (2), Jilin (1)] and two province-level municipalities [Beijing (4) and Tianjin (3)]—between January 16, 2020 and February 25, 2020. Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records using a standardized data collection form.

2.3 Diagnostic criteria for COVID-19^{7, 8}

Mild pneumonia referred to patients that did or did not involve fever, respiratory symptoms (e.g., cough), and chest imaging findings indicative of pneumonia; however, the manifestations did not meet the criteria for severe pneumonia.

Severe pneumonia referred to patients that met any of the following criteria: 1) increased respiratory rate: ≥ 70 breaths/min (for children under 1 year of age) or ≥ 50 breaths/min (for children above 1 year of age), following the exclusion of potential interference caused by fever or crying; 2) oxygen saturation < 92%; 3) hypoxia: assisted breathing (e.g., moans, nasal flaring, and/or retractions of supraclavicular, substernal, and intercostal spaces), cyanosis, and/or intermittent apnea; 4) disturbance of consciousness: somnolence, coma, or convulsion; 5) food refusal or feeding difficulty, with signs of dehydration.

Critically ill patients referred to patients who met any of the following criteria and required admission to the intensive care unit: 1) respiratory failure requiring mechanical ventilation; 2) shock; and 3) multi-organ failure.

2.4 Other definitions

The incubation period was defined as the interval between the putative earliest date of contact with the infectious source (i.e., person with suspected or confirmed infection) and the earliest date of symptom onset (e.g., cough, fever, fatigue, or myalgia). Lymphocytopenia was defined in accordance with the standards in the Zhu Futang Textbook of Pediatrics [reference ranges: (2.9–8.8) × 10⁹/L (< 3 months), (3.6–8.8) × 10⁹/L (4–8 months), (2.1–8.2) × 10⁹/L (9 months to 2 years), and (2.0–2.7) × 10⁹/L (3–18 years)].⁹

2.5 Statistical analysis

All analyses were conducted with SPSS Statistics, version 22.0. The Wilcoxon rank-sum test was used to compare continuous variables, while Fisher’s exact test was used to compare categorical variables. Results were considered statistically significant when P < 0.05.

3.1 Demographic and epidemiological features of pediatric patients

In total, 211 pediatric patients with COVID-19 were included in this study (107 girls and 104 boys); the median age was 7.0 years (range: 22 days to 18 years). Most patients (34.1%, 72/211) were aged 6–12 years. The age distribution of the patients is shown in Table 1. Among the 211 patients, two did not undergo chest imaging examinations and thus could not be classified in any clinical group. In this study, COVID-19 clinical statuses included asymptomatic infection (16.3%, 34/209), upper respiratory tract infection (23.0%, 48/209), and pneumonia (60.7%, 127/209). The forms of pneumonia were mild (n = 124, 59.3%), severe (n = 2), and critical (n = 1). Among the 211 patients, 12 (5.7%) had underlying conditions, including preterm birth (n = 4), recurrent respiratory tract infection (n = 6), congenital heart disease (n = 3), asthma (n = 2), suspected primary immunodeficiency (n = 2), epilepsy (n = 1), and tumor (n = 1). Eleven of the patients with underlying conditions were diagnosed with mild pneumonia, while one was critically ill.

Approximately 82.5% (174/211) of the patients had a history of exposure or contact with confirmed COVID-19 patients, 33.2% (70/211) had a history of travel to or residence in Wuhan, and two had a history of exposure to the South China Seafood Market. Moreover, 78.7% (166/211) of the patients occurred in familial clusters of infection (Table 1). The median incubation time was 10 days (range: 1–34 days). The median interval from symptom onset to disease confirmation was 1 day (range: 0–14 days).

3.2 Clinical features

The most common sign or symptom at the onset of disease was fever (54.5%, 115/211), defined as a body temperature > 37.3°C. Approximately 43.1% of the patients had low-grade fever (37.3–38.0°C); a few patients (17.2%) exhibited high-degree fever (> 39.0°C). The median duration of fever was 2.5 days (range: 0.5–20 days), while two patients exhibited persistent fever for 20 days. The second most common symptom was cough (49.3%, 104/211); 57 patients exhibited dry cough and 47 patients exhibited productive cough. The median duration of cough was 8.5 days (range: 1–32 days). Additionally, pharyngeal congestion, gastrointestinal symptoms (e.g., nausea and/ or vomiting, and diarrhea), fatigue, and headache were recorded in 20.8%, 10.7%, 2.4%, and 1.9% of the patients, respectively (Table 1). Only one patient developed respiratory failure and required invasive mechanical ventilation. Lung auscultation abnormalities were observed in 10.0% (21/211) of the patients: 10 with fine rales, 10 with coarse rales, and one with wheeze. In total, 127 patients showed radiologic features of pneumonia, among which 23 (18.2%) had no other symptom of infection. No pediatric patients developed multisystem inflammatory syndrome in this study.

3.3 Laboratory characteristics

In total, 199 pediatric patients were tested for full blood cell count. Most patients had normal white blood cell (WBC) counts (85.9%, 171/199), 26 had leukocytosis, and two had decreased WBC counts. The median lymphocyte count was 2.4 × 10⁹/L [range: (0.7–9.5) × 10⁹/L]; 17.6% of the patients had decreased lymphocyte count. The C-reactive protein concentration was increased in 20.1% (32/159) of the patients; the median concentration was 16.3 mg/L (range: 8.7–47.1 mg/L; reference range: < 8 mg/L). The procalcitonin concentration was increased in 14.5% (17/117) of the patients. Liver function assessment revealed that 6.2% of the patients had an increased alanine aminotransferase concentration (reference range: < 40 U/L); heart function assessment indicated that 12.9% of the patients had increased creatinine kinase-MB concentration (reference range: < 25 U/L) and two patients had an increased troponin concentration. Except for the one patient with critical illness, all patients had normal renal function (Table 2). Levels of IgG, IgA, and IgM were normal in most patients, as were the numbers of CD4⁺ T cells, CD8⁺ T cells, B cells, and NK cells.

All patients were confirmed to have SARS-CoV-2 infection according to viral nucleic acid analysis. The median interval from positive SARS-CoV-2 results to negative SARS-CoV-2 results according to throat swab analysis was 8 days. Additionally, 11 patients exhibited positive SARS-CoV-2 results according to rectal swab analysis at days 2, 3, 8, 11, 16, and 19 (three patients), and until days 21 and 22 (two patients) after diagnosis. Only one case exhibited recurrent positive SARS-CoV-2 results (for an interval of 4 days) according to throat swab analysis, following discharge 5 days prior; notably, that patient had no additional symptoms. Patients with other identified pathogens included four patients of influenza virus type A, two patients of influenza virus type B, and two patients of Mycoplasma pneumoniae. All eight co-infected patients had pneumonia.

3.4 Radiological characteristics

Chest radiographs were performed for 209 patients; abnormalities were visible in 60.8% (127/209) of patients. Among these patients, there were 63 patients (49.6%) with bilateral lung involvement, 38 patients (30.0%) with unilateral right lung involvement, and 26 patients (20.4%) with unilateral left lung involvement (Table 3). The most common feature on chest radiography was ground-glass opacity (47.2%), followed by patchy shadows (40.2%), and a combination of ground-glass opacity with patchy shadows (12.6%). There were no patients with pleural effusion in this study. Radiographic images from two patients with severe pneumonia and one case with critical illness showed bilateral lung involvement.

3.5 Treatments and clinical outcomes

In total, 196 patients received anti-viral treatment, including 124 patients treated with interferon alpha; the remaining patients were treated with either oseltamivir, Arbidol, ribavirin, or lopinavir/ritonavir. Intravenous immunoglobulins and systemic corticosteroids were used in the treatment of two patients with severe pneumonia and one case with critical illness for 3–4 days. Moreover, the patient with critical illness received mechanical ventilation. This patient had suspected immunodeficiency and a history of open-heart surgery due to congenital heart disease. Additionally, some patients were treated with traditional Chinese medicine. All 211 patients had improved conditions and were cured eventually. None of the included patients died.