Comparative study of hospitalized children with acute respiratory distress syndrome caused by SARS-CoV-2 and influenza virus

A total of 585 paediatric patients, including 248 with confirmed cases of COVID-19, 188 with confirmed cases of influenza A and 149 with confirmed cases of influenza B, from Wuhan Children’s Hospital were retrospectively studied. COVID-19 patients were hospitalized from January 26 to March 23, 2020, and influenza patients were admitted to the hospital from August 8, 2019, to January 26, 2020. All patients with confirmed COVID-19 recruited in this study were diagnosed by SARS-CoV-2 positivity in RT-PCR according to the World Health Organization interim guidance, and patients with confirmed influenza were diagnosed by the presence of IgM antibody against influenza virus A or B. The clinical information, including treatments, discharge dates and length of stay, was monitored up to March 28, 2020.

Data on epidemiological information, demographic characteristics, clinical manifestations, laboratory results, treatment measures and discharge date were extracted from electronic medical records. Clinical features consisted of the dates of illness onset and admission, symptoms, coexisting conditions and complications. Laboratory tests included a complete blood count, coagulation parameters, C-reactive protein, serum amyloid protein, procalcitonin, liver and renal function parameters, lactate dehydrogenase, lactate dehydrogenase isoenzyme 1, creatine kinase and creatine kinase isoenzyme 1. Treatment measures included oxygen therapy, antiviral agents, antibacterial agents, corticosteroids, budesonide suspension and immunomodulatory agents. All the clinical data were reviewed by team paediatricians. COVID-19 severity was classified according to experts’ consensus statement for COVID-19 in children [11]. Patients with asymptomatic cases were defined as children positive for SARS-CoV-2 without manifestations of clinical symptoms or abnormal chest imaging findings. Patients with mild cases were defined as patients who had only fever, cough, pharyngeal pain, nasal congestion, fatigue, headache, myalgia or discomfort but no abnormal radiological findings. Patients with moderate cases were defined as children who had pneumonia on chest CT with or without fever and respiratory symptoms such as cough but did not meet the criteria for severe pneumonia. Patients with severe cases were defined as those who met any of the following criteria: (1) increased respiratory rate: ≥ 70 times/min for those < 1 year of age or ≥ 50 times/min for those ≥ 1 year of age (after ruling out the effects of fever and crying); (2) oxygen saturation < 92%; (3) hypoxia: assisted breathing (moans, nasal flaring, and three-concave sign), cyanosis, or intermittent apnoea; (4) a disturbance of consciousness: somnolence, coma, or convulsion; and (5) food refusal or feeding difficulty, with signs of dehydration. Patients with critical cases met one of the following criteria and required intensive care unit (ICU) care: (1) respiratory failure requiring mechanical ventilation, (2) shock, or (3) other organ failure.

SARS-CoV-2 nucleic acid testing was performed by the laboratory department of Wuhan Children’s Hospital, and the procedure was the same as that described by Lu et al. [7]. In brief, nasopharyngeal or throat swabs were tested for the presence of SARS-CoV-2 nucleic acid using real-time reverse transcription polymerase chain reaction (RT-PCR). Viral nucleic acids were extracted with the High Pure Viral Nucleic Acid Kit (Zhongzhi, Wuhan, China). The primers for RT-PCR assays were as follows:

forward primer 5′-TCAGAATGCCAATCTCCCCAAC-3′;

reverse primer 5′-AAAGGTCCACCCGATACATTGA-3′; and.

probe 5′ CY5-CTAGTTACACTAGCCATCCTTACTGC-3′ BHQ1.

Amplifications were performed by incubation at 50 °C for 15 min and 95 °C for 3 min, followed by 45 cycles at 95 °C for 15 s and 60 °C for 30 s.

Continuous variables were described as median and interquartile range (IQR) values. The comparison of medians was analysed with the Kruskal-Wallis test. Categorical variables were calculated as the percentages of patients in each category and compared using χ2 or Fisher’s exact tests as appropriate. All statistical analyses were performed in SPSS software version 20.0. Two-sided α values of less than 0.05 indicated statistical significance.

This study recruited 248 paediatric patients with confirmed cases of COVID-19, 188 with confirmed cases of influenza A and 149 with confirmed cases of influenza B. The median ages were 6.96 years (IQR, 2–10.81) for COVID-19 patients, 2.67 years (IQR, 1.03–15.25) for influenza A patients and 3.67 years (IQR, 1.62–5.54) for influenza B patients. The sex ratio of males to females was close to 1.5 in the three groups. Familial clustering was defined based on family infection history, which was recorded in the medical record, and familial clustering of infection occurred in 192 (77.4%) COVID-19 patients (Table 1). Among confirmed COVID-19 cases, 39 (15.7%) patients had coexisting conditions, while the number of children with comorbidities was 67 (35.64%) in the influenza A group and 41 (27.52%) in the influenza B group. The most common comorbidity was leukopenia; other comorbidities included hyperglobulinemia, acute lymphoblastic leukaemia, arrhythmia, tympanitis, central atrial septal defect, rhinitis, convulsion, Kawasaki disease, epilepsy, jaundice, atrial septal defect, epididymitis, acute tonsillitis, acute laryngitis, acute cervical lymphadenitis, acute gastroenteritis, anaemia, eczema, diabetic ketosis, myocarditis, thrombocytopenia, viral encephalitis, infective myositis, cerebral palsy, and thrombocytopenia (Fig. 1).

Fever and cough were the most common symptoms in the three groups, and 86 (34.7%) COVID-19 patients presented with fever, compared to 132 (70.21%) influenza A patients and 111 (74.50%) influenza B patients, and the difference was statistically significant. For paediatric COVID-19 patients, nasal congestion, rhinorrhoea, diarrhoea and vomiting were other common symptoms, and abdominal pain and tachypnoea were less common symptoms. In the influenza groups, phlegm, asthma, sneezing, chills and vomiting were more frequently found as residual symptoms (Table 1). There were 172 (69.36%) mild or moderate COVID-19 cases, and 4 (1.61%) severe or critical cases; these numbers were 171 (90.96%) and 17 (9.04%), respectively, for influenza A and 141 (94.63%) and 8 (5.37%), respectively, for influenza B. In addition, the median duration from the onset of illness to admission was 5 (3–8) days for COVID-19 patients. The median length of stay (LOS) was 11 (8–15) days for paediatric patients with confirmed COVID-19 cases, 4 (3–6) days for those with confirmed influenza A cases and 5 (3–6) days for those with confirmed influenza B cases (Table 1).

Twenty-six (13.98%) influenza A patients and 18 (12.59%) of influenza B patients had decreased white blood cell counts, while 13 (5.33%) COVID-19 patients had decreased white blood cell counts. Eight (3.28%) COVID-19 patients had lymphocytopenia, whereas 23 (12.71%) and 21 (14.79%) influenza A and influenza B patients, respectively, had lymphocytopenia. The percentage of COVID-19 patients with abnormally elevated myocardial enzymes was less than that of influenza paediatric patients (41.95% vs 65.06 and 62.60%, p < 0.0001). For inflammatory markers, the most common abnormities in the three groups were found in the erythrocyte sedimentation rate, hypersensitive C-reactive protein (hsCRP) and serum amyloid A. Serum amyloid A was increased in 13 (16.46%) COVID-19 patients, 64 (85.33%) influenza A patients and 46 (80.70%) influenza B patients (p < 0.0001), and hsCRP was abnormally elevated in 40 (18.60%) COVID-19 patients, 93 (56.71%) influenza A patients and 69 (40.46%) influenza B patients (p < 0.0001) (Table 2).

No statistically significant difference was observed among the three groups in terms of comorbidities. SARS-CoV-2 co-infections with Mycoplasma (40.91%), cytomegalovirus (3.03%), and EB virus (1.99%) were observed, and the corresponding pathogens were detected in 55.42, 3.57 and 4.12% of influenza A patients and in 42.00, 7.03 and 2.24% of influenza B patients, respectively. There was one case of SARS-CoV-2 and influenza A virus co-infection and 4 cases of SARS-CoV-2 and influenza B virus co-infection (Table 2).

Common treatments, including antiviral therapy, antibiotic therapy, the use of corticosteroids and immunoglobulin, aerosol inhalation of interferon-α and budesonide suspension, were sympathetically applied in the studied patients. Among COVID-19 patients, 50 (20.16%) were treated with antiviral drugs, 109 (43.95%) with antibiotic therapy, 235 (94.76%) with interferon-ɑ, and 3 (1.21%) with corticosteroids; 4 COVID-19 patients (1.61%) received intensive care. The percentages of children receiving corticosteroids and intensive care in the influenza group were obviously higher than those in the COVID-19 group, The median length of stay in ICU for children was: 21 days for COVID-19, 8.38 days for Flu A and 13 days for Flu B. Regarding oxygen support, in the COVID-19 group, 3 (1.21%) children required nasal cannulation and 4 (1.61%) children needed invasive mechanical ventilation, while 28 (14.89%) influenza A paediatric patients and 15 (18.12%) influenza B patients received oxygen support with nasal cannulation. The dysfunction of important organs was uncommon in COVID-19 patients. Acute cardiac injury occurred in 18 (7.29%) COVID-19 patents, while 37 (19.68%) influenza A and 27 (18.12%) influenza B patients experienced acute cardiac injury. In total, only one patient in this study died, who was reported to have a severe co-existing disease, intussusception [7], and most of the patients had favourable clinical outcomes (Table 3).