key: cord-0870451-gdzx3vlt
authors: Du, Hui; Dong, Xiang; Zhang, Jin‐jin; Cao, Yi‐yuan; Akdis, Mubeccel; Huang, Pei‐qi; Chen, Hong‐wei; Li, Ying; Liu, Guang‐hui; Akdis, Cezmi A; Lu, Xiao‐xia; Gao, Ya‐dong
title: Clinical characteristics of 182 pediatric COVID‐19 patients with different severities and allergic status
date: 2020-06-10
journal: Allergy
DOI: 10.1111/all.14452
sha: da0505e55b70c7dfcd30a54016957910357548f6
doc_id: 870451
cord_uid: gdzx3vlt

BACKGROUND: The pandemic of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has made widespread impact recently. We aim to investigate the clinical characteristics of COVID‐19 children with different severities and allergic status. METHODS: Data extracted from the electronical medical records, including demographics, clinical manifestations, comorbidities, laboratory and immunological results and radiological images of 182 hospitalized COVID‐19 children were summarized and analyzed. RESULTS: The median age was 6 years old, ranging from 3 days to 15 years, and there were more boys (male‐female ratio about 2:1) within the studied 182 patients. Most of the children were infected by family members. Fever (43.4%) and dry cough (44.5%) were common symptoms, and gastrointestinal manifestations accounted for 11.0%, including diarrhea, abdominal discomfort and vomiting. 71.4% had abnormal chest computed tomography (CT) scan images, and typical signs of pneumonia were ground‐glass opacity and local patchy shadowing on admission. Laboratory results were mostly within normal ranges, and only a small ratio of lymphopenia (3.9%) and eosinopenia (29.5%) were observed. The majority (97.8%) of infected children were not severe, and 24 (13.2%) of them had asymptomatic infections. Compared to children without pneumonia(manifested as asymptomatic and acute upper respiratory infection), children with pneumonia were associated with higher percentages of the comorbidity history, symptoms of fever and cough, and increased levels of serum procalcitonin, alkaline phosphatase and serum interleukins (IL)‐2, IL‐4, IL‐6, IL‐10 and TNF‐α.There were no differences of treatments, duration of hospitalization, time from first positive to first negative nucleic acid testing and outcomes between children with mild pneumonia and without pneumonia. All the hospitalized COVID‐19 children had recovered except one death due to intussusception and sepsis. In 43 allergic children with COVID‐19, allergic rhinitis (83.7%) was the major disease, followed by drug allergy, atopic dermatitis, food allergy and asthma. Demographics and clinical features were not significantly different between allergic and non‐allergic groups. Allergic patients showed less increase in acute phase reactants, procalcitonin, D‐dimer and aspartate aminotransferase levels compared to all patients. Immunological profiles including circulating T, B and NK lymphocyte subsets, total immunoglobulin and complement levels and serum cytokines did not show any difference in allergic and pneumonia groups. Neither eosinophil counts nor serum total immunoglobulin E (IgE) levels showed a significant correlation with other immunological measures, such as other immunoglobulins, complements, lymphocyte subsets numbers and serum cytokine levels. CONCLUSION: Pediatric COVID‐19 patients tended to have a mild clinical course. Patients with pneumonia had higher proportion of fever and cough and increased inflammatory biomarkers than those without pneumonia. There was no difference between allergic and non‐allergic COVID‐19 children in disease incidence, clinical features, laboratory and immunological findings. Allergy was not a risk factor for developing and severity of SARS‐CoV‐2 infection and hardly influenced the disease course of COVID‐19 in children.

children with pneumonia and without pneumonia (asymptomatic and AURI), in aspects of clinical features, 20 laboratory findings, immunological changes and outcomes, were not reported. In addition, the allergy status, 21 and the information of the allergic diseases-related laboratory findings of these patients, have not been 22 reported yet. Allergic diseases are common and with increasing prevalence in children. [14] [15] [16] Previous studies 23 showed virus infection is one of the triggers for the exacerbation of asthma. 17 However, there was limited 24 information about the association between asthma and coronaviruses infection, especially SARS-CoV and 25 Middle East respiratory syndrome coronavirus (MERS-CoV) . 18, 19 Most animal models established for the 26 research of SARS-CoV and MERS-CoV are also found less relevant to asthma. 20 On the other hand, atopic 27 sensitization had no effect on the severity of viral pneumonia in children, as shown in a multi-center

This article is protected by copyright. All rights reserved 28 prospective study, butthehistoryof allergic diseases such as atopic dermatitis, food allergy and drug allergy 29 were associated with severe pneumonia. 21 In a previous study on 140 adult COVID-19 cases, allergic 30 diseases and asthma showed much less prevalence compared to population levels, suggesting that allergy is 31 not a predisposing factor for SARS-CoV-2 infection. 22 32 This study aims to investigate the clinical and laboratory characteristics of hospitalized pediatric patients, and to reveal the relationship between SARS-CoV-2 infection, immune response and 34 allergic status, with a special focus on disease severity and allergy in patients. 23 it should be noted that part of our cases had been reported concisely in a previous correspondence 46 paper about the main clinical, laboratory and radiological findings. 8 This study was approved by the 47 institutional ethics board of the Wuhan Children's Hospital (Approval No. WHCH 2020003) . 48 Data comprised of demographic information, clinical presentation, medical history and comorbidities, chest 49 computed tomography (CT) images, laboratory results, treatments (medications and oxygen therapy) and 50 outcomes were obtained from the medical records system and checked by two independent researchers. 51 Thedurationofhospitalization, andthe time of RT-PCR conversion (daysfromthefirstpositiveresultto the first 52 negative result of RT-PCR assays for SARS-CoV-2 nucleic acid), were also calculated. In particular, the

This article is protected by copyright. All rights reserved 53 information of previously diagnosed allergic diseases or related, including allergic rhinitis (AR), asthma, 54 atopic dermatitis (AD), urticaria, and food/drug allergy, and known allergens were collected, and 55 reconfirmed by telephone enquiries. 56 The severity of COVID-19 was also recorded according to the Chinese expert consensus on the diagnosis, 57 treatment and prevention of SARS-CoV-2 infection in children (2nd Version). 13 Severe cases were 58 identified when meeting one of the following criteria: (a) shortness of breath with increased respiratory rate 59 (RR) except for the influence of fever and crying (RR ≥ 60 breaths per minute for those younger than 2 60 months, RR ≥ 50 breaths per minute for those aged between 2 and 12 months, RR ≥ 40 breaths per minute 61 for those aged between 1 and 5 years, and RR ≥ 30 breaths per minute for those older than 5 years); (b) 62 oxygen saturation ≤ 92% at rest; (c) hypoxia with accessory respiration (groaning, flaring of nares, three 63 concave sign), cyanosis, and intermittent apnea; (d) disturbance of consciousness with somnolence and 64 convulsions; (e) food refusal or feeding difficulty, with signs of dehydration; (f) high-resolution CT 65 showing bilateral or multi-lobe involvement, with rapid aggressiveness or pleural effusion. Critical type 66 patients should meet one of the following conditions and admit to intensive care unit (ICU): (a) respiratory 67 failure with mechanical ventilation required; (b) shock; (c) complications with other organ failures. Patients 68 who only had mild symptoms without pneumonia changes in chest CT images were referred to as the acute 69 upper respiratory infection (AURI) type, and those who had COVID-19 pneumonia not meeting the above 70 criteria of severe cases as the mild type. Individuals only positive for SARS-CoV-2, without any symptoms 71 or changes in chest CT images were defined as asymptomatic (inapparent) infection. 72

Specimens of nasopharyngeal swabs from children younger than 2 years old and throat swabs from children 74 2 years or older were obtained for detection of SARS-CoV-2 nucleic acid using RT-PCR assay. The testing 75 was performed in the clinical laboratory of the Wuhan Children's Hospital, and the detailed protocol had 76 been described previously. 8 77 Some routine laboratory results were collected from the clinical testing reports, including the complete 78 blood count (CBC), and serum levels of biomarkers such as inflammatory indicators of C-reactive protein

This article is protected by copyright. All rights reserved 79 (CRP) and procalcitonin (PCT), the coagulation index of D-dimer, the myocardial injury marker of creatine 80 kinase (CK)-MB, the liver function of alanine aminotransferase (ALT), aspartate aminotransferase (AST) 81 and alkaline phosphatase (ALP), and the renal function of serum creatinine and blood urea nitrogen (BUN Accepted Article children, and the majority (83.5%) were 10 years and younger. There were more boys who got infected, 105 with the male-female ratio of nearly 2:1. Most of the children were infected through family members, such 106 as parents and/or grandparents. Forty-three children had the history of allergic diseases, including AR, 107 asthma, AD, food allergy, drug allergy and urticaria. Other pre-existing diseases included repetitive or 108 annual pneumonia, frequent colds, adenoid hypertrophy, tonsillitis, etc. (Table 2) . 109 Although the common symptoms in pediatric COVID-19 patients were fever (43.4%) and dry cough 110 (44.5%), almost one third (30.2%) of these children were asymptomatic. In addition, gastrointestinal 111 symptoms accounted for a perceptible proportion (11.0%), such as diarrhea, abdominal discomfort and Figure 2) , with the incidence of 28.0% and 27.5%, respectively, whereas the pulmonary consolidation was 127 much less (1.6%). It was worth noting that there were also 52 (28.6%) infected children without any 128 changes in chest CT images. Thus, the concurrence of normal chest CT scan and no symptom contributed 129 to 24 cases of asymptomatic infection, in the ratio of 13.2% (Table 1) .

This article is protected by copyright. All rights reserved 130 The median values of laboratory results were mostly within normal ranges, and the details were listed in 131 

As shown in Table 2 , the most common allergic disease was allergic rhinitis (36, 83.7%), followed by 145 atopic dermatitis, food allergy, asthma and urticaria. Only one child, a 13-year-old boy, was previously 146 diagnosed with asthma. Ten(23.3%) children had self-reported allergy to drugs, all of which were penicillin. 147 Among allergic children,9 (20.9%) hadmore than one kind of allergic diseases.Other few reported allergens 148 included dust mites, eggs and mangos, each in one child. 149 In comparison of COVID-19-related measurements between allergic and non-allergic children, no 150 statistical difference was found in the demographics, clinical features and disease course (Table 1 ). Blood 151 cell counts and biochemical results were mostly similar between two groups, except that eosinophils counts, 152 and serum levels of PCT, D-dimer and AST were lower in allergic group (p < 0.05), but these 153 measurements were all in normal ranges, without clinical relevance ( (Table 4) . 159 Thelymphocytesubsetswerenotfoundsignificantlydifferentbetweentheallergicandnon-allergicCOVID-19 160 children (Table 4 ), as well as between patients with and without pneumonia ( Table 6 ). The results of 161 correlation analysis between immunological parameters were displayed in Figure 

174 Fifty-four infectedchildren did notdeveloppneumonia, including 24 asymptomatic infections and 30 cases 175 with AURI, and they were compared to patients with mild pneumonia ( 

This article is protected by copyright. All rights reserved 183 and 10, TNF-α and IFN-γ) were higher, and the level of IgG was lower, in mild pneumonia group than 184 those in non-pneumonia group (p < 0.05), though most of them were in normal ranges. Other clinical and 185 laboratory parameters were not found different between the two groups. 186 There was only one severe case and three critically ill cases, which were individually described in Table 7 . 187 Three of them were male and one was female. Patient 1 was a 13 years and 5 months old boy, who had a 188 close contact with confirmed COVID-19 family members, his mother and grandparents. He was allergic to 

Given the physiological and immunological differences of younger and older children, we divided the cases 206 into two groups according to ages and compared the clinical features and laboratory results of them (Table   207 S3 and S4). Children aged 10 years or older experienced more fatigue and had more GGO lesions in chest 208 CT images (p < 0.05), but there remained more individuals to be further observed. The differences in

This article is protected by copyright. All rights reserved 209 several laboratory parameters were likely to be induced by their own changes with age, and the most results 210 were in normal ranges without clinical significance. In addition, there was no difference in the prevalence 211 of allergic diseases between the two age groups. Moreover, there was no difference in the proportion of 212 children with possible co-infections, such as MP, between children <10 years and children ≥10 years.

213 214

In 182 pediatric COVID-19 patients, the most common symptoms were fever and dry cough, consistent 216 with other reports. 25 A slightly male dominance was found in these patients, which was close to that 217 reported in the USA 26 and China. 27 Most children were infected by family cluster, as observed previously 28 , 218 which was different from that of adults who were infected during social activities. As for those with 219 abnormal CT images, ground glass opacity and patchy shadowing were the most common features, and 220 consolidation was rare in pediatric patients when compared to adult patients.

The proportion of patients with allergies andasthma in the current study was 23.6% ( which remains to be further observed and studied with more evidences. 

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SARS-CoV-2 infection in children

Allergic diseases and asthma

Trends in allergy prevalence among children aged 0-17 407 years by asthma status

Pediatric allergy and immunology in China

Accepted Article This article is protected by copyright. All rights reserved

T cells (/μl

Measurements of laboratory parameters are shown as median (IQR), and proportions of changes are shown as fractions and percentages

Ig, immunoglobulin; CD, cluster of differentiation; NK, natural killer (cells)

Tumor necrosis factor; p values denote the comparison between the subgroup without pneumonia and the subgroup with mild pneumonia

COVID-19, coronavirus disease

MODS, multiple organ dysfunction syndrome

Ig, immunoglobulin; CD, cluster of differentiation; NK, natural killer (cells)

Tumor necrosis factor

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This article is protected by copyright. All rights reserved B cells (/μl; 240-1317) 562 (397-723) 643 (352-936) 0.620

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