Edited by: Christoph Aebi, University Children's Hospital Bern, Switzerland
Reviewed by: Danilo Buonsenso, Catholic University of the Sacred Heart, Italy; Mark A. Travassos, University of Maryland, Baltimore, United States
This article was submitted to Pediatric Infectious Diseases, a section of the journal Frontiers in Pediatrics
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
An outbreak of the novel coronavirus disease 2019 (COVID-19) occurred in Wuhan, China, in December 2019, which then rapidly spread to more than 80 countries. However, detailed information on the characteristics of COVID-19 in children is still scarce. Five patients with non-respiratory symptoms as the first manifestation were hospitalized from the emergency department, and were later confirmed to have COVID-19, between 23 January and 20 February 2020, at the Wuhan Children's Hospital. SARS-CoV-2 nucleic acid detection was positive for all the patients. Four of the patients were male and one was female, and their ages ranged from 2-months to 5.6 years. All lived in Wuhan. One patient had a clear history of exposure to SARS-CoV-2, one had a suspected history of exposure, while the others had no exposure history. For three of the five patients, the primary onset disease required an emergency operation or treatment, and included intussusception, acute suppurative appendicitis perforation with local peritonitis, and traumatic subdural hemorrhage with convulsion, while for the other two it was acute gastroenteritis (including one patient with hydronephrosis and a stone in his left kidney). During the course of the disease, four of the five patients had a fever, whereas one case had no fever or cough. Two patients had leukopenia, and one also had lymphopenia. In the two cases of severe COVID-19, the levels of CRP, PCT, serum ferritin, IL-6, and IL-10 were significantly increased, whereas the numbers of CD3+, CD4+, CD8+ T lymphocytes, and CD16 + CD56 natural killer cells were decreased. We also found impaired liver, kidney, and myocardial functions; the presence of hypoproteinemia, hyponatremia, and hypocalcemia; and, in one case, abnormal coagulation function. Except for one patient who had a rotavirus infection, all patients tested negative for common pathogens, including the influenza virus, parainfluenza virus, respiratory syncytial virus, adenovirus, enterovirus, mycoplasma, Chlamydia, and Legionella. Chest CT images of all the patients showed patches or ground-glass opacities in the lung periphery or near the pleura, even large consolidations. This case series is the first report to describe the clinical features of COVID-19 with non-respiratory symptoms as the first manifestation in children.
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A novel coronavirus was identified in December 2019 in Wuhan, Hubei Province, China, following a series of pneumonia cases of unknown etiology in people with a history of exposure to the Huanan seafood market (
Similar to that observed for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), COVID-19 in children has low morbidity, and most either develop mild symptoms or are asymptomatic. The few severe cases have usually exhibited underlying or coexisting medical conditions (
In this report, the clinical stage of the patients was classified according to “diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement” (
A 10-month-old female infant was admitted to the hospital from the emergency department with suspicion of intussusception, presenting with paroxysmal crying and restlessness, vomiting, and currant jelly-like stool for 30 h (
Epidemiology and clinical characteristics of five COVID-19 cases.
Age (y/m) | 10 m | 5.6 y | 8 m | 1.2 y | 2 m |
Exposure history | No | Grandmother confirmed | No | No | Parents and grandparents suspected |
First clinical manifestation | Paroxysmal crying, vomiting, currant jelly-like stool | Abdominal pain | Convulsion | Vomiting, diarrhea | Drowsiness and poor feeding, diarrhea |
Time from illness onset to fever | 30 h | 2 days | 6 h | 5 days | — |
Fever at presentation or prior to presentation | At presentation | No | At presentation | At presentation | No |
Highest temperature (°C) during the course | 39.8 | 39 | 38.5 | 37.9 | — |
Days from illness onset to admission | 1.25 | 2 | 0.25 | 6 | 3 |
Underlying or coexisting disease | Intussusception | Acute suppurative appendicitis perforation with localized peritonitis | Traumatic brain injury | Hydronephrosis and stone in the left kidney, rotavirus infection | No |
Complications | Shock; MODS (liver, kidney, myocardium, blood coagulation, intestinal); acute respiratory failure | No | No | Acute respiratory failure; acute heart failure; shock; MODS (liver, kidney, myocardium) | Myocardium function damaged |
Antiviral therapy | Intravenous ribavirin, aerosol inhalation of interferon | Aerosol inhalation of interferon | Intravenous ribavirin, aerosol inhalation of interferon | Intravenous ribavirin, aerosol inhalation of interferon | Aerosol inhalation of interferon |
Methylprednisolone | 2 mg/(kg·d) × 5d | No | No | 2 mg/(kg·d) × 3d | No |
Intravenous immunoglobulin | 500 mg/(kg·d) × 3d | No | No | 500 mg/(kg·d) × 4d | No |
Oxygen inhalation | Nasal cannula | No | Nasal cannula | Nasal cannula | No |
Invasive mechanical ventilation | Yes | No | No | Yes | No |
Blood purification | PE+CRRT | No | No | PE+CRRT | No |
Length of stay (days) | 36 | 10 | 14 | 17 | 15 |
Outcomes | Died | Cured | Cured | Cured | Cured |
Laboratory findings of the five cases.
White blood cell count, × 109/L | 5.5–12 | 3.27 | 3.79 | 18.16 | 11.96 | 7.36 |
Neutrophil count, × 109/L | 1.08–5.9 | 2.08 | 1.2 | 8.14 | 7.77 | 1.86 |
Lymphocyte count, × 109/L | 1.15–6 | 1.06 | 2.01 | 8.93 | 2.48 | 4.2 |
Platelet count, × 109/L | 100–378 | 29 | 247 | 386 | 184 | 338 |
Urine analysis | PRO3+, BLD3+ | Normal | Normal | PRO±, BLD3+ | — | |
Stool routine | Positive occult blood | Normal | Normal | Positive occult blood | Loose stool | |
CRP, mg/L | 0–3 | 202 | 5.01 | 24.8 | 69.1 | 5 |
PCT, ng/mL | ≤ 0.05 | >100 | 0.46 | 0.09 | 2.66 | — |
Serum ferritin, ng/mL | 12–135 | 1179.11 | — | 30.3 | 1796.8 | — |
IL-2 | 0–11.4 | 1.75 | — | 2.00 | 1.32 | 1.43 |
IL-4 | 0–12.9 | 3.01 | — | 3.78 | 3.37 | 0.86 |
IL-6 | 0–20.9 | 3868.86 | — | 70.83 | 177.86 | 7.06 |
IL-10 | 0–5.9 | 326.93 | — | 6.68 | 26.85 | 8.45 |
TNF-α | 0–5.5 | 2.15 | — | 2.08 | 3.52 | 1.01 |
IFN-r | 0–17.3 | 16.98 | — | 3.74 | 2.26 | 8.35 |
Albumin, g/L | 35–50 | 20.9 | 46.7 | 41.2 | 31.8 | 39.1 |
Alanine aminotransferase, U/L | 9–52 | 375 | 20 | 50 | 54 | 21 |
Aspartate aminotransferase, U/L | 15–46 | 1,093 | 31 | 50 | 124 | 46 |
Blood urea nitrogen, mmol/L | 2.5–6.1 | 22.84 | 5.94 | — | 15.91 | 2.00 |
Creatinine, μmol/L | 46–92 | 206.3 | 24.5 | — | 224.5 | 17.7 |
K+ | 3.5–5.1 | 3.49 | 4.05 | 4.09 | 5.46 | 4.59 |
Na+ | 137–145 | 133.6 | 138.2 | 136.6 | 129.2 | 136.9 |
Cl− | 98–107 | 104 | 100.1 | 98.7 | 94.7 | 97.3 |
Ca2+ | 2.1–2.55 | 1.32 | 2.39 | 2.27 | 1.87 | 2.55 |
Lactate dehydrogenase, U/L | 161–371 | 3,171 | 242 | 363 | 751 | 562 |
Creatine kinase, U/L | 30–170 | 20,702 | 84 | 107 | 177 | 97 |
Creatine kinase—MB, U/L | 0–24 | 840 | 14 | 41 | 98 | 90 |
Troponin (ng/mL) | 0–0.014 | 0.007 | — | 0.01 | 0.272 | — |
NT-proBNP (pg/mL) | 0–300 | >9,000 | — | 395 | >9,000 | — |
PT, s | 10.2–13.4 | 22.1 | 11 | 11.2 | 14.3 | 9.6 |
APTT, s | 25.7–39 | 76 | 30.3 | 31 | 31.8 | 47.7 |
Fibrinogen, g/L | 2–4 | 3.08 | 2.1 | 2.89 | 2.47 | 2.45 |
D-dimer, mg/L | 0–0.55 | 40.34 | — | — | — | 1.18 |
CD3+T | 805–4459 | 268 | — | 5,643 | 705 | — |
CD8+T | 314–2080 | 102 | — | 1,869 | 318 | — |
CD4+T | 345–2350 | 155 | — | 3,110 | 342 | — |
CD16+CD56 NK | 210–1514 | 11 | — | 1,695 | 6 | — |
CD19+B | 240–1317 | 820 | — | 9.21 | 1,180 | — |
CD4+/CD8+T (Th/Ts) | 0.96–2.05 | 1.52 | — | 1.66 | 1.07 | — |
Common pathogens | Neg | Neg | Neg | Rotavirus | Neg |
Chest CT images for case 1 showing a small dense shadow in the left lung on day 4 after symptom onset
A 5.6 year-old boy was admitted to the hospital for acute suppurative appendicitis perforation with localized peritonitis accompanied by continuous lower right abdominal pain for 2 days (
Chest CT images for case 2 showing a round-like mass shadow in the dorsal segment of the lower right lobe with a slight ground-glass opacity on the edge, a strip shadow in the local area of the left lower lobe, and an arc dense under the bilateral pleura on day 3 after symptom onset
An 8-month-old male infant came to the emergency department because of a 6 h episode of intermittent convulsion (
Chest CT images for case 3 showing a patchy dense shadow in the posterior part of the left lung with a blurred boundary on day 2 after symptom onset
A 1.2 year-old boy was transferred directly from the emergency department to the PICU because of intermittent diarrhea, vomiting for 6 days, and fever, lethargy, and shortness of breath for half a day in the emergency observation room (
Chest CT images for case 4 showing a large dense shadow with some consolidation in the right lung and a few high-density shadows in the upper lobe of the left lung on day 6 after symptom onset
A 2-month-old male infant came to the emergency department because of drowsiness and poor feeding for 3 days, and diarrhea for 2 days (
Chest CT images for case 5 showing bilateral scattered spots of shadows and consolidation in the upper right lobe on day 3 after symptom onset
Wuhan Children's Hospital was the first to be assigned, by the government, for the treatment of children with COVID-19 in Hubei Province, China. During the outbreak, only the fever clinic and emergency department were open for outpatients. All outpatients required pre-examination and a triage system was employed. All medical staff in the emergency department took the required level 2 protective measures. If emergency endotracheal intubation or sputum suction was necessary, level 3 protective measures were to be taken.
The five cases were interesting because the patients initially had no respiratory symptoms at presentation; instead, they had to seek medical advice for unrelated problems in the emergency department. Three of the cases (cases 1, 2, and 3) had to be admitted to the hospital for an emergency operation or treatment. Cases 4 and 5 mainly showed gastrointestinal symptoms at the onset of illness. Case 4 was transferred directly from the emergency department to the PICU in a critical condition. Case 5 was a 2-month-old infant without a fever or cough, whose parents reported that the infant displayed drowsiness and had poor feeding. Among the 5 cases, only case 2 had a clear history of exposure to COVID-19, case 5 had a suspected contact history, while the others had no clear exposure history. The onset symptoms of these patients may not have been related to SARS-CoV-2 infection, or, the symptoms of SARS-CoV-2 infection were relatively hidden or mild before COVID-19 was confirmed. It is also possible that the initial medical and contact history provided by the parents was insufficient for an accurate determination of COVID-19 diagnosis. However, all the cases had pneumonia confirmed by chest CT scan before or soon after admission. Because the pneumonia could not be explained by their primary disease and given that COVID-19 was breaking out in Wuhan, the infants were immediately isolated and tested for SARS-CoV-2 by nucleic acid RT-PCR. The five patients were all infected with the virus.
Most children infected with SARS-CoV-2 show mild clinical manifestations and recover within 1–2 weeks after disease onset (
Seven coronaviruses are known to cause disease in humans. Of these, HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 usually cause mild upper respiratory symptoms, and rarely cause serious disease. SARS-CoV and MERS-CoV infections can lead to severe lower respiratory tract symptoms with acute severe respiratory syndrome. SARS-CoV-2 belongs to the betacoronaviruses and can also infect the lower respiratory tract and cause pneumonia. The mortality rate associated with COVID-19 is generally lower than that of SARS and MERS (
Similar to adults (
Importantly, four of the five cases had digestive tract symptoms as the first manifestation. Wang et al. reported that 10.1% of adult COVID-19 patients initially presented with diarrhea and nausea 1 to 2 days before the development of fever and dyspnea (
Similar to that observed for SARS and MERS, children infected with SARS-CoV-2 exhibit relatively mild symptoms and the incidence of infection is lower than in adults. Although the specific reasons are not clear, it has been suggested that this might be related to an immature immune system in children (
Studies on adults have shown that severe cases of COVID-19 are often accompanied by underlying conditions (hypertension, diabetes, cardiovascular disease, cerebrovascular disease) (
The outbreak of SARS-CoV-2 is a major challenge for clinicians. The pathogenesis of COVID-19 remains to be elucidated and there is no effective antiviral treatment to date (
Our study had some limitations. First, all five cases were confirmed by detection of SARS-CoV-2 nucleic acid in throat swab samples, and false-positive results can occur. We did not test other samples of the patients (such as stool and blood). However, through a combination of exposure history, clinical manifestations, and chest CT scan results we could were reasonably certain that these five cases were confirmed with SARS-CoV-2 infection. Second, owing to the sudden outbreak of COVID-19, SARS-CoV-2 detection kits were in short supply, and some of the patients could not be immediately tested. The sensitivity and specificity of the kits can also differ, which can lead to false-positive or false-negative results. We are certain that four of the five patients in this case series had SARS-CoV-2 infection before admission. Patient 4 was tested three times for SARS-CoV-2 after admission, and only tested positive the third time and it was unclear whether SARS-CoV-2 infection occurred before or after admission. However, he had fever and shortness of breath for half a day in the emergency observation room. Although he had no other respiratory symptoms, we immediately decided to perform a chest CT scan before admission and found some consolidation in the images (
Based on our experience, in regions with significant COVID-19 incidence, we suggest consideration of an approach similar to that in our hospital, with SARS-CoV-2 nucleic acid testing and chest CT scans carried out for children with COVID-19 exposure history and/or fever. All suspected and confirmed patients should be admitted to isolation wards. If there is no fever or exposure history, a pediatric patient with gastrointestinal symptoms may not need to be screened for COVID-19, particularly if testing kits are limited.
In brief, COVID-19 in children is relatively occult or mild, and it is easy to miss the diagnosis in the early stages when present with a non-respiratory disease. Severe COVID-19 can also occur in children with underlying or coexisting diseases. In epidemic areas, the possibility of SARS-CoV-2 infection should be suspected when children show digestive tract symptoms, especially with fever and/or exposure history.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
The studies involving human participants were reviewed and approved by Institutional ethics board of Wuhan children's Hospital Affiliated to Tongji Medical College of Huazhong University of science and technology. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
XC designed the study, drafted the initial manuscript, reviewed, and revised the manuscript. YM, SL, YC, and ZR designed the data collection instruments, collected data, and reviewed and revised the manuscript. WL designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
coronavirus disease 2019
severe acute respiratory syndrome coronavirus 2
World Health Organization
the International Committee on Taxonomy of Viruses
Middle East respiratory syndrome coronavirus
computed tomography
pediatric intensive care unit
natural killer
continuous renal replacement therapy
C-reactive protein
procalcitonin
prothrombin time
activated partial thromboplastin time
interleukin
electroencephalogram
angiotensin converting enzyme 2.
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