Clinical Feature Difference of Children and Adults in Covid-19 Infected Family Clusters in Shenzhen China: A Retrospective Cohort Study

Introduction: An outbreak of novel coronavirus disease (COVID-19) had posed an unprecedented emergency to public health. Documented information on clinical features in infected households comprising pediatric and adult patients was scarce. Methods: We retrospectively retrieved clinical data of family clusters with confirmed COVID-19 in Shenzhen city, China. Clinical features and treatment outcome were compared between these children and adults. Results: Of 433 laboratory-confirmed COVID-19 cases in Shenzhen from January 15 to March 20, 2020, 29 family clusters of 29 children (median age 7.17 years) and 54 adults (median age 40 years) were identified. 84% of patients had Hubei exposure two weeks before the onset of symptoms. On presentation, common symptoms were fever (35%), dry cough (34%) and fatigue (24%) for children and fever (59%), dry cough (30%), fatigue (30%) and dyspnea (20%) for adults. Lymphocytopenia was not observed in children but 35% adults. Radiographic findings revealed viral pneumonia in 45% children and 78% adults. No children and 30% adults needed oxygen therapy. Two adults required invasive mechanical ventilation, of them one died. The median time from illness onset to absence of symptoms and viral replication duration was 6.5 days vs 13 days, and 12 days vs 14 days in children and adults, respectively. Interpretation: In comparison to adults, children had milder clinical manifestations, less immune-related organ injury and shorter viral replication cycle. The age-specific immune difference seems to favor children more in developing less severe clinical conditions and clearing the virus faster.

family [1]. Most coronavirus infections in children used to be mild and were able to be resolved quickly, even in cases of severe illness caused by Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Most reported fatal cases in children with MERS and SARS were caused by underlying comorbidities [2][3][4]. Numerous studies of COVID-19 infection among infants and children have been reported since the outbreak [5][6][7][8], but no studies have compared the clinical and virological course and treatment outcomes among pediatric and adult patients in infected household settings. In this study, we retrospectively analyzed the clinical course and treatment outcome of all laboratory-confirmed COVID-19 family clusters from Jan 15, 2019 to Mar 20, 2020 in Shenzhen City, China.
We aim to describe the clinical difference between children and their simultaneously SARS-CoV-2-infected adult family members.
We hope our study findings can provide some insights in clinical management of infected pediatric and adult patients, and disease containment measure for COVID-19.

Study Design and Participants
Shenzhen is a city of 12.5 million registered population in 2017 and is located at Southern China [9]. From January 15 to March 20, 2020, 433 patients with laboratory-confirmed COVID-19 were admitted to The Third People's Hospital of Shenzhen, the only designated hospital for COVID-19 treatment in the city. Among these patients, 83 (29 children ≤14 years and 54 adults) were family infections, accounting for 19% of the total confirmed infection in the city. Each child was residing with at least one infected adult parent. Some of these households had three generations living under the same roof and being infected together. This retrospective cohort study enrolled these 29 families. The study was approved by the Research Ethics Commission of The Third People's Hospital of Shenzhen (No.2020-120) and the requirement for informed consent was waived by the Ethics Commission as part of a public health outbreak investigation.

Data Collection
These patient's epidemiology linkage to Hubei province, sociodemographic characteristics, medical history, clinical features, comorbidities, complications, hospital duration and treatment outcomes were retrospectively collected using a standardized data collection form. All data were checked by two physicians (PZ and ZZ) and a third researcher (JW). Exposure to Hubei province, the place where the COVID-19 epidemic started was defined as residing in or visiting Hubei or have close contact with visitors from Hubei within two weeks before the onset of infection symptoms. Clinical features were reported in the form of symptoms at admission, clinical type classification, diagnosis, chest imaging and laboratory findings. Treatment outcomes were recorded as cured and death.

Laboratory Procedures
Nasopharyngeal swabs were collected for diagnosis at admission. Reverse transcriptionpolymerase chain reaction (RT-PCR) testing was performed according to the recommended protocol to detect SARS-CoV-2. Diagnosis of infection was confirmed when positive test results were attained from both hospital laboratory and local branches of the Centers for Disease Control and Prevention.Blood examinations and chest radiographs were routine procedures and were completed at admission. Tests were arranged for all patients on blood cell count, serum biomarkers (including renal and liver function and electrolytes), D-Dimer, C-reactive protein and procalcitonin. Frequency of re-examinations was determined by the treating physician. Throat-swab specimens were obtained for SARS-CoV-2 RT-PCR re-examination every other day after symptoms remission. The criteria for hospital discharge were absence of fever and respiratory symptoms for at least three days, substantial improvement in both lungs in X-ray or chest CT, and two throat-swab samples and one anus-swab sample negative for SARS-CoV-2 RNA obtained at least 24 h apart.

Definitions
Children are defined as below 18 years of age. Fever is defined as axillary temperature of equal to or above 37•3°C. On admission, all patients were assessed and classified into one of these four clinical types according to the Chinese management guideline for COVID-19 (version 6.0) [10]. Critical type is used to classify patients who need intubation and mechanical ventilation, with sepsis or septic shock; severe type is used to classify patients whose arterial oxygen tension (PaO 2 ) over inspiratory oxygen fraction (FiO 2 ) is less than 300mm Hg (PaO 2 /FiO 2 <300mm Hg) and need oxygen therapy and invasive ventilation; moderate type refers to patients with flu symptom with lung infiltration but PaO 2 /FiO 2 >300; mild type refers to patients with flu symptom without lung infiltration.
Lymphocytopenia is defined as lymphocyte count of less than 1.1*10 9 /L.

Statistical Analysis
Continuous variables are expressed as mean (± SD) and median

Difference in Clinical Features Between Children and Adults
Median age was 7.17 years (IQR 1.58-13.0) for the 29 children and 40.0 years (IQR 34.0-57.0) for the 54 adults in this cohort.
In terms of comorbidities, one (3%) child had asthma and one (3%) had chronic pharyngitis, seven (13%) adults suffered from diabetes and five (9%) from hypertension. In terms of clinical type classification, all children were in the mild and moderate categories. 69% adults were classified as moderate, 19% severe, 2% critical.
Significant difference was shown between children and adults in clinical type categorization (P=0.004) ( Table 1).

Difference in Laboratory and Radiographic Findings Between Children and Adults
Blood routine test results for white blood cell count were normal in all COVID-19 children. Lymphocytopenia was not observed in children (0%) but in 19 (35%) adults. Blood biochemistry test result abnormality for liver function (including albumin and aminotransferase) was unremarkable among all children and adults with COVID-19. No procalcitonin elevation of more than 0.5ng/ml was observed in children. Elevated C-reactive protein (CRP) and D-Dimer was seen in 28 (52%) and 18 (33%) adults, respectively.
Significant difference was observed in serum creatinine level and radiographic findings between children and adults (P=0.001) ( Table 2).

Difference in Treatment and Clinical Outcome Between Children and Adults
No administration of antibiotics, steroid or gamma globulin was needed for children. Two (4%) adults were on antibiotics and ten (19%) had been given immunoglobulin and methylprednisolone.
No children required oxygen therapy, but 16 (30%) adults did. when this manuscript was being prepared (Table 3).  Previous studies suggested that SARS-CoV-2 was less likely to infect children [14][15][16]. There were only a small number of confirmed cases in children compared to adults, even in the epicenter at the time of disease outbreak [5,6]. Most documented literature showed that a substantial proportion of children with COVID-19 were either asymptomatic or only manifested mild fever and prominent upper respiratory tract symptoms with a much lower mortality rate than adults [17]. Progression to respiratory or organ failure and death cases were rare but had been reported in China as early as February and other places of the world afterwards [18].
In our study, all pediatric patients acquainted COVID-19 through family infection. Contact tracing showed a rather straightforward infection source with 83% children and 84% of the enrolled patients in this study reported Hubei-related exposure 2 weeks before the onset of symptoms. But in contrast to adults, clinical symptoms of pediatrics were mild, even among those with underlying comorbidities (chronic pharyngitis and asthma). Viral pneumonia indicated by mild ground-glass opacities in bilateral lungs were observed in 45% (13) children. None of them progressed to ARDS or other complications. This was like other HCoV infection in children [2,3,19]. The lack of prominent clinical symptoms on disease onset in pediatric patients suggests that they could be a threat in the transmission chain which is a crucial concern in disease management regimen designs.
Older age has been reported a risk factor for mortality in patients with SARS, MERS and COVID-19 in several studies [20,21]. Immune over reaction and T cell exhaustion were demonstrated in patients with sepsis and other life-threatening infections [23].
Lymphopenia is an important sign of T cell exhaustion [24].
Progressive lymphopenia had been reported a risk factor for Intensive Care Unit admission and mortality of adult patients with COVID-19 [13,21]. Progressive drop in lymphocyte count was obvious in patients with severe and critical clinical types. In the case of the deceased patient in this study, progressive lymphopenia had been recorded since the patient was hospitalized. The patient's clinical conditions deteriorated rapidly with an acute progression to ARDS. Even with invasive mechanical ventilation the patient still failed treatment and died. Our study showed that lymphocyte count between children and adult differed significantly, despite the physiological difference. None of the children but 35% adults exhibited lymphopenia. This might attribute to the prolonged illness and viral shedding in adults. In addition, some inflammationrelated biomarker such as CRP and D-Dimer elevated in adults but not in children during the treatment process. D-dimer greater than 1μg/ml at early stage of illness onset had been identified with poor prognosis in adults [21]. The level and duration of viral replication on the upper respiratory tract are vital factors in assessing the risk of transmission. A study reported that detectable SARS-CoV-2 RNA persisted for a median duration of 20 days in adults infected with COVID-19 and sustained until death of the host cell in non-survivors [21]. In the current study, the length of viral replication also lasted longer in adults than children (14 days vs 12 days). Though certain medications demonstrated effective treatment outcome [25][26][27], no specific antiviral medications have been proven to be effective in clinical trials for this novel coronavirus infection as of to date.
Our study has some limitations. First, no complete genotype was available for every family. The transmission model of the virus in the families was not clear, whether children or adults were the source of transmission was difficult to determine. Second, this is a modest-sized case series of children and their family admitted to a single center. As all children had mild symptoms, it is difficult to take blood test frequently to assess their immune reaction at different time points. Third, how antibody titers changed during the clinical course in all these patients was not available. More effort should be made to address these areas in future studies.Observing from our study, children are equally susceptible to contracting COVID-19 as adults, but pediatric patients had milder symptoms, less immunerelated organ injury and shorter viral replication cycle than adults when being infected. More medical attention could be diverted to elderly patients and patients with pre-existing medical conditions to decrease fatality especially in places with shortage in medical resources. In the absence of specific therapeutic drugs or vaccines for COVID-19, we believe it is noteworthy to find out the potential correlation between different age specific immune state for hostdirected interventions to improve treatment outcomes in adults.