key: cord-0826845-60zq5dkw
authors: Önal, Pınar; Kılınç, Ayşe Ayzıt; Aygün, Fatih; Durak, Cansu; Çokuğraş, Haluk
title: COVID‐19 IN Turkey: A tertiary center experience
date: 2020-11-15
journal: Pediatr Int
DOI: 10.1111/ped.14549
sha: d3700d5df789a1c9991d3bd40d9a58ee31a20df3
doc_id: 826845
cord_uid: 60zq5dkw

BACKGROUND: The severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) has been causing a serious epidemic in our country and all over the world since December 2019 and has become a global health problem. The disease caused by the SARS‐CoV‐2 virus has been named as coronavirus disease 19 (COVID‐19). METHODS: We report on the epidemiological and clinical features of 37 children diagnosed with COVID‐19. RESULTS: The median age was 10 years, and 57.1% of the children were male. In addition, 78.3% of the children had histories of contact with adult patients who had been diagnosed with COVID‐19, and 27.0% of our patients had coexisting medical conditions. We found that 40.5% of our patients had mild infection, while 32.4% had moderate infection, and 27.1% had developed severe or critical illness. The most common abnormal laboratory findings in our patients were decreased lymphocytes (45.9%) and increased D‐dimer values (43.2%), while abnormal radiological findings were detected in 56.7% of the children. In addition, 64.8% of the patients had received azithromycin, 59.4% of the patients had received oseltamivir, and hydroxychloroquine was used in combination with azithromycin in 35.1% of the children. Non‐invasive mechanical ventilation was required in 27.0% of the children. CONCLUSIONS: Although COVID‐ 19 infection is usually mild in childhood, severe clinic can be seen in children with comorbidities or even in children who were previously healthy.

. Epidemiologic and clinical characteristics of children with SARS-CoV-2 Table 2 . Baseline charecteristics of children infected with SARS-CoV-2 Table 3 . Laboratory findings of children infected with SARS-CoV-2 Table   4 . Statistical analysis of laboratory data

Coronavirus is one of the viral pathogens that affect the human airways. Before 2019, coronaviruses such as SARS-CoV and MERS-CoV, which cause acute respiratory distress and threaten public health, had been identified (1) . However, on 7 January 2020, Chinese authorities declared that a number of cases of severe pneumonia were clustered in the Wuhan region of China, and when these patients were examined it was determined that these cases were associated with animal market contacts (2) . The disease, which was caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), then spread rapidly to other countries and became a global health problem. The World Health Organization (WHO) described the disease which was caused by SARS-CoV-2 as coronavirus disease 2019 . The COVID-19 disease was described as a pandemic on 11 March 2020.

The first case in Turkey was reported on 11 March 2020 (3). By early May 2020, the WHO had reported more than 3.5 million definitive cases and 247,503 deaths worldwide (4) . SARS-CoV-2, which is mainly transmitted through respiratory droplets and contact routes, is an enveloped positive stranded RNA virus. Based on the current epidemiological data, the incubation period of the infection from SARS-CoV-2 ranges from 1 to 14 days and the most common initial symptoms include fever, cough, sore throat, headache, myalgia and sometimes gastrointestinal symptoms (5) . Clinical manifestations range from mild upper respiratory infections to pneumonia or acute respiratory distress syndrome (ARDS). In addition, most of the patients who are infected by the SARS-CoV-2 have chronic underlying diseases, mainly cardiovascular and cerebrovascular diseases and diabetes (6) . Although children are known to have clinically milder cases of the disease, it has been reported that some children have had severe respiratory failure and needed hospitalization at intensive care units (ICU) (7) . We have some information about the clinical courses and treatment

This article is protected by copyright. All rights reserved strategies for children. In addition, it was reported that SARS-CoV-2 may trigger some diseases such as Kawasaki Disease, so it appears that more information about children is needed. Here, we report on the epidemiological and clinical features of 37 children diagnosed with COVID-19 in a university hospital in İstanbul.

We collected the epidemiological and clinical data from medical records and included all pediatric patients (aged 0-18 years). This study was approved by the Istanbul University Cerrahpaşa-Cerrahpaşa Medical Faculty ethics committee. Every patient who applied with complaints of fever, cough or other upper/lower respiratory tract symptoms was considered as a possible case and was evaluated. The combined nasopharyngeal-oropharyngeal real-time polymerase chain reaction (RT-PCR) swab samples, blood counts, biochemical examinations and D-dimer examinations were obtained from these patients. Chest radiographies were performed in all patients suspected with mild or severe pneumonia. Computed tomography (CT) was performed in patients with suspicious findings on chest radiography or whose respiratory distress could not be explained by chest radiography findings.

We defined patients as having COVID-19 according to whether they met one of the following two criteria *Patients who had positive combined nasopharyngeal-orapharyngeal RT-PCR swab samples. *Patients whose samples were negative but whose clinical and radiological features were compatible with COVID-19.

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We divided the patients who had been diagnosed with COVID-19 into groups according to the categories described by Dong et al (8) . Patients were classified into three groups as mild, moderate and severe or critically ill.

• Upper respiratory symptoms (e.g., pharyngeal congestion, sore throat and fever) for a short duration or asymptomatic infection All hospitalized patients were followed up at the isolation section of the general pediatric ward or ICU. We followed up all children who had mild disease without hospitalization and all of them were regularly called by a trained physician and questioned about their symptoms and medications on the 1st, 3rd and 7th days to learn about their clinical conditions. Children who were asymptomatic or had mild disease were followed up without treatment. We gave azithromycin treatment to all diagnosed patients, except those who had mild clinical conditions. We added hydroxychloroquine to the treatment of those who had abnormal findings in CT scans or who had severe/critical illness. Critically ill patients with ARDS received favipiravir.

Statistical analyses were made between patient groups in terms of laboratory data. SPSS (version 20.0; SPSS Inc, Chicago, IL) statistics package was used for analysis. For all statistical analysis, p <0.05 was considered significant. Anova test p-values were considered for test significance. The significance value for parameters in different class were also tested using the Anova-one-way

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A total of 326 children who had respiratory symptoms, fever or had had contact with a patient with a definitive COVID-19 diagnosis applied to our hospital between 1 March and 1 May 2020, and 37 of these children who had been confirmed as having COVID-19 were retrospectively enrolled in our study. The age distribution of our patients was from 7 months to 17 years 9 months (median: 10 years). Most of our patients (40.5%) were over 11 years of age, while 35.1% of them were 1 to 6 years old, and 21.6% were 6 to 11 years old, with only 2. patients with negative PCR results, and these tests were also negative. We did not send samples from the lower respiratory tract due to the risk of transmission. Among 8

This article is protected by copyright. All rights reserved patients whose RT-PCR test results were negative, two of them had a history of household contact. We followed up remaining 6 patients after discharge and we sent COVID-19 serology and we detected immunglobuline G positive in these patients.

While 17 (45.9%) of the patients were followed up without hospitalization, 10 children (27%) were admitted to the ICU. The remaining 10 (27%) children were hospitalized in general pediatric ward.

If we examine the initial symptoms of our patients, the most common was dry cough that was recorded in 28 (75.6%) patients, followed by fever which was seen at 26 (70.2%) children, Troponin levels in all patients were within normal limits. While C-reactive protein (CRP) was high in 14 patients (37.8%), procalcitonin (PCT) was above the normal limit in 5 patients (13.5%). Only one patient had a high creatine value, which returned to normal after fluid replacement. We detected thrombocytopenia in 2 patients and thrombocytosis in 1 patient.

When the laboratory parameters were compared, there were no statistically significant difference between laboratory parameters of three different patient classes except of D-dimer

This article is protected by copyright. All rights reserved value. D-dimer value was significantly high in moderate patient group as shown in Table 4 (p <0.05).

Of the 21 (56.7%) patients we found abnormal findings in radiological imaging, 17 were followed up in ICU or general pediatric ward, while 4 of them were followed up without hospitalization.

Twenty four (64.8%) patients received azithromycin and 22 (59.4%) patients received oseltamivir. We used favipiravir in 3 (8.1%) patients. Hydroxychloroquine was used in combination with azithromycin in 13 (35.1%) children all of whom were hospitalized. Non invasive mechanical ventilation support was required in 8 patients (21.6%) One patient was given oxygen support with nasal cannula while the other one had received invasive ventilation for one day. Therapeutic plasma exchange (TPE) was used in 3 (8.1%) children. While one of these patients was diagnosed with diabetes, the other had a neurological disorder and hydrocephalus. The other patient who received plasmapheresis treatment was a previously healthy adolescent girl, except for obesity. The median duration of hospitalization was 7 days (range 4-17 days) except of a child who is still in general pediatric ward.

While COVID-19 is spreading rapidly around the world, a large amount of data has been published about the adult patient group, but publications and information about children have been relatively limited. The COVID-19 clinic has some different and similar aspects among adults and children. In the literature, the prevalence of COVID-19 in children ranges from 1 to 5%, with a large proportion reported to be under the age of 10. In a study conducted by Dong et al (8) , the median age of patients was 7 years and 65.1% of patients were < 10 year, while 34.9% of patients over the age of 10. According to the report of Centers for Disease

This article is protected by copyright. All rights reserved Control and Prevention (CDC) in the US, the median age of 2,572 COVID-19 pediatric patients is 11 years and 59.0% of the patients were over 10 years of age (9) . By march 30, 117 pediatric cases confirmed in Turkey and 49.5% of patients were over 10 years of age. The median age was 8 years (10). In our study similar to these reports, we found that the median age of patients was 10 (7 months to 17 years 9 months) and 40.5% of them were over 11 years old.

According to recently published literature, which described demographic and clinical characteristics of 44,672 adult patients in China, COVID-19 has infected both men and women equally (male to female ratio =1.06:1) (11). We have found slightly more boys than girls (57.1% vs 43.3%) in our study, which is similar to the other epidemiological children studies (8, 14) .

In recent studies, it was reported that the rate of COVID-19 in children is similar to the general population although children are less likely to have severe symptoms and understanding the role of pediatric population in transmission dynamics of SARS-CoV-2 is very important (12, 13) . On the other hand, infected adults who have close contact with children are important sources of infection for children as stated in many studies (14, 15) . According to Lu et al (14), 90.1% of patients were reported having a household contact. Similar to other studies, we found 78.3 % of our patients had a close contact with infected adults.

Although the effect of comorbid conditions on the severity of the disease is not as clearly defined as adults, there is a current publication reporting that the most common underlying conditions among 345 children are chronic lung disease (including asthma) ,cardiovascular disease and immunosuppression (9) . All infected children with a comorbid disease, except a patient were hospitalized in our study. One child with a diagnosis of juvenil idiopathic arthritis was managed as outpatient. Two asymptomatic patients who were followed up with

This article is protected by copyright. All rights reserved the diagnosis of neuroblastoma and medulloblastoma and found positive after the contact history, were transferred from pediatric oncology department to general pediatric ward. These two patients received azithromycin treatment and were discharged without any deterioration in their clinical condition. Unlike these 2 patients, the clinic was more severe in an adolescent patient diagnosed with Hodgkin lymphoma. Patients in the moderate and severe groups had similar rates in terms of comorbid diseases. In the mild patient group, only one patient had a comorbid disease.

In an editorial reported from a liver transplant center in Italy, no severe pneumonia was In several studies (8, 15) , SARS-CoV-2 infected children were classified into groups, according to severity of their symptoms, 94.0% of the pediatric patient group was reported to have COVID-19 infection asymptomatic, mild or moderate (8) . Among the pediatric patients in our study, we found 72.9 % of patients having mild or moderate infection while 27.1 % of them were severe or critically ill. This rate is higher than similar studies (8, 19) . This may be

This article is protected by copyright. All rights reserved related to the presence of a large pediatric ICU, where a large number of patients are followed in our hospital. This study was performed in a tertiary university hospital located in İstanbul, Turkey. It is a referral hospital with 106-bed capacity, containing 20 pediatric intensive care unit (ICU) beds. During the process, a physically separate part of the ICU was allocated to COVID-19 positive patients. We also have a 14-bed pediatric isolation ward, where patients whom doesn't require ICU admission were followed.

The clinical symptoms of COVID-19 in children are non-specific. Cough, fever, sore throat, fatigue, myalgia, headache, vomiting and diarrhea can be seen. In several studies, most common symptoms on admission were, fever and cough (14, 15) . Similarly we found cough (75.6%) and fever (70.2%) as the most common symptoms in our study. We found rhinorrhea in 32.4% of our patients, this rate seems higher than adult studies (9) and may be related to coinfections which are common in children. While the rate of diarrhea was 9.0% in Parri et al's (19) study and 8.8% in Lu et al's (14) study, in our study, diarrhea was detected in 10.0% of our patients similarly. If we compare clinical characteristics of the patient groups in our study, the mild and moderate groups mostly presented with upper respiratory tract complaints whereas, patients in the severe group also presented with respiratory distress.

Laboratory investigations of SARS-CoV-2 infected patients, are usually non specific.

Aminotransferase levels, prothrombin time, creatine, D-dimer, CK and LDH values may be high in relation to the severity of infection. Additionally, lymphopenia is a common finding (20, 21) . In a meta-analysis which involves predominantly adult patients, the most common laboratory findings are hypoalbuminemia (75.8%), high CRP (58.3%), high lactate dehydrogenase (57.0%), lymphopenia (43.1%), and high erythrocyte sedimentation rate (41.8%) (22) . In our study, CRP value was high in 14 (37.8%) patients and LDH was high in 3 (8.1%) patients. While D-dimer levels were high in 43.2% of our patients, Wang et al (23) 

This article is protected by copyright. All rights reserved showed that D-dimer increased in 6.5% of 31 children. Lymphopenia is claimed to be an effective and reliable indicator of severity and hospitalization in COVID-19 patients (24) . In a meta-analysis in which 66 pediatric patients were examined, only 3.0% of patients had lymphopenia, and this low rate was thought to be due to the small number of critically ill children (25) . Differently lymphopenia was detected in 45.9 % of our patients which would be related to our high critically ill children rate but there was no statistically significant difference in the rate of lymphopenia between the patient groups in our study.

Typical radiological findings seen in COVID-19 disease are ground-glass opacity and consolidation, especially in the lower lobes and subpleural areas (26) .

Qui et al found 19 (53%) paediatric patients had pulmonary ground-glass opacities on CT scan, suggesting pneumonia, similarly we found 56.7% of our patients to have positive radiological findings (15) . Different treatments modalities have been tried in several studies but there is no special therapeutic medication for COVID-19 yet and treatment strategies generally consist of supportive and symptomatic treatment. Interferon alfa and lopinavir-ritonavir were used in one study (15) while azithromycin, hydroxychloroquine, remdesivir and tocilizumab were used in critically ill children who were hospitalized in ICU in another(27). We used azithromycin for patients who were classified as moderate, severe or critically ill and added hydroxychloroquine to treatment for severe and critically ill children. In addition, 4 children who has moderate disease received hydroxychloroquine. Three of them were over 15 years old and had CT findings, compatible with COVID-19. The other patient was an infant with suspected immune deficiency. In a current publication which included 48 children who were admitted to ICU, 44 % of patients received hydroxychloroquine while 17 % of them received azithromycin, similar to our study. Unlike our study, remdesivir and tocilizumab were reported to be used in this study but favipiravir was not preferred (27).

This article is protected by copyright. All rights reserved Generally, NIV is not recommended for SARS-CoV-2 infected patients because of potential risk for aerosolization (28) . On the other hand, patients with severe respiratory distress whom NIV were used, benefited clinically and these patients were discharged without the need for intubation. We used all personal protective equipment such as N95 respirators, goggles, face shields and disposable gowns both in ICU and general pediatric ward to protect healthcare workers, also a physically separate part of the ICU was allocated to COVID-19 positive children to protect other non-COVID-19 patients.

Our study has several limitations. It's single center nature and small sample size are the main limitations. Second, we couldn't evaluate other viral infections such as influenza or respiratory syncytial virus which could provide more information about interactions between SARS-CoV-2 and other respiratory viruses. Although this issue is important, the focus of this study is SARS-CoV-2.

COVID-19 is rapidly spreading around the world and children are at similar risk as adults.

The main source of infection in children is usually their household contacts and most common symptoms are fever and cough. Although COVID-19 infection is mostly mild in childhood, severe clinic can be observed in previously healthy children and there may be underlying genetic predisposition. D-dimer elevation and lymphopenia can be detected not only in adults but also in children.

PÖ, AAK, FA, CD and HÇ designed the study; collected and analyzed data; CD contributed to the concept and design of this work Accepted Article 

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High:1 (2.7%) High:14 (37.8%) High:16 (43.2% ) LDH: median

High:3 (8.1%) High:4 (10.8%) Low:1 (2.7 %) High:6 (16.2%)

Low:17 (45.9%) High:0 (0%) Platelet count

CRP: C-reactive protein, LDH: Lactate dehydrogenase, PCT: Procalcitonin, IU/L: international unit / liter mg/dl: milligram / deciliter