Advertisement

Human Coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 in Children

  • Elahe Aleebrahim-Dehkordi
    Affiliations
    Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Iran

    Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Iran
    Search for articles by this author
  • Faezeh Soveyzi
    Affiliations
    Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Iran

    School of Medicine, Tehran University of Medical Sciences, Iran
    Search for articles by this author
  • Niloofar Deravi
    Affiliations
    Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Iran

    Student's Research Committee, School of medicine, Shahid Beheshti University of Medical Sciences, Iran
    Search for articles by this author
  • Zahra Rabbani
    Affiliations
    Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Iran

    School of Medicine, Tehran University of Medical Sciences, Iran
    Search for articles by this author
  • Amene Saghazadeh
    Affiliations
    Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Iran

    Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Iran
    Search for articles by this author
  • Author Footnotes
    1 Mailing address: Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14,194, Iran
    Nima Rezaei
    Correspondence
    Corresponding author at: Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
    Footnotes
    1 Mailing address: Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14,194, Iran
    Affiliations
    Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Iran

    Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Iran

    Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Iran
    Search for articles by this author
  • Author Footnotes
    1 Mailing address: Children's Medical Center Hospital, Dr. Qarib St, Keshavarz Blvd, Tehran 14,194, Iran
Published:October 22, 2020DOI:https://doi.org/10.1016/j.pedn.2020.10.020

      Highlights

      • COVID-19 has caused an epidemic with high mortality and morbidity since December 2019, in Wuhan, China.
      • The pediatric population is just as likely as adults to become infected with COVID-19.
      • The pediatric population may be asymptotic or have milder symptoms than adults; they can be potential carriers of the disease.
      • COVID-19 mainly cause fever, respiratory symptoms, and other flu-like manifestations in pediatrics.
      • Public education as well as isolation of the contaminated people, should be taken into consideration.

      Abstract

      The novel coronavirus, known as 2019-nCoV or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an epidemic with high mortality and morbidity since December 2019, in Wuhan, China. The infection has now been transmitted to more than 210 countries worldwide and caused more than 200,000 deaths. Similar to other coronaviruses such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), SARS-CoV-2 appears to less commonly affect pediatrics and to cause less severe disease along with fewer symptoms compared to adults. Available data suggest that the pediatric population is just as likely as adults to become infected with SARS-CoV-2. However, they may be asymptotic or have milder symptoms than adults; they can be potential carriers of the disease. This article reviews the present understanding of SARS-CoV-2 infection in the pediatric age group in comparison with MERS-CoV and SARS-CoV.

      Keywords

      Introduction

      Coronaviruses (CoVs) are single-stranded positive-sense RNA viruses belonging to the family Coronaviridae and the order Nidovirales (
      • Chen Y.
      • Liu Q.
      • Guo D.
      Emerging coronaviruses: Genome structure, replication, and pathogenesis.
      ;
      • Wu A.
      • Peng Y.
      • Huang B.
      • Ding X.
      • Wang X.
      • Niu P.
      • et al.
      Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
      ;
      • Yang Y.
      • Lu Q.
      • Liu M.
      • Wang Y.
      • Zhang A.
      • Jalali N.
      • et al.
      Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China.
      ). These enveloped viruses possess a non-segmented genome and have the potential to cause respiratory diseases, with varying severity in humans and animals (
      • Guy J.S.
      • Breslin J.J.
      • Breuhaus B.
      • Vivrette S.
      • Smith L.G.
      Characterization of a coronavirus isolated from a diarrheic foal.
      ). They fall into the four genera: alpha, beta, gamma, and delta. Both alpha and beta coronaviruses can infect humans (hCoVs) (
      • Zhu N.
      • Zhang D.
      • Wang W.
      • Li X.
      • Yang B.
      • Song J.
      • et al.
      A novel coronavirus from patients with pneumonia in China, 2019.
      ). Of these, three beta CoVs have been epidemic causes: SARS-CoV, MERS-CoV, and SARS-CoV-2.
      Severe acute respiratory syndrome (SARS) develops as a sudden onset unusual type of viral pneumonia. The 2002–2003 SARS outbreak started from one of the southern states of China and spread to more than 30 East Asian countries. The incubation period takes between 2 and 7 days up to 10 days. Cold symptoms, such as low-grade fever, muscle aches, and dry cough, are the first signs of illness. There might be unilateral or bilateral pneumonia in chest imaging. Lymphopenia, hypoxia, and elevated creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) (
      • Alsaad K.O.
      • Hajeer A.H.
      • Al Balwi M.
      • Al Moaiqel M.
      • Al Oudah N.
      • Al Ajlan A.
      • et al.
      Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection – Clinicopathological and ultrastructural study.
      ;
      • Luk H.K.H.
      • Li X.
      • Fung J.
      • Lau S.K.P.
      • Woo P.C.Y.
      Molecular epidemiology, evolution and phylogeny of SARS coronavirus.
      ;
      • Momattin H.
      • Al-Ali A.Y.
      • Al-Tawfiq J.A.
      A systematic review of therapeutic agents for the treatment of the Middle East respiratory syndrome coronavirus (MERS-CoV).
      ) commonly occur in patients with SARS-CoV.
      The 2012 MERS coronavirus (MERS-CoV) outbreak is associated with a wide range of diseases, from mild fever and respiratory symptoms to upper respiratory tract infection, diarrhea, weakness, and lethargy. In severe cases, it can lead to progressive infection of the lungs and respiratory failure, renal failure, or multiple organ failure (
      • Bosch B.J.
      • Raj V.S.
      • Haagmans B.L.
      Spiking the MERS-coronavirus receptor.
      ;
      • Drosten C.
      • Meyer B.
      • Muller M.A.
      • Corman V.M.
      • Al-Masri M.
      • Hossain R.
      • et al.
      Transmission of MERS-coronavirus in household contacts.
      ;
      • Widagdo W.
      • Okba N.M.A.
      • Stalin Raj V.
      • Haagmans B.L.
      MERS-coronavirus: From discovery to intervention.
      ).
      COVID-19 is a recently emerged coronavirus disease first reported from Wuhan, China. Due to the worldwide spread of the disease, the World Health Organization has declared COVID-19 a global epidemic on March 21 (
      • Hanaei S.
      • Rezaei N.
      COVID-19: Developing from an outbreak to a pandemic.
      ;
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ;
      • Hui D.S.
      • I Azhar E.
      • Madani T.A.
      • Ntoumi F.
      • Kock R.
      • Dar O.
      • et al.
      The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China.
      ). The causative pathogen of COVID-19 shares structural similarities with that of SARS and therefore has adopted the name SARS-CoV-2. Pneumonia is the most common manifestation of COVID-19 in the early stages, characterized by fever, cough, shortness of breath, and bilateral infiltration in chest imaging (
      • Lotfi M.
      • Rezaei N.
      SARS-CoV-2: A comprehensive review from pathogenicity of the virus to clinical consequences.
      ). Moreover, COVID-19 can lead to fatal lung injury, multiple organ failure, and death (
      • Huang C.
      • Wang Y.
      • Li X.
      • Ren L.
      • Zhao J.
      • Hu Y.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ).
      Children are differently affected by COVID-19. Compared to adults, children are more asymptomatic and develop a severe form of COVID-19 at an incomparably lower rate (
      • Rezaei N.
      COVID-19 affects healthy pediatricians more than pediatric patients.
      ;
      • Shen K.
      • Yang Y.
      • Wang T.
      • Zhao D.
      • Jiang Y.
      • Jin R.
      • et al.
      Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement.
      ). Despite this, children are generally one of the most susceptible groups to infectious diseases of viral origin. Mainly related to the subject is the recently reported development of a multi-system inflammatory syndrome in children (MIS-C) affected by COVID-19. This review mainly focuses on the clinical manifestations of the MERS, SARS, and COVID-19 and, in the meantime, aims to compare these three hCoVs in terms of prognosis, epidemiology, prevention, transmission, and treatment in children.

      Epidemiology of SARS, MERS, and COVID-19

      In the last two decades, the world has faced three epidemics caused by coronaviruses, resulting in significant global health concerns (
      • Guarner J.
      Three emerging coronaviruses in two decades: The story of SARS, MERS, and now COVID-19.
      ).
      In 2002–2003, SARS-CoV emerged in Guangdong, China. It spread rapidly to other areas and countries, including Hong Kong, China's particular administrative area, Singapore, Vietnam, and Canada (
      • Mao Y.
      • Lin W.
      • Weng J.
      • Chen G.
      Epidemiological and Clinical Characteristics of SARS-CoV-2 and SARS-CoV: A System Review.
      ). After having infected more than 8000 people and resulting in 774 deaths with a mortality rate calculated at 9.5%, the latest patient diagnosed with SARS-CoV occurred in September 2003 (
      • Guarner J.
      Three emerging coronaviruses in two decades: The story of SARS, MERS, and now COVID-19.
      ). The first pediatric patients with SARS-CoV were hospital staff contacts (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ). Stockman et al. (
      • Stockman L.J.
      • Massoudi M.S.
      • Helfand R.
      • Erdman D.
      • Siwek A.M.
      • Anderson L.J.
      • et al.
      Severe acute respiratory syndrome in children.
      ). state that of the 135 pediatric cases with SARS documented in the six publications, 80 had laboratory-confirmed SARS, and 27 existed in the SARS-affected regions (3%). There was no known source of SARS in less than 2% of pediatric patients.
      In 2012, MERS-CoV first happened in Saudi Arabia. To date, most patients with MERS-C0V have occurred in or nearby the Arabian Peninsula. Whereas a low reproduction number of about 1 indicates that each patient with MERS-CoV transfers the disease to one other individual only, models estimate an R0 of 4 for SARS-CoV that corresponds to relatively higher transmissibility of this virus (
      • Guarner J.
      Three emerging coronaviruses in two decades: The story of SARS, MERS, and now COVID-19.
      ;
      • Schwartz D.A.
      • Graham A.L.
      Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-ncov infecting pregnant women: Lessons from SARS, MERS, and other human coronavirus infections.
      ). However, as compared to SARS-CoV, MERS-CoV is more deadly, with the death rate of about 35%.
      There are at least 31 pediatric patients with MERS-CoV reported to WHO from June 2012 to April 19, 2016. The mean age of the patients was 9.8 years. More than 80% of pediatric patients with MERS-CoV registered in Saudi Arabia, and other cases were reported in Korea, Jordan, and the United Arab Emirates (
      • Bartenfeld M.
      • Griese S.
      • Uyeki T.
      • Gerber S.I.
      • Peacock G.
      Middle East respiratory syndrome coronavirus and children: What pediatric health care professionals need to know.
      ).
      In December 2019, the novel coronavirus disease (COVID-19) was recognized in Wuhan, China, in some patients with an unknown form of viral pneumonia, along with a common history of being in the Huanan seafood market (
      • Peeri N.C.
      • Shrestha N.
      • Rahman M.S.
      • Zaki R.
      • Tan Z.
      • Bibi S.
      • et al.
      The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: What lessons have we learned?.
      ). By March 22, the new coronavirus pandemic has been spread to over 185 countries from China and appears not to be more fatal than other similar viruses, such as MERS and SARS (
      • Andersen K.G.
      • Rambaut A.
      • Lipkin W.I.
      • Holmes E.C.
      • Garry R.F.
      The proximal origin of SARS-CoV-2.
      ;
      • Pal R.
      • Bhansali A.
      COVID-19, diabetes mellitus and ACE2: The conundrum.
      ). The director-general of the WHO, Tedros Adhanom Ghebreyesus, at a meeting on February 17, stated that over 80% of cases with COVID-19 have “mild disease and will recover”, and in 2% of reported patients, it appears to be fatal (
      • Mahase E.
      Coronavirus: Covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate.
      ). Although the case fatality rate is lower in COVID-19 infected individuals, COVID-19 has resulted in about 3 million confirmed cases as well as more than 200,000 deaths by April 26, 2020. It forms a contrast with SARS and MERS that were totally accounted for less than 2000 deaths (1632). During the pandemic of COVID-19, the older population, people with comorbid conditions, such as cardiovascular diseases and cancer, and individuals with a certain genetic background appear as the most vulnerable populations (
      • Ahmadi M.
      • Saffarzadeh N.
      • Habibi M.A.
      • Hajiesmaeili F.
      • Rezaei N.
      Colon cancer and SARS-CoV-2: impact of ACE2 expression in susceptibility to COVID-19.
      ;
      • Darbeheshti F.
      • Rezaei N.
      Genetic predisposition models to COVID-19 infection.
      ;
      • Shamshirian D.
      • Rezaei N.
      Cardiovascular diseases burden in COVID-19: Systematic review and meta-analysis.
      ;
      • Yousefzadegan S.
      • Rezaei N.
      Case report: Death due to COVID-19 in three brothers.
      ). In the early stages of the COVID-19 epidemic, pediatric SARS-CoV-2 infected individuals appeared infrequent. Therefore, the pediatric age group is not yet considered at high risk of this disease. However, the pediatric population infected by SARS-CoV-2 was gradually increased in line with the increase of familial clusters (
      • Pal R.
      • Bhansali A.
      COVID-19, diabetes mellitus and ACE2: The conundrum.
      ). By February 11, 2020, the Chinese Centers for Diseases Control and Prevention has reported 44,672 confirmed SARS-CoV-2 infected cases, 549 cases (1.2%) of whom were 10–19 years old and 416 cases (0.9%) of whom were 0–10 years old. Of these infected children, 134 cases had clinical records (
      • 今井由美子
      新型コロナウイルスに対する重症化阻止治療. 日本薬理学会年会要旨集 第 93 回日本薬理学会年会.
      ). There have been two reported deaths in the pediatric age group, who tested positive for SARS-CoV-2 infection in China; however, no deaths have been reported in the published papers from other countries (
      • Sinha I.P.
      • Harwood R.
      • Semple M.G.
      • Hawcutt D.B.
      • Thursfield R.
      • Narayan O.
      • et al.
      COVID-19 infection in children.
      ). Furthermore, a cohort of 31 patients (under the age of 18, with 28 patients under the age of 14) who were hospitalized with SARS-CoV-2 infection in Shenzhen city of China reported that apart from some common characteristics between children and adults, a few epidemical characteristics were found in children that sharply differed from what was formerly known about adult patients. Accordingly, no gender preference was revealed in the pediatric patients (
      • Chen C.
      • Cao M.
      • Peng L.
      • Guo X.
      • Yang F.
      • Wu W.
      • et al.
      Coronavirus Disease-19 Among Children outside Wuhan, China. China (2/25/2020).
      ).

      Clinical manifestations of SARS, MERS, and COVID-19

      SARS

      According to the reported results of the disease, the virus has occurred in adults between 25 and 70 years. Moreover, there have been reported a few cases in adolescents (15 years old). The latent period of the disease is between 2 and 7 days, and sometimes up to 10 days. During this period, patients might have a low-grade fever, which may be accompanied by chills and flu-like symptoms (including rapid and high fever, muscle pain, headache, and sore throat). After 3–7 days, lower respiratory problems begin with a dry cough. It can lead to shortness of breath, and in some cases (10–20%), blood oxygen depletion. Two clinical phases characterize SARS. In the first phase, the symptoms are mild and related to the upper part of the respiratory system (symptoms of cold, cough, shortness of breath). In the second phase, by the invasion of the virus to the lower respiratory system, it causes cough, shortness of breath, and, ultimately, a decrease in blood oxygenation (
      • Lau J.T.
      • Fung K.S.
      • Wong T.W.
      • Kim J.H.
      • Wong E.
      • Chung S.
      • et al.
      SARS transmission among hospital workers in Hong Kong.
      ). All of these symptoms exist in adults and children, and only symptom severity varies between them.
      According to research reports, clinical manifestations in children include a low-grade fever or no fever, fatigue, and dry cough. Also, in the early stage of the disease, the number of white blood cells and the number of lymphocytes may decrease. Children with suspected SARS have shown clinical manifestations, including cough, chills, fatigue, vomiting, diarrhea, rhinorrhea, diarrhea, and respiratory distress, and laboratory abnormalities, including leukopenia, elevated AST, elevated AST, and lymphopenia. Laboratory results such as thrombocytopenia, lymphopenia, and elevation in CPK and liver transaminase levels appeared mild in young children. Results suggest that SARS is a relatively mild and nonspecific respiratory illness in young children. The clinical features observed in teenagers resemble those of adults (
      • Bitnun A.
      • Allen U.
      • Heurter H.
      • King S.M.
      • Opavsky M.A.
      • Ford-Jones E.L.
      • et al.
      Children hospitalized with severe acute respiratory syndrome-related illness in Toronto.
      ;
      • Leung C.W.
      • Chiu W.K.
      Clinical picture, diagnosis, treatment and outcome of severe acute respiratory syndrome (SARS) in children.
      ).

      MERS

      MERS-CoV can cause a wide range of symptoms from mild fever and respiratory symptoms (upper respiratory tract infection), diarrhea, weakness, and lethargy, to progressive respiratory failure, renal failure, or multiple organ failure in severe cases. The most common manifestations of the disease are fever and respiratory symptoms, and all patients develop respiratory symptoms during their illness (
      • Bartenfeld M.
      • Griese S.
      • Uyeki T.
      • Gerber S.I.
      • Peacock G.
      Middle East respiratory syndrome coronavirus and children: What pediatric health care professionals need to know.
      ;
      • Schwartz D.A.
      • Graham A.L.
      Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-ncov infecting pregnant women: Lessons from SARS, MERS, and other human coronavirus infections.
      ). Cases of anemia, coagulopathy, and intravascular coagulation have also been reported in patients with MERS-CoV. There have also been reports of increased levels of serum transaminases, lactate dehydrogenase, potassium, creatine kinase, troponin, C-reactive (CRP) protein, and procalcitonin, and decreased serum sodium and albumin levels (
      • Das K.M.
      • Lee E.Y.
      • Enani M.A.
      • AlJawder S.E.
      • Singh R.
      • Bashir S.
      • et al.
      CT correlation with outcomes in 15 patients with acute Middle East respiratory syndrome coronavirus.
      ;
      • Moniri A.
      • Marjani M.
      • Tabarsi P.
      • Yadegarynia D.
      • Nadji S.A.
      Health care associated Middle East respiratory syndrome (MERS): A case from Iran.
      ). The MERS-CoV virus produces symptoms similar to SARS, but with a distinct clinical course and high mortality rates of between 35 and 50%. The rate of death from MERS is higher in men as well as in patients with underlying diseases. The average time from the onset of symptoms to hospitalization is approximately four days, and the average time from admission to hospital to admission to the ICU is one day. The ICU admission period is approximately 30 days. However, death occurs, on average, 12 days after the onset of symptoms (
      • Mohd H.A.
      • Al-Tawfiq J.A.
      • Memish Z.A.
      Middle East respiratory syndrome coronavirus (MERS-CoV) origin and animal reservoir.
      ;
      • Omrani A.S.
      • Saad M.M.
      • Baig K.
      • Bahloul A.
      • Abdul-Matin M.
      • Alaidaroos A.Y.
      • et al.
      Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study.
      ;
      • Scobey T.
      • Yount B.L.
      • Sims A.C.
      • Donaldson E.F.
      • Agnihothram S.S.
      • Menachery V.D.
      • et al.
      Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus.
      ).
      Furthermore, out of 701 patients with confirmed MERS-CoV, only 14 were pediatric cases (2%). Compared to adult patients, MERS-CoV in children is less frequent and seems to be associated with less mortality unless the patient has an underlying disease or a history of infection with other respiratory viruses. Based on the results of the screening, it has been found that one of the children (9-month-old child) with MERS-CoV disease has nephrotic syndrome. Different results show that although few cases of MERS-CoV in children have been reported, MERS remains mainly a disease of adults.

      COVID-19

      According to the first study of patients with new coronavirus (SARS-CoV-2), the incubation period of the virus was, on average, five days, with a range between 4 and 7 days (
      • Li Q.
      • Guan X.
      • Wu P.
      • Wang X.
      • Zhou L.
      • Tong Y.
      • et al.
      Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.
      ). According to the present epidemiological evidence, the incubation period of COVID-19 infections varies from 1 to 14 days, generally ranging from 3 to 7 days. SARS-CoV-2 tends to locate and replicate in the cells of the lower respiratory tract (
      • Heymann D.L.
      • Shindo N.
      COVID-19: what is next for public health?.
      ). At the initial stage of infection with SARS-CoV-2, people have general nonspecific symptoms such as fatigue, body aches, fever, dry cough, nausea, and diarrhea. Also, patients may develop neurological manifestations, such as headach and anosmia (
      • Jahanshahlu L.
      • Rezaei N.
      Central nervous system involvement in COVID-19.
      ;
      • Saleki K.
      • Banazadeh M.
      • Saghazadeh A.
      • Rezaei N.
      The involvement of the central nervous system in patients with COVID-19.
      ;
      • Yazdanpanah N.
      • Saghazadeh A.
      • Rezaei N.
      Anosmia: A missing link in the neuroimmunology of coronavirus disease 2019 (COVID-19).
      ;
      • Zu Z.Y.
      • Jiang M.D.
      • Xu P.P.
      • Chen W.
      • Ni Q.Q.
      • Lu G.M.
      • et al.
      Coronavirus Disease 2019 (COVID-19): A perspective from China.
      ).
      Infected children might appear asymptomatic or present with a dry cough, fever, and fatigue, and gastrointestinal symptoms such as diarrhea, abdominal discomfort, nausea, and vomiting. Most children infected with SARS-CoV-2 have mild clinical manifestations. Most children recover within 1 to 2 weeks after disease onset. Few may progress to lower respiratory infections (
      • Zimmermann P.
      • Curtis N.
      Coronavirus infections in children including COVID-19: An overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children.
      ). According to the results of research on 26 children with COVID-19 infection, nine patients had no apparent clinical symptom. The most common symptom was fever found in 11 patients. Less common symptoms included cough, diarrhea, rhinorrhea, and vomiting. Few children had lymphocytopenia and elevated alanine transaminase. According to the chest CT scan, 11 patients showed unilateral pneumonia, and eight patients had no pulmonary infiltration. No severe complications such as acute respiratory syndrome and acute lung damage have occurred in children with COVID-19. Also, the leukocyte counts in children were the same as in adults, and most of them appeared normal or decreased. Lymphocyte counts in adult patients decreased significantly (
      • Fathi N.
      • Rezaei N.
      Lymphopenia in COVID-19: Therapeutic opportunities.
      ), while they increased beyond the normal range in most children with COVID-19. It might reflect the fact that children have a higher percentage of lymphocytes that gradually decrease with age (
      • Lai C.-C.
      • Shih T.-P.
      • Ko W.-C.
      • Tang H.-J.
      • Hsueh P.-R.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): The epidemic and the challenges.
      ;
      • Li J.
      • Zhang Y.
      • Wang F.
      • Liu B.
      • Li H.
      • Tang G.
      • et al.
      Sex differences in clinical findings among patients with coronavirus disease 2019 (COVID-19) and severe condition.
      ).
      At the disease onset, some cases show fever, cough, and fatigue that is accompanied by nasal congestion, expectoration, runny nose, headache, and diarrhea. The majority of children have a low-grade fever or no fever at all (
      • Stockman L.J.
      • Massoudi M.S.
      • Helfand R.
      • Erdman D.
      • Siwek A.M.
      • Anderson L.J.
      • et al.
      Severe acute respiratory syndrome in children.
      ). As the condition progresses, dyspnea, cyanosis, and other signs may arise after typically one week of the disease, along with systemic toxic signs, including restlessness or malaise, decreased appetite, poor feeding, and less activity. Children's condition might progress quickly and turn to respiratory failure, which cannot be improved by conventional oxygen (nasal catheter, mask) within 1–3 days. Metabolic acidosis, septic shock, irreversible bleeding, and coagulation dysfunction can take place in such severe cases (
      • Hui D.S.
      • Sung J.J.
      Severe acute respiratory syndrome.
      ). Xia et al. (
      • Ng E.K.
      • Ng P.-C.
      • Hon K.E.
      • Cheng W.F.
      • Hung E.C.
      • Chan K.A.
      • et al.
      Serial analysis of the plasma concentration of SARS coronavirus RNA in pediatric patients with severe acute respiratory syndrome.
      ) reported that 7 of 20 pediatric cases had a history of acquired or congenital diseases, indicating that children with underlying diseases can be more vulnerable to COVID-19. Pediatric patients usually have a better prognosis, with an average stay of 12.9 days in the hospital. As for adults, COVID-19 can rapidly spread in children. However, it is more likely to remain asymptomatic in children than adults (
      • Zeng L.
      • Tao X.
      • Yuan W.
      • Wang J.
      • Liu X.
      • Liu Z.
      First case of neonate infected with novel coronavirus pneumonia in China.
      ).

      Multi-system inflammatory syndrome in children with COVID-19

      Unlike adults, most children with COVID-19 have mild symptoms. However, COVID-19 may cause an inflammatory reaction in some children (
      • release WFoPIaCCSm
      Expert panel conclusions following the 2 May Pediatric Intensive Care-COVID-19 International Collaborative Conference Call.
      ;
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • Wilkinson N.
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      ). In late April 2020, a group of children was admitted to the intensive care unit for a multi-system inflammatory disease. It appeared that the disease could be related to COVID-19. Also, there were eight children from England, in whom excessive hyperinflammatory shock was observed (
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • Wilkinson N.
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      ) and COVID-19 related antibodies were present as well (
      • Abrams J.Y.
      • Godfred-Cato S.E.
      • Oster M.E.
      • Chow E.J.
      • Koumans E.H.
      • Bryant B.
      • et al.
      Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: A systematic review.
      ). The so-called multi-system inflammatory syndrome in children (MIS-C) is very similar to a type of childhood disease known as Kawasaki disease. Kawasaki disease causes inflammation in the blood vessel walls (
      • Prevention CfDCa
      Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19).
      ;
      • Verdoni L.
      • Mazza A.
      • Gervasoni A.
      • Martelli L.
      • Ruggeri M.
      • Ciuffreda M.
      • et al.
      An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study.
      ). Coronary artery aneurysm is a major complication of Kawasaki disease. The diagnosis is based on the persistent presence of symptoms such as eczema, lymphadenopathy, fever, conjunctival injection, and changes in the mucous membranes and organs (
      • Dietz S.
      • Van Stijn D.
      • Burgner D.
      • Levin M.
      • Kuipers I.
      • Hutten B.
      • et al.
      Dissecting Kawasaki disease: A state-of-the-art review.
      ;
      • McCrindle B.W.
      • Rowley A.H.
      • Newburger J.W.
      • Burns J.C.
      • Bolger A.F.
      • Gewitz M.
      • et al.
      Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association.
      ). Examination of the clinical and laboratory characteristics of MIS-C shows that the syndrome is distinct from Kawasaki's disease. Children with MIS-C are older and systemic inflammation is more severe in them, and they have more myocardial damage than patients with Kawasaki's disease (
      • Whittaker E.
      • Bamford A.
      • Kenny J.
      • Kaforou M.
      • Jones C.E.
      • Shah P.
      • et al.
      Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
      ). Children with MIS-C show both the symptoms of COVID-19 and toxic shock syndrome (TSS) and Kawasaki disease (
      • Prevention CfDCa
      Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19).
      ; (
      • (PICS) PICS
      PICS Statement: Increased number of reported cases of novel presentation of multi-system inflammatory disease.
      ). MIS-C can affect different parts of the including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal tract. Children with MIS-C mostly have abdominal pain or sometimes diarrhea, neck pain, rash, bloodshot eyes, and vomiting. They may also experience excessive fatigue (
      • Network CHA
      Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19).
      ;
      • Toubiana J.
      • Poirault C.
      • Corsia A.
      • Bajolle F.
      • Fourgeaud J.
      • Angoulvant F.
      • et al.
      Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study.
      ). Cases of MIS-C have been reported in several countries (
      • Bahrami A.
      • Vafapour M.
      • Moazzami B.
      • Rezaei N.
      Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran.
      ;
      • Cheung E.W.
      • Zachariah P.
      • Gorelik M.
      • Boneparth A.
      • Kernie S.G.
      • Orange J.S.
      • et al.
      Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City.
      ;
      • Organization WH
      Multisystem inflammatory syndrome in children and adolescents with COVID-19.
      ). This syndrome appears to occur two to four weeks after infection with COVID-19. In countries where the prevalence of COVID-19 is high, more cases of MIS-C have been reported in children (
      • Control ECfDPa
      Rapid risk assessment: Pediatric inflammatory multisystem syndrome and SARS -CoV-2 infection in children.
      ;
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • Wilkinson N.
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      ). Children with this syndrome might suffer from heart problems and need immediate care (
      • Belhadjer Z.
      • Méot M.
      • Bajolle F.
      • Khraiche D.
      • Legendre A.
      • Abakka S.
      • et al.
      Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic.
      ). It is not yet fully understood what causes MIS-C (
      • Riphagen S.
      • Gomez X.
      • Gonzalez-Martinez C.
      • Wilkinson N.
      • Theocharis P.
      Hyperinflammatory shock in children during COVID-19 pandemic.
      ).

      Virology and pathogenesis of coronaviruses

      Coronaviruses (CoVs) are a family of enveloped RNA viruses (
      • Scobey T.
      • Yount B.L.
      • Sims A.C.
      • Donaldson E.F.
      • Agnihothram S.S.
      • Menachery V.D.
      • et al.
      Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus.
      ) that display crown-like spikes on their surfaces (
      • Bermingham A.
      • Chand M.
      • Brown C.
      • Aarons E.
      • Tong C.
      • Langrish C.
      • et al.
      Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012.
      ;
      • Cowling B.J.
      • Park M.
      • Fang V.J.
      • Wu P.
      • Leung G.M.
      • Wu J.T.
      Preliminary epidemiologic assessment of MERS-CoV outbreak in South Korea, May–June 2015.
      ;
      • Ksiazek T.G.
      • Erdman D.
      • Goldsmith C.S.
      • Zaki S.R.
      • Peret T.
      • Emery S.
      • et al.
      A novel coronavirus associated with severe acute respiratory syndrome.
      ). In particular, SARS-CoV-2 possesses a typical RNA that encodes 27 proteins. The orf1ab and orf1a genes, which are located at the 5′ end of the genome, encode the pp1ab and pp1a proteins, respectively. Together, these two genes express 15 nonstructural proteins nsp1-nsp10 and nsp12-nsp16. On the other hand, at the 3′ end of the genome, four structural proteins, including the spike surface protein (S), an envelope protein (E), membrane protein (M), nucleocapsid protein (E), and eight subunit proteins, including 3a, 3b, p6, 7a, 7b, 8b, 9b, and orf 14 are coded (
      • Mou H.
      • Raj V.S.
      • van Kuppeveld F.J.
      • Rottier P.J.
      • Haagmans B.L.
      • Bosch B.J.
      The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies.
      ;
      • Wu A.
      • Peng Y.
      • Huang B.
      • Ding X.
      • Wang X.
      • Niu P.
      • et al.
      Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
      ).
      Although coronaviruses are more common in animals, seven of them can affect humans (hCoVs). Four coronaviruses, including HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1, regularly cause respiratory infections in children and adults. Some coronaviruses, such as SARS-CoV, MERS-CoV, and SARS-CoV-2, are highly pathogenic to humans and can cause more severe symptoms leading to fatal cases of pneumonia (lung infection), renal failure, multiorgan failure, and death.
      HCoVs can invade the respiratory tract, intestine, and stomach and cause respiratory and gastrointestinal diseases. Usually, coronaviruses first infect the respiratory mucosa in the pharynx and nose and produce symptoms similar to the common Cold. coronaviruses cause about 15% of cases of colds. Occasionally, colds that coronaviruses cause can progress to infantile bronchitis, ear infections, or exacerbation of asthma in children and adolescents, and even pneumonia in adults, the elderly, and people with pre-existing conditions. Symptoms of respiratory coronavirus infections in humans are partly similar to those of rhinovirus infections and include nasal congestion and restlessness.

      Transmission and source of infection

      SARS-CoV and MERS-CoV can be transmitted through the fomite route, aerosol transmission, and droplet transmission (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ;
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ;
      • Perlman S.
      Another decade, another coronavirus.
      ;
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ). Person-to-person transmission of MERS-CoV occurs by large droplets (
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ). People who have exposure to health care centers, for example, hospitals or clinics, are at increased risk for MERS infection. Some MERS outbreaks are related to these centers as one occurred in Jeddah (Saudi Arabia), due to contact transmission in 2014 (
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ). There are MERS cases that at first appear as primary cases, but after more consideration, they are confirmed as secondary because they have a history of contact with patients (
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ). In another study by Schuster et al., pediatric cases could be infected with MERS-CoV secondarily as they were contacts of adults with MERS. Adults become infected with MERS-CoV at the workplace or due to contact with intermediate host animals (
      • Schuster J.E.
      • Williams J.V.
      Emerging respiratory viruses in children.
      ).
      Patients infected with SARS-CoV-2 may have symptoms or be asymptomatic. Symptomatic patients are the most contagious. The mechanisms to spread the disease are not yet fully elucidated, especially regarding the relative contributions of the airborne versus contact transmission routes to the COVID-19 pandemic (
      • Zhang R.
      • Li Y.
      • Zhang A.L.
      • Wang Y.
      • Molina M.J.
      Identifying airborne transmission as the dominant route for the spread of COVID-19.
      ). Although contact transmission via respiratory droplets was regarded as the main route in transmitting SARS-CoV-2 virus initially (
      • Van Doremalen N.
      • Bushmaker T.
      • Morris D.H.
      • Holbrook M.G.
      • Gamble A.
      • Williamson B.N.
      • et al.
      Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1.
      ;
      • Chin A.W.
      • Poon L.L.
      Stability of SARS-CoV-2 in different environmental conditions–Authors’ reply.
      ; (
      • (CDC) CfDCaP
      Coronavirus disease 2019 (COVID-19) - social distancing, quarantine, and isolation.
      ; (
      • (WHO) WHO
      Coronavirus disease (COVID-2019) situation reports (Geneva, Switzerland).
      ), present experimental and epidemiological evidence has suggested airborne transmission of the virus via respiratory aerosols as one probable route for the spreading of COVID-19 (
      • Liu Y.
      • Ning Z.
      • Chen Y.
      • Guo M.
      • Liu Y.
      • Gali N.K.
      • et al.
      Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals.
      ;
      • Morawska L.
      • Milton D.K.
      It is time to address airborne transmission of COVID-19.
      ; ;
      • Van Doremalen N.
      • Bushmaker T.
      • Morris D.H.
      • Holbrook M.G.
      • Gamble A.
      • Williamson B.N.
      • et al.
      Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1.
      ). A recent study of the COVID-19 pandemic trends in New York City, Italy, and Wuhan suggested that the airborne transmission route dominated the spread of the disease, and face-covering considerably shaped the trends of the outbreak in the three mentioned epicenters (
      • Zhang R.
      • Li Y.
      • Zhang A.L.
      • Wang Y.
      • Molina M.J.
      Identifying airborne transmission as the dominant route for the spread of COVID-19.
      ). Therefore, presently, the probable transmission routes (i.e., airborne vs. contact) for SARS-CoV-2 is a highly debated topic among the research communities worldwide (
      • Morawska L.
      • Milton D.K.
      It is time to address airborne transmission of COVID-19.
      ).
      It might also be possible for SARS-CoV-2 to be transmitted via the oral-fecal route as well. Supporting this, the fecal samples of some patients with COVID-19 were positive for the viral nucleic acid. However, the accuracy of this pattern of transmission needs more investigation (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ).
      There is documented data about the vertical transmission of SARS-CoV and MERS-CoV (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ;
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ). A mother with SARS-CoV is at increased risk for complications such as spontaneous miscarriage, intrauterine growth retardation, preterm labor, and coagulopathy problems (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ;
      • Mardani M.
      • Pourkaveh B.
      A controversial debate: Vertical transmission of COVID-19 in pregnancy.
      ). The data from six newborns born from mothers with COVID-19 showed that samples from amniotic fluid and the umbilical cord lacked SARS-CoV-2 RNA. Also, the neonatal pharynx sample and mother breastmilk were negative for the nuclear acid of COVID-19 (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ). The results of another study in china on nine mothers who had COVID-19 associated pneumonia were similar to the previous one, and there was no virus detected in all samples. The Apgar score of nine neonates was high, and there were no signs of asphyxia in them (
      • Mardani M.
      • Pourkaveh B.
      A controversial debate: Vertical transmission of COVID-19 in pregnancy.
      ). The current evidence is not enough to conclude that SARS-CoV-2 can be transmitted from an infected mother to her fetus (
      • Favre G.
      • Pomar L.
      • Qi X.
      • Nielsen-Saines K.
      • Musso D.
      • Baud D.
      Guidelines for pregnant women with suspected SARS-CoV-2 infection.
      ;
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ;
      • Mirbeyk M.
      • Rezaei N.
      The impact of COVID-19 on pregnancy and neonatal health: A systematic review.
      ). Because the perinatal transmission is suspicious, pregnant women who have a history of travel to affected areas or have a history of exposure to infected patients are recommended to be tested for COVID-19, even if they are asymptomatic (
      • Favre G.
      • Pomar L.
      • Qi X.
      • Nielsen-Saines K.
      • Musso D.
      • Baud D.
      Guidelines for pregnant women with suspected SARS-CoV-2 infection.
      ).
      The outbreak of SARS-CoV is related to wildlife (
      • Daszak P.
      • Olival K.J.
      • Li H.
      A strategy to prevent future epidemics similar to the 2019-nCoV outbreak.
      ). The source of MERS-CoV infections may be related to camels. The origin of the novel coronavirus is not completely clear, but a zoonotic origin of the disease is well-documented. The first confirmed cases of COVID-19 were related to markets that sell seafood, the meat of wild animals (
      • Daszak P.
      • Olival K.J.
      • Li H.
      A strategy to prevent future epidemics similar to the 2019-nCoV outbreak.
      ), snakes, and other animals like livestock animals and live rabbits too. Furthermore, high similarities between the SARS-CoV-2 and bat coronaviruses support the bat origin of SARS-CoV-2 (
      • Perlman S.
      Another decade, another coronavirus.
      ).

      Diagnosis

      First of all, the history of exposure to infected patients or travel to the affected areas and laboratory data such as procalcitonin (PCT), complete blood count, and C-reactive protein can help us to diagnose this infection (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ). A very advantageous instrument for distinguishing SARS infected children from the others is real-time reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR is also used for MERS-CoV nucleic acid detection, too (
      • Schuster J.E.
      • Williams J.V.
      Emerging respiratory viruses in children.
      ). It takes a few hours for the test to count the RNA viruses in the serum (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ). However, the value of conventional RT-PCR decreases along the first week of the SARS-COV infection (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ), and its sensitivity is not acceptable. In a study of pediatric cases with SARS, conventional RT-PCR of fecal and nasopharyngeal specimens could detect less than 50% of real patients (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ). Laboratory findings of SARS-COV in children include increased lactate dehydrogenase (LDH), decreased neutrophil count, and elevated creatinine phosphokinase (CPK) (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ). Incomplete airspace filling at the edge of the lung indicates the SARS-CoV infection.
      Nowadays, the nucleic acid test is the gold standard for the diagnosis of COVID-19 (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ). Among the specimens taken for the diagnosis of COVID-19, the most convenient one is nasopharyngeal swab, with the sensitivity rate close to 50% and less (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ). Lower respiratory tract secretions such as bronchoalveolar lavage fluid that contains a high amount of viral RNA are more valid specimens for the detection of the novel coronavirus (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ;
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ). Also, the pharyngeal swab was used one day after labor for an asymptomatic newborn infected with COVID-19 (). Some children who tested negative for COVID-19 might be infected with this virus and could spread the virus among other people, so the test should be repeated for them (). Imaging data could help us with the diagnosis of COVID-19 in children. High resolution computed tomography (HRCT) can be more helpful than a chest X-ray in this regard. Imaging abnormalities related to COVID-19 include ground-glass opacities (GGO) and peribronchial thickening (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ).

      Predisposing factors

      Among children affected by SARS-CoV and MERS-CoV, females are infected slightly more than males (
      • Al-Sehaibany F.S.
      Middle East respiratory syndrome in children. Dental considerations.
      ;
      • Chang L.Y.
      • Huang F.Y.
      • Wu Y.C.
      • Su I.J.
      • Chiu N.C.
      • Chen K.T.
      • et al.
      Childhood severe acute respiratory syndrome in Taiwan and how to differentiate it from childhood influenza infection.
      ;
      • Hon K.L.
      • Leung C.W.
      • Cheng W.T.
      • Chan P.K.
      • Chu W.C.
      • Kwan Y.W.
      • et al.
      Clinical presentations and outcome of severe acute respiratory syndrome in children.
      ;
      • Memish Z.A.
      • Al-Tawfiq J.A.
      • Assiri A.
      • AlRabiah F.A.
      • Al Hajjar S.
      • Albarrak A.
      • et al.
      Middle East respiratory syndrome coronavirus disease in children.
      ;
      • Thabet F.
      • Chehab M.
      • Bafaqih H.
      • Al M.S.
      Middle East respiratory syndrome coronavirus in children.
      ). Most of the children with SARS did not have underlying conditions except for two children reported with epilepsy and spontaneous pneumothorax. In contrast, children with MERS showed underlying diseases, like renal failure, cystic fibrosis, and Down syndrome. Also, coinfection with influenza is reported in children with MERS (
      • Bartenfeld M.
      • Griese S.
      • Uyeki T.
      • Gerber S.I.
      • Peacock G.
      Middle East respiratory syndrome coronavirus and children.
      ;
      • Chang L.Y.
      • Huang F.Y.
      • Wu Y.C.
      • Su I.J.
      • Chiu N.C.
      • Chen K.T.
      • et al.
      Childhood severe acute respiratory syndrome in Taiwan and how to differentiate it from childhood influenza infection.
      ;
      • Memish Z.A.
      • Al-Tawfiq J.A.
      • Assiri A.
      • AlRabiah F.A.
      • Al Hajjar S.
      • Albarrak A.
      • et al.
      Middle East respiratory syndrome coronavirus disease in children.
      ;
      • Thabet F.
      • Chehab M.
      • Bafaqih H.
      • Al M.S.
      Middle East respiratory syndrome coronavirus in children.
      ). Searching the exposure history of contaminated children, the majority of them had at least one of the history of traveling to endemic areas, contact with health care workers, household contact, or experiencing community outbreaks in 14 days before the initiation of the disease (
      • Bartenfeld M.
      • Griese S.
      • Uyeki T.
      • Gerber S.I.
      • Peacock G.
      Middle East respiratory syndrome coronavirus and children.
      ;
      • Chang L.Y.
      • Huang F.Y.
      • Wu Y.C.
      • Su I.J.
      • Chiu N.C.
      • Chen K.T.
      • et al.
      Childhood severe acute respiratory syndrome in Taiwan and how to differentiate it from childhood influenza infection.
      ;
      • Hon K.L.
      • Leung C.W.
      • Cheng W.T.
      • Chan P.K.
      • Chu W.C.
      • Kwan Y.W.
      • et al.
      Clinical presentations and outcome of severe acute respiratory syndrome in children.
      ;
      • Memish Z.A.
      • Al-Tawfiq J.A.
      • Assiri A.
      • AlRabiah F.A.
      • Al Hajjar S.
      • Albarrak A.
      • et al.
      Middle East respiratory syndrome coronavirus disease in children.
      ;
      • Ng P.C.
      • Leung C.W.
      • Chiu W.K.
      • Wong S.F.
      • Hon E.K.
      SARS in newborns and children.
      ;
      • Thabet F.
      • Chehab M.
      • Bafaqih H.
      • Al M.S.
      Middle East respiratory syndrome coronavirus in children.
      ).
      Previously it was thought that among children with COVID-19, female ones are affected more than male ones. However, recent reports show the reverse, raising the need to further surveys to investigate the issue. The manifestations of COVID-19 vary from asymptomatic, mild, and moderate to severe and critical ones. Some of the underlying conditions like malnutrition, congenital heart disease, and hydronephrosis might make children susceptible to severe COVID-19. Moreover, children may develop respiratory coinfections like mycoplasma pneumonia, influenza virus, Epstein-Barr virus, respiratory syncytial virus, parainfluenza virus, and adenovirus (
      • Lu Q.
      • Shi Y.
      Coronavirus disease (COVID-19) and neonate: What neonatologist need to know.
      ;
      • Shen K.L.
      • Yang Y.H.
      Diagnosis and treatment of 2019 novel coronavirus infection in children: A pressing issue.
      ;
      • Wong J.E.
      • Leo Y.S.
      • Tan C.C.
      COVID-19 in Singapore—Current experience: Critical global issues that require attention and action.
      ;
      • Xia W.
      • Shao J.
      • Guo Y.
      • Peng X.
      • Li Z.
      • Hu D.
      Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults.
      ;

      Zhang C, Gu J, Chen Q, Deng N, Li J, Huang L, et al. 2020.

      ).
      Possible sources of infection in children affected by COVID-19 include contact with infected adults (with the history of travel to endemic areas or contact with a person living in such areas), having at least one family member infected with COVID-19, presence in population clusters, living in or traveling to affected areas, having visited a hospital or a history of contact with animals (
      • Cai J.
      • Xu J.
      • Lin D.
      • Yang Z.
      • Xu L.
      • Qu Z.
      • et al.
      A case series of children with 2019 novel coronavirus infection: Clinical and epidemiological features.
      ;
      • Chen Z.M.
      • Fu J.F.
      • Shu Q.
      • Chen Y.H.
      • Hua C.Z.
      • Li F.B.
      • et al.
      Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus.
      ;
      • Shen K.L.
      • Yang Y.H.
      Diagnosis and treatment of 2019 novel coronavirus infection in children: A pressing issue.
      ;
      • Wang Y.
      • Wang Y.
      • Chen Y.
      • Qin Q.
      Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures.
      ;
      • Yang P.
      • Liu P.
      • Li D.
      • Zhao D.
      Corona Virus Disease 2019, A growing threat to children?.
      ). Vertical transmission from infected mothers needs further investigations to be clarified as a predisposing factor (
      • Chen H.
      • Guo J.
      • Wang C.
      • Luo F.
      • Yu X.
      • Zhang W.
      • et al.
      Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records.
      ;
      • Liu W.
      • Wang Q.
      • Zhang Q.
      • Chen L.
      • Chen J.
      • Zhang B.
      • et al.
      Coronavirus Disease 2019 (COVID-19) during pregnancy: A case series.
      ;
      • Lu Q.
      • Shi Y.
      Coronavirus disease (COVID-19) and neonate: What neonatologist need to know.
      ;
      • Zhu H.
      • Wang L.
      • Fang C.
      • Peng S.
      • Zhang L.
      • Chang G.
      • et al.
      Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
      ).

      Prevention

      In a case-control study in five hospitals in Hong Kong, Seto et al. revealed that the use of masks could markedly reduce the risk of SARS-CoV infection among healthcare workers. Among surveyed noninfected staff members who wore masks, 15.3% of them were reported to have used paper masks, 30.7% surgical masks, and 54.4%, N95 masks. Contact and droplet precautions alone were shown to be sufficient to protect against SARS-CoV infection. Additionally, no marked difference was revealed between the surgical and N95 masks (
      • Seto W.H.
      • Tsang D.
      • Yung R.W.
      • Ching T.Y.
      • Ng T.K.
      • Ho M.
      • et al.
      Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).
      ). In its May 2003 interim Domestic Guidance on the use of respirators to prevent transmission of SARS, the US Centers for Disease Control and Prevention (CDC) reported that disposable N95 respirators are sufficient for routine airborne isolation precautions. However, in case N95 masks were not available, a surgical mask should be worn ((
      • (CDC) CfDCaP
      Interim Domestic Guidance on the Use of Respirators to Prevent Transmission of SARS 6 May.
      ). Regarding SARS, children with mild symptoms and patients with the common flu-like manifestations of the disease at the initial phase could transmit the infection, which demanded early detection and separation of these children (
      • Tian S.
      • Hu N.
      • Lou J.
      • Chen K.
      • Kang X.
      • Xiang Z.
      • et al.
      Characteristics of COVID-19 infection in Beijing.
      ;
      • Yang P.
      • Liu P.
      • Li D.
      • Zhao D.
      Corona Virus Disease 2019, A growing threat to children?.
      ). Also, suspension of schools, contact tracing, preparing wards with negative pressure ventilation for the infected patients, and practicing hygiene preventions by schools were recommended (
      • Leung T.F.
      • Wong G.W.
      • Hon K.L.
      • Fok T.F.
      Severe acute respiratory syndrome (SARS) in children: Epidemiology, presentation and management.
      ;
      • Li A.M.
      • Ng P.C.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ).
      Additionally, WHO supported the use of surgical (procedure) masks when caring for suspects with either possible or confirmed MERS-CoV infection as well as particulate respirators in case of aerosol-generating procedures ((
      • (WHO) WHO
      Infection prevention and control during health care for probable or confirmed cases of novel coronavirus (nCoV) infection: interim guidance.
      ). CDC also supported the use of particulate respirators additional to airborne precautions for all MERS patient care activities ((
      • (CDC) CfDCaP
      Interim Infection Prevention and Control Recommendations for Hospitalised Patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
      ). For MERS prevention, besides points stated for SARS, cooking or pasteurization of camel products and avoidance of contact with camels and their products, touching nose, eyes, and mouth while working with camels were considered (
      • Al-Tawfiq J.A.
      • Memish Z.A.
      An update on Middle East respiratory syndrome: 2 years later.
      ; ;
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ).
      COVID-19 has now turned into an endemic matter, which is spreading rapidly. In order to break this cascade of distribution, some preventive measures are needed both in society and healthcare levels. Some of the precautions needed to be considered by the healthcare system include early identification and isolation of the infected patients in wards with appropriate environmental ventilation, isolation of the neonates born from infected mothers and examining them for COVID-19, training the health care personnel to use adequate personal protective equipment, and optimization of medical intervention and personnel visiting in order to reduce nosocomial transmission. Besides, carrying patients with special vehicles and by fully protected staffs, standard elimination of the dischargeable productions of the patients, and isolation of the infants with the underlying disease early after delivery is necessary to be considered. For the public preventive measures, training via trustable sources, travel controlling and inhibition of the entry from endemic areas, the boundary of the population clusters and canceling the family unions, protection of the susceptible population, and probing the children of the families with at least one contaminated member should be regarded. Also, people should be trained to practice hand hygiene and surface cleaning, use protective outfits when visiting and taking care of the patients, control the source of infection and the route of transmission, and use protective tools while having contact with animals. It is required to disinfect the toys and provide specific protective equipment for children younger than 12 months (
      • Chen Z.M.
      • Fu J.F.
      • Shu Q.
      • Chen Y.H.
      • Hua C.Z.
      • Li F.B.
      • et al.
      Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus.
      ;
      • Lai C.C.
      • Shih T.P.
      • Ko W.C.
      • Tang H.J.
      • Hsueh P.R.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges.
      ;
      • Liu W.
      • Wang Q.
      • Zhang Q.
      • Chen L.
      • Chen J.
      • Zhang B.
      • et al.
      Coronavirus Disease 2019 (COVID-19) during pregnancy: A case series.
      ;
      • Lu Q.
      • Shi Y.
      Coronavirus disease (COVID-19) and neonate: What neonatologist need to know.
      ;
      • Shen K.L.
      • Yang Y.H.
      Diagnosis and treatment of 2019 novel coronavirus infection in children: A pressing issue.
      ;
      • Wang Y.
      • Wang Y.
      • Chen Y.
      • Qin Q.
      Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures.
      ;
      • Wei M.
      • Yuan J.
      • Liu Y.
      • Fu T.
      • Yu X.
      • Zhang Z.-J.
      Novel coronavirus infection in hospitalized infants under 1 year of age in China.
      ;
      • Wong J.E.
      • Leo Y.S.
      • Tan C.C.
      COVID-19 in Singapore—Current experience: Critical global issues that require attention and action.
      ;
      • Xu X.W.
      • Wu X.X.
      • Jiang X.G.
      • Xu K.J.
      • Ying L.J.
      • Ma C.L.
      • et al.
      Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.
      ;
      • Yang P.
      • Liu P.
      • Li D.
      • Zhao D.
      Corona Virus Disease 2019, A growing threat to children?.
      ). Furthermore, due to the immunologic and phylogenetic similarities between SARS-CoV, MERS-CoV, and SARS-CoV-2, infection control precautions may be extrapolated from the previous experience with MERS and SARS (
      • Jabbari P.
      • Jabbari F.
      • Ebrahimi S.
      • Rezaei N.
      COVID-19: A chimera of two pandemics.
      ). Moreover, Esposito et al. stated that the common use of facial masks is necessary for people's everyday outdoor lives. Masks of different sizes capable of perfectly adapting to the face should be available. Moreover, it is crucial that by strong parental work as well as school lessons on this issue, child cooperation is obtained, and thus, the use of masks in children is preceded (
      • Esposito S.
      • Principi N.
      To mask or not to mask children to overcome COVID-19.
      ). However, protecting healthy children with mask faces difficulties. Children younger than two years of age are recommended not to wear any type of masks since their very small airways might then struggle to breathe. Furthermore, since without assistance, they may be unable to remove the masks, they can be at high risk of suffocation ((
      • (CDC) CfDCaP
      Coronavirus disease 2019 (COVID-19). Use of cloth face coverings to help slow the spread of COVID-19 9 April.
      ). Surgical masks suitable for children from 3 to 12 years old are now widely marketed, and they can also be prepared at home from commonly available materials at low cost, according to the US Centers for Disease Prevention and Control (
      • Balasubramanian S.
      • Rao N.M.
      • Goenka A.
      • Roderick M.
      • Ramanan A.V.
      Coronavirus Disease 2019 (COVID-19) in children - what we know so far and what we do not.
      ).
      During the process of delivery in the infected mothers, merely essential staff with appropriate personal protective equipment should be present, and the mother has to wear masks and maintain hand hygiene. The resuscitation personnel should keep a distance of at least 2 m between the newborn and the mother. After the delivery, the mother should be encouraged to breastfeeding while wearing a mask (
      • Balasubramanian S.
      • Rao N.M.
      • Goenka A.
      • Roderick M.
      • Ramanan A.V.
      Coronavirus Disease 2019 (COVID-19) in children - what we know so far and what we do not.
      ). Tele triaging patients and quarantines are important strategies to be provided by the health care system (
      • Moazzami B.
      • Razavi-Khorasani N.
      • Dooghaie Moghadam A.
      • Farokhi E.
      • Rezaei N.
      COVID-19 and telemedicine: Immediate action required for maintaining healthcare providers well-being.
      ). People should be educated to practice appropriate interpersonal distance and to restrain themselves from touching their eyes and mouth with unwashed hands (
      • Adhikari S.P.
      • Meng S.
      • Wu Y.J.
      • Mao Y.P.
      • Ye R.X.
      • Wang Q.Z.
      • et al.
      Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review.
      ;
      • Unni J.C.
      Coronavirus Disease (COVID-19) with relevance to pediatrics.
      ).

      Treatment

      There is no specific antiviral drug to treat COVID-19, SARS, and MERS. The primary treatment of these conditions involves the correction of electrolyte and acid-base imbalance and oxygenation. In this context, there are no adequate clinical trials in pediatric cases. The treatment protocols for children are, therefore, similar to those for adults (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ).
      Studies recommend a combination of drug therapy for patients with MERS infection. This combination therapy consists of a nucleoside inhibitor named Ribavirin and subcutaneous interferons (IFNs) such as IFNα-2b and IFNβ. It could decrease pulmonary damage and boost the 14-day survival but failed to improve 28-day survival (
      • Schuster J.E.
      • Williams J.V.
      Emerging respiratory viruses in children.
      ;
      • Zumla A.
      • Hui D.S.
      • Perlman S.
      Middle East respiratory syndrome.
      ). Broad-spectrum antibiotics were considered for children with SARS who had symptoms of fever and pneumonia. In phase 2 of SARS infection, systemic corticosteroids might be administrated to regulate the immune system and reduce lung damage. Intravenous methylprednisolone pulse therapy was associated with better clinical and radiological outcomes in children with severe SARS infection (
      • Li A.
      • Ng P.
      Severe acute respiratory syndrome (SARS) in neonates and children.
      ).
      Corticosteroid therapy is also used in patients with severe COVID-19 (;
      • Saghazadeh A.
      • Rezaei N.
      Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids.
      ), even though the incorrect use of broad-spectrum antibiotics and corticosteroids could increase the mortality rate in adults with COVID-19. However, patients with severe COVID-19 disease might develop hyper inflammation and a cytokine storm (
      • Bahrami A.
      • Vafapour M.
      • Moazzami B.
      • Rezaei N.
      Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran.
      ;
      • Nasab M.G.
      • Saghazadeh A.
      • Rezaei N.
      SARS-CoV-2-a tough opponent for the immune system.
      ;
      • Rokni M.
      • Hamblin M.R.
      • Rezaei N.
      Cytokines and COVID-19: Friends or foes?.
      ;
      • Saghazadeh A.
      • Rezaei N.
      Immune-epidemiological parameters of the novel coronavirus - a perspective.
      ;
      • Yazdanpanah F.
      • Hamblin M.R.
      • Rezaei N.
      The immune system and COVID-19: Friend or foe?.
      ). Interestingly, COVID-19 seems to happen and become severe in people with primary immune deficiency disorders less than in the general population (
      • Ahanchian H.
      • Moazzen N.
      • Faroughi M.S.D.
      • Khalighi N.
      • Khoshkhui M.
      • Aelami M.H.
      • et al.
      COVID-19 in a child with primary specific antibody deficiency.
      ;
      • Babaha F.
      • Rezaei N.
      Primary immunodeficiency diseases in COVID-19 pandemic: A predisposing or protective factor?.
      ). This suggests the role of the immune system in contributing to COVID-19 (
      • Yazdanpanah F.
      • Hamblin M.R.
      • Rezaei N.
      The immune system and COVID-19: Friend or foe?.
      ) and therefore indicates the diagnosis and treatment of hyperinflammatory state as crucial for reducing mortality. Hence for this subgroup, immunosuppression using corticosteroids, Janus kinase (JAK) inhibitors, selective cytokine blockade, and intravenous immunoglobulin can be considered (
      • Jahanshahlu L.
      • Rezaei N.
      Monoclonal antibody as a potential anti-COVID-19.
      ;
      • Mansourabadi A.H.
      • Sadeghalvad M.
      • Mohammadi-Motlagh H.R.
      • Rezaei N.
      The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19.
      ;
      • Mehta P.
      • McAuley D.F.
      • Brown M.
      • Sanchez E.
      • Tattersall R.S.
      • Manson J.J.
      COVID-19: consider cytokine storm syndromes and immunosuppression.
      ;
      • Pashaei M.
      • Rezaei N.
      Immunotherapy for SARS-CoV-2: Potential opportunities.
      ;
      • Pourahmad R.
      • Moazzami B.
      • Rezaei N.
      Efficacy of Plasmapheresis and immunoglobulin replacement therapy (IVIG) on patients with COVID-19.
      ;
      • Ritchie A.I.
      • Singanayagam A.
      Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?.
      ).
      Moreover, a recent study investigated the role of extracorporeal membrane oxygenation (ECMO) in the management of severely ill individuals with confirmed COVID-19 who develop acute respiratory and cardiac compromise refractory to conventional therapies. This analysis of 32 COVID-19 patients with severe pulmonary compromise supported with ECMO stated that ECMO could be useful in salvaging critically ill participants with COVID-19. However, further studies are necessary to enhance our understanding of the role of ECMO in patients with COVID-19 and ARDS (
      • Jacobs J.P.
      • Stammers A.H.
      • St Louis J.
      • Hayanga J.W.A.
      • Firstenberg M.S.
      • Mongero L.B.
      • et al.
      Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus Disease 2019: Experience with 32 patients.
      ).
      Except in critical cases, children with COVID-19 did not require antiviral drug treatment because they could be recovered on their own (). The administration of Remdesivir seems to have positive effects (
      • Mohamed K.
      • Yazdanpanah N.
      • Saghazadeh A.
      • Rezaei N.
      Computational drug discovery and repurposing for the treatment of Covid-19: A systematic review.
      ), but its efficacy has not been proven for children.

      Current concerns on pediatric COVID-19

      Debate on the epidemiology of COVID-19 in children

      In the early stages of COVID-19, it was thought that children were rarely affected by the virus (
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
      ). However, current reports suggest that children are just as affected as adults but with milder symptoms, lower disease severity, and lower mortality (
      • Bi Q.
      • Wu Y.
      • Mei S.
      • Ye C.
      • Zou X.
      • Zhang Z.
      • et al.
      Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study.
      ;
      • Zimmermann P.
      • Curtis N.
      Coronavirus infections in children including COVID-19: An overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children.
      ). SARS-CoV-2 is transmitted through human-to-human contact and occurs within both family and social relationships (
      • Lotfi M.
      • Hamblin M.R.
      • Rezaei N.
      COVID-19: Transmission, prevention, and potential therapeutic opportunities.
      ). It is difficult for children, especially toddlers, to follow the principles of hygiene, and baby carriers are expected to transmit the COVID-19. The lack of awareness of the disease in affected children is another possible explanation for the high rate of disease transmission (
      • Fan C.
      • Lei D.
      • Fang C.
      • Li C.
      • Wang M.
      • Liu Y.
      • et al.
      Perinatal transmission of COVID-19 associated SARS-CoV-2: Should we worry?.
      ). Children are likely to expose themselves to other children, friends, and family members, and this directly correlates with the person to person transmission of COVID-19 (
      • Phan L.T.
      • Nguyen T.V.
      • Luong Q.C.
      • Nguyen T.V.
      • Nguyen H.T.
      • Le H.Q.
      • et al.
      Importation and human-to-human transmission of a novel coronavirus in Vietnam.
      ).

      PCR limitation and antibody detection

      There are many limitations to the PCR method, such as high rates of people with false-negative tests. It also takes a long time for the PCR test to tell us the result, so rapid tests are needed to prevent the spread of the coronavirus from suspect cases to the general population (
      • Basiri A.
      • Heidari A.
      • Nadi M.F.
      • Fallahy M.T.P.
      • Nezamabadi S.S.
      • Sedighi M.
      • et al.
      Microfluidic devices for detection of RNA viruses.
      ).
      Serological testing based on antibodies can be used for patients with asymptomatic infection. Recently studies reported the development of rapid antibody tests with the use of nucleocapsid and spike proteins as antigens. These tests work based on the detection of both IgG and IgM antibodies in whole blood or serum samples simultaneously. They might take about 15 min and have reasonable specificity and sensitivity (
      • GeurtsvanKessel C.H.
      • Okba N.M.A.
      • Igloi Z.
      • Bogers S.
      • Embregts C.W.E.
      • Laksono B.M.
      • et al.
      An evaluation of COVID-19 serological assays informs future diagnostics and exposure assessment.
      ;
      • Li Z.
      • Yi Y.
      • Luo X.
      • Xiong N.
      • Liu Y.
      • Li S.
      • et al.
      Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis.
      ;
      • Long Q.-X.
      • Liu B.-Z.
      • Deng H.-J.
      • Wu G.-C.
      • Deng K.
      • Chen Y.-K.
      • et al.
      Antibody responses to SARS-CoV-2 in patients with COVID-19.
      ).

      Asymptomatic infection in children

      6.7% of children get the infection severely, and the rest is known as asymptomatic carriers. It is, therefore, essential to identify asymptomatic or mild infected children to prevent the virus from spreading (
      • Tezer H.
      • Bedir D.T.
      Novel coronavirus disease (COVID-19) in children.
      ). Based on the current evidence, viral load in symptomatic cases and asymptomatic carriers is approximately the same. The late identification of asymptomatic carriers makes them a source of uncontrollable infection (
      • Yu X.
      • Yang R.
      COVID-19 transmission through asymptomatic carriers is a challenge to containment.
      ). As a result, paying attention to children who get the infection less severe than adults and identifying early asymptomatic ones will help prevent the transmission of the virus (
      • Ciuca I.M.
      COVID-19 in children: An ample review.
      ).

      Social-emotional functioning in children during the pandemic

      According to the recommendations of the WHO, it is better not to separate children from their families during this pandemic and ask children to speak about their emotions to give them a sense of calm. There are simple but effective ways to entertain children, such as painting or playing with them. Depending on the age of the children, it is appropriate to provide them with useful disease-related information to the extent of their understanding because they will become more curious during the crisis and ask more questions of their parents (
      • WHO
      Mental health and psychosocial considerations during the COVID-19 outbreak.
      ). According to the behavioral research conducted on children aged between 3 and 18 in Shaanxi, clinginess is the most prevalent problem, especially in younger children (3–6 years old). Since children in epidemic areas suffer from fear, using media as a hobby could help them to forget about their bad feelings (
      • Jiao W.Y.
      • Wang L.N.
      • Liu J.
      • Fang S.F.
      • Jiao F.Y.
      • Pettoello-Mantovani M.
      • et al.
      Behavioral and Emotional Disorders in Children during the COVID-19 Epidemic.
      ).

      Conclusion

      In the past two decades, the world has witnessed three outbreaks caused by coronaviruses: SARS-CoV, MERS-CoV, and SARS-CoV-2. Studies propose a zoonotic origin for these three coronaviruses. These pathogens can affect pediatrics as well as adults. However, the majority of the children show mild manifestations except for the ones with underlying conditions. Among pediatrics, the main signs and symptoms include fever, respiratory symptoms, and other flu-like manifestations. Nucleic acid tests and imaging techniques are used for the diagnosis. Serological tests have reasonable specificity and sensitivity and can also be used for diagnosis of a new infection, recent infection, and re-infection as well (
      • Jabbari P.
      • Rezaei N.
      With risk of reinfection, is COVID-19 Here to stay?.
      ). Public education for practicing hygiene and contact avoidance with infected patients, as well as isolation of the contaminated people, should be taken into consideration. As no precise drug treatment has been discovered up to date, supportive and symptom alleviating treatments are the principal therapies. However, regenerative medicine and targeted therapies pose potentials to the COVID-19 (
      • Basiri A.
      • Pazhouhnia Z.
      • Beheshtizadeh N.
      • Hoseinpour M.
      • Saghazadeh A.
      • Rezaei N.
      Regenerative medicine in COVID-19 treatment: Real opportunities and range of promises.
      ;
      • Fathi N.
      • Rezaei N.
      Lymphopenia in COVID-19: Therapeutic opportunities.
      ;
      • Mansourabadi A.H.
      • Sadeghalvad M.
      • Mohammadi-Motlagh H.R.
      • Rezaei N.
      The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19.
      ;
      • Pashaei M.
      • Rezaei N.
      Immunotherapy for SARS-CoV-2: Potential opportunities.
      ;
      • Rabiee N.
      • Rabiee M.
      • Bagherzadeh M.
      • Rezaei N.
      COVID-19 and picotechnology: Potential opportunities.
      ;
      • Rezaei N.
      COVID-19 and medical biotechnology.
      ;
      • Sharifkashani S.
      • Bafrani M.A.
      • Khaboushan A.S.
      • Pirzadeh M.
      • Kheirandish A.
      • Yavarpour Bali H.
      • et al.
      Angiotensin-converting enzyme 2 (ACE2) receptor and SARS-CoV-2: Potential therapeutic targeting.
      ). The potentials need testing at large, and this would be well-achieved when all collaborate (
      • Kafieh R.
      • Arian R.
      • Saeedizadeh N.
      • Minaee S.
      • Yadav S.K.
      • Vaezi A.
      • et al.
      COVID-19 in Iran: A Deeper Look Into The Future.
      ;
      • Mohamed K.
      • Rodríguez-Román E.
      • Rahmani F.
      • Zhang H.
      • Ivanovska M.
      • Makka S.A.
      • et al.
      Borderless collaboration is needed for COVID-19-a disease that knows no borders.
      ;
      • Momtazmanesh S.
      • Ochs H.D.
      • Uddin L.Q.
      • Perc M.
      • Routes J.M.
      • Vieira D.N.
      • et al.
      All together to fight COVID-19.
      ;
      • Moradian N.
      • Ochs H.D.
      • Sedikies C.
      • Hamblin M.R.
      • Camargo Jr., C.A.
      • Martinez J.A.
      • et al.
      The urgent need for integrated science to fight COVID-19 pandemic and beyond.
      ;
      • Rzymski P.
      • Nowicki M.
      • Mullin G.E.
      • Abraham A.
      • Rodríguez-Román E.
      • Petzold M.B.
      • et al.
      Quantity does not equal quality: Scientific principles cannot be sacrificed.
      ).

      Ethics approval and consent to participate

      Not applicable.

      Consent for publication

      Not applicable.

      Availability of data and materials

      Not applicable.

      Funding

      There is no funding for the present study.

      Authors' contributions

      E.A.D., F.S., N.D., and Z.R. conceptualized the study and prepared the initial draft. A.S. prepared the final draft. N.R. supervised the project and critically appraised the manuscript.

      Declaration of Competing Interest

      The authors declare that they have no competing interests.

      Acknowledgments

      Not applicable.

      References

        • (CDC) CfDCaP
        Interim Domestic Guidance on the Use of Respirators to Prevent Transmission of SARS 6 May.
        2003 (Available from)
        • (CDC) CfDCaP
        Interim Infection Prevention and Control Recommendations for Hospitalised Patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
        (February 13)2014
        • (CDC) CfDCaP
        Coronavirus disease 2019 (COVID-19) - social distancing, quarantine, and isolation.
        2020 (15 July 2020 [Available from)
        • (CDC) CfDCaP
        Coronavirus disease 2019 (COVID-19). Use of cloth face coverings to help slow the spread of COVID-19 9 April.
        2020 (Available from)
        • (PICS) PICS
        PICS Statement: Increased number of reported cases of novel presentation of multi-system inflammatory disease.
        (29 April)2020
        • (WHO) WHO
        Infection prevention and control during health care for probable or confirmed cases of novel coronavirus (nCoV) infection: interim guidance.
        (6 May)2013
        • (WHO) WHO
        Coronavirus disease (COVID-2019) situation reports (Geneva, Switzerland).
        2020 (15 July 2020 [Available from)
        • Abrams J.Y.
        • Godfred-Cato S.E.
        • Oster M.E.
        • Chow E.J.
        • Koumans E.H.
        • Bryant B.
        • et al.
        Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: A systematic review.
        The Journal of Pediatrics. 2020; 226: 45-54.e1
        • Adhikari S.P.
        • Meng S.
        • Wu Y.J.
        • Mao Y.P.
        • Ye R.X.
        • Wang Q.Z.
        • et al.
        Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review.
        Infectious Diseases of Poverty. 2020; 9: 29
        • Ahanchian H.
        • Moazzen N.
        • Faroughi M.S.D.
        • Khalighi N.
        • Khoshkhui M.
        • Aelami M.H.
        • et al.
        COVID-19 in a child with primary specific antibody deficiency.
        2020
        • Ahmadi M.
        • Saffarzadeh N.
        • Habibi M.A.
        • Hajiesmaeili F.
        • Rezaei N.
        Colon cancer and SARS-CoV-2: impact of ACE2 expression in susceptibility to COVID-19.
        bioRxiv. 2020; https://doi.org/10.1101/2020.06.11.146878
        • Alsaad K.O.
        • Hajeer A.H.
        • Al Balwi M.
        • Al Moaiqel M.
        • Al Oudah N.
        • Al Ajlan A.
        • et al.
        Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection – Clinicopathological and ultrastructural study.
        Histopathology. 2018; 72: 516-524
        • Al-Sehaibany F.S.
        Middle East respiratory syndrome in children. Dental considerations.
        Saudi Medical Journal. 2017; 38: 339-343
        • Al-Tawfiq J.A.
        • Memish Z.A.
        An update on Middle East respiratory syndrome: 2 years later.
        Expert Review of Respiratory Medicine. 2015; 9: 327-335
        • Andersen K.G.
        • Rambaut A.
        • Lipkin W.I.
        • Holmes E.C.
        • Garry R.F.
        The proximal origin of SARS-CoV-2.
        Nature Medicine. 2020; 26: 450-452
        • Babaha F.
        • Rezaei N.
        Primary immunodeficiency diseases in COVID-19 pandemic: A predisposing or protective factor?.
        The American Journal of the Medical Sciences. 2020; https://doi.org/10.1016/j.amjms.2020.07.027
        • Bahrami A.
        • Vafapour M.
        • Moazzami B.
        • Rezaei N.
        Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran.
        Journal of Paediatrics and Child Health. 2020; https://doi.org/10.1111/jpc.15048
        • Bahrami A.
        • Vafapour M.
        • Moazzami B.
        • Rezaei N.
        Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: First case from Iran.
        Journal of Paediatrics and Child Health. 2020; https://doi.org/10.1111/jpc.15048
        • Balasubramanian S.
        • Rao N.M.
        • Goenka A.
        • Roderick M.
        • Ramanan A.V.
        Coronavirus Disease 2019 (COVID-19) in children - what we know so far and what we do not.
        Indian Pediatrics. 2020; 57: 435-442
        • Bartenfeld M.
        • Griese S.
        • Uyeki T.
        • Gerber S.I.
        • Peacock G.
        Middle East respiratory syndrome coronavirus and children: What pediatric health care professionals need to know.
        Clinical Pediatrics. 2017; 56: 187-189
        • Bartenfeld M.
        • Griese S.
        • Uyeki T.
        • Gerber S.I.
        • Peacock G.
        Middle East respiratory syndrome coronavirus and children.
        Clinical Pediatrics. 2017; 56: 187-189
        • Basiri A.
        • Heidari A.
        • Nadi M.F.
        • Fallahy M.T.P.
        • Nezamabadi S.S.
        • Sedighi M.
        • et al.
        Microfluidic devices for detection of RNA viruses.
        Reviews in Medical Virology. 2020; : e2154https://doi.org/10.1002/rmv.2154
        • Basiri A.
        • Pazhouhnia Z.
        • Beheshtizadeh N.
        • Hoseinpour M.
        • Saghazadeh A.
        • Rezaei N.
        Regenerative medicine in COVID-19 treatment: Real opportunities and range of promises.
        Stem Cell Reviews and Reports. 2020; : 1-13
        • Belhadjer Z.
        • Méot M.
        • Bajolle F.
        • Khraiche D.
        • Legendre A.
        • Abakka S.
        • et al.
        Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic.
        Circulation. 2020; 142: 429-436
        • Bermingham A.
        • Chand M.
        • Brown C.
        • Aarons E.
        • Tong C.
        • Langrish C.
        • et al.
        Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012.
        Eurosurveillance. 2012; 17: 20290
        • Bi Q.
        • Wu Y.
        • Mei S.
        • Ye C.
        • Zou X.
        • Zhang Z.
        • et al.
        Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study.
        The Lancet Infectious Diseases. 2020; 20: 911-919
        • Bitnun A.
        • Allen U.
        • Heurter H.
        • King S.M.
        • Opavsky M.A.
        • Ford-Jones E.L.
        • et al.
        Children hospitalized with severe acute respiratory syndrome-related illness in Toronto.
        Pediatrics. 2003; 112e261
        • Bosch B.J.
        • Raj V.S.
        • Haagmans B.L.
        Spiking the MERS-coronavirus receptor.
        Cell Research. 2013; 23: 1069-1070
        • Cai J.
        • Xu J.
        • Lin D.
        • Yang Z.
        • Xu L.
        • Qu Z.
        • et al.
        A case series of children with 2019 novel coronavirus infection: Clinical and epidemiological features.
        Clinical Infectious Diseases. 2020; 71 (Article En | MEDLINE | ID: mdl-32112072): 1547-1551
        • Chang L.Y.
        • Huang F.Y.
        • Wu Y.C.
        • Su I.J.
        • Chiu N.C.
        • Chen K.T.
        • et al.
        Childhood severe acute respiratory syndrome in Taiwan and how to differentiate it from childhood influenza infection.
        Archives of Pediatrics & Adolescent Medicine. 2004; 158: 1037-1042
        • Chen C.
        • Cao M.
        • Peng L.
        • Guo X.
        • Yang F.
        • Wu W.
        • et al.
        Coronavirus Disease-19 Among Children outside Wuhan, China. China (2/25/2020).
        2020
        • Chen H.
        • Guo J.
        • Wang C.
        • Luo F.
        • Yu X.
        • Zhang W.
        • et al.
        Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records.
        The Lancet. 2020; 395: 809-815
        • Chen Y.
        • Liu Q.
        • Guo D.
        Emerging coronaviruses: Genome structure, replication, and pathogenesis.
        Journal of Medical Virology. 2020; 92: 418-423
        • Chen Z.M.
        • Fu J.F.
        • Shu Q.
        • Chen Y.H.
        • Hua C.Z.
        • Li F.B.
        • et al.
        Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus.
        World Journal of Pediatrics. 2020; 16: 240-246https://doi.org/10.1007/s12519-020-00345-5
        • Cheung E.W.
        • Zachariah P.
        • Gorelik M.
        • Boneparth A.
        • Kernie S.G.
        • Orange J.S.
        • et al.
        Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City.
        JAMA. 2020; 324: 294-296
        • Chin A.W.
        • Poon L.L.
        Stability of SARS-CoV-2 in different environmental conditions–Authors’ reply.
        The Lancet Microbe. 2020; 1e146
        • Ciuca I.M.
        COVID-19 in children: An ample review.
        Risk Manag Healthc Policy. 2020; 13: 661-669
        • Control ECfDPa
        Rapid risk assessment: Pediatric inflammatory multisystem syndrome and SARS -CoV-2 infection in children.
        European Centre for Disease Prevention and Control. 2020;
        • Cowling B.J.
        • Park M.
        • Fang V.J.
        • Wu P.
        • Leung G.M.
        • Wu J.T.
        Preliminary epidemiologic assessment of MERS-CoV outbreak in South Korea, May–June 2015.
        Euro Surveillance: Bulletin Europeen sur les Maladies Transmissibles= European Communicable Disease Bulletin. 2015; 20
        • Darbeheshti F.
        • Rezaei N.
        Genetic predisposition models to COVID-19 infection.
        Medical Hypotheses. 2020; 142: 109818
        • Das K.M.
        • Lee E.Y.
        • Enani M.A.
        • AlJawder S.E.
        • Singh R.
        • Bashir S.
        • et al.
        CT correlation with outcomes in 15 patients with acute Middle East respiratory syndrome coronavirus.
        AJR American Journal of Roentgenology. 2015; 204: 736-742
        • Daszak P.
        • Olival K.J.
        • Li H.
        A strategy to prevent future epidemics similar to the 2019-nCoV outbreak.
        Biosafety and Health. 2020; 2: 6-8
        • Dietz S.
        • Van Stijn D.
        • Burgner D.
        • Levin M.
        • Kuipers I.
        • Hutten B.
        • et al.
        Dissecting Kawasaki disease: A state-of-the-art review.
        European Journal of Pediatrics. 2017; 176: 995-1009
      1. Disease-a-month : DM. 2017; 63: 262-272
        • Drosten C.
        • Meyer B.
        • Muller M.A.
        • Corman V.M.
        • Al-Masri M.
        • Hossain R.
        • et al.
        Transmission of MERS-coronavirus in household contacts.
        The New England Journal of Medicine. 2014; 371: 828-835
        • Esposito S.
        • Principi N.
        To mask or not to mask children to overcome COVID-19.
        European Journal of Pediatrics. 2020; 1
        • Fan C.
        • Lei D.
        • Fang C.
        • Li C.
        • Wang M.
        • Liu Y.
        • et al.
        Perinatal transmission of COVID-19 associated SARS-CoV-2: Should we worry?.
        Clinical Infectious Diseases. 2020; (PMID: 32182347 PMCID: PMC7184438)https://doi.org/10.1093/cid/ciaa226
        • Fathi N.
        • Rezaei N.
        Lymphopenia in COVID-19: Therapeutic opportunities.
        Cell Biology International. 2020; 44: 1792-1797
        • Favre G.
        • Pomar L.
        • Qi X.
        • Nielsen-Saines K.
        • Musso D.
        • Baud D.
        Guidelines for pregnant women with suspected SARS-CoV-2 infection.
        The Lancet Infectious Diseases. 2020; 20: 652-653
        • GeurtsvanKessel C.H.
        • Okba N.M.A.
        • Igloi Z.
        • Bogers S.
        • Embregts C.W.E.
        • Laksono B.M.
        • et al.
        An evaluation of COVID-19 serological assays informs future diagnostics and exposure assessment.
        Nature Communications. 2020; 11: 3436
        • Guarner J.
        Three emerging coronaviruses in two decades: The story of SARS, MERS, and now COVID-19.
        Oxford University Press US, 2020
        • Guy J.S.
        • Breslin J.J.
        • Breuhaus B.
        • Vivrette S.
        • Smith L.G.
        Characterization of a coronavirus isolated from a diarrheic foal.
        Journal of Clinical Microbiology. 2000; 38: 4523-4526
        • Hanaei S.
        • Rezaei N.
        COVID-19: Developing from an outbreak to a pandemic.
        Archives of Medical Research. 2020; 51: 582-584
        • Heymann D.L.
        • Shindo N.
        COVID-19: what is next for public health?.
        Lancet (London, England). 2020; 395: 542-545
        • Hon K.L.
        • Leung C.W.
        • Cheng W.T.
        • Chan P.K.
        • Chu W.C.
        • Kwan Y.W.
        • et al.
        Clinical presentations and outcome of severe acute respiratory syndrome in children.
        Lancet (London, England). 2003; 361: 1701-1703
        • Huang C.
        • Wang Y.
        • Li X.
        • Ren L.
        • Zhao J.
        • Hu Y.
        • et al.
        Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
        The Lancet. 2020; 395: 497-506
        • Hui D.S.
        • I Azhar E.
        • Madani T.A.
        • Ntoumi F.
        • Kock R.
        • Dar O.
        • et al.
        The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China.
        International Journal of Infectious Diseases. 2020; 91: 264-266
        • Hui D.S.
        • Sung J.J.
        Severe acute respiratory syndrome.
        Chest. 2003; 124: 12-15
        • Jabbari P.
        • Jabbari F.
        • Ebrahimi S.
        • Rezaei N.
        COVID-19: A chimera of two pandemics.
        Disaster Medicine and Public Health Preparedness. 2020; : 1-2
        • Jabbari P.
        • Rezaei N.
        With risk of reinfection, is COVID-19 Here to stay?.
        Disaster Medicine and Public Health Preparedness. 2020; 1
        • Jacobs J.P.
        • Stammers A.H.
        • St Louis J.
        • Hayanga J.W.A.
        • Firstenberg M.S.
        • Mongero L.B.
        • et al.
        Extracorporeal membrane oxygenation in the treatment of severe pulmonary and cardiac compromise in coronavirus Disease 2019: Experience with 32 patients.
        ASAIO Journal. 2020; 66: 722-730
        • Jahanshahlu L.
        • Rezaei N.
        Central nervous system involvement in COVID-19.
        Archives of Medical Research. 2020; (PMID: 32471704 PMCID: PMC7242947)https://doi.org/10.1016/j.arcmed.2020.05.016
        • Jahanshahlu L.
        • Rezaei N.
        Monoclonal antibody as a potential anti-COVID-19.
        Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2020; 129: 110337
        • Jiao W.Y.
        • Wang L.N.
        • Liu J.
        • Fang S.F.
        • Jiao F.Y.
        • Pettoello-Mantovani M.
        • et al.
        Behavioral and Emotional Disorders in Children during the COVID-19 Epidemic.
        J Pediatr. 2020; 221 (e1): 264-266
        • Kafieh R.
        • Arian R.
        • Saeedizadeh N.
        • Minaee S.
        • Yadav S.K.
        • Vaezi A.
        • et al.
        COVID-19 in Iran: A Deeper Look Into The Future.
        medRxiv. 2020; (preprint)
        • Ksiazek T.G.
        • Erdman D.
        • Goldsmith C.S.
        • Zaki S.R.
        • Peret T.
        • Emery S.
        • et al.
        A novel coronavirus associated with severe acute respiratory syndrome.
        New England Journal of Medicine. 2003; 348: 1953-1966
        • Lai C.C.
        • Shih T.P.
        • Ko W.C.
        • Tang H.J.
        • Hsueh P.R.
        Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges.
        International Journal of Antimicrobial Agents. 2020; 55: 105924
        • Lai C.-C.
        • Shih T.-P.
        • Ko W.-C.
        • Tang H.-J.
        • Hsueh P.-R.
        Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): The epidemic and the challenges.
        International Journal of Antimicrobial Agents. 2020; 105924
        • Lau J.T.
        • Fung K.S.
        • Wong T.W.
        • Kim J.H.
        • Wong E.
        • Chung S.
        • et al.
        SARS transmission among hospital workers in Hong Kong.
        Emerging Infectious Diseases. 2004; 10: 280-286
        • Leung C.W.
        • Chiu W.K.
        Clinical picture, diagnosis, treatment and outcome of severe acute respiratory syndrome (SARS) in children.
        Paediatric Respiratory Reviews. 2004; 5: 275-288
        • Leung T.F.
        • Wong G.W.
        • Hon K.L.
        • Fok T.F.
        Severe acute respiratory syndrome (SARS) in children: Epidemiology, presentation and management.
        Paediatric Respiratory Reviews. 2003; 4: 334-339
        • Li A.
        • Ng P.
        Severe acute respiratory syndrome (SARS) in neonates and children.
        Archives of Disease in Childhood-Fetal and Neonatal Edition. 2005; 90 (F461-F5)
        • Li A.
        • Ng P.
        Severe acute respiratory syndrome (SARS) in neonates and children.
        Archives of Disease in Childhood Fetal and Neonatal Edition. 2005; 90: F461-F465
        • Li A.M.
        • Ng P.C.
        Severe acute respiratory syndrome (SARS) in neonates and children.
        Archives of Disease in Childhood Fetal and Neonatal Edition. 2005; 90: F461-F465
        • Li J.
        • Zhang Y.
        • Wang F.
        • Liu B.
        • Li H.
        • Tang G.
        • et al.
        Sex differences in clinical findings among patients with coronavirus disease 2019 (COVID-19) and severe condition.
        medRxiv. 2020; (preprint)
        • Li Q.
        • Guan X.
        • Wu P.
        • Wang X.
        • Zhou L.
        • Tong Y.
        • et al.
        Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia.
        The New England Journal of Medicine. 2020; 382: 1199-1207
        • Li Z.
        • Yi Y.
        • Luo X.
        • Xiong N.
        • Liu Y.
        • Li S.
        • et al.
        Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis.
        Journal of Medical Virology. 2020; 92: 1518-1524
        • Liu W.
        • Wang Q.
        • Zhang Q.
        • Chen L.
        • Chen J.
        • Zhang B.
        • et al.
        Coronavirus Disease 2019 (COVID-19) during pregnancy: A case series.
        2020
        • Liu Y.
        • Ning Z.
        • Chen Y.
        • Guo M.
        • Liu Y.
        • Gali N.K.
        • et al.
        Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals.
        Nature. 2020; 582: 557-560
        • Long Q.-X.
        • Liu B.-Z.
        • Deng H.-J.
        • Wu G.-C.
        • Deng K.
        • Chen Y.-K.
        • et al.
        Antibody responses to SARS-CoV-2 in patients with COVID-19.
        Nature Medicine. 2020; 26: 845-848
        • Lotfi M.
        • Hamblin M.R.
        • Rezaei N.
        COVID-19: Transmission, prevention, and potential therapeutic opportunities.
        Clinica Chimica Acta; International Journal of Clinical Chemistry. 2020; 508: 254-266
        • Lotfi M.
        • Rezaei N.
        SARS-CoV-2: A comprehensive review from pathogenicity of the virus to clinical consequences.
        Journal of Medical Virology. 2020; 92: 1864-1874
        • Lu Q.
        • Shi Y.
        Coronavirus disease (COVID-19) and neonate: What neonatologist need to know.
        Journal of Medical Virology. 2020; 92: 564-567
        • Luk H.K.H.
        • Li X.
        • Fung J.
        • Lau S.K.P.
        • Woo P.C.Y.
        Molecular epidemiology, evolution and phylogeny of SARS coronavirus.
        Infection, Genetics and Evolution. 2019; 71: 21-30
        • Mahase E.
        Coronavirus: Covid-19 has killed more people than SARS and MERS combined, despite lower case fatality rate.
        British Medical Journal Publishing Group, 2020
        • Mansourabadi A.H.
        • Sadeghalvad M.
        • Mohammadi-Motlagh H.R.
        • Rezaei N.
        The immune system as a target for therapy of SARS-CoV-2: A systematic review of the current immunotherapies for COVID-19.
        Life Sciences. 2020; 258: 118185
        • Mao Y.
        • Lin W.
        • Weng J.
        • Chen G.
        Epidemiological and Clinical Characteristics of SARS-CoV-2 and SARS-CoV: A System Review.
        (Available at SSRN 3541144)2020
        • Mardani M.
        • Pourkaveh B.
        A controversial debate: Vertical transmission of COVID-19 in pregnancy.
        Arch Clin Infect Dis. 2020; 15e102286
        • McCrindle B.W.
        • Rowley A.H.
        • Newburger J.W.
        • Burns J.C.
        • Bolger A.F.
        • Gewitz M.
        • et al.
        Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association.
        Circulation. 2017; 135 (e927-e99)
        • Mehta P.
        • McAuley D.F.
        • Brown M.
        • Sanchez E.
        • Tattersall R.S.
        • Manson J.J.
        COVID-19: consider cytokine storm syndromes and immunosuppression.
        Lancet (London, England). 2020; 395: 1033-1034
        • Memish Z.A.
        • Al-Tawfiq J.A.
        • Assiri A.
        • AlRabiah F.A.
        • Al Hajjar S.
        • Albarrak A.
        • et al.
        Middle East respiratory syndrome coronavirus disease in children.
        The Pediatric Infectious Disease Journal. 2014; 33: 904-906
        • Mirbeyk M.
        • Rezaei N.
        The impact of COVID-19 on pregnancy and neonatal health: A systematic review.
        2020
        • Moazzami B.
        • Razavi-Khorasani N.
        • Dooghaie Moghadam A.
        • Farokhi E.
        • Rezaei N.
        COVID-19 and telemedicine: Immediate action required for maintaining healthcare providers well-being.
        Journal of Clinical Virology. 2020; 126: 104345
        • Mohamed K.
        • Rodríguez-Román E.
        • Rahmani F.
        • Zhang H.
        • Ivanovska M.
        • Makka S.A.
        • et al.
        Borderless collaboration is needed for COVID-19-a disease that knows no borders.
        Infection Control and Hospital Epidemiology. 2020; : 1-2
        • Mohamed K.
        • Yazdanpanah N.
        • Saghazadeh A.
        • Rezaei N.
        Computational drug discovery and repurposing for the treatment of Covid-19: A systematic review.
        (Available at SSRN 3583748)2020
        • Mohd H.A.
        • Al-Tawfiq J.A.
        • Memish Z.A.
        Middle East respiratory syndrome coronavirus (MERS-CoV) origin and animal reservoir.
        Virology Journal. 2016; 13: 87
        • Momattin H.
        • Al-Ali A.Y.
        • Al-Tawfiq J.A.
        A systematic review of therapeutic agents for the treatment of the Middle East respiratory syndrome coronavirus (MERS-CoV).
        Travel Medicine and Infectious Disease. 2019; 30: 9-18
        • Momtazmanesh S.
        • Ochs H.D.
        • Uddin L.Q.
        • Perc M.
        • Routes J.M.
        • Vieira D.N.
        • et al.
        All together to fight COVID-19.
        The American Journal of Tropical Medicine and Hygiene. 2020; 102: 1181-1183
        • Moniri A.
        • Marjani M.
        • Tabarsi P.
        • Yadegarynia D.
        • Nadji S.A.
        Health care associated Middle East respiratory syndrome (MERS): A case from Iran.
        Tanaffos. 2015; 14: 262-267
        • Moradian N.
        • Ochs H.D.
        • Sedikies C.
        • Hamblin M.R.
        • Camargo Jr., C.A.
        • Martinez J.A.
        • et al.
        The urgent need for integrated science to fight COVID-19 pandemic and beyond.
        Journal of Translational Medicine. 2020; 18: 205
        • Morawska L.
        • Milton D.K.
        It is time to address airborne transmission of COVID-19.
        Clin Infect Dis. 2020; 6 (ciaa939)
        • Mou H.
        • Raj V.S.
        • van Kuppeveld F.J.
        • Rottier P.J.
        • Haagmans B.L.
        • Bosch B.J.
        The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies.
        Journal of Virology. 2013; 87: 9379-9383
        • Nasab M.G.
        • Saghazadeh A.
        • Rezaei N.
        SARS-CoV-2-a tough opponent for the immune system.
        Archives of Medical Research. 2020; 51: 589-592
        • Network CHA
        Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19).
        CDC Health Alert Network, 2020
        • Ng E.K.
        • Ng P.-C.
        • Hon K.E.
        • Cheng W.F.
        • Hung E.C.
        • Chan K.A.
        • et al.
        Serial analysis of the plasma concentration of SARS coronavirus RNA in pediatric patients with severe acute respiratory syndrome.
        Clinical Chemistry. 2003; 49: 2085-2088
        • Ng P.C.
        • Leung C.W.
        • Chiu W.K.
        • Wong S.F.
        • Hon E.K.
        SARS in newborns and children.
        Biology of the Neonate. 2004; 85: 293-298
        • Omrani A.S.
        • Saad M.M.
        • Baig K.
        • Bahloul A.
        • Abdul-Matin M.
        • Alaidaroos A.Y.
        • et al.
        Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study.
        The Lancet Infectious Diseases. 2014; 14: 1090-1095
        • Organization WH
        Multisystem inflammatory syndrome in children and adolescents with COVID-19.
        World Health Organization, 2020
        • Pal R.
        • Bhansali A.
        COVID-19, diabetes mellitus and ACE2: The conundrum.
        Diabetes Research and Clinical Practice. 2020; 162: 108132
        • Pashaei M.
        • Rezaei N.
        Immunotherapy for SARS-CoV-2: Potential opportunities.
        Expert Opinion on Biological Therapy. 2020; : 1-5
        • Peeri N.C.
        • Shrestha N.
        • Rahman M.S.
        • Zaki R.
        • Tan Z.
        • Bibi S.
        • et al.
        The SARS, MERS and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: What lessons have we learned?.
        International Journal of Epidemiology. 2020; (dyaa033)https://doi.org/10.1093/ije/dyaa033
        • Perlman S.
        Another decade, another coronavirus.
        New England Journal of Medicine. 2020; 382: 760-762
        • Phan L.T.
        • Nguyen T.V.
        • Luong Q.C.
        • Nguyen T.V.
        • Nguyen H.T.
        • Le H.Q.
        • et al.
        Importation and human-to-human transmission of a novel coronavirus in Vietnam.
        The New England Journal of Medicine. 2020; 382: 872-874
        • Pourahmad R.
        • Moazzami B.
        • Rezaei N.
        Efficacy of Plasmapheresis and immunoglobulin replacement therapy (IVIG) on patients with COVID-19.
        SN Comprehensive Clinical Medicine. 2020; : 1-5
        • Prather K.A.
        • Wang C.C.
        • Schooley R.T.
        Reducing transmission of SARS-CoV-2.
        Science. 2020; https://doi.org/10.1126/science.abc6197
        • Prevention CfDCa
        Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19).
        (18 May)2020
        • Rabiee N.
        • Rabiee M.
        • Bagherzadeh M.
        • Rezaei N.
        COVID-19 and picotechnology: Potential opportunities.
        Medical Hypotheses. 2020; 144: 109917
        • release WFoPIaCCSm
        Expert panel conclusions following the 2 May Pediatric Intensive Care-COVID-19 International Collaborative Conference Call.
        (22 June)2020
        • Rezaei N.
        COVID-19 affects healthy pediatricians more than pediatric patients.
        Infection Control and Hospital Epidemiology. 2020; 1
        • Rezaei N.
        COVID-19 and medical biotechnology.
        Avicenna Journal of Medical Biotechnology. 2020; 12: 139
        • Riphagen S.
        • Gomez X.
        • Gonzalez-Martinez C.
        • Wilkinson N.
        • Theocharis P.
        Hyperinflammatory shock in children during COVID-19 pandemic.
        The Lancet. 2020; 395: 1607-1608
        • Ritchie A.I.
        • Singanayagam A.
        Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?.
        Lancet (London, England). 2020; 395: 1111
        • Rokni M.
        • Hamblin M.R.
        • Rezaei N.
        Cytokines and COVID-19: Friends or foes?.
        Human Vaccines & Immunotherapeutics. 2020; : 1-3
        • Rzymski P.
        • Nowicki M.
        • Mullin G.E.
        • Abraham A.
        • Rodríguez-Román E.
        • Petzold M.B.
        • et al.
        Quantity does not equal quality: Scientific principles cannot be sacrificed.
        International Immunopharmacology. 2020; 86: 106711
        • Saghazadeh A.
        • Rezaei N.
        Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids.
        International Immunopharmacology. 2020; 84: 106560
        • Saghazadeh A.
        • Rezaei N.
        Immune-epidemiological parameters of the novel coronavirus - a perspective.
        Expert Review of Clinical Immunology. 2020; 16: 465-470
        • Saleki K.
        • Banazadeh M.
        • Saghazadeh A.
        • Rezaei N.
        The involvement of the central nervous system in patients with COVID-19.
        Reviews in the Neurosciences. 2020; 31: 453-456
        • Schuster J.E.
        • Williams J.V.
        Emerging respiratory viruses in children.
        Infectious Disease clinics of North America. 2018; 32: 65-74
        • Schwartz D.A.
        • Graham A.L.
        Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-ncov infecting pregnant women: Lessons from SARS, MERS, and other human coronavirus infections.
        Viruses. 2020; 12: 194
        • Scobey T.
        • Yount B.L.
        • Sims A.C.
        • Donaldson E.F.
        • Agnihothram S.S.
        • Menachery V.D.
        • et al.
        Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus.
        Proceedings of the National Academy of Sciences of the United States of America. 2013; 110: 16157-16162
        • Seto W.H.
        • Tsang D.
        • Yung R.W.
        • Ching T.Y.
        • Ng T.K.
        • Ho M.
        • et al.
        Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS).
        Lancet. 2003; 361: 1519-1520
        • Shamshirian D.
        • Rezaei N.
        Cardiovascular diseases burden in COVID-19: Systematic review and meta-analysis.
        2020
        • Sharifkashani S.
        • Bafrani M.A.
        • Khaboushan A.S.
        • Pirzadeh M.
        • Kheirandish A.
        • Yavarpour Bali H.
        • et al.
        Angiotensin-converting enzyme 2 (ACE2) receptor and SARS-CoV-2: Potential therapeutic targeting.
        European Journal of Pharmacology. 2020; 884: 173455
        • Shen K.
        • Yang Y.
        • Wang T.
        • Zhao D.
        • Jiang Y.
        • Jin R.
        • et al.
        Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement.
        World Journal of Pediatrics. 2020; 16: 223-231
        • Shen K.L.
        • Yang Y.H.
        Diagnosis and treatment of 2019 novel coronavirus infection in children: A pressing issue.
        World journal of pediatrics : WJP. 2020; 16: 219-221
        • Sinha I.P.
        • Harwood R.
        • Semple M.G.
        • Hawcutt D.B.
        • Thursfield R.
        • Narayan O.
        • et al.
        COVID-19 infection in children.
        The Lancet Respiratory Medicine. 2020; 8: 446-447
        • Stockman L.J.
        • Massoudi M.S.
        • Helfand R.
        • Erdman D.
        • Siwek A.M.
        • Anderson L.J.
        • et al.
        Severe acute respiratory syndrome in children.
        The Pediatric Infectious Disease Journal. 2007; 26: 68-74
        • Tezer H.
        • Bedir D.T.
        Novel coronavirus disease (COVID-19) in children.
        Turkish Journal of Medical Sciences. 2020; 50: 592-603
        • Thabet F.
        • Chehab M.
        • Bafaqih H.
        • Al M.S.
        Middle East respiratory syndrome coronavirus in children.
        Saudi Medical Journal. 2015; 36: 484-486
        • Tian S.
        • Hu N.
        • Lou J.
        • Chen K.
        • Kang X.
        • Xiang Z.
        • et al.
        Characteristics of COVID-19 infection in Beijing.
        Journal of Infection. 2020; 80: 401-406
        • Toubiana J.
        • Poirault C.
        • Corsia A.
        • Bajolle F.
        • Fourgeaud J.
        • Angoulvant F.
        • et al.
        Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study.
        BMJ. 2020; 369: m2094
        • Unni J.C.
        Coronavirus Disease (COVID-19) with relevance to pediatrics.
        Indian Pediatrics. 2020; 57: 582-583
        • Van Doremalen N.
        • Bushmaker T.
        • Morris D.H.
        • Holbrook M.G.
        • Gamble A.
        • Williamson B.N.
        • et al.
        Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1.
        New England Journal of Medicine. 2020; 382: 1564-1567
        • Verdoni L.
        • Mazza A.
        • Gervasoni A.
        • Martelli L.
        • Ruggeri M.
        • Ciuffreda M.
        • et al.
        An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study.
        The Lancet. 2020; 395: 1771-1778
        • Wang Y.
        • Wang Y.
        • Chen Y.
        • Qin Q.
        Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures.
        Journal of Medical Virology. 2020; 2020: 568-576
        • Wei M.
        • Yuan J.
        • Liu Y.
        • Fu T.
        • Yu X.
        • Zhang Z.-J.
        Novel coronavirus infection in hospitalized infants under 1 year of age in China.
        Jama. 2020; 323: 1313-1314
        • Whittaker E.
        • Bamford A.
        • Kenny J.
        • Kaforou M.
        • Jones C.E.
        • Shah P.
        • et al.
        Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.
        Jama. 2020; 324: 259-269https://doi.org/10.1001/jama.2020.10369
        • WHO
        Mental health and psychosocial considerations during the COVID-19 outbreak.
        WHO, 2020
        • Widagdo W.
        • Okba N.M.A.
        • Stalin Raj V.
        • Haagmans B.L.
        MERS-coronavirus: From discovery to intervention.
        One Health (Amsterdam, Netherlands). 2017; 3: 11-16
        • Wong J.E.
        • Leo Y.S.
        • Tan C.C.
        COVID-19 in Singapore—Current experience: Critical global issues that require attention and action.
        Jama. 2020; 323: 1243-1244
        • Wu A.
        • Peng Y.
        • Huang B.
        • Ding X.
        • Wang X.
        • Niu P.
        • et al.
        Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
        Cell Host & Microbe. 2020; 27: 325-328
        • Wu A.
        • Peng Y.
        • Huang B.
        • Ding X.
        • Wang X.
        • Niu P.
        • et al.
        Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China.
        Cell Host & Microbe. 2020; 27: 325-328
        • Wu Z.
        • McGoogan J.M.
        Characteristics of and important lessons from the coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
        Jama. 2020; 323: 1239-1242
        • Xia W.
        • Shao J.
        • Guo Y.
        • Peng X.
        • Li Z.
        • Hu D.
        Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults.
        Pediatric Pulmonology. 2020; 55: 1169-1174
        • Xu X.W.
        • Wu X.X.
        • Jiang X.G.
        • Xu K.J.
        • Ying L.J.
        • Ma C.L.
        • et al.
        Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.
        BMJ. 2020; 368: m606
        • Yang P.
        • Liu P.
        • Li D.
        • Zhao D.
        Corona Virus Disease 2019, A growing threat to children?.
        The Journal of Infection. 2020; 80: 671-693
        • Yang Y.
        • Lu Q.
        • Liu M.
        • Wang Y.
        • Zhang A.
        • Jalali N.
        • et al.
        Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China.
        medRxiv. 2020; (preprint), 2020.02.10.20021675
        • Yazdanpanah F.
        • Hamblin M.R.
        • Rezaei N.
        The immune system and COVID-19: Friend or foe?.
        Life Sciences. 2020; 256: 117900
        • Yazdanpanah N.
        • Saghazadeh A.
        • Rezaei N.
        Anosmia: A missing link in the neuroimmunology of coronavirus disease 2019 (COVID-19).
        Reviews in the Neurosciences. 2020; 31: 691-701
        • Yousefzadegan S.
        • Rezaei N.
        Case report: Death due to COVID-19 in three brothers.
        The American Journal of Tropical Medicine and Hygiene. 2020; 102: 1203-1204
        • Yu X.
        • Yang R.
        COVID-19 transmission through asymptomatic carriers is a challenge to containment.
        Influenza and Other Respiratory Viruses. 2020; 14: 474-475
        • Zeng L.
        • Tao X.
        • Yuan W.
        • Wang J.
        • Liu X.
        • Liu Z.
        First case of neonate infected with novel coronavirus pneumonia in China.
        Zhonghua er ke za zhi= Chinese Journal of Pediatrics. 2020; 58 (E009)
      2. Zhang C, Gu J, Chen Q, Deng N, Li J, Huang L, et al. 2020.

        • Zhang R.
        • Li Y.
        • Zhang A.L.
        • Wang Y.
        • Molina M.J.
        Identifying airborne transmission as the dominant route for the spread of COVID-19.
        Proceedings of the National Academy of Sciences. 2020; 117: 14857-14863
        • Zhu H.
        • Wang L.
        • Fang C.
        • Peng S.
        • Zhang L.
        • Chang G.
        • et al.
        Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.
        Translational Pediatrics. 2020; 9: 51-60
        • Zhu N.
        • Zhang D.
        • Wang W.
        • Li X.
        • Yang B.
        • Song J.
        • et al.
        A novel coronavirus from patients with pneumonia in China, 2019.
        The New England Journal of Medicine. 2020; 382: 727-733
        • Zimmermann P.
        • Curtis N.
        Coronavirus infections in children including COVID-19: An overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children.
        The Pediatric Infectious Disease Journal. 2020; 39: 355-368