key: cord-287156-3plpi6i9
authors: Lassandro, Giuseppe; Palladino, Valentina; Amoruso, Anna; Palmieri, Viviana Valeria; Russo, Giovanna; Giordano, Paola
title: Children in Coronaviruses’ Wonderland: What Clinicians Need to Know
date: 2020-07-01
journal: Mediterr J Hematol Infect Dis
DOI: 10.4084/mjhid.2020.042
sha: 
doc_id: 287156
cord_uid: 3plpi6i9

Human coronaviruses (HCoVs) commonly cause mild upper-respiratory tract illnesses but can lead to more severe and diffusive diseases. A variety of signs and symptoms may be present, and infections can range in severity from the common cold and sore throat to more serious laryngeal or tracheal infections, bronchitis, and pneumonia. Among the seven coronaviruses that affect humans (SARS)-CoV, the Middle East respiratory syndrome (MERS)-CoV, and the most recent coronavirus disease 2019 (COVID-19) represent potential life-threatening diseases worldwide. In adults, they may cause severe pneumonia that evolves in respiratory distress syndrome and multiorgan failure with a high mortality rate. Children appear to be less susceptible to develop severe clinical disease and present usually with mild and aspecific symptoms similar to other respiratory infections typical of childhood. However, some children, such as infants, adolescents, or those with underlying diseases may be more at-risk categories and require greater caution from clinicians. Available data on pediatric coronavirus infections are rare and scattered in the literature. The purpose of this review is to provide to clinicians a complete and updated panel useful to recognize and characterize the broad spectrum of clinical manifestations of coronavirus infections in the pediatric age.

structural proteins, including the spike (S), envelope (E), membrane (M), nucleocapsid (N), and sometimes a hemagglutinin-esterase protein (HE). The HE protein binds to specific receptors and guides membrane fusion; the S protein is responsible for cell entry, the M and E proteins mediate viral assembly process, the inner N protein develops ribonucleoprotein complexes binding to viral RNA. [1] [2] [3] [4] [5] To date, seven coronaviruses affect humans: in 1960s

HCoV-229E and HCoV-OC43 were firstly reported; 6, 7 HCoV-NL63 and HCoV-HKU1 were discovered subsequently in 2004 and 2005, respectively. 8, 9 Additionally, three HCoVs responsible for outbreaks involving high case fatality rates have been detected in humans in the last two decades: the severe acute respiratory syndrome (SARS)-CoV, the Middle East respiratory syndrome (MERS)-CoV and the new coronavirus disease 2019 (COVID-19) ( Table 1) . Table 1 . Principal features of severe acute respiratory syndrome (SARS)-CoV, the Middle East respiratory syndrome (MERS)-CoV and the most recent coronavirus disease 2019 (COVID- 19) .

Classification beta-CoV beta-CoV beta-CoV In several studies a similar prevalence in the detection of HCoVs in patients with respiratory symptoms compared to healthy children has been found. [36] [37] [38] [39] Moreover, patients with other underlying medical conditions or immunocompromised appear more susceptible to developing severe infections than healthy patients. [40] [41] [42] [43] Additionally, human coronaviruses are responsible for other common childhood diseases such as acute otitis media [44] [45] [46] [47] , asthma exacerbations 48, and conjunctivitis 8 . They have also been involved in nosocomial infections, especially in the neonatal intensive care units (NICU). Gagneur et al. in a prospective study determined the incidence of HCoVrelated respiratory infections in newborns hospitalized in a NICU. Among 64 neonates, seven positive nasal samples for HCoVs (11%) were detected. All children were symptomatic. Oxygen and ventilatory support were frequently needed. 49 Sizun et al. evaluated the clinical role of coronaviruses respiratory infections in premature newborns. All premature infants infected had severe respiratory symptoms, including bradycardia, apnea, and hypoxemia, while chest X-ray revealed diffuse infiltrates. 50 It has also been shown that coronavirus infections are not only responsible for respiratory symptoms but can also affect other organs and systems in children. Several studies have also reported that respiratory symptoms caused by coronavirus infection may be associated with central nervous system (CNS) involvement. HCoVs have an intrinsic capacity to affect neurons and diffuse centrifugally from CNS via the transneuronal route. 51, 52 Among neurological symptoms, febrile seizures, convulsions, loss of consciousness, encephalomyelitis, and encephalitis have been reported. [53] [54] [55] Primarily in 1980, the viral genome was detected post-mortem in the cerebrospinal fluid of two patients with multiple sclerosis (MS). 56 Subsequently, the HCoVs neuroinvasion capacity was confirmed in a large panel of human brain autopsy samples affected by MS and other neurological diseases. 57 58 In 2017, a prospective study on 192 children with febrile seizures demonstrated that coronaviruses were frequently detected. 59 Additionally, HCoVs have been implicated as possible causes of many gastrointestinal disorders in children, and gastrointestinal symptoms have been reported in several studies in more than 50% of pediatric patients 28, 60, 61 . Firstly, HCoVs could be associated with neonatal necrotizing enterocolitis 62 all HCoVs can also be detected in stool samples of patients affected by gastroenteritis. 60, 66 Moreover, most of the HCoVs found were coinfections with well-known gastroenteric viruses, including norovirus and rotavirus. HCoVs may also be found occasionally in healthy children's stool samples. 67 Although HCoVs have always been associated with respiratory symptoms, these findings suggest that other systems may also be involved in children. The absence of serious symptoms may not be coupled with serological negativity. Therefore, these viruses should be considered in the differential diagnoses of most of the common diseases of childhood.

The 2002-2004 severe acute respiratory syndrome outbreak was a viral respiratory illness caused by SARS-CoV. The outbreak firstly emerged in the southern Chinese province of Guangdong in November 2002 and 68 then spread to 29 countries with 8,096 people infected and 774 died. 69 The SARS global outbreak was contained in July 2003. Since 2004, there have not been any known cases of SARS reported anywhere in the world. 70 Probably, civet cats or bats could be the initial step of the transmission to humans. Humans to humans infection occurs by respiratory droplets or direct contact. Healthcare or household contacts are critical routes of transmission. 71, 72 SARS-CoV infection cases were classified by the World Health Organization (WHO) into suspected, probable, and confirmed ( Table 2) . 73 The median incubation period ranges between 2-11 days. SARS causes atypical pneumonia, which may progress to respiratory failure. Symptoms include fever, malaise, myalgia, headache, diarrhea, and rigors. Adults are more likely to develop severe illness characterized by dyspnea, lymphopenia, acute respiratory distress syndrome (ARDS), and a fatal clinical course in 10% of cases. The exact number of children affected by SARS worldwide is unknown. However, children appear to be less susceptible to SARS with a lower incidence of the disease and no reported mortality. The majority of children had documented exposure to adults with SARS, usually a family member. Most infected children had previously attended school, but the spread of the infection in the school environment has not been demonstrated, and this could probably be linked to lower infectiousness of the virus among children. 74, 75 Children have less severe symptoms than adults, and they rarely need intensive care. However, subclinical and asymptomatic infections appear uncommon. Most children reported worldwide were healthy, previously and underlying conditions were infrequently reported. [75] [76] [77] Usually, children require hospitalization after 3-4 days the onset of symptoms: fever (90-100%), dry cough (43-80%), sore throat (5-30%), rhinorrhea (33-60%), malaise and myalgia (10-40%), headache (14-40%) are common. Dyspnea, tachypnea, and febrile seizures are infrequent. Aspecific gastrointestinal symptoms, including abdominal pain, appetite lack, vomiting, and diarrhea, have been reported. Physical examination at presentation is negative in the majority of children, and chest auscultation does not reveal significant findings. Moreover, sometimes crackles or signs of lung consolidation can be detected. As well as the clinical examination, laboratory findings are not specific in children with SARS and can be confused with those of other respiratory infections typical of childhood. Commonly lymphopenia, the elevation of transaminases, lactic dehydrogenase, and creatine phosphokinase are detected. Other hematological abnormalities such as leukopenia, thrombocytopenia, the elevation of D-dimer levels and mildly prolonged activated partial thromboplastin times are also observed. [78] [79] [80] Circulating interleukin (IL)-1β levels might be increased, resulting in caspase-1-dependent pathway activation responsible for an exaggerated and persistent inflammatory response and the consequent respiratory failure in severe cases. 81 In children, radiological findings are nonspecific and similar to other viral respiratory abnormalities. 

high fever (>38 °C) AND cough or breathing difficulty AND one or more of the following exposures during the 10 days prior to onset of symptoms:

close contact with a person who is a suspect or probable case of SARS cough or breathing difficulty history of travel, to an area with recent local transmission of SARS residing in an area with recent local transmission of SARS

1) A suspect case with radiographic evidence of infiltrates consistent with pneumonia or respiratory distress syndrome (RDS) on chest X-ray (CXR). 2) A suspect case of SARS that is positive for SARS coronavirus by one or more assays. See Use of laboratory methods for SARS diagnosis. 3) A suspect case with autopsy findings consistent with the pathology of RDS without an identifiable cause.

www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020042

Commonly, the chest X-ray shows ground-glass opacity or focal consolidation. Linear atelectasis and peribronchial thickening have also been reported.

Computed tomography (CT) shows more extensive airspace consolidation and ground-glass attenuation than chest X-ray, but it is performed in selective cases in pediatric age. [78] [79] [80] 82 Usually, the clinical course is less severe in children compared to adults, and few patients require oxygen supplementation and assisted ventilation but preterm newborns, children younger than one year and older than 12 years of age have more severe symptoms and are likely to develop respiratory distress. [78] [79] [80] In pediatric age, SARS infection commonly has a "biphasic" pattern. The first stage of the disease is characterized by virus replication and clinically by the onset of symptoms. The second phase is characterized by pulmonary involvement, which is typically less severe in children than in adults. Most children will become afebrile within seven days, and they usually do not progress to respiratory distress, the adult third phase, that is only reported in a minimal number of cases, commonly among teenagers. 83, 84 In pregnant women, SARS infection is associated with a high incidence of spontaneous miscarriage, prematurity, and intrauterine growth retardation (IUGR). The increased morbidities during pregnancy are likely to be due to the hypoxic state and circulatory insufficiency that worsen placental blood flow and cause miscarriage or IUGR. Significantly, among pregnant women, mortality is 25%. 85 However, perinatal SARS infections have not been documented. In none infants born from pregnant women affected, real-time PCR (RT-PCR) assays and viral cultures conducted on neonatal blood, body secretions and amniotic fluid were positive for SARS. In infants, no congenital malformations have been reported. However, in premature newborns, severe gastrointestinal complications such as jejunal perforation and necrotizing enterocolitis have been described 86 . However, it is not known if these neonatal morbidities are related to prematurity or if maternal infection is a factor that increases their incidence.

It is unclear why children develop a less serious disease than adults. Recurrent viral respiratory infections typical of the pediatric age could be helpful to the immune system in promptly recognizing and defeating new viral pathogens. Furthermore, the immaturity of the immune system could be protective because the inflammatory cascade that causes respiratory failure in adults is more difficult to activate. Additionally, children generally have fewer comorbidities than adults.

Children recovered quickly from SARS. Li et al. assessed the radiological and clinical outcomes of fortyseven children with SARS after 6 months from diagnosis. All children were asymptomatic while mild pulmonary abnormalities including ground-glass opacities and air trappings were found at CT in sixteen patients. 87 Although clinical and laboratory findings of SARS are aspecific in children, certain features can be useful to distinguish SARS from other respiratory viral infections. Children with SARS have a lower incidence of rhinorrhea and productive cough and higher incidence of monocytopenia than children with influenza. 88 Additionally, serum lactate dehydrogenase in the presence of a low neutrophil count and low serum creatine phosphokinase could be suggestive of SARS infection. 89 SARS infections in children appear to be a relatively mild and aspecific disease, and the diagnosis should be accompanied by laboratory assessment. Although infants and teenagers are more likely to have a worse clinical course, usually, all pediatric patients recover entirely without significant long-term sequelae.

The Middle East respiratory syndrome (MERS) is a viral respiratory infection caused by the MERS-coronavirus (MERS-CoV). The first identified case occurred in 2012 in Saudi Arabia. 11, 90 Subsequently, a total of 2494 confirmed cases of MERS, including 858 associated deaths with a case-fatality rate of 34% were reported globally; the majority of these cases were reported from Arabian Peninsula, and in the Middle East. 91 Currently, MERS is an extremely rare disease: in the last year MERS was signaled only in Saudi Arabia. 92 MERS-CoV is a zoonotic virus: dromedary camels are the primary reservoir hosts. Humans are infected through contact with infected dromedary camels, animal products, or humans, especially among close contact between family members and health care workers. MERS-CoV infection cases were classified by the WHO into suspected, probable, and confirmed ( Table 3) . 93 Usually, the mean incubation period ranges from 2 to 15 days. Clinical severity of the disease varies from asymptomatic to fatal forms, and the impact of asymptomatic spread is unclear. The infection can cause severe pneumonia, which may progress to ARDS, respiratory failure, and death, particularly in older people, immunocompromised patients, and those with chronic diseases. Common symptoms include fever, cough, and shortness of breath. Gastrointestinal symptoms (including diarrhea, vomiting, abdominal pain), pericarditis, septic shock and disseminated intravascular coagulation have been reported. [94] [95] [96] [97] Children appear to be less susceptible to MERS-CoV infection, and pediatric cases described in the literature are rare with a low proportion (0.1%-4%) of infected children. 98 age hospitalized with acute respiratory symptoms and/or fever. Among these, none of 474 children tested resulted positive for MERS-CoV. 103 In pediatric age, few cases of MERS CoV infection have been described. Most of the children were asymptomatic and positive during routine screening of MERS-CoV. Al-Tawfiq et al. reported a total of 31 pediatric MERS-CoV cases with a mean age of 10 years. Overall, 42% were asymptomatic, while in symptomatic cases, fever and mild respiratory symptoms were common. 104 Subsequently, Alfaraj et al. reported a total of 7 pediatric MERS-CoV cases with a mean age of 8 years. In this case series, common symptoms were fever (57%), cough (14%), shortness of breath (14%), and gastrointestinal symptoms (28%). Two (28.6%) patients had abnormal chest radiographic findings with bilateral infiltration, one (14.3%) required ventilatory support, and two (28.6%) required supplemental oxygen. 99 Four with underlying conditions (cystic fibrosis, nephrotic syndrome, craniopharyngioma, and a right ventricular tumor) had a fatal outcome. These children developed a critical form of MERS infection complicated by respiratory and multiorgan failure. Frequently, clinical examination revealed bilateral rhonchi and crackles while chest X-ray showed diffuse bilateral infiltrates, ground-glass opacification and pleural effusion. [105] [106] [107] [108] [109] Thrombocytopenia, leukopenia, increased creatinine and prolonged prothrombin time were the only laboratory findings reported in literature. 99, 105, 106 MERS-CoV in children is less frequent than adults and appears to be associated with low mortality unless the patients have underlying comorbidities. Few cases of MERS-CoV have been reported during pregnancy. A pregnant woman, aged 39 years, had a stillbirth at approximately five months of gestation 110 and another woman gave birth to a healthy term baby, but she died after delivery. 107 In conclusion, although MERS-CoV represents a clinical concern for the adult population with a high fatality rate, it remains a sporadic disease in childhood. Clinicians should learn to recognize and suspect MERS-CoV infection, as the symptoms and signs are nonspecific, based on epidemiological criteria to avoid the spread of the disease in patients at higher risk of worse clinical course.

The outbreak of COVID-19 infection (coronavirus disease 2019; previously 2019-nCoV) began in Wuhan, Hubei, China, in December 2019, which then spread rapidly to other provinces of China and around the world. 111 On January 30, 2020, the WHO declared the outbreak of a Public Health Emergency of International Concern and, on March 11, 2020, a pandemic. 112 As of June 5, 2020, 188 other countries and regions, with more than 6.669.358 confirmed cases, are declared. Among the confirmed cases, 2.904.828 are recovered, and 393.205 died. 113 Recent genetic analysis suggests the COVID-19 emerged from an animal source. The full genome sequences showed high homology between COVID-19, bat coronavirus, and pangolin coronavirus, but further genetic study is required.

Moreover, according to current evidence, the principal route of transmission of COVID-19 is from human to human. 114, 115 COVID-19 spread between people through respiratory droplets and contact routes. Droplet transmission occurs when there is close contact with a person with respiratory symptoms such as coughing or sneezing, who may spread potentially infectious droplets. Transmission may also occur by direct contact with infected persons and indirect contact with infected surfaces or objects. COVID-19 can persist on inanimate objects for days but can be efficiently inactivated by common disinfectants. Airborne transmission may be possible when a high risk of aerosolization procedures are performed, such as endotracheal intubation and bronchoscopy. The virus is also detected in stool specimens, and consequently, the feco-oral transmission is also hypothesized. [116] [117] [118] [119] The high transmissibility of COVID-19 may be explained by its demonstrated presence in the upper respiratory tract of asymptomatic or presymptomatic subjects with viral loads comparable to those detected from symptomatic patients. The real proportion of asymptomatic cases is unclear, ranging from 1% to 78% in different studies. Transmission from asymptomatic patients infected with COVID-19 most likely contributed to the rapid and extensive spread of pandemic but further studies are needed to more accurately estimate the proportion of genuinely asymptomatic cases and their risk of transmission. [120] [121] [122] [123] [124] [125] [126] COVID-19 has been reported among all age groups. The median incubation period of COVID-19 infection is 4-5 days with a range up to 24 days. 119, 127 COVID-19 infection case is classified by the WHO into suspected, probable, and confirmed ( Table 4) . 128 Clinical severity of the infection varies, ranging from asymptomatic forms to critical diseases. Common symptoms are fever, dry cough, malaise, lethargy, shortness of breath, sore throat, and myalgia. Headache, conjunctivitis, productive cough, and diarrhea are also described. Mild forms present as a common cold, and severe cases may worsen in pneumonia that may evolve to ARDS, shock, and multiple organ dysfunction. More severe clinical pictures are associated with stronger immune response and with the production of proinflammatory cytokines, including IL-2, IL-7, IL-10, and tumor necrosis factor-α (TNF-α). Adverse outcomes are common in elderly patients and those with underlying diseases. The need for intensive care admission is in 25-30% of patients. The fatality rate is estimated to range between 2 and 3%. [129] [130] [131] [132] [133] About 2% of COVID-19 confirmed cases are children. [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] 135 Generally, children appear to be less likely to develop a severe form of COVID-19 infection, and commonly they have a mild clinical course with a good prognosis. Few children may evolve into lower respiratory infections. Probable reasons include having an immune system still immature, healthier respiratory tract, and less underlying conditions than adults. 136 Most of them have an infected contact history with family members. Moreover, children, especially those with asymptomatic or milder form, may represent significant spreaders. Pediatric patients appear to be likely as adults to become infected but are less likely to develop symptoms. However, future studies are needed to understand the role of children in the transmission of the virus. [137] [138] [139] Current researches show that the median age of infection in pediatric cases is 6-7 years. In symptomatic cases, symptoms are typical of acute respiratory infections and frequently included fever (59%) and cough (46%), which may be accompanied by nasal congestion, runny nose, conjunctivitis, pharyngitis, wheezing, myalgia, and expectoration. Few children have an atypical presentation with gastrointestinal manifestations, including nausea, vomiting, and diarrhea. Low oxygen saturation of less than 92%, dyspnea, cyanosis, and poor feeding, are less common than adults. Among infants, symptoms such as irritability, reduced response, and poor feeding could be the main signs of infection. Family clustering occurred for all infected infants. Rarely infants require intensive care or mechanical ventilation or have any severe complications. Common symptoms of pediatric age are summarized in figure 1 . The majority of children recovers 1-2 weeks after the onset of the disease. Regarding biochemical results, leukopenia and lymphopenia are frequent in children. Elevation of transaminases, myoglobin, muscle enzymes, and D-dimers might be seen in severe cases. [140] [141] [142] [143] [144] [145] [146] Dong et al. reported that 94% of 2143 pediatric patients affected by COVID-19 developed an asymptomatic, mild, or moderate form of infection. A severe disease characterized by dyspnea, central cyanosis, and oxygen saturation of less than 92% was reported in 5% of cases. A critical disease characterized by ARDS and multiple organs failure was reported in less than 1% of cases. 141 The prevalence of severe and critical disease appears higher in younger children, particularly in children aged <1-year-old and in children with underlying diseases. To date, death was an uncommon event reported in one 10month-old infant with intussusception and multiorgan failure and in one 14-year-old boy. 145, 147 Other systemic symptoms appear to be related to the infection, but their link has not yet been demonstrated. Since the outbreak of the pandemic, a large number of rashes, urticaria, and vasculitis affecting hands and feet of healthy children and adolescents have been reported as well as itching, burning, difficulty in joint movements and pain. 142 Recently, the relationship between COVID-19 infection and the development of cardiac diseases in children has been hypothesized. Belhadjer et al. have reported a large number of febrile children resulted positive for COVID-19 admitted in intensive care units for acute heart failure associated with a multisystem inflammatory state. In most of the children, clinical features appeared similar to those of Kawasaki syndrome: lasting fever, cutaneous rash, lymphadenopathy, persistent activation of systemic inflammation and positive response to intravenous immunoglobulin. 148 Similar clinical features have subsequently been reported in children with COVID-19 positive serology. 149, 150 As in COVID-19 infection, Kawasaki syndrome is triggered by proinflammatory cascade activated primarily by innate immunity response. However, further studies are needed to establish the real pathogenetic relationship between emerging COVID-19 and Kawasaki-like syndromes. 151 Dufort et al. 152 have recently reported the emergence of a multisystem inflammatory syndrome in children in New York State coincidental with widespread SARS-CoV-2 transmission, which can better clarify the relationship between Kawasaki Disease and COVID-19. Among 191 children admitted to the New York hospitals for multisystem inflammatory syndrome in children (MIS-C), 95 patients had a laboratory-confirmed acute or recent severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection. This hyperinflammatory syndrome manifested with dermatologic, mucocutaneous, and gastrointestinal features associated with cardiac dysfunction. Of these 95 patients, a total of 36 patients (37%) received a diagnosis of Kawasaki's disease or atypical (or incomplete) Kawasaki's disease; 7 of the 9 patients with coronary-artery aneurysms also received a diagnosis of Kawasaki's disease. 152 COVID-19 infection may also trigger the onset of other immune-mediated diseases such as immune thrombocytopenia, [153] [154] [155] [156] Evans syndrome, 157 and autoimmune hemolytic anemia. 158 Among radiological findings, ground-glass opacity, mono or bilateral infiltrates, mesh shadows, and tiny nodules are frequently detected. In severe cases, radiological alterations are diffused, presenting as a "white lung." However, radiologic evidence of pneumonia might be absent in 15-20% of children. 139, 140, [159] [160] [161] [162] [163] In selected cases, lung ultrasound might be useful in the managing and follow-up of COVID-19 infection. This radiological technique can precociously identify abnormalities including small pleural effusion and subpleural consolidation and appear more available then X-ray and CT. [164] [165] Clinical examination appears mostly negative for pulmonary signs, and in rare cases, rales and thoracic retractions have been reported. 161 Whether pregnant women and children born to affected mothers are more likely to have a worse outcome is currently unclear. Maternal-infant vertical transmission has not been documented. Amniotic fluid, cord blood, neonatal throat swab, and breastmilk samples from newborns delivered by infected women were tested for COVID-19, and all samples tested negative. 166 Data on the maternal and perinatal outcomes of pregnant women infected with COVID-19 is limited. Most pregnant women with COVID-19 present with fever and coughing. Severe and critical maternal symptomatology have also been reported, but no women died. The most common adverse pregnancy outcome is preterm birth, occurring in 41% of cases while the rate of perinatal death is 7%, including one case of stillbirth and one neonatal death. There is no data on miscarriage for COVID-19 occurring during the first trimester. In more than a third of cases, fetal distress and frequent admission neonatal intensive care units have been reported. 166, 167 Rarely, cases of COVID-19 positivity in newborns have been reported. Common symptoms are fever, cough, lethargy, and vomiting milk. Mottled skin and moderate respiratory distress presented with tachycardia, tachypnoea, subcostal retractions, and low oxygen saturation are also described in newborn babies. [169] [170] [171] [172] [173] Although it can be severe in some cases, compared with SARS-CoV and MERS-CoV, COVID-19 causes less severe disease in children. A recent meta-analysis shows that children infected with COVID-19 have less fever than that other epidemic HCoVs. 174 Despite the rapid worldwide spread of COVID-19 infection, additional data are needed to define the severity of the disease in children. The severity of the symptoms and the mortality rate will be better assessed in the future.

Differential diagnosis with common viral respiratory infections of childhood, such as influenza virus, adenovirus, respiratory syncytial virus, and metapneumovirus, should be considered. In the diagnosis of suspected cases, epidemiological and clinical criteria must be assessed. 73, 93, 138 RT-PCR represents the gold standard to confirm the diagnosis of HCoVs infections performed on samples of respiratory secretions. [175] [176] [177] [178] [179] [180] [181] The viral load is higher in lower respiratory tract secretion samples than in upper respiratory tract samples.

Therefore, suspected cases resulted in firstly negative could be re-tested with a second swab, better if with a low respiratory sampling is performed as proved for SARS and MERS infection. 182, 183 Currently, few data have been published about the sensitivity and specificity of RT-PCR nasopharyngeal swabs for COVID-19. In vitro analyses suggest that the RT-PCR test is highly specific and sensitive. 184 In vivo, sensitivity is estimated to be higher than 70% but seems to be lower for "mild" cases while specificity is close to 100%. 185, 186 Accuracy of RT-PCR swabs in clinical practice differs depending on the site and quality of the sample. Taking swabs from children may be more difficult given the intrusive nature of the procedure and further reduce the specificity and sensitivity of the test. RT-PCR of bronchoalveolar lavage fluid appears the most accurate technique of virologic confirmation, but it may not always be easily collected in all patients, especially in pediatric age. Although a negative test cannot currently rule out the disease, further studies are needed to define the exact specificity and sensitivity of RT-PCR nasopharyngeal swabs. 187, 188 Moreover, RT-PCR appears to be useful in virus detection on stool samples. 116 To date, serology is not considered a diagnostic method. Although most patients with COVID-19 appear positive for immunoglobulin-G (IgG) within 19 days while IgM reaches a peak 20-22 days after symptom onset, the serological response is not useful for early individuation of positive patients. 189 Additionally, numerous cross-reactions occur between COVID-19 and common HCoVs 190, and protective immunity against COVID-19 is not proved. Despite its potential role in supporting RT-PCR in the diagnosis of COVID-19, the clinical and immunological meaning of serology is still unclear. 191 The spread of the infection can be prevented if children and family members were educated about proper hygienic practices and infection control measures, including regular hand washing, cover the mouth with napkin or towel when coughing or sneezing, avoid crowded places and contact with sick people. Children with HCoVs should receive early supportive therapy and continuous monitoring. Additional oxygen, caloric, and hydro electrolytic support should be performed if necessary. Frequent checks of oxygen saturation and hematological, urinary, and biochemical parameters, including liver, kidney, myocardial enzymes, and coagulation parameters should be analyzed. Finally, blood gas analysis and radiological diagnostics of the chest should be done when necessary. This strategy could be useful in the prevention of ARDS, multiorgan failure, and other nosocomial infections possibly treated, if bacterial, with appropriate antibiotics. In critical cases, mechanical ventilation with endotracheal intubation and other more invasive interventions, such as blood purification and extracorporeal membrane oxygenation (EMCO), should be adopted. Additionally, the use of antiviral drugs in children with severe HCoVs infections may help to reduce viral load and the duration of symptoms. However, their safety and real effectiveness

have not yet been proven. Interferon alfa and beta, corticosteroids, lopinavir/ritonavir, and ribavirin, were used in the treatment of SARS-CoV and MERS-CoV in adults and children. 75, 76, 78, 192 However, ribavirin can cause hemolytic anemia and liver dysfunction, as well as corticosteroids, increase the risk of iatrogenic immune immunosuppression. 193 To date, there is no evidence regarding the management and treatment of COVID-19 infection in children. In addition to supportive therapy, the use of nebulized interferonalpha-2b and oral lopinavir/ritonavir together with corticosteroids for complications and hydroxychloroquine or intravenous immunoglobulin for severe cases have been suggested. 145, 194, Recently, a position paper of the Italian Society of Pediatric Infectious Disease on the treatment of children with COVID-19 infection has been published. 195 In asymptomatic or mild cases, only antipyretic therapy is recommended. In severe or critical cases, the use of hydroxychloroquine ± azithromycin or lopinavir/ritonavir must be considered. Immunomodulating therapy with methylprednisolone or tocilizumab or anakinra must be considered in case of the simultaneous presence of ARDS or progressive deterioration of respiratory function, the elevation of proinflammatory biomarkers and an interval of at least seven days from symptoms onset. Supportive therapy should include antipyretic therapy, inhalation therapy with topical steroids and/or bronchodilators and venous thromboembolism prophylaxis therapy. [196] [197] [198] [199] [200] [201] [202] [203] Discharge from the hospital is recommended when the patient is without fever for almost three days, respiratory symptoms have improved, and RT-PCR samples are negative. 195 Conclusions. Most cases of HCoVs infection in children have clinically mild symptoms and a relatively short time to resolution. Children seem to have a better prognosis compared to adults, and death is a sporadic event. However, some children, such as infants, adolescents, or those with underlying diseases may be more at-risk categories and require greater caution from clinicians. Learning to recognize pediatric clinical presentations often indefinite or similar to other typical infections of this age, allows clinicians to perform a correct and early diagnosis and prevent the spread of infections in the general population. Furthermore, the psychological and social impact of the pandemic outbreak should be considered, especially in the pediatric age. Moreover, we think it is necessary to implement innovative clinical tools, such as narrative medicine, to recognize the burden of disease in children and caregivers. [201] [202] [203] [204] References:

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Aetiological role of common respiratory viruses in acute lower respiratory infections in children under five years: A systematic review and meta-analysis

Genetic variability of human coronavirus OC43-, 229E-, and NL63-like strains and their association with lower respiratory tract infections of hospitalized infants and immunocompromised patients

Coronavirus 229E-related pneumonia in immunocompromised patients

Acute respiratory viral infections in pediatric cancer patients undergoing chemotherapy

A Multicenter Consortium to Define the Epidemiology and Outcomes of Inpatient Respiratory Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients

Acute otitis media and respiratory viruses

Etiology of Acute Otitis Media and Characterization of Pneumococcal Isolates After Introduction of 13-Valent Pneumococcal Conjugate Vaccine in Japanese Children

Genetic characteristics and antibiotic resistance of Haemophilus influenzae isolates from pediatric patients with acute otitis media after introduction of 13-valent pneumococcal conjugate vaccine in Japan

Polymerase chain reaction-based detection of rhinovirus, respiratory syncytial virus, and coronavirus in otitis media with effusion

Regional, age and respiratorysecretion-specific prevalence of respiratory viruses associated with asthma exacerbation: a literature review

Coronavirusrelated nosocomial viral respiratory infections in a neonatal and paediatric intensive care unit: a prospective study

Neonatal nosocomial respiratory infection with coronavirus: a prospective study in a neonatal intensive care unit

Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain

Susceptibility of laboratory mice to intranasal and contact infection with coronaviruses of other species

Detection of SARS coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome

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Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients

Neuroinvasion by human respiratory coronaviruses

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children

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Human coronaviruses are uncommon in patients with gastrointestinal illness

Detection of the new human coronavirus HKU1: a report of 6 cases

Association of coronavirus infection with neonatal necrotizing enterocolitis

Human coronavirus NL63, France

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New Vaccine Surveillance Network. Coronavirus infection and hospitalizations for acute respiratory illness in young children

The Role of Human Coronaviruses in Children Hospitalized for Acute Bronchiolitis, Acute Gastroenteritis, and Febrile Seizures: A 2-Year Prospective Study

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Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection

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Severe Acute Respiratory Syndrome [Internet]. World Health Organization (WHO)

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Severe acute respiratory syndrome in children: experience in a regional hospital in Hong Kong

Severe acute respiratory syndrome among children

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Severe acute respiratory syndrome (SARS): chest radiographic features in children

Serial analysis of the plasma concentration of SARS coronavirus RNA in pediatric patients with severe acute respiratory syndrome

Clinical progression and viral load in a community outbreak of coronavirusassociated SARS pneumonia: a prospective study

Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome

Infants born to mothers with severe acute respiratory syndrome

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Childhood severe acute respiratory syndrome in Taiwan and how to differentiate it from childhood influenza infection

A case-control study of SARS versus community acquired pneumonia

Middle East respiratory syndrome

Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Available at: www.emro.who.int/pandemic-epidemic-diseases/mers-cov/merssituation-update

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Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

Middle East respiratory syndrome

Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission

Acute viral respiratory infections among children in MERS-endemic Riyadh, Saudi Arabia, 2012-2013

Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia

El Hadi Mohamed RA. Outbreak of Middle East respiratory syndrome coronavirus in Saudi Arabia: a retrospective study

Correction: Case characteristics among Middle East respiratory syndrome coronavirus outbreak and non-outbreak cases in Saudi Arabia from 2012 to 2015

Surveillance and Testing for Middle East Respiratory Syndrome Coronavirus, Saudi Arabia

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Middle East respiratory syndrome coronavirus disease is rare in children: An update from Saudi Arabia

Middle East respiratory syndrome coronavirus in children

Middle East respiratory syndrome coronavirus disease in children

Middle East Respiratory Syndrome Coronavirus during Pregnancy

Acute Middle East Respiratory Syndrome Coronavirus: Temporal Lung Changes Observed on the Chest Radiographs of 55 Patients

CT correlation with outcomes in 15 patients with acute Middle East respiratory syndrome coronavirus

Stillbirth during infection with Middle East respiratory syndrome coronavirus

China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China

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COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak

Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding

Community Transmission of Severe Acute Respiratory Syndrome Coronavirus 2

Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations

Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Public Health-Seattle and King County and CDC COVID-19 Investigation Team. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility

Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths

SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

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

Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19)

The COVID-19 Task force of the Department of Infectious Diseases and the IT Service Istituto Superiore di Sanità. Integrated surveillance of COVID-19 in Italy

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

Global surveillance for COVID-19 caused by human infection with COVID-19 virus. Case definition

Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020:e201585

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

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Epidemiology and transmission of COVID-19 in Shenzhen China: analysis of 391 cases and 1,286 of their close contacts

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A 55-Day-Old Female Infant infected with COVID 19: presenting with pneumonia, liver injury, and heart damage

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Multisystem Inflammatory Syndrome in Children during the COVID-19 pandemic: a case series

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Chest computed tomography in children with COVID-19 respiratory infection

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Radiographic and Clinical Features of Children with 2019 Novel Coronavirus (COVID-19) Pneumonia

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Lung Ultrasound Can Influence the Clinical Treatment of Pregnant Women With COVID-19

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Maternal and perinatal outcomes with COVID-19: A systematic review of 108 pregnancies

Outcome of Coronavirus spectrum infections (SARS, MERS, COVID 1 -19) during pregnancy: a systematic review and meta-analysis

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Novel coronavirus in a 15-dayold neonate with clinical signs of sepsis, a case report

A case report of neonatal COVID-19 infection in China

Clinical characteristics and diagnostic challenges of pediatric COVID-19: A systematic review and metaanalysis

Direct diagnosis of human respiratory coronaviruses 229E and OC43 by the polymerase chain reaction

Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome

Genomic sequencing of the severe acute respiratory syndrome-coronavirus

Genomic sequencing of a SARS coronavirus isolate that predated the Metropole Hotel case www.mjhid.org

Evaluation of a Real-Time Reverse Transcription-PCR (RT-PCR) Assay for Detection of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Clinical Samples from an Outbreak in South Korea in 2015

Analytical and Clinical Validation of Six Commercial Middle East Respiratory Syndrome Coronavirus RNA Detection Kits Based on Real-Time Reverse-Transcription PCR

MERS-CoV diagnosis: An update

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False-negative results of initial RT-PCR assays for covid-19: a systematic review

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Antibody responses to SARS-CoV-2 in patients with COVID-19

Antigenic cross-reactivity between severe acute respiratory syndrome-associated coronavirus and human coronaviruses 229E and OC43

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Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study

SARS: systematic review of treatment effects. Version 2

National Health Commission of People's Republic of China. Diagnosis and treatment of pneumonia caused by novel coronavirus

China National Clinical Research Center for Respiratory Diseases

Chinese Medical Doctor Association Committee on Respirology Pediatrics; China Medicine Education Association Committee on Pediatrics; Chinese Research Hospital Association Committee on Pediatrics; Chinese Non-government Medical Institutions Association Committee on Pediatrics; China Association of Traditional Chinese Medicine

Committee on Children's Safety Medication; Global Pediatric Pulmonology Alliance. Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement

Treatment of children with COVID-19: position paper of the Italian Society of Pediatric Infectious Disease

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EMA gives advice on the use of nonsteroidal anti-inflammatories for COVID-19

Recommendations for inhaled asthma controller medications

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Discovering drugs to treat coronavirus disease 2019 (COVID-19)

Delle Fave A. Perceived well-being and mental health in haemophilia

A Narrative Approach to Describe QoL in Children With Chronic ITP. Front Pediatr

ITP-QoL questionnaire for children with immune thrombocytopenia: Italian version validation's