key: cord-0909223-4oz6r7op authors: Hon, Kam Lun; Leung, Karen Ka Yan; Leung, Alexander K. C.; Sridhar, Siddharth; Qian, Suyun; Lee, So Lun; Colin, Andrew A. title: Overview: The history and pediatric perspectives of severe acute respiratory syndromes: Novel or just like SARS date: 2020-06-01 journal: Pediatr Pulmonol DOI: 10.1002/ppul.24810 sha: b2bfa9d8e5f2be4bf3346a381bfd943a9fc6494f doc_id: 909223 cord_uid: 4oz6r7op Many respiratory viral infections such as influenza and measles result in severe acute respiratory symptoms and epidemics. In the spring of 2003, an epidemic of coronavirus pneumonia spread from Guangzhou to Hong Kong and subsequently to the rest of the world. The WHO coined the acronym SARS (severe acute respiratory syndrome) and subsequently the causative virus as SARS‐CoV. In the summer of 2012, epidemic of pneumonia occurred again in Saudi Arabia which was subsequently found to be caused by another novel coronavirus. WHO coined the term MERS (Middle East respiratory syndrome) to denote the Middle East origin of the novel virus (MERS‐CoV). In the winter of 2019, another outbreak of pneumonia occurred in Wuhan, China which rapidly spread globally. Yet another novel coronavirus was identified as the culprit and has been named SARS‐CoV‐2 due to its similarities with SARS‐CoV, and the disease as coronavirus disease‐2019. This overview aims to compare and contrast the similarities and differences of these three major episodes of coronavirus outbreak, and conclude that they are essentially the same viral respiratory syndromes caused by similar strains of coronavirus with different names. Coronaviruses have caused major epidemics and outbreaks worldwide in the last two decades. From an epidemiological perspective, they are remarkably similar in the mode of spread by droplets. Special focus is placed on the pediatric aspects, which carry less morbidity and mortality in all three entities. 2.1 | Origin of the virus SARS is a viral respiratory disease of zoonotic origin caused by the SARS coronavirus (SARS-CoV). The origin of SARS-CoV is still unsettled and remains a controversial subject to date. SARS-CoV is phylogenetically divergent from other coronaviruses associated with human infections such as OC43, NL63, 229E, and HKU1, but is closely related to civet and bat CoVs. 4 However, none of the currently known bat severe acute respiratory syndrome-related coronaviruses (SARS-CoV) is thought to be the direct ancestor of SARS-CoV. 5 SARS was the first severe and readily transmissible new communicable disease of the 21 st century. 6 The epidemic first started around mid-November 2002 in Guangzhou where at least two patients had atypical pneumonia of unknown cause. 7 The initial cases were meat handlers who had regular contact with wild game. 4 Shortly after, similar cases were reported in five cities in Guangdong province, however, no escalation of public health measures was announced. By February 2003, the outbreak had unfolded and there were 305 cases reported with five mortalities. 7 8 In Hong Kong, 1755 people were infected and 299 died; 386 infected cases were healthcare workers and eight of them died. 8, 9 No case of SARS has been reported worldwide since 2004. However, suspicious cases were reported from time to time. 3 The incubation period for SARS-CoV is between 2 and 10 days with a mean of 5 days and up to 13 days, symptoms usually develop 2 to 10 days after the initial infection. The immune response includes immunoglobulin M (IgM) antibody to the SARS-CoV-this peaks during the acute or early convalescent phase (week 3), and declines by week 12. IgG antibody is produced later and peaks at week 12. 10 The first symptom of SARS is fever of 38°C (100.4°F) or higher, followed by nonspecific flu-like symptoms such as chills/rigor, muscle aches and pain, headaches, diarrhea, sore throat, runny nose and malaise. The symptoms usually last about 2 to 7 days. Affected patients may develop a dry cough, shortness of breath, and pneumonia. In severe cases, the patient can develop respiratory failure and acute respiratory distress syndrome (ARDS). In the SARS outbreak of 2003, about 9% of patients with confirmed SARS infection died. 11 The mortality rate was much higher for those over 60 years old, with mortality rates approaching 50% for this subset of patients. 11 In the SARS epidemic, there were around 135 pediatric SARS cases reported worldwide, the majority of them in Hong Kong. [12] [13] [14] [15] [16] In pediatric cases, the presenting features can be nonspecific, hence a postive contact history and environmental exposure became very important diagnostic clues. Fever was a consistent symptom in all affected children, and lasted for a median duration of 6 days, while other common symptoms included cough (60%) and nausea or vomiting (41%). 12, 13, 17 Teenage patients present with symptoms of malaise, myalgia, chill, and rigor in addition to cough and respiratory symptoms similar to those of adults, while the younger children presented mainly with cough and runny nose. 13 The symptoms and clinical course were milder and shorter in young children. Lymphopenia was an important laboratory finding but more severe among teenagers. 13 The most prominent radiological features included patchy infiltrates, opacities, and areas of consolidation predominantly in the lower lobes. 14 No pediatric mortalities were reported in the literature. 12 In a case series of 43 children with SARS in Hong Kong, five required PICU care and one patient required invasive ventilatory support. 17, 18 Children who were 12 years of age or younger generally had a milder illness and more favorable outcome. 12 The pathophysiology of a milder disease course in children is not clear, and proposed yet putative mechanisms include relatively low dosage of ribavirin, shorter course of corticosteroids, and a less mature immune system, resulting in less autoinflammatory injury in the young. 19 Follow-up of SARS patients at 6 months after the illness only showed mild residual changes in exercise tolerance and pulmonary function. 12 Osteonecrosis was reported in children whose SARS treatment included steroids; they remained mostly asymptomatic and managed conservatively. 16 There were two reported cases of transmission from children to adults and no reports of transmission from children to children. 6 As to vertical transmission, in all reported cases of maternal SARS during pregnancy, the infants survived and no perinatal transmission was detected. 6 In summary, respiratory symptoms are milder and nonrespiratory symptoms are present in pediatric patients. The mean incubation period for MERS-CoV is 5.2 days, and ranges from 2 to 13 days. Symptoms may range from mild to severe and include fever, cough, diarrhea, and shortness of breath. Spread between humans typically involves close contact with an infected person. Human-to-human transmission has been limited and mainly among family members and healthcare workers. There have been clusters of cases in healthcare facilities, where infection prevention and control practices were suboptimal, however, its spread was uncommon outside of hospitals. 20, 22 Overall, 17.9% of the cases reported were healthcare workers. 21 There have been no reports of sustained human-to-human transmission; thus, its risk to the global population is currently deemed to be fairly low. 20 The high morbidity associated with MERS may be spurious due to bias of inadequate sampling that had missed a much larger denominator with elusive milder cases. 23 As of 2019, there was no specific vaccine or treatment for the disease; a number of antiviral medications were being studied. 20 The WHO recommends that those who come in contact with camels wash their hands frequently and not touch sick camels, and that camelbased food products should be appropriately cooked. In essence, symptomatic and supportive treatments constitute therapies. Of the cases reported to WHO, 20.8% had mild to no symptoms while 46.5% had severe disease or died. 21 MERS is typically more severe in those with other health problems, more than half of the reported cases had had comorbidities (eg, diabetes mellitus, hypertension, heart disease, chronic renal failure, or lung disease), which might explain the high mortality rate. 20, 21 The overall risk of death may be lower than reported as those with mild symptoms may be undiagnosed. 24 The rate of pediatric MERS-CoV infection is relatively low in comparison to adults. 23 A large Saudi Arabian study that screened for MERS-CoV by polymerase chain reaction (PCR) testing in a selected at-risk population, including 8032 children (<14 years old) found 0.1% who tested positive when compared with 0.7% in adults. 25 The most common source of infection was household contact and acquired infection within a healthcare facility. 26 Approximately 42% of affected children are asymptomatic. 26 The most common presenting symptoms are fever (57%), vomiting (28%), diarrhea (28%), and cough (14%). 26 The severity is lower in comparison to the adult population. In one series of 31 pediatric cases, only one patient required intensive care support and there were no deaths. 26 Only two fatal pediatric MERS-CoV cases were found in the literature, and both cases had comorbidities (infantile nephrotic syndrome and cystic fibrosis). 27 4 | COVID-19 The culprit of the recent pandemic in 2020, termed by the WHO as 30 According to Wuhan health officials, the pneumonia appeared to be viral in nature and patients were placed in isolation. Potential causes including influenza, avian infleuenza, adenovirus, SARS-CoV, and MERS-CoV were ruled out. 31 Since there was highly suggestive evidence that the outbreak was associated with exposure in Wuhan's Huanan Seafood Wholesale Market, the market was closed on 1 January, 2020. 32 The mean incubation period for SARS-CoV-2 is estimated to be between 2 and 14 days, with an average of 5 days. 35 There is evidence of humanto-human transmission through droplets or direct contact; and precautions should be practiced in the healthcare settings to prevent airborne transmission, which may be underestimated, among many uncertainties about this novel virus. 36 There have been confirmed cases in healthcare workers, and the reported cases were 3.8% and 20% of the total confirmed cases in China and Italy, respectively. 31, 37, 38 With the ascertainment of asymptomatic carriage, the risk of transmission within the community is very high. 39 The most common symptoms include fever, cough, dyspnea, myalgia, or fatigue. 30 In a series of 41 cases, only a few patient had prominent upper respiratory tract signs even though abnormalities in chest computed tomography (CT) images were detected among all patients. 30 CT chest scans have a higher sensitivity for diagnosis of COVID-19 as compared with PCR swab samples; and the findings include bilateral, subpleural, ground-glass opacities with air bronchograms, ill-defined margins, and a slight predominance in the right lower lobe. 40, 41 Indeed, CT chest abnormalities are now diagnostic criteria in the latest "Novel coronavirus diagnosis and treatment plan" published by the National Health Commission of the People's Republic of China. 42 In a report of 72 314 cases prepared by the Chinese Center for Disease Control and Prevention (CDC), a majority (80.9%) of the cases were classified as mild, while 4.7% were critical cases. 31 The age group ≥80 years old had the highest case-fatality rate at 14.8%. 31 Treatment is mainly supportive, as no antiviral treatment has been clinically proven to be effective against SARS-CoV-2 and there are no standard treatment guidelines recommended by the WHO. The protease inhibitors lopinavir-ritonavir can be considered, but the results of a recent clinical trial are discouraging. 43 Remdesivir and chloroquine have been shown to have good inhibitory effect on SARS-CoV-2 in vitro. 44 Remdesivir is now undergoing phase II clinical trials in treating patients with COVID-19. 45 Hydroxychloroquine, sometimes in combination with azithromycin, has been widely used in both Europe and the US with little evidence of efficacy, and early analyses point to increased risk and higher mortality. 46, 47 Long-term outcome for COVID-19 patients is yet to be de- reported that about 14% of recovered patients were tested postive for SARS-CoV-2 in follow-up checks several weeks after discharge. This is deemed most likely due to residual RNA in clinical samples rather than reinfection. 48 Given that a robust test has yet to be developed, speculations about results of the testing include false negativity at the time of discharge, inadequate specimen, less desirable site of specimen acquisition (eg, specimen taken from the throat vs the nasopharynx), testing discrepancies, new tests finding the virus in the lower respiratory tract, and reinfection. Most infected children had relatively milder symptoms and recovered within 1 to 2 weeks. 53 Several of the patients had no overt clinical symptoms and were found by positive screening of infected close contacts. 53 A study reviewing the epidemiology of 2135 pediatric cases in China revealed the proportion of severe and critical illness to be higher in the younger age group, in particular infants. 54 In the report by the US Centres for Disease Control and Prevention, among the aged less than 1 year with known hospitalized status, 62% were hospitalized; compared to 4.1 to 14% among those aged 1 to 17 years. 50 Around 2% of the pediatric cases require admission to the intensive care, which is low comparing to the adult population. 55 There were less than 10 pediatric deaths reported worldwide. 31, 50 Children may play a major role in community-based viral transmission and there were evidence of COVID-19 infections in children occurring early in the epidemic. 56, 57 There is no convincing evidence HON ET AL. | 1587 of vertical transmission to neonates so far with only a couple of studies finding IgM in neonatal blood, but no viral RNA in samples from the respiratory tract. 58, 59 However, early onset COVID-19 disease in neonates has been reported. 60 The reason for the decreased incidence in childhood is yet to be clarified, but it has been postulated that children are less susceptible to COVID-19 because of lesser maturity and function of ACE2 receptor, the cell entry receptor of SARS-CoV-2, compared to adults. [61] [62] [63] Officials and experts compared similarities and differences of the acronyms and believed that they are all novel and impactful syndromes. They may have fever, respiratory symptoms, history of contact or travel, an animal vector and a novel coronavirus, and significant mortality and morbidity. There are relatively minimal or no differences in these acronyms except for the nomenclatures ( Table 1 ). The fact that a significant number of patients with COVID-19 are mildly symptomatic vs patients with SARS and MERS, with low mortality rates, reflects that SARS-CoV-2 resembles other common circulating respiratory viruses. However, the lack of any population immunity against SARS-CoV-2 gives it the ability to cause high attack rates, which can overwhelm and cripple healthcare systems if not managed carefully. Similarities and differences between SARS, MERS, and COVID-19 are tabulated hereunder (Table 1) . It is perhaps unnecessary to coin confusing and seemingly different acronyms for each of these recurring epidemics and coronaviruses. 1 The syndrome approach (as in SARS) as opposed to disease approach (as in COVID) has its pros and cons (Table 2) • The clinical definition can be applied to any similar epidemics for surveillance without knowing the culprit pathogen. • Sensitive. • The SARS concept of surveillance is easy to apply in epidemics. • The acronym is used even in afebrile, asymptomatic carriers or patients with mild and extrapulmonary symptoms in some laboratory-confirmed SARS patients. • Stigmatizing many patients because the definition is too nonspecific or too sensitive. • May not be used for a non-coronavirus (eg, influenza or measles) or another novel coronavirus (eg, MERS) even if the symptoms are severe, acute and respiratory. • May miss nonfebrile patients or patients with extrapulmonary symptoms. • Contact or travel history is only good in early phase of an epidemic. • New acronym has to be coined ( | 1589 these characteristics. Whether beyond the virus there might be environmental changes that have occurred over the two-decade history of these infections, that enhance its spread, such as rising temperatures, or other yet to be determined atmospheric changes. It is hoped that because of the devastation that COVID-19 carries in its wake, large efforts will be invested in a search for answers to these questions, and with that, we will all be able to be wiser in dealing with the threats of the future. This will require the combined efforts of a global community, since the current events clearly manifested our interconnectedness and interdependence and hence shared vulnerability in the face of a calamity of previously unexperienced magnitude. 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