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Clinical Infection & Immunity

Review

Volume 5, Number 2, June 2020, pages 17-24

Insights Into Challenges in Coronavirus Disease 2019 in Pediatrics

The novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes coronavirus disease 2019 (COVID-19), the exact origin and transmission routes are rigorously investigated; one theory is that it has been originated in bats and was transmitted to humans through unknown mechanisms. The virus has been emerging in Wuhan, Hubei Province, China in late 2019 [1]. It is further spread to quite 210 countries around the world, and has reached a state of a pandemic. Up to date April 25, 2020, WHO reported about 2,836,338 cases of COVID-19 and 197,694 deaths with case fatality rate of 6.97% all over the world [2].

In general, coronaviruses cause mild upper tract infections (UTIs). However, SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV) have all been related to severe illness and even death [3]. The disease has a more severe presentation in older adults especially with comorbidities, and there are fewer hospitalizations in children compared with adults. Fortunately, children are affected less frequently than adults with a really low death rate. The long-run course of this virus remains unknown [4]. This literary criticism gives insights into epidemiological features, clinical characteristics, and management plans of this new virus in newborns, infants, and youngsters.

Human coronaviruses belong to the family Coronaviridae, either Alphacoronavirus or Betacoronavirus. On December 31, 2019, WHO was notified by the emergence of the latest cases of pneumonia of undetermined etiology. A unique coronavirus was identified because of the explanation for such cases of pneumonia on January 7, 2020, with subsequent name SARS-CoV-2, a beta coronavirus, and therefore the disease COVID-19 [5].

The first report on the novel virus was published by Public Health England (PHE) on January 22, 2020. Royal London Hospital swabbed the first COVID-19 patient on January 23, 2020. By March 9, 24,641 people have tested negative while 319 have tested positive within the UK. Three people with positive screening for SARS-CoV-2 have died [4].

SARS-CoV-2 is very infectious; all ages of the whole population are susceptible. The virus spreads faster than SARS-CoV and MERS-CoV, but has lower fatality rate ranging from 2% to 3%. The most routes of transmission are respiratory droplets and contact with patients. History of epidemiological exposure is crucial [6, 7].

Viral load is more within the cavum compared to the throat, with no difference in viral burden regardless of symptoms [8]. These droplets can spread 1 - 2 m and deposit on the encircling surfaces. The virus can remain viable on these surfaces for days in favorable conditions. Common disinfectants like hypochlorite, oxide, etc., can kill SARS-CoV-2 within 1 min [9].

The virus will be isolated in urine and feces. So, urine- and feces-contaminated environments can cause aerosol and call transmission [10]. Neonatal infections are reported, but no evidence of vertical maternal-fetal transmission. Aerosol particles carrying viruses are also the way of transmission [11]. The typical incubation period is 3 - 7 days with a variety of 1 - 14 days. In Chinese study to spot the epidemiological characteristics of pediatric patients with COVID-19, it had been concluded that children in the slightest degree ages are liable to COVID-19 with no significant difference in gender.

Clinical manifestations of COVID-19 in children were less severe than those of adults. Infants were a vulnerable group to COVID-19 infection. The distribution of COVID-19 cases varies with time and space, and most of them were from Hubei Province. This study provides evidence for human-to-human transmission [12].

The course of COVID-19 in children varies from an asymptomatic state to ARDS and even multi-organ dysfunction. The common presentations include fever (not universal), cough, and shortness of breath, raw throat, headache, fatigue, and myalgia. Red eyes and discharge with conjunctivitis have also been described. So, these manifestations are indistinguishable from other viral UTIs [13].

By the top of the primary week, some patients showed the progressive course of the disease resulting in different complications like pneumonia, sepsis, septic shock (hypotension and abnormal cellular changes caused by sepsis), ARDS (a condition characterized by fluid accumulation within the air sacs of the lungs), and acute kidney injury. At this stage, a patient may require mechanical ventilation until control of infection in a very minority of cases (about 2%); a unique coronavirus infection in children can cause the death of the patient [14]. However, the death rate approaches the next estimate in elderly patients especially those with underlying comorbidities (50-75% of fatal cases). Overall, the case mortality rate is 2-3% of the total cases.

This progressive stage coincides with the height inflammatory response with the release of various mediators (cytokine storm) e.g., interleukin-2 (IL-2), IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), IP10, MCP1, MIP1A, and tumor necrosis factor α (TNFα) [13]. Recovery usually started within the second or third week of illness. The median duration of hospitalization was 10 days in people who showed complete recovery [14].

According to clinical presentation, laboratory results, and CXR, the severity of COVID-19 was classified into: 1) Asymptomatic: With no symptoms or signs, and therefore the CXR is normal, while polymerase chain reaction (PCR) for 2019-nCoV is positive. 2) Mild: Symptoms of acute URTIs include fever, cough, raw throat, runny nose, and sneezing. Examination shows congested pharynx and normal chest examination. Some cases are also afebrile or have only digestive symptoms like nausea, vomiting, diarrhea, and abdominal pain. 3) Moderate with pneumonia: Fever is frequent, and initial dry cough followed by productive cough, wheezy chest on auscultation, but no obvious hypoxemia like dyspnea, and sputum or dry snoring and/or wet snoring can be heard on auscultation of lungs. Some cases are also asymptomatic, but chest computed tomography (CT) shows positive findings, which are subclinical. 4) Severe: An early respiratory symptom is also among gastrointestinal symptoms like diarrhea. By the top of the first week, the disease usually progresses with dyspnea and central cyanosis. Hypoxic manifestations with oxygen saturation below 92% become established. 5) Critical: the condition progress rapidly to ARDS or respiratory failure, and will even have a shock, encephalopathy, coagulation dysfunction, acute kidney injury, myocardial injury, or failure. Multi-organ dysfunction can cause death [15].

In neonates, infants and youngsters, the disease includes a milder course compared to adults. In a study conducted on 34 children from China, 14 were males and 20 were females with a median age of 8 years and 11 months. In 28 children the infection was linked to a loved one and 26 children had a history of travel/residence to Hubei Province in China. It was reported that each patient was asymptomatic or had mild disease. None had a severe or critical condition. Fever (50%) and cough (38%) were the foremost frequent symptoms. All patients showed good results with supportive care and symptomatic therapy without a fatality. Only one case of severe pneumonia and multi-organ dysfunction was reported [16]. All neonatal cases were mild with complete recovery [17]. In an exceedingly series of 171 pediatric patients admitted at a hospital in Wuhan, China, about 42% were asymptomatic and just one died [18].

Interestingly, most cases of COVID-19 in children were less severe than adults. This may be attributed to exposure and host factors. Children have relatively fewer opportunities for exposure to pathogens and/or sick patients. The cell receptor for SARS-CoV is thought to be angiotensin-converting enzyme II (ACE2) [19]. The 2019-nCov is sharing some aminoalkanoic acid sequence with SARS-CoV, and will be ready to use ACE2 as a cell surface receptor. Recently, ACE2 is taken into account the foremost likely cell receptor of 2019-nCoV [20, 21]. Children are considered less sensitive to 2019-nCoV because the maturity and performance (e.g., binding ability) of ACE2 in children are also below that in adults [22].

A suspected COVID-19 case is defined jointly with acute respiratory illness (sudden onset of a minimum of one in all the following: fever or recent history of fever, cough, or shortness of breath) and within the 14 days before symptoms, onset has a history of travel abroad or contact with patients with similar travel history or those with confirmed COVID-19 infection. However, cases are also asymptomatic or maybe without fever. A confirmed case could be a suspected case with a positive molecular test [23].

Laboratory investigations included complete blood count (CBC), and the white blood cell count showed leucopenia or the normal count. The differential count showed lymphopenia, with lymphocyte count < 1,000 in severe cases. However, the platelet count is normal or mildly low.

Inflammatory markers like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated. Serum levels of procalcitonin are within normal limits. Elevated serum procalcitonin levels may indicate the presence of bacterial infection. Liver enzymes (alanine aminotransferase (ALT)/aspartate aminotransferase (AST)), prothrombin time, serum creatinine, D-dimer, creatine phosphokinase (CPK), and lactate dehydrogenase (LDH) are also elevated, and high levels are related to severe and complex cases [23].

Real-time quantitative polymerase chain reaction (RT-qPCR) and high-throughput sequencing are the commonly used macromolecule detection technologies for SARS-CoV-2. In clinical practice, high-throughput sequencing technology is of limited value because of equipment dependency and high cost [20]. So RT-qPCR is the most effective method for detecting pathogenic viruses in respiratory samples and blood. This specific test is carried on respiratory samples including throat swab, nasopharyngeal swab, sputum, endotracheal aspirates, and bronchoalveolar lavage to verify the diagnosis. Also, the virus may be detected within the stool, and the blood in severe cases [24]. In response to COVID-19 spreading pandemic and shortages of molecular testing capacity and reagents, multiple manufacturers have developed and begun selling rapid and easy devices to facilitate outside laboratory testing. These test kits are supported by the detection of antigenic proteins from the COVID-19 virus in respiratory samples or detection, in blood or serum, of human antibodies secreted in response to infection.

It detects the presence of viral proteins (antigens) expressed by the COVID-19 virus in an exceedingly sample from the tract of someone when available in sufficient concentrations. Its antigen-antibody reaction within 0.5 h leads to a visually detectable signal. The antigens are expressed when the virus is actively replicating. So, this test is employed to spot acute or early infection. The standard of the test depends on the time of sampling, viral load, sample technique and processing, and accuracy of the reagent. The sensitivity of this test is 34-80% [25].

It detects antibodies within the blood of someone suspected to be with COVID-19 [26]. Production of antibodies takes days to weeks in response to infection. Antibody response depends on age, nutritional status, disease severity, and medicines or infections that suppress the system [27]. In some COVID-19 confirmed cases, antibody responses are weak, late, or absent.

It was suggested that the majority of patients develop antibodies only within the second week after onset of symptoms [26-28].

The diagnosis of COVID-19 supported by antibody response is going to be possible within the recovery phase when the chance for intervention has already passed. Taking into consideration that this test can cross-react with other pathogens including other coronaviruses [27, 29], however, WHO does not currently recommend the employment of both antigen-detecting and antibody-detecting rapid diagnostic tests for patient care, but encourages the continuation of laboratory and research studies to determine their usefulness in disease surveillance and epidemiologic research [30].

The chest film is insensitive early within the disease. CXR usually shows bilateral infiltrates. These X-ray series are of a confirmed COVID-19 patient. On admission to the hospital, the chest film was normal. Four days later the patient is on mechanical ventilation and there are bilateral consolidations on the chest film [31].

The chest CT is more sensitive and specific than plain films. Although PCR is incredibly specific for COVID-19, its sensitivity of 65-95% is lower, which suggests that the test may be negative in some truly infected patients. Another limitation in the use of PCR is that you simply need to look ahead to the test results, which might take over 24 h, while CT results are available instantly. Common laboratory findings in COVID-19 as lymphopenia and an increased CRP and ESR are nonspecific [32].

Initial CT findings in COVID-19 cases include bilateral, multilobar ground glass opacification (GGO) with a posterolateral distribution, mainly in the lower lobes and less frequently in the middle lobe. Consolidation superimposed on GGO as the initial finding is found in a minority of cases, mainly in the elderly population. Septal thickening, bronchiectasis, pleural thickening, and subpleural involvement are less common findings in the later stages of the disease. Pleural effusion, pericardial effusion, lymphadenopathy, cavitation, CT halo sign, and pneumothorax are some of the uncommon but possible findings seen with disease progression. There is much overlap of the CT patterns of COVID-19 with other viral types of pneumonia [33].

It is difficult to tell COVID-19 apart from viral respiratory infections, such as cases of pneumonia caused by the influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, respiratory syncytial virus, SARS-CoV, MERS coronavirus, and other viral types of pneumonia.

COVID-19 must be differentiated from bacterial pneumonia, mycoplasma, and chlamydia pneumonia. Bacterial pneumonia occurs within the lung parenchyma and manifests as bronchial pneumonia with many inflammatory secretions within the bronchioles and alveoli. Its CT findings are mainly extensive patchy consolidations of the lung parenchyma. Mycoplasma pneumonia commonly occurs in school-age children and adolescents [34]. Also, COVID-19 must be differentiated from lung disease caused by other diseases as heart failure-induced pulmonary edema usually exhibits the high-attenuation butterfly appearance in chest radiography with both hila because of the center, among signs of interstitial pulmonary edema [35]. Although various varieties of pneumonia have certain imaging features, COVID-19, and other viral pneumonia, bacterial pneumonia, and a few lesions share some common imaging features [36]. In some cases, it is difficult to differentiate COVID-19 from them by imaging alone. Therefore, clinical scenario, travel history, contact history, and laboratory tests become important to create the ultimate diagnosis.

No specific antiviral therapy is out there for the correct treatment of COVID-19. Infected patients should receive supportive care and symptomatic treatment to alleviate symptoms. Support of significant organs should be implemented in severe and complex cases [37]. Currently, there is no available vaccine for SARS-CoV-2. Avoidance of infection is the main principle method of deterrence. Liberal efforts to find and evaluate the efficacy of various treatment modalities (antivirals, monoclonal antibodies, immunotherapies, convalescent plasma, and vaccines) are ongoing [38]. The first step in the treatment of youngsters with COVID-19 is to confirm adequate isolation to stop transmission of infection to other contacts, patients, and healthcare workers. Not all children with COVID-19 require admission. Many children with confirmed COVID-19 could also be managed with counseling about dangerous signs.

CXRs and CT scans showed nonspecific findings in children with COVID-19 even those who are asymptomatic. They must be done if there is a clinical indication not on a routine basis whether or not a little amount of oxygen is required on admission. Also, CXRs should be portable to reduce the chance of spread of infection. CXRs should be considered in children who still require oxygen during admission or who require continuous positive airway pressure (CPAP) therapy [23].

The main lines of therapy are maintaining good hydration and nutrition, as well as controlling fever and cough. Routine use of antivirals and antibiotics should be avoided in confirmed cases [39].

Fluid restriction is indicated in children with a respiratory compromise to scale back the risk of development of ARDS and in children with acute kidney injury. However, most youngsters with mild illnesses do not require this fluid restriction.

Taking into consideration those children with fever, and people who are tachypnoeic will have increased insensible fluid losses, diuretics should be considered with worsening respiratory failure requiring CPAP or non-invasive ventilation, particularly if there is evidence of pulmonary edema on CXR [23].

Paracetamol is the preferred antipyretic agent. Avoid ibuprofen in children with poor fluid intake or suspected cases of AKI. There are unproven data about ibuprofen being implicated in severe cases of COVID19. These potential theoretical risks of ibuprofen are often explained by overexpression of ACE receptors within the lung [40].

Respiratory failure is unlikely to develop in most kids with COVID-19 even with pulmonary involvement. In children with hypoxia, oxygen should be provided through low flow nasal cannula (LFNC) instead of high flow nasal cannula (HFNC). If LFNC did not maintain proper oxygenation, HFNC is often used with precautions (full PPE). Other methods of oxygen administration include non-invasive ventilation, mechanical ventilation, and additional extracorporeal membrane oxygenator (ECMO) [39].

Chest wheeze is not a priority in children with COVID-19 as lung involvement tends to be within the alveoli instead of the tiny airways. So, bronchodilators should be used only when there is a strong suspicion of bronchoconstriction as evidenced by wheeze and prolonged expiratory phase. In asthmatic children, the use of bronchodilators via metered-dose inhaler (MDI)/spacer instead of nebulization is usually recommended as this reduces the chance of droplet spread [41].

Previously, it was absolutely reported that the utilization of systemic corticosteroids is related to a better risk of death in patients with pneumonia. This observation could also be confounded by the fact that sicker patients tend to receive corticosteroids. Very limited data from COVID-19, SARS, and MERS-CoV patients indicate that treatment with systemic corticosteroids could also be harmful. This is often attributed to lack of evidence of lung inflammation in children with COVID-19, so immunomodulation is not required. Steroids could also be useful in ventilated children with ARDS. However, no patient with previous exposure to chronic glucocorticoid therapy for quite 3 months should die inconsiderately for a stress dose of replacement glucocorticoid therapy [42, 43].

Antibiotics do not seem to be effective in preventing or treating COVID-19, as COVID-19 is caused by an endemic, not bacteria. However, antibiotics could also be used if bacterial pneumonia is suspected in children with COVID-19. In comorbid disorders, like cystic fibrosis, antibiotics should be in step with disease-specific guidelines and cultures. Also, antibiotics should be considered in children with COVID-19 without premorbid disorders if: 1) The patient looks unusually sick on the first day or not improving by the third day of admission. 2) Inflammatory markers like CRP and total leukocyte counts are rising. 3) Macrolide antibiotics can be accustomed to treat suspected mycoplasma or atypical infection. 4) Productive cough has a lower threshold for using antibiotics.

In cases of suspected sepsis, local guidelines for antibiotic use should be followed, taking into consideration that COVID-19 may share some clinical features with sepsis [44]. Few pediatric studies observing the rates of bacterial coinfection in cases of COVID-19 reported a lower rate of bacterial coinfection in children with COVID-19 (the evidence base was poor with variable results) [45].

Bacterial coinfection is likely related to morbidity in children and mortality in adults [46].

Till now, no trials of antiviral regimens with exact efficacy are recommended to be employed in children with COVID-19.

One randomized controlled trial (RCT) conducted on 199 adults with COVID-19 to match lopinavir/ritonavir with usual care. It was relatively found that no difference within the clinical improvement and/or mortality, but did report that hospital stay, intensive care unit (ICU) admission, and risk of complications were lower [47].

According to the present guidelines for the management of COVID-19 in adults and kids and available resources in antiviral drugs, herein one study provided a simplified representation of the SARS-COV-2 viral life cycle and potential drug targets [48].

The importance of elevated liver enzymes in children with COVID-19 is not clear. Liver dysfunction is sometimes transient during virus infection. It is likely in children who are unwell and people with pneumonia. If liver dysfunction persists, liver support and assessment of coagulation profile are crucial [37].

It was suggested that chloroquine and hydroxychloroquine may modify the receptor binding sites of SARS-COV-2. Currently, no evidence supports the utilization of hydroxychloroquine in mild disease, or to scale back severe illness or mortality. It would be suggested in adult populations and kids who need pediatric intensive care unit (PICU) admission [49].

Guidelines for critical care management for kids with COVID-19 are published by the WHO [50].

As no approved treatments for COVID- 19 till now, prevention is of paramount importance. However, many difficulties are facing the preventive strategies, such as the prolonged incubation period of SARS-CoV-2 and duration of the illness, the virus is infective within the incubation period and even after clinical recovery, features of the disease are nonspecific, and affinity for mucosal surfaces like nose, mouth, and conjunctiva.

Home isolation of confirmed or suspected cases with mild illness is usually recommended.

Good ventilation and exposure to sunlight should be considered during home isolation. Patients should wear a surgical mask with cough hygiene. Also, caregivers should wear a surgical mask when in close contact with the patient, and use frequent hand hygiene every 15 - 20 min [23]. Healthcare workers are at the best risk of infection, and will be protected to confirm continuity of health care and forestall further transmission of infection. Patients should be isolated in separate rooms (negative pressure rooms do not seem to be generally needed) or cohort together.

Regular decontamination of rooms, handles, tables, doorknobs, desks, toilets, surfaces, and equipment should be finished whitener. Although the National Health Commission of China places SARS-CoV-2 (droplet pathogen) in category B of infectious agents for infection control, infection control measures recommended are those for category A agents.

Personal protective equipment (PPE) should be available for healthcare workers including fit-tested N95 respirators, gowns, gloves, and goggles.

Precautions for transmission mechanisms should be considered during aerosol-generating procedures like intubation and suction.

All healthcare workers with further contacts should be monitored for the development of any symptoms of COVID-19.

Patients are often discharged from isolation as long as they are afebrile for a minimum of 3 days and have two consecutive negative PCR results with at least 1-day interval [51].

What can practitioners do to slow the spread of the virus? The measures include: 1) Access control (patients and visitors) by screening patients before entering your facility; and putting a mask on patients who are express/display symptoms. 2) Protect your workforce with virtual care/stay reception if sick; hand hygiene, social distancing, avoid touching face, and avoid sick persons; and cough hygiene by coughing in sleeve/tissue instead of hands. 3) Be prepared with alternative staffing plans; and keep emergency contact list (e.g. state and native health departments) [52].

Preventive measures include avoidance of crowded areas, social distance, travel restrictions, proper hand hygiene, coughs etiquette, and surgical masks especially in crowded places. However, with the worldwide spread of the virus, it is not clear that these efforts will result in a slowing of viral spread.

A proper vaccine is under trials and development [53].

There is no clear evidence that SARS-COV-2 is teratogen. No fetal congenital anomalies are reported in babies delivered to mothers with COVID-19. However, the neonatal problems which may be encountered include: prematurity, respiratory distress, and even fetal death. It is not clear that health problems are associated with COVID-19 itself or to the clinical condition of affected mothers [54]. It had been recommended that neonates born to mothers with COVID-19 should be considered suspected cases and isolated [55]. Although Qia and Liang recommended the maternal separation of the newborn for a minimum of 2 weeks, others recommend mother and neonate to be kept together in the immediate postpartum period provided no neonatal care is indicated. This separation will minimize close contact with the infected mother and subsequent risk of viral transmission [55, 56]. Also, mother/neonate separation will facilitate care to both mother and neonate, and minimize contact and exposure of health care workers. Direct breastfeeding is not recommended, because it requires close contact. The rules for the management of neonate born to mothers with suspected or confirmed COVID-19 infection are shown in these two studies [57, 58].

The recent emergence of COVID-19 remains severe everywhere in the globe. WHO has designated COVID-19 as a public health emergency of international concern. Although children are vulnerable to COVID-19, they are doing not develop a big disease. This raises the chance that children might be facilitators of viral spread and transmission. Neonatal infections are reported, but no proof of vertical maternal-fetal transmission, or that SARS-COV-2 is teratogen. Neonates born to mothers with COVID-19 may suffer some health problems and should be monitored for evidence of transmission. So, here is an urgent need to reinforce infection control policies, and perform proper health management within the families, which must increase public awareness.

Acknowledgments

All authors offer many thanks and great appreciation to Colonel Dr. Fahad Alzolafi, assistant hospital director, Prince Sultan Military Hospital, Taif, Saudi Arabia, for his continuous encouragement and moral support.

Financial Disclosure

The authors declared no financial support for the research, authorship, and/or publication of this review article.

Conflict of Interest

None to declare.

Author Contributions

HHE and NFB contributed to conception, data analysis, interpretation of data, and drafting of the manuscript. FKA and HMA contributed to data analysis, interpretation of data, and revision of the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work in ensuring that questions relating to the accuracy or integrity of any part of the work are appropriately investigated and resolve.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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