Dataset: 11.1K articles from the COVID-19 Open Research Dataset (PMC Open Access subset)
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Like other related coronaviruses, patients with 2019-nCoV frequently present with non-specific symptoms resembling that of influenza. Physicians may consider differential diagnoses related to a wide variety of respiratory infections. In order to relate these symptoms to 2019-nCoV, it is imperative that the identification of a potential exposure event (epidemiologic risk factor) within 14 days of symptom onset is made so that a more focused work-up for 2019-nCoV can be completed. Although the likelihood of co-infection of 2019-nCoV and another respiratory virus is thought to be low, a positive finding of another respiratory pathogen does not exclude the diagnosis of 2019-nCoV. Many commercially available respiratory panels include “coronavirus” in the results, but neither a positive nor a negative finding on these panels should be used to include or exclude a diagnosis of 2019-nCoV.
Clinicians working with local public health departments must arrange to have specimens from patients under investigation (PUIs) sent to the CDC laboratory. At this time, the CDC has the only laboratory that can definitively test for 2019-nCoV, though laboratory testing capacity is being rapidly expanded. Polymerase chain reaction (PCR) assays conducted on samples from a patient’s upper and lower respiratory tracts will be used to confirm potential cases. In addition, serum antibody titers can be analyzed for confirmation of infection or evidence of immunity. Up-to-date information about the needed specimens and handling requirements to test for 2019-nCoV are available on the CDC website.35
Nasopharyngeal swab or sputum samples of patients were available for testing by specific RT-PCR assays for 2019-nCoV to detect the highly conserved RdRp and variable S gene. The cycle threshold values of the sputum samples were 8–13 cycles earlier than those of throat swabs, indicating higher viral loads detected in the lower respiratory tract. It is consistent with the observations in patients with MERS who had higher viral loads in lower respiratory tract samples than in upper respiratory tract samples.
Serum samples for 2019-nCoV which might indicate some virus spillover from the more severely infected lung into the systemic circulation, as previously reported in patients with SARS. However, the first case of 2019-nCoV in the United States report the stool and respiratory specimens from the patients tested positive by RT-PCR for 2019-nCoV, whereas the serum remained negative.
Importantly, the ground glass changes on chest CT scan appeared earlier than the positive for RT-PCR test in some cases. Repeat testing of nasopharyngeal swab or sputum samples are recommended in clinical suspected cases with an initially negative result.
The diagnosis of 2019-nCoV infection in the precision medicine approach involves both nucleic acid detection and chest computed tomography (CT) scan.
The National Health Commission issued a guidance on 27 January 2020, to remind medical institutions of the importance of chest CT and pathogen detection in diagnosing the virus.4 Thin-slice high-resolution CT algorithms are strongly recommended for the scanning and reconstruction of CT images. The imaging findings from chest CT scans of 2019-nCoV patients are characteristics of viral pneumonia, including multiple patch shadows and interstitial changes with significant peripheral distribution (Fig. 3). At early stage they are mainly ground-glass opacities with air bronchogram sign, but may progress to become dense consolidation shadows in the later stage, or in severe cases.4 Though suggestive to 2019-nCoV infection, these radiological features alone are not enough for diagnosis of 2019-nCoV pneumonia, since they are oftentimes very similar to those of other viral pneumonia.
The WHO guidance recommends testing the nucleic acid of 2019-nCoV with RT-PCR.11 Currently, the targeting regions of RT-PCR testing kits consist of open reading frames 1a or 1b (ORF1ab) and the envelope gene (E gene) or the nucleocapsid protein gene (N gene).
According to the Diagnosis and Treatment Scheme released by the National Health Commission,4 and after testing and evaluating the efficacy of various viral nucleic acid detection diagnostic kits, we propose the following interpretations (Fig. 4):
(i) The diagnosis is ‘Confirmed’ in patients with positive RT-PCR results for both ORF1ab and N gene/E gene amplification (Fig. 4a).(ii) The diagnosis is ‘Highly Suspected’ in patients with an RT-PCR result positive for ORF1ab and negative for N gene/E gene. The analyses should be repeated with a different RT-PCR kit or replicated with a nucleic acid test kit based on a different methodology (Fig. 4b) or further genomic sequencing should determine whether the virus has a potential mutation.(iii) The diagnosis is ‘Uncertain’ when ORF1ab gene amplification is negative. In this case, regardless of the N gene/E gene result, a replicate test should be done with another kit, or the process of sampling and testing should be repeated (Fig. 4c).(iv) The interpretations of 2019-nCoV RT-PCR results (Fig. 4d): a positive nucleic acid test result includes a cycle threshold (Ct) value less than 35 and a standard S-shaped amplification curve of ORF1ab, N gene/E gene, and internal control (IC) on RT-PCR. A negative RT-PCR result is one with absence of amplification curve for ORF1ab and N gene/E gene and, at the same time, presence of an S-shaped amplification curve for IC (Fig. 4e). When the Ct value is between 35 and 40, the result is a suspected positive and should be reviewed before a diagnosis is done.
Quality control of specimen collection is vital to the diagnostic procedure. Collection of appropriate specimens from suspected cases and their close contacts as early as possible is a cornerstone of RT-PCR testing. The WHO recommends sampling from the lower respiratory tract12 that should meet the following standards:
(i) Bronchoalveolar lavage fluid should be collected using a fiber bronchoscope by clinicians or respiratory therapists. After 100–300 mL of sterilized saline being injected into the bronchia, the liquid is collected by negative pressure (∼100 mm Hg) with sterile containers. The total volume (pooled aliquots) retrieved should be >5 mL and at least 30% of the instilled volume (Fig. 5a).13,14(ii) Sputum from deep in the lung collected in the morning in sterile containers is optimal for testing. Patients with a low sputum volume should be provided with aerosol inhalation using a 0.9% NaCl solution at 25°C (Fig. 5b).(iii) Laboratory experts should collect secretions from the palatine arch, pharynx, and tonsils with flocked swabs. Two or three swabs are required for accurate detection (Fig. 5c and d)14.
On 18 January 2020, after the admission of the suspected cases in West China Hospital, a multi-disciplinary team was organized for patients with fevers of unknown cause. The team (also co-authors of this article) includes experts from the Department of Respiratory and Critical Care Medicine, Center of Infectious Diseases, Department of Emergency Medicine, Department of Critical Care Medicine, Department of Radiology, and Department of Laboratory Medicine. The multi-disciplinary team collects pulmonary specimens, performs RT-PCR testing, acquires CT scans, collectively discusses the data, and makes the diagnosis.
Early identification of infected patients and timely medical intervention are key to preventing rapid spread of the virus. We attempt to adopt a strategy of screening patients for 2019-nCoV early after the admission. Currently, diagnosis is based on epidemiological associations, clinical manifestations, laboratory findings, and radiological characteristics.4 Both WHO and The National Health Commission have issued definitions of suspected cases.4,11(i) Patients must meet any one of the four epidemiological criteria:(a) A history of travel or residency in Wuhan, Hubei Province, China or other epidemic areas, since December 2019;(b) Close contact with a person who has traveled to Wuhan or other epidemic areas since December 2019 or presented with respiratory symptoms in the 14 days before the onset of signs and symptoms, or close contact with a patient confirmed to have the 2019-nCoV virus;(c) A health worker without enough protection but took care of patients who have the earlier-mentioned conditions;(d) An individual case in a cluster outbreak of the infection.(ii) Patients must present with the following clinical manifestations within 10 days of likely exposure:(a) A history of fever or a high temperature;(b) A dry cough or sore throat;(c) Malaise;(d) Shortness of breath.
Patients who meet any of these epidemiological criteria and who present with some of the above clinical manifestations should be quickly referred to designated hospitals for further examination.
Chinese health officials posted the full 2019-nCoV genome sequence on January 10, 2020, to inform the development of specific diagnostic tests for this emergent coronavirus (1). Within a week, CDC developed a Clinical Laboratory Improvement Amendments–approved real-time RT-PCR test that can diagnose 2019-nCoV respiratory samples from clinical specimens. On January 24, CDC publicly posted the assay protocol for this test (https://www.cdc.gov/coronavirus/2019-nCoV/lab/index.html). On January 4, 2020, the Food and Drug Administration issued an Emergency Use Authorization to enable emergency use of CDC’s 2019-nCoV Real-Time RT-PCR Diagnostic Panel. To date, this test has been limited to use at CDC laboratories. This authorization allows the use of the test at any CDC-qualified lab across the country. CDC is working closely with FDA and public health partners, including the American Public Health Laboratories, to rapidly share these tests domestically and internationally through CDC’s International Reagent Resource (https://www.internationalreagentresource.org/). In addition, CDC uploaded the genome of the virus from the first reported cases in the United States to GenBank, the National Institutes of Health genetic sequence database of publicly available DNA sequences (https://www.ncbi.nlm.nih.gov/genbank/). CDC also is growing the virus in cell culture, which is necessary for further studies, including for additional genetic characterization. Once isolated, the virus will be made available through BEI Resources (https://www.beiresources.org/) to assist research efforts.
Additional information about 2019-nCoV is needed to better understand transmission, disease severity, and risk to the general population. Although CDC and partners are actively learning about 2019-nCoV, initial CDC guidance is based on guidance for management and prevention of respiratory illnesses including influenza, MERS, and SARS. No vaccine or specific treatment for 2019-nCoV infection is currently available. At present, medical care for patients with 2019-nCoV is supportive.
On January 31, CDC published its third Health Advisory with interim guidance for clinicians and public health practitioners.††† In addition, CDC issued a Clinical Action Alert through its Clinician Outreach and Communication Activity network on January 31.§§§ Interim guidance for health care professionals is available at https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html. Health care providers should identify patients who might have been exposed and who have signs or symptoms related to 2019-nCoV infection, isolate these patients, and inform public health departments. This includes obtaining a detailed travel history for patients being evaluated with fever and lower respiratory tract illness. Criteria to guide evaluation and testing of PUIs for 2019-nCoV include 1) fever or signs or symptoms of lower respiratory tract illness (e.g., cough or shortness of breath) in any person, including health care workers, who has had close contact¶¶¶ with a patient with laboratory-confirmed 2019-nCoV infection within 14 days of symptom onset; 2) fever and signs or symptoms of lower respiratory tract illness (e.g., cough or shortness of breath) in any person with a history of travel from Hubei Province, China, within 14 days of symptom onset; or 3) fever and signs or symptoms of lower respiratory tract illness (e.g., cough or shortness of breath) requiring hospitalization in any person with a history of travel from mainland China within 14 days of symptom onset. Additional nonhospitalized PUIs may be tested based on consultation with state and local public health officials. Clinicians should evaluate PUIs for other possible causes of illness (e.g., influenza and respiratory syncytial virus) as clinically indicated.
CDC currently recommends a cautious approach to the examination of PUIs. These patients should be asked to wear a surgical mask as soon as they are identified, and directed to a separate area, if possible, separated by at least 6 ft (2 m) from other persons. Patients should be evaluated in a private room with the door closed, ideally an airborne infection isolation room, if available. Health care personnel entering the room should use standard precautions, contact precautions, airborne precautions, and eye protection (e.g., goggles or a face shield).
Clinicians should immediately notify the health care facility’s infection control personnel and local health department. The health department will determine whether the patient needs to be considered a PUI for 2019-nCoV and be tested for infection. If directed by the health department, to increase the likelihood of detecting 2019-nCoV infection, CDC recommends collecting and testing both upper and lower respiratory tract specimens.**** Additional specimen types (e.g., stool or urine) may be collected and stored. Specimens should be collected as soon as possible once a PUI is identified regardless of time since symptom onset.
For persons who might have 2019-nCoV infection and their close contacts, information and guidance on how to reduce the risk for transmitting and acquiring infection is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-prevent-spread.html. Close contacts should immediately call their health care providers if they develop symptoms. In addition, CDC is working closely with state and local health partners to develop and disseminate information to the public on general prevention of respiratory illness, including the 2019-nCoV. This includes everyday preventive actions such as washing your hands, covering your cough, and staying home when you are ill. Additional information and resources for this outbreak are available on the CDC website (https://www.cdc.gov/coronavirus/2019-ncov/index.html).
The internal use of samples for diagnostic workflow optimisation was agreed under the medical ethical rules of each of the participating partners.
2019-nCoV pneumonia are emerging attack at China and worldwide in the winter of 2019-2020. The identified 2019-nCoV genome has been sequenced the closest to some beta-coronaviruses detected in bats. Person-to-person transmission in family homes or hospital, and intercity spread of 2019-nCoV are occurring. At present, the mortality of 2019-nCoV in China is 2.3%, compared with 9.6% of SARS and 34.4% of MERS reported by WHO. It seems the new virus is not as fatally as many people thought. The most common symptoms were onset of fever, generalized weakness and dry cough. Notably, some patients were afebrile or confirmed biologically to have an asymptomatic infection. And the ground glass changes on chest CT scan were earlier than the positive for RT-PCR test in some cases. Repeat testing of nasopharyngeal swab or sputum samples are recommended in clinical suspected cases with an initially negative result. According to the current status, blocking transmission, isolation, respiratory and eye protection, and hand hygiene are the urgent management strategies against 2019-nCoV.
A person with laboratory confirmation of SARS-CoV-2 infection, performed at National Reference Laboratory (“Istituto Superiore di Sanita”), irrespective of clinical signs and symptoms.
Suspected and confirmed cases should be treated in isolation in hospitals with effective isolation and protective conditions. The suspected cases should be isolated in a single room, and the confirmed cases can be accepted in the same room. Critical cases should be treated in ICU as soon as possible.
Mild cases: have mild symptoms, no pneumonia manifestation in chest image;
Common cases: have fever, respiratory symptoms, and pneumonia manifestation in chest image;
Severe cases: comply with any item of the follows. (A) dyspnea, respiratory rate ≥30 times/min; (B) at resting state, finger oxygen saturation ≤ 93%; (C) PaO2/FiO2 ≤ 300 mmHg (1mmHg = 0.133 kPa, PaO2: arterial partial pressure of oxygen, FiO2: fractional concentration of inspired oxygen);
Critical cases: comply with any item of the follows. (A) show respiratory failure and mechanical ventilation is required; (B) present with shock; (C) combine with other organ failure needing Intensive Care Unit (ICU) monitoring and treatment; (D) chest imaging shows multilobe lesions or progress of lesion focus within 48 h ≥ 50%; (E) combine with other clinical conditions requiring hospitalization.
In order to find relevant studies, international databases including PubMed, Scopus, Web of Science, Google scholar, and Embase were searched for articles published until 16 February 2020. The following search terms were used (designed using English MeSH keywords and Emtree terms): [SARS-CoV-2 AND characteristics] OR , [2019-nCoV AND Characteristics]” OR “COVID-19 AND Comorbidities] OR [new coronavirus AND Characteristics AND Comorbidities] OR [Wuhan Coronavirus AND Characteristics AND Comorbidities] OR [Coronavirus AND characteristics AND Comorbidities]. Additionally, extra searches were performed in the reference lists of included studies to avoid missing papers. Moreover Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) portals as the national public health institute were evaluated. Due to the huge number of articles in Chinese language, the abstracts were evaluated in these studies.
Inclusion and Exclusion Criteria
Any relevant articles that reported clinical characteristics and epidemiological information on infected patients were included in the analysis. All articles with any design (randomized controlled trials, non-randomized controlled trials, case-control studies, cross-sectional studies) were included. Articles were excluded if appropriate information was not reported.
Data extraction and paper quality evaluation
Two authors (A.E. and F.J.) screened and evaluated the literature independently. All the included papers were assessed using the Newcastle-Ottawa Scale and the results are provided in table 1 (13). The following features were extracted for pooled estimation: name of the first authors and age, sex, and coexisting condition of the patients.
Overall prevalence with 95% confidence interval was estimated via inverse variance method. Heterogeneity was evaluated using chi-square and I2. The random effect model was used in case of considerable heterogeneity, which was defined as I²>75%. Sensitivity analysis was done according to outlier data. Egger’s regression test was used to evaluate publication biases. All statistical analyses were performed using STATA 13, metaprop command.
Using the E and RdRp gene assays, we tested a total of 297 clinical samples from patients with respiratory disease from the biobanks of five laboratories that provide diagnostic services (one in Germany, two in the Netherlands, one in Hong Kong, one in the UK). We selected 198 samples from three university medical centres where patients from general and intensive care wards as well as mainly paediatric outpatient departments are seen (Germany, the Netherlands, Hong Kong). The remaining samples were contributed by national public health services performing surveillance studies (RIVM, PHE), with samples mainly submitted by practitioners. The samples contained the broadest range of respiratory agents possible and reflected the general spectrum of virus concentrations encountered in diagnostic laboratories in these countries (Table 2). In total, this testing yielded no false positive outcomes. In four individual test reactions, weak initial reactivity was seen but they were negative upon retesting with the same assay. These signals were not associated with any particular virus, and for each virus with which initial positive reactivity occurred, there were other samples that contained the same virus at a higher concentration but did not test positive. Given the results from the extensive technical qualification described above, it was concluded that this initial reactivity was not due to chemical instability of real-time PCR probes but most probably to handling issues caused by the rapid introduction of new diagnostic tests and controls during this evaluation study.
Control the number of scheduled surgeries
Non-emergency surgeries, such as elective cataract operations and ophthalmic plastic surgery, should be postponed. Emergency surgeries, such as endophthalmitis, eyeball rupture, macula-on rhegmatogenous retinal detachment and intraocular foreign body, can continue. Elective surgeries should still be appropriately reduced in areas where the infection is under good control.
b)Improve preoperative infection screening of inpatients
Preoperative CT examination, SARS-CoV-2 (RNA) detection, and blood routine examination are recommended. Testing of nasopharyngeal swab two or more times is recommended in suspected cases with an initially negative result. If CT examination is not available for specialized hospitals or primary hospitals (lack of medical imaging department), or due to some limitations with regards to special groups (such as pregnant women), inspection of hematological indices including C-reactive protein (CRP) and serum amyloid A (SAA) are suggested as routine tests of preoperative screening for ocular surgery patients.
The infection screening results need to be checked and confirmed before surgery appointment. In general, a patient with COVID-19 is not recommended to undergo ocular surgeries unless urgent. The emergency surgeries for a COVID-19 infected patient should be arranged in a negative pressure operating room, with advance notice given to the ward and operating room. If there is no negative pressure operating room in the hospital, COVID-19 patients should go to other qualified hospitals.
A suspected case in which the result of SARS-COV-2 Real Time PCR performed at Regional reference laboratories is doubtful or not conclusive or the result of a pan-coronavirus test is positive.
Practice social distancing in the registration and waiting areas
Patients should stay at least 1.5 m apart from one another when in registration and waiting area.
b)Limit the number of people in the room
Keeping 1 doctor and 1 patient in 1 room is required except for visually impaired patients, patients with communication/mobility difficulties or parents of small children. The room should be well-ventilated. After each patient’s consultation or treatment, the used instruments such as slit lamp must be disinfected immediately.
c)Reduce outpatient examinations
Operation of many ophthalmic equipment requires close proximity, reducing outpatient examinations helps protect both doctors and patients.
Micro-aerosols can be generated when non-contact tonometry is used. Air-puff ophthalmic equipment like non-contact tonometry should be avoided if unnecessary. It is advised to place the tonometer in a ventilated place, and that the measurement interval between patients should be extended. During the measurement, patients should wear a face mask.
Direct ophthalmoscope examination is not recommended, which can be replaced by slit light lens or fundus photography. Protective shields (better transparent) should be installed on slit lamps and any other equipment used which needs close doctor-patient contact. Both doctor and patient should refrain from bare face-to-face speaking during any examination.
At present, there are no drugs available that can target SARS-CoV-2. Therefore, treatment was focused on symptomatic and respiratory support. All the children inhaled interferon and one of the twins was prescribed ribavirin (10–15 mg/kg.d) in addition. Ten (71.4%) adults with pneumonia were treated Lopinaviritonavir (200/50 mg, 2 tablets, bid), interferon and Chinese medicine. The patients with higher infection index (such as CRP, PCT, ESR, SAA, IL-6) were prescript antibiotics for 5–7 days in addition. All the nine children and 14 adult patients recovered in 2–3 weeks and were discharged after two negative nucleic acid tests. Unfortunately, our follow up found that there were five discharged children were admitted again before we submit this article because their stool showed positive result in SARS-CoV-2 PCR. Meanwhile, all their families were negative in all the specimen.
COVID-19 related pediatric disease has an array of symptomatic presentations and outcomes. While the majority of those on the spectrum of the disease will recover well with symptomatic care, this article serves to highlight how myocardial disease, lung pathology, and the substantially higher risk of mortality in certain sub-populations should be kept in the mind. As such, based on our limited data, the authors favor an approach that relies on ensuring potential markers of poorer outcomes, such as evidence of organ dysfunction, evidence of superimposed bacterial infection, and other metrics highlighted in the article, are screened for at an earlier stage. For those children that are deemed sick enough to require admission, the potential need for further investigation for myocardial disease, coagulopathy, and organ damage should be kept in mind.
All nine pediatric patients came from eight families. As shown in Table 1, six children had no information on symptoms available, but have positive results in nucleic acid detection after the positive diagnosis of their families. By contrast, only one child has wild cough and two children have a mild fever (37.4–38.5°C). None of the nine children required intensive care or mechanical ventilation or had any severe complications.
For the 14 adult patients, the main clinical symptoms were fever (8/14, 57.1%), cough (5/14, 35.7%), chest tightness/pain (3/14, 21.4%), fatigue (3/14, 21.4%) and sore throat (1/14, 7.1%). Meanwhile, there were four patients had no clinical symptoms. From the epidemiological data, 7/14(50%) of the adults were infected through household contact, 5 (35.8%) was found to be infected after returning from Wuhan or Hubei in late January 2019 and 2 (14.2%) patients couldn’t find the exact source of infection.
A very important question for understanding SARS-CoV-2 infection is what systems can be used for study. Early studies on SARS-CoV-2 determined that the cellular receptor for the virus is ACE2, similarly to SARS-CoV (3). This knowledge helps to develop an understanding of susceptibility of certain in vitro cell lines to infection with the novel virus. The likelihood is that if cells were not permissive for growth of SARS-CoV, they probably will not support growth of SARS-CoV-2. As more labs around the world start researching the new virus, a better understanding of the permissive cell lines will be developed, an important step to testing therapeutic options and developing a better understanding of basic aspects of SARS-CoV-2 virology. The more challenging aspect of lab-based research on the novel human coronavirus will be developing small-animal models. The early research on receptor usage suggests the virus is not able to infect cells expressing mouse ACE2 (3), thus making a mouse model potentially challenging. Whether expression of human ACE2 in mouse lungs using adenovirus or mouse adaptation of SARS-CoV-2 can develop appropriate models, as was done for SARS-CoV (18), is a pressing question. Whether other small-animal models can be used also needs to be investigated. These models will be essential for thoroughly testing therapeutic candidates and vaccine strategies and understanding the pathology of disease.
All statistical analyses were conducted using SPSS, version 21 (IBM Inc., Armonk, NY, USA). Quantitative and qualitative variables were presented as absolute frequencies, proportions for categorical variables, and interquartile ranges for continuous variables. Independent t-test was used for surveying the mean difference of some quantitative variables by gender. Logistic regression was used to assess the relationship between probable risk factors and outcome (death/survival) of laboratory-confirmed MERS-CoV cases. A P-value of less than 0.05 was considered to indicate statistical significance.
The complete clinical manifestation is not clear yet, as the reported symptoms range from mild to severe, with some cases even resulting in death. The most commonly reported symptoms are fever, cough, myalgia or fatigue, pneumonia, and complicated dyspnea, whereas less common reported symptoms include headache, diarrhea, hemoptysis, runny nose, and phlegm-producing cough [3, 16]. Patients with mild symptoms were reported to recover after 1 week while severe cases were reported to experience progressive respiratory failure due to alveolar damage from the virus, which may lead to death. Cases resulting in death were primarily middle-aged and elderly patients with pre-existing diseases (tumor surgery, cirrhosis, hypertension, coronary heart disease, diabetes, and Parkinson’s disease). Case definition guidelines mention the following symptoms: fever, decrease in lymphocytes and white blood cells, new pulmonary infiltrates on chest radiography, and no improvement in symptoms after 3 days of antibiotics treatment.
For patients with suspected infection, the following procedures have been suggested for diagnosis: performing real-time fluorescence (RT-PCR) to detect the positive nucleic acid of SARS-CoV-2 in sputum, throat swabs, and secretions of the lower respiratory tract samples [13, 14, 43].
Reviewing published literature, Jiehao et al., in their case series of 10 children with the 2019 novel coronavirus, reported that the age group of patients affected was between three and 131 months with a mean age of 74 months with a male to female ratio of 1:1.5.
Xia et al. noted 65% of the affected patients to be male within their subset of 20 pediatric inpatients with COVID-19 infection. The age range within this group of affected patients was one day to 14 years with a median age of two years. Seventy percent of the affected patients within this subset were under the age of three years. One of the patients had a history of epilepsy as a sequela of previous viral encephalitis and two patients had a history of atrial septal defect (ASD) repair surgery. The authors noted five further patients with a history of congenital or acquired diseases (unspecified within the reported study), which the authors purported to indicate that children with underlying diseases would have a greater susceptibility to COVID-19. Jiehao et al. noted within their study that the mean incubation period in their set of pediatric patients from household exposure to a symptomatic adult case was six and a half days, which they noted to be suggestive of a longer incubation period than what is being reported in adults.
Dong et al., in their pre-publication release data looking at the epidemiology of COVID-19 among children in China, reviewed 2143 cases of which 731 were laboratory confirmed and 1412 were suspected cases. They found the median age among these cases to be seven years with 56.6% of the cases being boys.
Overall, the epidemiological data suggests a slightly higher percentage of affected cases to be male. The age range of affected patients is wide, with concern regarding a higher propensity of illness in patients with pre-existing diseases. This may represent either worse symptoms resulting in a higher rate of testing or may indicate an increased susceptibility to illness with underlying disease.
Xia et al. noted in their study of pediatric COVID-19 cases that eight (80%) patients had a fever, six (60%) had a cough, four (40%) had a sore throat, three (30%) had a stuffy nose, and two (20%) had sneezing and rhinorrhea. None of the patients had diarrhea or dyspnea during the course of their illness.
Xia et al. report the presence of fever, which was defined as axillary temperature over 37.3°C in 12 cases (12/20, 60%), cough in 13 cases (13/20, 65%), diarrhea in three cases (3/20, 15%), nasal discharge in three cases (3/20, 15%), sore throat in one case (1/20, 5%), vomiting in two cases (2/20, 10%), tachypnea in two cases (2/20, 10%), and fatigue in one case (1/20, 5%). They also further noted physical exam findings when assessed by medical personnel to be rales in three cases (3/20, 15%), retraction signs in one case (1/20, 5%), and cyanosis in one case (1/20, 5%).
Dong et al. characterized, in looking at their data of 2143 pediatric patients with laboratory diagnosed and/or clinically suspicious cases of COVID-19 infection, the severity of illness as asymptomatic, mild (predominantly upper respiratory tract infectious symptoms with no frank respiratory distress), moderate (presence of pneumonia, frequent fever and cough but with no obvious hypoxemia), severe (presence of dyspnea with central cyanosis, oxygen saturation <92% with other hypoxia manifestations) and critical (acute respiratory distress syndrome (ARDS), respiratory failure, shock, encephalopathy, myocardial injury, heart failure, coagulation dysfunction, and organ dysfunction). With these clinical parameters, they found 4.4% of cases to be asymptomatic, 50.9% of cases to be mild, and 38.8% of the cases to be in the moderate range accounting for 94.1% of all cases. They also noted the proportion of severe and critical cases to be inversely proportional to the age range, with the age group of less than one year old having 10.6% of the severe and/or critical cases.
Chest radiographs revealed a unilateral patchy infiltrate in four (40%) of 10 patients with COVID-19 reported by Jiehao et al.. Xia et al. further looked to examine the chest CT findings at various stages of the COVID 19 process. At the early stage of the disease, they noted six patients presented with unilateral pulmonary lesions (6/20, 30%), 10 with bilateral pulmonary lesions (10/20, 50%), and one pediatric patient and three neonates had no abnormalities on chest CT (4/20, 20%). Sub-pleural lesions with localized inflammatory infiltration were found in all children. Ten patients (10/20, 50%) were noted to have “halo sign” consolidation, 12 patients (12/20, 60%) had ground-glass opacities, four patients (4/20, 20%) had “fine mesh shadows,” and tiny nodules were detected in three patients (3/20, 15%). No patients were noted to have signs of pleural effusion and lymphadenopathy on CT scan.
Jiehao et al. noted within their laboratory findings: median white blood cell count (WBC) 7.35×109/L, C-reactive protein (CRP) 7.5 mg/L, procalcitonin (PCT) 0.07 ng/dL, creatine kinase-myocardial band (CK-MB) 23 U/L, alanine aminotransferase (ALT) 18.5 U/L, aspartate aminotransferase (AST) 27.7 U/L, urea 3.1 mmol/L, creatinine 35.5 μmol/L, lactate dehydrogenase (LDH) 25 U/L, and D-dimer 0.45 μg/mL; influenza virus A and B were negative. The study also showed that all patients had 2019-nCoV RNA detected in nasopharyngeal and throat swabs within four to 48 hours after the onset of symptoms and 2019-nCoV RNA in nasopharyngeal or throat swabs was no longer detectable within six to 22 days (with a mean of 12 days) after the onset of illness. Six of these patients had fecal samples tested, and 5 (83.3%) were positive for 2019-nCoV RNA. The authors also noted with concern that the five patients still had 2019-nCoV RNA detected in feces within 18-30 days after illness onset at the time of publication of their findings. Five patients also had serum and urine samples tested and were negative for 2019-nCoV RNA.
For Xia et al. (per their reference ranges used), WBC was normal (5.5-12.2) in 14 cases (14/20, 70%), decreased (<5.5) in four cases (4/20, 20%), and increased (>12.2) in two cases (2/20, 10%); ALT increased (>40 IU/L) in five cases (5/20, 25%),CK‐MB increased in 15 cases (15/20, 75%), and PCT (>0.05) increased in 16 cases (16/20, 80%). Eight patients were co-infected with other pathogens (8/20, 40%), including influenza viruses A and B, mycoplasma, respiratory syncytial virus (RSV), and cytomegalovirus (CMV). Further, four cases had abnormal electrocardiogram (EKG) events, including atrial arrhythmia, first-degree atrioventricular (AV) block, atrial and ventricular premature beats, and incomplete right bundle branch block.
Elevations in CK-MB and EKG changes are of particular concern, as they may be indicative of myocarditis as a potential complication of COVID-19. Lippi et al., in their electronic data review (which was not specific for pediatric patients), also noted the cardiac Troponin I value significantly increased in patients with severe COVID-19 infection.
Jiehao et al. noted the mean number of secondary symptomatic cases in the household exposure setting was 2.43, which is indicative of the basic reproductive number for pediatric COVID-19 cases and proof of direct transmission. Xia et al. noted within their subset of 20 cases that 13 pediatric patients (13/20, 65%) had an identified history of close contact with COVID‐19 diagnosed family members, again supporting proof of direct transmission.
A particular source of concern is the paucity of data on the vertical transmission potential of COVID-19 pneumonia in pregnant women. Chen et al. retrospectively reviewed the medical records for nine pregnant women with laboratory-confirmed COVID-19. The evidence of intrauterine vertical transmission through testing for the presence of SARS-CoV-2 in amniotic fluid, cord blood, and neonatal throat swab samples was assessed. Breastmilk samples were also collected and tested from patients after the first lactation.
They reported that within this subset of patients nine live-births delivered via cesarian section were recorded. No neonatal asphyxia was observed in the newborn babies. All nine newborns had a one-minute Apgar score of eight to nine and a five-minute Apgar score of nine to 10. Six patient’s amniotic fluid, cord blood, neonatal throat swab, and mother’s breastmilk samples were tested for SARS-CoV-2, and all samples tested negative for the virus. They noted within this subset of patients that the clinical characteristics of the disease were similar in pregnant and non-pregnant adults and that they did not note any evidence of intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy.
At the time of publication of this article, the U.S. Food and Drug Administration (FDA) currently has no approved medications to treat patients with COVID-19. As such, management algorithms, particularly for the pediatric patient, are based at least in part on clinical opinion. Partially based on the data reviewed above and partially upon the opinion of the authors of the article, looking specifically at pediatric COVID-19, we recommend the investigation and management pathway as displayed in Figure 1.
Prevention and control strategies and methods are reported at three levels: national level, case-related population level, and general population level. At the national level, the National Health Commission of the People’s Republic of China issued the “No.1 announcement” on 20 January 2020, which officially included the COVID-19 into the management of class B legal infectious diseases, and allowed for class A infectious disease preventive and control measures to be implemented. Under this policy, medical institutes can adopt isolation treatment and observation protocols to prevent and control the spread of the COVID-19. On 22 January 2020, the National Health Commission published national guidelines for the prevention and control of COVID-19 for medical institutes to prevent nosocomial infection. On 28 January 2020, the National Health Commission issued protocols for rapid prevention and control measures in order to effectively contain the spread of the epidemic through a “big isolation and big disinfection” policy during the Chinese Spring Festival. National-level strategies have also been issued with targeted measures for rural areas (issued on 28 January 2020) and the elderly population (issued on 31 January 2020) [48, 49]. Several public health measures that may prevent or slow down the transmission of the COVID-19 were introduced; these include case isolation, identification and follow-up of contacts, environmental disinfection, and use of personal protective equipment.
To date, no specific antiviral treatment has been confirmed to be effective against COVID-19. Regarding patients infected with COVID-19, it has been recommended to apply appropriate symptomatic treatment and supportive care [3, 16]. There are six clinical trials registered in both the International Clinical Trials Registry platform and the Chinese Clinical Trial Registry to evaluate the efficacy or safety of targeted medicine in the treatment or prognosis of COVID-19 (Additional file 2) [51, 52]. Regarding infected patients with COVID-19, it has been recommended to apply appropriate symptomatic treatment and supportive care [3, 16]. Studies have also explored the prevention of nosocomial infection and psychological health issues associated with COVID-19. A series of measures have been suggested to reduce nosocomial infection, including knowledge training for prevention and control, isolation, disinfection, classified protections at different degrees in infection areas, and protection of confirmed cases [18, 50, 53]. Concerning psychological health, some suggested psychological intervention for confirmed cases, suspected cases, and medical staff [18, 54].
For the general population, at this moment there is no vaccine preventing COVID-19. The best prevention is to avoid being exposed to the virus. Airborne precautions and other protective measures have been discussed and proposed for prevention. Infection preventive and control (IPC) measures that may reduce the risk of exposure include the following: use of face masks; covering coughs and sneezes with tissues that are then safely disposed of (or, if no tissues are available, use a flexed elbow to cover the cough or sneeze); regular hand washing with soap or disinfection with hand sanitizer containing at least 60% alcohol (if soap and water are not available); avoidance of contact with infected people and maintaining an appropriate distance as much as possible; and refraining from touching eyes, nose, and mouth with unwashed hands.
The WHO also issued detailed guidelines on the use of face masks in the community, during care at home, and in the health care settings of COVID-19. In this document, health care workers are recommended to use particulate respirators such as those certified N95 or FFP2 when performing aerosol-generating procedures and to use medical masks while providing any care to suspected or confirmed cases. According to this guideline, individuals with respiratory symptoms are advised to use medical masks both in health care and home care settings properly following the infection prevention guidelines. According to this guideline, an individual without respiratory symptoms is not required to wear a medical mask when in public. Proper use and disposal of masks is important to avoid any increase in risk of transmission.
In addition to articles published in research journals, the China CDC published a guideline to raise awareness of the prevention and control of COVID-19 among the general population. The key messages of the guideline include causes, how to choose and wear face masks, proper hand washing habits, preventive measures at different locations (e.g., at home, on public transportation, and in public space), disinfection methods, and medical observation at home. In addition to scientific knowledge on ways to handle the COVID-19 outbreak, the guideline also suggests ways to eliminate panic among the general population.