Co-exposed persons are defined as people who shared the same risks of exposure as a possible or confirmed case of COVID-19. Contact and co-exposure identification is done for all identified possible cases. Contacts are traced from the date of onset of clinical symptoms in a case. If the diagnosis of SARS-CoV-2 infection is confirmed in the index case, active surveillance of contacts/co-exposed persons is initiated immediately.

Three levels of risk of infection are defined for contacts/co-exposed persons of a possible/confirmed COVID-19 case (Table). Co-exposed persons of a confirmed case are followed-up according to the same procedure as a moderate-/high-risk contact. The follow-up procedure for the contacts/co-exposed persons differs according to the evaluation of the level of risk of infection (Table).

During the initial implementation phase of the procedure, owing to the limited number of contacts involved, it was decided to also implement an active follow-up for low risk contacts.

Patients are interviewed by the clinicians, with the help of a translator if needed, who recover relevant information on their contacts since onset of clinical symptoms and the nature and intensity of exposure. The involved regional health agencies work closely with the regional entities of Santé publique France (cellules régionales) in order to implement contact tracing and follow-up. Santé publique France coordinates the surveillance at national level in liaison with the national Health Authorities.

Respiratory samples from the patients were sent to the KCDC and RT-PCR for detecting SARS-CoV-2 was performed as in previous study.17 In brief, RNA was extracted from clinical samples with a QIAamp® viral RNA mini kit (QIAGEN, Hilden, Germany). The primer and probe sequences used for RNA-dependent RNA polymerase gene detection were: 5′-GTGARATGGTCATGTGTGGCGG-3′ (Forward), 5′-CARATGTTAAASACACTATTAGCATA-′3 (Reverse) and 5′-CAGGTGGAACCTCATCAGGAGATGC-3′ (Probe in 5-FAM/3′-BHQ format) and the primer and probe sequences used for E gene detection were: 5′-ACAGGTACGTTAATAGTTAATAGCGT-3′ (Forward), 5′-ATATTGCAGCAGTACGCACACA-3′ (Reverse) and 5′-ACACTAGCCATCCTTACTGCGCTTCG-3′ (Probe in 5-FAM/3′-BHQ format). Reverse transcription was performed at 50°C for 30 minutes, followed by inactivation of the reverse transcriptase at 95°C for 10 minutes. PCR amplification was performed with 40 cycles at 95°C for 15 seconds and 60°C for 1 minute using an ABI 7500 Fast instrument (Thermo Fisher Scientific, Waltham, MA, USA).

Primary physicians from each participating hospital retrospectively collected clinical medical record data then two infectious disease physicians from KNCCMC reassessed the accuracy of the raw data. Patients were hospitalized in the isolation units in each hospital from January 19th, 2020, with final follow-up for the study on February 17th, 2020. Epidemiologic, demographic, and clinical information including laboratory and radiologic findings were obtained. Clinical severity and changes according to days after first symptom onset were assessed as follows: 1, no limit of daily activity; 2, limit of daily activity but no need for supplemental O2 therapy; 3, need for supplemental O2 therapy via nasal prong; 4, need for supplemental O2 therapy via facial mask; 5, need for high flow supplemental O2 therapy or non-invasive ventilation; 6, need for invasive ventilation; 7, multi-organ failure or need for extracorporeal membrane oxygenation (ECMO) therapy; 8, death.

Chest radiograph scoring was performed as described in a previous study18: in brief, serial chest radiographs were retrospectively reviewed in consensus by four physicians who were unaware of the clinical conditions of the patients. Each lung was divided into the upper, middle, and lower zone, and infiltrations on each zone were scored from 0 to 4, with a total range of 0 to 24.

From 17 to 29 January 2020, a possible case was defined either as a patient with a severe acute lower respiratory infection requiring admission to hospital and with a history of travel to or residence in Wuhan, China in the 14 days before symptom onset, or a patient with an acute respiratory illness whatever the severity and with a history of at-risk exposure, mainly to a confirmed case. A confirmed case was defined as a possible case with a positive SARS-CoV-2 RT-PCR on respiratory samples, performed by an accredited laboratory. Testing relied on the real-time RT-PCR procedure developed by the Charité as well as on the use of real-time RT-PCR specific for the RdRp gene (four targets) designed at Institut Pasteur (RdRp-IP).

The case definition was first set up on 10 January and adapted over time. The detailed case definition used for the cases presented here as well as the most up-to-date case definition are available in the Supplement.

Since rRT-PCR tests serve as the gold standard method to confirm the infection of SARS-CoV-2, false-negative results could hinder the prevention and control of the epidemic, particularly when this test plays a key reference role in deciding the necessity for continued isolated medical observation or discharge. Regarding the underlying reasons for false-negative rRT-PCR results, a previous published study suggested that insufficient viral specimens and laboratory error might be responsible (3). We speculated from these two cases that infection routes, disease progression status (specimen collection timing and methods), and coinfection with other viruses might influence the rRT-PCR test accuracy, which should be further studied with more cases.

False-negative rRT-PCR results were seen in many hospitals. By monitoring data collected at our hospital from January 21 to 31, 2020, two out of ten negative cases shown by the rRT-PCR test were finally confirmed to be positive for COVID-19, yielding an approximately 20% false-negative rate of rRT-PCR. Although the false-negative estimate would not be accurate until we expand the observational time span and number of monitored cases, the drawback of rRT-PCR was revealed. Clinical manifestations, laboratory examination results, and chest CT features of patients with COVID-19 were also of great value in helping the detection and diagnosis. Thus, an integrated criterion should be established for the diagnosis of SARS-CoV-2 infection. In addition to the epidemiological information, we focused on two aspects of information: chest CT features and laboratory examination results.

Of note, approximately 96% of patients with COVID-19 presented with chest CT abnormalities, such as multiple bilateral and peripheral ground-glass opacities and consolidation (34), making chest CT features essential in recognizing COVID-19. The National Health Commission of China revised the diagnostic criteria in the Hubei province, where a severe epidemic occurred (5). A new diagnostic type called “Clinical diagnosis” was set according to the presence of pneumonia on chest CT, regardless of rRT-PCR results. To some extent, CT features and rRT-PCR results were complimentary in the diagnosis of COVID-19. From a clinical perspective, CT features could be utilized as the first and immediate reference for doctors to screen the highly suspected cases and to take necessary actions while rRT-PCR serves as a confirmation tool, the results of which could be utilized later to decide the subsequent action of continuing isolated treatment or discharge. Notably, our hospital was facilitated with a DL-based computer-aided diagnostic system (InferRead CT Pneumonia, Infervision, Beijing, China) for pneumonia, which greatly improved the detection efficiency for patients highly suspected with COVID-19 by alarming the technician within 2 minutes when any suspected cases was found after CT examination. The automatic lesion segmentation on CT was also helpful to evaluate the progression of COVID-19 quantitatively. With an integrated approach of DL, CT features, and rRT-PCR results, the screening and treatment of COVID-19 would be more effective.

Furthermore, we observed conflicting laboratory examination results in these two patients. Patient in Case 2 was infected only by SARS-CoV-2 and presented decreased lymphocytes and elevated C-reactive protein, consistent with the typical tendency found in the COVID-19 cohort. In contrast, the patient in Case 1 was coinfected with influenza A and presented with increased lymphocytes and elevated C-reactive protein. The difference in laboratory examination results could be a potential indicator of a different infection status, including SARS-CoV-2 infection alone or coinfection with other viruses, which, however, should be further validated with more cases.

In conclusion, we reported two false-negative results of rRT-PCR for SARS-CoV-2 infection and mentioned the possible tandem approaches for clinical practices to ensure an early and accurate diagnosis of COVID-19. In addition, the potential role of laboratory examination results in differentiating the infection status was revealed as well.

Search methods and strategies for identification of studies

Literature search was performed in “PubMed”, “Web of Science”, "Scopus", "ScienceDirect" and also in "JAMA", "BMJ", "Oxford" and "THE LANCET" journals using following terms: coronavirus, COVID-19 and 2019-nCoV, to find articles published from January 5 to February 28, 2020. Moreover, we used the findings of literature retrieved via searching authoritative texts and hand searches in WHO reports. We checked the reference lists of all studies identified by the above methods. Studies were excluded if used old data, had inappropriate topics and were not pertinent to the focused purpose of the study.

Data collection and analysis

In order to identify studies meeting the inclusion criteria, seven review authors screened the titles and abstracts of all retrieved records. The studies were selected independently and the results were discussed to make the final selection. After reading the full text of all potentially eligible articles, a final decision was made for each study.

Data extraction and management

Extraction of data was performed by the same seven review authors who conducted the study selection independently, using a structured form that contained study characteristics including genetic diversity of coronavirus genus, mode of transmission, incubation period, infectivity, pathogenicity, virulence, immunogenicity, diagnosis, surveillance, clinical case management, special measures in community level and health care facility. Any disagreement was discussed after completion of data collection process and reviewers were consulted for each topic.

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.

Search Strategy

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.

Statistical analysis

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.

A 36-year-old man presented with fever for 5 days (peak body temperature: 40℃) and was admitted to the Fever Clinic of the Beijing Haidian Hospital. The patient had no direct contact history with patients with COVID-19 or people from the Hubei province, but a recent travel history to Chongqing was reported. Physical examination showed fever with a body temperature of 38.5℃. Respiratory symptoms at admission included dry throat and difficulty breathing; no cough, sputum, or stuffy/runny nose was observed. Other symptoms included nausea, vomiting, and diarrhea. Laboratory examination revealed increased leukocyte (13.69 × 109/L) and neutrophil (10.42 × 109/L) counts, decreased differential count of lymphocytes (12.6%), and an elevated C-reactive protein level (155 mg/mL).

Chest CT showed emphysema in both upper lungs and diffuse ground-glass opacities in the right lower lobe, highly suggestive of viral pneumonia. In addition, the DL-based computer-aided diagnostic system also indicated a high risk of pneumonia with the infected area accounting for 8.9% of the whole lungs (Fig. 2). Subsequently, throat swab specimens were promptly collected for SARS-CoV-2 rRT-PCR. A negative result for SARS-CoV-2 was observed in the first rRT-PCR test. A second consecutive SARS-CoV-2 rRT-PCR test was conducted immediately thereafter, and a positive result was obtained. The patient was further confirmed with COVID-19 with additional positive rRT-PCR tests.

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.

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.

Death and severity of COVID-19 are associated with age and comorbidities across the world. Especially in countries with the highest outbreaks, such as China, Italy, and Iran, strategies must be employed to ensure that high-risk groups, such as old people and those with other underlying diseases such as diabetes and cancer, received adequate protection from COVID-19. Therefore, early access to medical care when infected is vital for improving chances of survival. Improving medical supplies to countries such as Iran, which is significantly influenced by US punitive policies, can reduce the deterioration of this politically sensitive situation.

Furthermore, taking detailed and accurate medical history, and scoring CFR alongside RR, may highlight the highest risk areas, and more efficiently direct the intervention to decrease the spread of the virus globally. This may enable the development of point-of-care tools to help clinicians in stratifying patients, based on possible requirements in the level of care to improve probabilities of survival from COVID-19 disease.

Epidemiological, clinical, laboratory, therapeutic and outcome data were collected from patients’ medical records, with verification by independent doctors. Clinical outcomes were followed up to 8 February 2020, when specimens were obtained from throat swabs and sputum. For missing or vague data, direct communications with attending doctors and other healthcare providers were performed. Laboratory confirmation of SARS-CoV-2 was performed in our hospital and the Centre for Disease Control and Prevention of Zhejiang province/city level under authorisation by previously reported real-time RT-PCR.5 All patients received chest radiography or CT at admission, while other respiratory viruses were excluded, such as influenza A (H1N1, H3N2 and H7N9), influenza B, respiratory syncytial virus, parainfluenza virus, adenovirus, SARS-CoV and MERS-CoV.

The detection of SARS-CoV-2 RNA via reverse-transcriptase polymerase chain reaction (RT-PCR) was used as the major criteria for the diagnosis of COVID-19. However, due to the high false-negative rate, which may accelerate the epidemic, clinical manifestations started to be used for diagnosis (which no longer solely relied on RT-PCR) in China on February 13, 2020. A similar situation also occurred with the diagnosis of SARS 59. Therefore, a combination of disease history, clinical manifestations, laboratory tests, and radiological findings is essential and imperative for making an effective diagnosis. On February 14, 2020, the Feng Zhang group described a protocol of using the CRISPR-based SHERLOCK technique to detect SARS-CoV-2, which detects synthetic SARS-CoV-2 RNA fragments at 20 × 10-18 mol/L to 200 × 10-18 mol/L (10-100 copies per microliter of input) using a dipstick in less than an hour without requiring elaborate instrumentation 60. Hopefully, the new technique can dramatically enhance the sensitivity and convenience if verified in clinical samples.

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].

Epidemiology

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.

Symptomatology

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.

Imaging

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.

Labs

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.

Transmission

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.

Management algorithm

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.

In this study, we collected and calculated epidemiological data (exposure to infected area, contact with confirmed/suspected patients with COVID-19, cluster situation and median incubation period) and other anthropometrics, demographics, symptoms and signs on admission. Laboratory and chest X-ray/CT results, comorbidities, treatments (including drugs, intensive care and mechanical ventilation) and clinical outcomes were also summarised.

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.

The data were retrieved from accurate databases including Worldometer 2, WHO 3, the Center of Disease Control and Prevention, and the Morbidity and Mortality Weekly Report series (provided from Center of Disease Control and Prevention), according to the user’s guide of data sources for patient registries. Due to the rapid increase in data, the analysis in this study was performed on the 12th and 23rd of March 2020.

Raw data was mapped according to countries and CFR and RR were compared for countries with ≥ 1,000 cases. All countries with < 1,000 cases are presented in supplementary Table 1. A comparison of CFR with different known viral diseases was performed.

The viral research institution in China has conducted preliminary identification of the SARS-CoV-2 through the classical Koch’s postulates and observing its morphology through electron microscopy. So far, the golden clinical diagnosis method of COVID-19 is nucleic acid detection in the nasal and throat swab sampling or other respiratory tract samplings by real-time PCR and further confirmed by next-generation sequencing.

A recent study led by Prof. Nan-Shan Zhong’s team, by sampling 1099 laboratory-confirmed cases, found that the common clinical manifestations included fever (88.7%), cough (67.8%), fatigue (38.1%), sputum production (33.4%), shortness of breath (18.6%), sore throat (13.9%), and headache (13.6%). In addition, a part of patients manifested gastrointestinal symptoms, with diarrhea (3.8%) and vomiting (5.0%). The clinical manifestations were in consistence with the previous data of 41, 99, and 138 patients analysis in Hubei province [46, 48, 50]. Fever and cough were the dominant symptoms whereas upper respiratory symptoms and gastrointestinal symptoms were rare, suggesting the differences in viral tropism as compared with SARS-CoV, MERS-CoV, and influenza. The elderly and those with underlying disorders (i.e., hypertension, chronic obstructive pulmonary disease, diabetes, cardiovascular disease), developed rapidly into acute respiratory distress syndrome, septic shock, metabolic acidosis hard to correct and coagulation dysfunction, even leading to the death (lower panel, Fig. 1).

In laboratory examination results, most patients had normal or decreased white blood cell counts, and lymphocytopenia [16, 54]. But in the severe patients, the neutrophil count, D-dimer, blood urea, and creatinine levels were higher significantly, and the lymphocyte counts continued to decrease. Additionally, inflammatory factors (interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α) increase, indicating the immune status of patients. The data showed that ICU patients had higher plasma levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (GCSF), 10 kD interferon-gamma-induced protein (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1-α (MIP-1α), and TNF-α.

Moreover, the CT imaging showed that computed tomography on the chest was ground-glass opacity (56.4%) and bilateral patchy shadowing (51.8%), sometimes with a rounded morphology and a peripheral lung distribution, analyzed from the patients in the Fifth Affiliated Hospital, Sun Yat-Sen University. Clinicians have been aware that, a part of confirmed patients appeared the normal CT image presentations. The diagnostic sensitivity of radiologic is limited, so it is necessary to verify with clinical symptoms and virus RNA detections.

As a novel disease, COVID-19 has just started to manifest its full clinical course throughout thousands of patients. In most cases, patients can recover gradually without sequelae. However, similar to SARS and MERS, COVID-19 is also associated with high morbidity and mortality in patients with severe cases. Therefore, building a prognosis model for the disease is essential for health-care agencies to prioritize their services, especially in resource-constrained areas. Based on clinical studies reported thus far, the following factors may affect or be associated with the prognosis of COVID-19 patients (Table 3):Age: Age was the most important factor for the prognosis of SARS 99, which is also true for COVID-19. COVID-19 mainly happened at the age of 30-65 with 47.7% of those patients being over 50 in a study of 8,866 cases as described above 37. Patients who required intensive care were more likely to have underlying comorbidities and complications and were significantly older than those who did not (at the median age of 66 versus 51) 34, suggesting age as a prognostic factor for the outcome of COVID-19 patients.Sex: SARS-CoV-2 has infected more men than women (0.31/100,000 versus 0.27/100,000), as described above 37.Comorbidities and complications: Patients with COVID-19 who require intensive care are more likely to suffer from acute cardiac injury and arrhythmia 34. Cardiac events were also the main reason for death in SARS patients 55,65,99. It has been reported that SARS-CoV-2 can also bind to ACE2-positive cholangiocytes, which might lead to liver dysfunctions in COVID-19 patients 100. It is worth noting that age and underlying disease are strongly correlated and might interfere with each other 55.Abnormal laboratory findings: The C-reactive protein (CRP) level in blood reflects the severity of inflammation or tissue injury and has been proposed to be a potential prognostic factor for disease, response to therapy, and ultimate recovery 101. The correlation of CRP level to the severity and prognosis of COVID-19 has also been proposed 101. In addition, elevated lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) may also help predict the outcome. These enzymes are expressed extensively in multiple organs, especially in the heart and liver, and are released during tissue damage 102,103. Thus, they are traditional markers for heart or liver dysfunctions.Major clinical symptoms: Chest radiography and temporal progression of clinical symptoms should be considered together with the other issues for the prediction of outcomes and complications of COVID-19.Use of steroids: As described above, steroids are immunosuppressant commonly used as an adjunctive therapy for infectious diseases to reduce the severity of inflammatory damage 104. Since a high dosage of corticosteroids was widely used in severe SARS patients, many survivors suffered from avascular osteonecrosis with life-long disability and poor life quality 105. Thus, if needed, steroids should be used at low dosage and for a short time in COVID-19 patients.Mental stress: As described above, during the COVID-19 outbreak many patients have suffered from extraordinary stress as they often endured long periods of quarantine and extreme uncertainty and witnessed the death of close family members and fellow patients. It is imperative to provide psychological counseling and long-term support to help these patients recover from the stress and return to normal life 66.

Genetic differences between SARS, MERS, and COVID-19 epidemics

The animal reservoir of the virus has not yet been identified, but genomic of COVID-19 is so similar to bat coronavirus (98%), reinforcing the presumption that the virus was transmitted by an animal in the shopping center in Wuhan. With regard to genomic similarity, the virus differs from its predecessors, namely SARS (79%) and MERS (50%). As indicated by genetic data, CVOID-19 pathogen is classified as a member of the beta-coronavirus genus, and can bind to the angiotensin-converting enzyme 2 receptor in humans (1,2).

Transmission and Incubation period

Human to human transmission via either respiratory droplets or close contacts was initially proposed as the main routes of transmission of the pathogen based on experience gained in the previous two epidemics caused by coronaviruses (MERS-CoV and SARS-CoV)(8). According to the world Health Organization (WHO) report, 2019-nCoV is a unique virus that causes respiratory disease, which spreads via oral and nasal droplets. Moreover, the pathogen of COVID-19 can float in the air in the form of aerosols and cause infection in healthy people (9). Evidence of a study in Singapore revealed higher loads of virus in confirmed cases of COVID-19 in early stages of the disease, which decreased dramatically over time (10).

There is a limited number of evidence on oral-fecal transmissibility of the pathogen. However, COVID-19 RNA was found in fecal specimens of 2 to 10% of confirmed patients with gastrointestinal symptoms such as diarrhea (11,12), so fecal-oral transmission should be taken into account as a probable route through case investigation.

Incubation period (the time from infection to the onset of symptoms) for the new pathogen varies from 2 to 14 days in human to human transmission (13). Furthermore, median incubation period was reported as 5-6 days (ranged from 0-14 days) in WHO report (14). Studies that were conducted on those who had traveled to Wuhan and Guangdong mean incubation period of 4.8 (±2.6) days was reported. In some other studies the mean incubation period was reported to be 6.4 days (15,16), while another study in China reported longer incubation times up to 24 days (13).

Infectivity

An important question about COVID-19, which has raised much concern among health care providers, health policy makers and the general population, is the degree of transmissibility or contagiousness of the coronavirus (infectivity). In general, epidemiologists use mathematical formulas with clear and acceptable assumptions to calculate the infectivity index. For this purpose, "basic reproduction number" termed R0 is used, and it indicates the expected number of cases directly infected by one contagious case in a population that everyone is supposed to be susceptible. For viral pathogens in MERS and SARS epidemics, the index was approximated to be 2, indicating that each infected person could infect two people on average in an effective contact. However, for COVID-19, the calculated value in a study was slightly higher and the index value based on data calculated in Wuhan, China was 2.2 (95% CI, 1.4 to 3.9) (17) and it shows that the infectivity of COVID-19 is higher than previous epidemics originated by coronavirus (18). In other studies, R0 has been reported with different values, the lowest of which corresponds to the WHO report of 1.95 (1.4-2.5) (19) and the highest value is 6.47 (95% CI 5.71–7.23) (20). A review study estimated an average R0 for COVID-19 of 3.28 with a median of 2.79 and an IQR of 1.16 (21). As an explanation for variety of the calculated indices is that different calculation methods were used and calculations were done at different times of epidemics.

As previously noted, certain assumptions have been made in calculation of this index. Initial reports on a family in one of the provinces of China show that all six-members of a family, aged 10-66 years were infected within a short period after one member returned from Wuhan (8). As a conclusion, this index is changing over time, and its reduction may reflect effectiveness of preventive measures, so that reaching a value less than one (less than one new case per effective contact with an infected person and transmission) implies that the epidemic is controlled in the community (6).

Pathogenicity

An important concern in the recent pandemic is the capability of the pathogen to establish and induce infection with different clinical manifestations in human. According to WHO report, about 82 percent of COVID-19 patients have mild symptoms and were recovered immediately. As of 20 February, there were 18264 (24%) recovered cases in China and recovery and mortality rates of the disease among severe cases in Guangdong were 26.4 % and 13.4%, respectively. Median time for onset of symptoms to recovery in mild and severe cases was 2 and 3-6 weeks, respectively. Furthermore, time interval between onset and developing severe symptoms such as hypoxia was one week (22).

In case studies that were conducted outside of mainland China, time of onset of symptom(s) to recovery was 22.2 days (95% confidence interval 18-83). Moreover, average time of onset of symptom(s) to death varies from 20.2 (95% confidence interval 15.1-29.9) to 22.3 days (95% confidence interval 18-82) (23,24). Results of a case-series study on six infants (45-days to one-year) infected with COVID-19 in China indicated mild symptoms of the disease in this age group with no need for further intensive care (25). According to WHO report, COVID-19 disease among children seems to be rare with mild symptoms, about 2.4% of total cases were reported in children and adolescents (aged under 19 years), while older cases aged over 60 years and those with a background of chronic diseases were at higher risk of developing severe disease and death (22).

Even though age is an important deterministic factor for severity of symptoms, other risk factors such as having a history of underlying diseases and/or co-infection with other infections like Influenza virus and Klebsiella may accelerate the progress of symptoms and lead to poor prognosis of the disease (26). However, findings from a study in Singapore shows that infected patients with no history of underlying diseases may also develop severe disease and need for intensive care (4).

Virulence

The virulence of a disease is usually measured on the basis of indicators such as mortality rate and disability. Compared with the previous two epidemics (SARS and MERS), the case fatality rate was lower and approximately 2% in COVID-19, and only less than 15% of patients would seek hospital services. However, the case fatality rate of SARS and MERS was 10% and 34%, respectively (18). Results of a study in China revealed the overall case fatality rate of 2.3% for COVID-19 (27) and some studies reported case fatality rate of 0.9% in Beijing (28). In another study, Jung and colleagues reported a confirmed case fatality risk of 5.3% to 8.4% for COVID-19(23). However, due to the rapid spread of COVID-19, there is a higher number of death cases in the recent pandemic (N=3043, up to 02 March 2020) compared to SARS and MERS (N=1871) (29).

There is a poor prognosis for the disease in middle and older aged patients (28). In a study on 44672 confirmed cases in China, case fatality rate was highest in the group of over 80 years (14.77%), followed by the age group between 70 to 80 years (7.96%) and no mortality was reported in age group below 10 years (30). Even though death outcome is uncommon in young people, a few deaths are reported in this age group in China and Iran.

Availability of and access to healthcare facilities has likely contributed to increase in death outcome. As a probable explanation for the difference between fatality rate in Wuhan (3%) and other provinces (0.7%) in China, death rates are likely affected by shortage in health resources due to increasing number of patient who had sought diagnosis and treatment services in the early phase of the epidemic in Wuhan (31).

Immunogenicity

Exploring and understanding the immunogenicity of COVID-19 is essential for developing the most effective treatment regimens and vaccine. However, evidence on immunogenicity of COVID-19 is limited. Study on B-cell and T-cells epitopes revealed that SARS-CoV and the virus causing COVID-19 had identical proteins (32). A few clinical trials have evaluated the efficacy of new vaccines in MERS-CoV and SARS-CoV. Results of these studies in Phase-1 showed some degree of efficacy and one of these studies has been certified to begin Phase-2 (33,34).

Absence of clinical symptoms, respiratory lesions in CT scan and two negative RT-PCR tests in two consecutive days are introduced as criteria of discharge from hospital or quarantine center in China (35). However, recent studies reported several cases of COVID-19 with clinical manifestations of the disease along with a positive test after discharging from hospital (36,37). False positive and false negative results have been reported in RT-PCR test (10,38); hence, hospitals in China have considered additional antibody test (negative IgM and positive IgG results) as a recovery criteria and discharge requirement (39). In conclusion, recurrence of COVID-19 in recovered cases highlights the necessity for development of a more effective vaccine.

Diagnosis

Pathogen of COVID-19 has been detected in upper and lower respiratory tracts in initial assessments. Moreover, viral RNA has been detected in fecal and blood samples in later studies. According to WHO guideline, laboratory diagnosis of COVID-19 is based on a positive RT-PCR test. Target gene for diagnosis may be different by country. Accordingly, target genes for screening and confirmatory assays by RT-PCR are ORF1ab and N in Chinese laboratory protocol, while RdRP, E and N are checked in Germany. Furthermore, three targets in N gene are considered in the US protocol (40).

RT-PCR is an expensive test and no access to diagnostic facility during COVID-19 pandemic advocates conducting new researches on other diagnostic approaches such as Chest CT. However, results of recent studies in China demonstrate low specificity for this diagnostic approach (41). As a critical point in diagnostic studies, accuracy of a new test is compared to the gold standard. This comparison resulted in lower values of diagnostic accuracy for the new test. On the other hand, the sensitivity and specificity of a test depend on the severity of cases, which may vary between different populations according to their type of surveillance system (42). In the mentioned study that compared CT scan with RT-PCR as a gold standard, sensitivity of CT scan was appropriate (41). However, the study population consisted of suspected cases and generalizability of the findings is questionable (43). Furthermore, the large number of hospitalized cases due to false positive results by CT scan may increase the risk of transmission to healthy people. On the other hand, RT-PCR test may be subject to some limitations, especially in the earlier phase of an epidemic, as the specialists should be trained for running related procedures and interpretation of results. Moreover, false negative results due to either low quality of specimen in use or inadequate number of organisms in the samples are introduced as main challenges (44). Results of a recent study on rapid IgM-IgG combined test revealed some limitation for RT-PCR test as a standard diagnostic method for COVID-19. The following limitations were indicated for RT-PCR test: long turnaround times, complex operation, and need for quality controlled laboratories, expensive equipment and trained specialists (38).

Surveillance The outbreak surveillance is the anticipation, early warning, prompt detection and response to unusual increase in the number of cases. Establishing a surveillance system for a new epidemic is believed to be a core intervention in controlling the disease (45). Surveillance system data provides reliable information for epidemiologists to identify weak chains of transmission and facilitates evidence-based decisions by policymakers both inside and outside the healthcare service. Moreover, updating and sharing interpretations of data with media, especially in earlier phase of an epidemic, will aid community engagement and participation in control activities and prevention of spreading rumors. Although, it may be too soon to compare the effectiveness of surveillance systems for COVID-19 epidemic in different countries, it seems that the Chinese surveillance system is highly effective as it ensures timely detection, recording, tracking, updating and sharing information on media for an outbreak with unknown origin and high burden of cases (4).

In a large number of countries, the initial focus of the surveillance system for CIVID-19 is examination of all suspected cases with symptoms of the disease (mostly fever) and all people with a travel history to China or visiting Chinese travelers or citizens it the previous two weeks. However, this type of screening program mainly relies on fever cases and those with direct flights from China, so it misses pre-symptomatic cases as well as infected travelers who are arriving from regions with high burden of disease via indirect flights, which could be a source of infection in COVID-19-free countries (46).

In a communicable disease outbreak, essential data are usually collected in parallel from different available information sources in the country including data of weekly outpatient visits to health care centers and hospital referrals with a chief complaint of fever, data of weekly inpatient fever cases and deaths with unknown origin (45). Furthermore, increase in the number of cases and deaths due to pneumonia may raise an alarm in COVID-19 free areas.

A prerequisite for establishing a surveillance system is to provide basic laboratory facilities, particularly at "point of care" (10). This system should be constantly monitored and evaluated using sensitive indicators to ensure the quality of case detection, diagnosis and management.

Detection of primary confirmed cases with poor prognosis in early phase of the epidemic without any link to confirmed cases from other regions emphasis on the insensitivity of a national and local surveillance systems and low performance of control activities against the disease in community level. In this case, it should be immediately addressed and capability and capacity of the surveillance system should be checked.

Examples of surveillance systems in different countries (

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National authorities are actively looking for cases in all provinces of China and efforts for finding additional cases inside and outside of Wuhan City have been expanded. Moreover, active and reactive case detection along with tracing close contacts have been started in medical institutions.

The Department of Disease Control in Thailand scaled up the Emergency Operations Center to Level 3 to closely monitor the ongoing situation in both national and international levels. This country has started a screening program to check for fever in all travelers who arrived from Wuhan through direct flights in airports.

Japan’s Ministry of Health requested local health governments to be aware of the respiratory illnesses in Wuhan using the existing surveillance system for serious infectious illnesses with unknown etiology. It has strengthened surveillance for undiagnosed severe acute respiratory illnesses. Quarantine and screening measures have been intensified for travelers from Wuhan at the points of entry. Furthermore, National Institute of Infectious Disease (NIID) established an in-house PCR assay for COVID-19.

Contact tracing and other epidemiological investigation are ongoing in the Republic of Korea to prevent the spread of the disease. The government has scaled up the national alert level from Blue (Level 1) to Yellow (Level 2 of the 4-level national crisis management system). Surveillance of pneumonia cases has been strengthened in health facilities nationwide and quarantine and screening measures have been enhanced for travelers from Wuhan at the points of entry.

The US centers for disease control and prevention (CDC) activated its Emergency Response System to provide ongoing support against COVID-19. Screening of passengers on direct and indirect flights from Wuhan China to the 3 main ports of entry in the United States has begun and will expand to Atlanta and Chicago in the coming days. CDC deployed a team to support ongoing investigation in the state of Washington and tracing close contacts following the first reported case of COVID-19.

Clinical Case Management

Diagnosis of COVID-19 based on clinical manifestations is complicated and initial symptoms of the disease are usually nonspecific. A large number of patients present to clinics and health centers with mild common cold symptoms such as dry cough, sore throat, low-grade fever or body aches. Patients usually go to the emergency departments if the symptoms of the clinical manifestations worsen after a few days. Because of the wide spectrum of clinical symptoms, research on biomarkers and clinical criteria predicting prognosis is of high priority to enable differentiating cases that require further interventions in the early phase of the disease (10).

No approved drug regimen has been introduced to treat infected cases so far, antiviral treatments are used to alleviate the disease symptoms. Studies on Remedesevir, as an antiviral agent, revealed its in vitro activity against the COVID-19 virus and its safety was proven in Ebola trials. Another proposed treatment is Chloroquine, an old drug for treatment of malaria, with apparent effectiveness and acceptable safety against COVID-19 associated pneumonia (48,49). Evaluating the efficacy of anti-influenza drugs such as Umifenovir and Oseltamivir against COVID-19 virus is interesting but lacks any biological plausibility. Using monoclonal antibodies has been suggested as an attractive choice among inactive prophylactic methods; however, its effectiveness has not been proven in other viral respiratory diseases and influenza, yet (50,51).

Steroids and methylprednisolone seem to be widely used in the recent pandemic. However, in case of MERS, it has been shown that the drug prolongs the presence of the virus and WHO does not recommend its use for COVID-19, except for patients with acute respiratory distress syndrome (ARDS) (52,53).

The effectiveness of other medicines and regimens such as Chloroquine, Vitamin C, and Chinese medicine, as well as Lopinavir/Ritonavir combination therapy and Remedesevir are being evaluated in China. Even though randomized clinical trials are important for improving prognosis and interrupting transmission of disease, researchers and healthcare providers should concentrate on alleviation of the disease among subgroups of patients and in different phases of the disease (54).

In addition, since the emerging virus has become a serious global concern, there is a need for rapid development of a vaccine. There are a few vaccine candidates developed in response to outbreak. However, an effective anti-viral medication or a vaccine that has been evaluated for safety and efficacy against COVID-19 is not available yet, and most vaccines are still in the preclinical testing stage (55,56,57).

Special intervention in community level

So after the rise of an emerging disease, goverments have a special responsibility to balance between civil liberties and special measures for protecting susceptible populations (46). However, three components of "scientific", "voluntary" and civil liberty should be considered as guiding principles for decision-making and operating each special protective measure at the community level. Through their experiences in previous communicable disease epidemics, US public health authorities found that enhanced screening programs, monitoring healthy people and quarantine at the community level were not effective measures against progressive spreading of disease. Therefore, specific regulations and waivers were declared to prevent traveling to mainland china and flights to and from China were temporarily suspended. Passengers and US citizens with a history of traveling to China during the previous month were encouraged to stay home and self-quarantine for up to 14 days. However, these interventions and recommendations were deemed insufficint, so public health experts warned about expanding transmission throughout the country in the coming weeks as a consequence of population movements and large scale spread of the disease all over the world (46,58).

Even though children are important sources of influenza virus transmission in the community, initial data analysis on COVID-19 indicated that children were mainly infected from adults rather than the other way around. However, clinical attack rates are low in children and teenagers (0-19) (59), so this age-group may contribute to continuous transmission in the communty. Therefore, countries with high prevalnece of the disease, such as China, Iran, Italy, South korea and Japan, closed or postponed the start of school and extended holidays.

Other special measures considered for control of the pandemic at community level include: cancellin mass gatherings, religious services, tourism, cultural and sport events, concerts and other events. In the mentioned countries, healthcare authorities issued travel ban to and from affected areas and allowed non-essential personnel and employees to work from home.

Special interventions for healthcare providers

Healthcare authorities are responsible for predicting and supplying the essential protective equipment for general population as well as healthcare providers. By ensuring their availability through effective supply chain management, they gain public trust. They also have to plan for deploying healthcare perssonel from less affected areas to epidemic regions (10). With this method, a large number of medical staff and nurses were voluntarily deployed to Wuhan, China (60).

According to primary reports from China and Singapre, working with protective equipment for a long time is cumbersome for healthcare providers and they are under tremendous stress due to probability of being infection and transmitting the disease to their families through close contact (57). The high rates of hospital infection in the recent pandemic emphasizes the importance of regular examination for symptoms among healthcare providers who are in close contact with confirmed patients in order to isolate them in case of positive laboratory test.